Chemotherapy for Ovarian Cancer
Table Of Contents
Gunter Deppe, MD
EPITHELIAL OVARIAN CANCER
Ovarian cancer is the most common cause of death from gynecologic malignancies in the United States. Of approximately 23,100 women diagnosed with ovarian cancer in 2000, 14,000 will die of the disease.1 Epithelial ovarian carcinomas constitute almost 90% of these; the other ovarian malignancies consist of germ cell carcinomas, sex cord stromal tumors, and miscellaneous tumors.
|EPITHELIAL OVARIAN CANCER|
Epithelial ovarian cancer is a disease that occurs in women between 50 and 80 years old. The incidence increases with age and peaks in the 75- to 79-year-old age group. In the United States, the age-adjusted rate of ovarian cancer for whites is significantly higher than for African-American women.
The course of epithelial ovarian cancer remains unknown. Data on dietary and environmental factors are conflicting. Evidence suggests that the more ovulatory cycles a woman experiences, the greater her risk of ovarian cancer.
In addition, 5% to 10% of ovarian cancers result from inherited defects in the BRCA1, BRCA2, and nonpolyposis colorectal cancer (HNPCC) genes. Lynch and colleagues2 describe the hereditary breast-ovarian cancer syndrome, site-specific ovarian cancer syndrome, and breast-ovarian-endometrial-nonpolyposis colorectal cancer syndrome.
Most patients with early stage epithelial ovarian cancer often lack specific symptoms. Up to 75% of women with newly diagnosed ovarian cancer have stage III or IV disease. There is no proven method of screening for ovarian cancers. A sensitive and specific biologic marker in conjunction with rectovaginal examination and transvaginal ultrasound could improve the detection of early stage epithelial ovarian cancer.3,4
Serum CA-125, which is elevated in about 50% of patients with early ovarian cancer with transvaginal ultrasound, seems to be reasonable for periodic surveillance of high-risk patients.
The use of oral contraceptives until childbearing is complete followed by prophylactic oophorectomy is recommended in women with a hereditary predisposition to ovarian cancer.5
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.
A laparotomy is necessary for definitive staging of ovarian cancer (Table 1). If disease appears confined to the ovaries, it is essential to perform a complete evaluation of all visceral and peritoneal surfaces within the peritoneal cavity, as well as omentectomy and biopsy of the aortic and pelvic lymph nodes.
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.
The goals of initial surgery are to establish the diagnosis, to stage the patient's cancer, and to debulk the tumor. After surgical debulking, the patient's disease is categorized as optimally debulked (less than 1 cm of postoperative residual disease) or suboptimally debulked (more than 1 cm postoperative residual disease.
Prospective studies are needed to determine the role of neoadjuvant chemotherapy and“interval” cytoreductive surgery, and the applicability of CA-125 and laparoscopy to predict resectability.8–11
Chemotherapy of Early Stage Epithelial Ovarian Cancer
Only approximately 25% of women are diagnosed with stage I or II disease. Careful surgical staging determines the patient's risk of recurrence (Table 2). Low-risk patients have a 5-year survival rate greater than 90% and do not require postsurgical treatment. The 5-year mortality rate of high-risk patients is 25% to 30%. Additional postsurgical therapy appears to lower the significant risk of recurrence in this group of patients.12,13
Many different adjuvant treatments, including whole-abdominal radiation,14 intraperitoneal radioactive isotopes, and single alkylating agents,15 have been effective. Gynecologic Oncology Group Protocol 9516 and the Italian studies17 show the effectiveness of platinum-based adjuvant chemotherapy.
Whether adjuvant therapy is better for patients with high-risk early stage epithelial ovarian cancers than continued observation with chemotherapy only for those who relapse depends on the outcome of current ongoing trials (Table 3). The results of a recently completed GOG trial evaluating three versus six cycles of paclitaxel and carboplatin are pending. The GOG replacement protocol is evaluating IV carboplatin (AUC 6) and paclitaxel, 175 mg/m2 every 21 days for three courses, plus low-dose paclitaxel, 40 mg/m2/week given 24 times, versus IV carboplatin (AUC 6) and paclitaxel, 175 mg/m2 every 21 days for three courses, plus observation in patients with early stage epithelial ovarian cancer. The standard approach for nonprotocol patients with high-risk early stage epithelial ovarian cancer should be taxane and platinum-based chemotherapy.
EORTC, European Organization; GOG, Gynecologic Oncology Group.
Chemotherapy of Advanced Epithelial Ovarian Cancer
Systemic chemotherapy after cytoreductive surgery is indicated for all women with advanced epithelial ovarian cancer (stages III and IV). Before the 1980s, standard chemotherapy consisted of a single alkylating agent with response rates of about 50% and clinical complete response of 20%.
The introduction of the platinum drugs led to overall response rates of 70% to 80% and clinical complete response rates of 40% to 50%. Platinum-based combination chemotherapy was considered by most investigators to be superior to single-agent platinum in overall response and progression-free survival but not in overall survival.18 In the United States, the initial postoperative chemotherapy for patients with advanced epithelial ovarian cancer has been a platinum-based combination.
Anthracyclines (doxorubicin) have been added to initial platinum-based chemotherapy with questionable benefit.13 In the 1980s, it was demonstrated that a new class of compounds, the taxanes, were active in platinum-resistant epithelial ovarian cancer.
Based on these observation, large randomized trials, which included cisplatin in combination with paclitaxel, were initiated.19–22 The paclitaxel-cisplatin combination resulted in higher overall response rates, higher clinical complete remission rates, and improved median survival.
Carboplatin was developed as an alternative to cisplatin. It is easier to administer with less gastrointestinal, neurologic, and renal toxicity. Cisplatin and carboplatin appear to achieve similar response rates when combined with paclitaxel.
The final results of a recently completed GOG study, which compares cisplatin (75 mg/m2) plus paclitaxel (135 mg/m2, 24-hour infusion) with carboplatin (AUC 7.5) and paclitaxel (175 mg/m2, 3-hour infusion) in patients with optimally debulked epithelial ovarian cancer, are pending. The carboplatin-paclitaxel combination appears to be better tolerated (less nausea, vomiting, peripheral neuropathy) and can be administered on an inpatient basis. The number of platinum-paclitaxel treatment cycles needed is unknown.
Second-look laparotomy in patients who achieved a clinical and radiographic complete response and normalization of tumor markers (CA-125) after six cycles of platinum-paclitaxel therapy remains controversial. There appears to be no impact on time to progression or overall survival for patients selected for a second-look laparotomy.23
About half of patients found to have a pathologic complete response ultimately relapse. Currently, there is no evidence that continuation of chemotherapy or consolidation therapy, including whole-abdominal radiation, high-dose chemotherapy with hematologic support, or intraperitoneal chemotherapy, prolongs disease-free or overall survival in patients who are in complete clinical remission after six cycles of platinum-taxol therapy.
The current recommended chemotherapy of choice for patients with stage III and IV epithelial ovarian cancer consists of carboplatin together with paclitaxel. No data from randomized trials demonstrate that high-dose systemic chemotherapy with bone marrow transplantation, peripheral progenitor cell support, or intraperitoneal chemotherapy results in improved therapeutic outcomes.
Most patients with stage III and IV epithelial ovarian cancer experience recurrence some time in the course of their disease and become candidates for salvage chemotherapy. The goal of second-line chemotherapy is optimization of quality of life. Cure is an unrealistic expectation.
The role of secondary surgical cytoreduction remains controversial. Patients who relapse more than 2 years after completion of initial chemotherapy sometimes gain some benefit from repeat surgical resection. The response to second-line therapy depends on several factors (treatment-free interval, toxicity from prior therapy, volume of disease, ascites, performance status).
Patients are considered “platinum-sensitive” when recurrence occurs 6 months or more after the completion of platinum-based therapy. They are classified as“platinum resistant” if disease progresses during platinum-based therapy or within 6 months after completion. The platinum-free interval also predicts sensitivity to other drugs. The longer the interval between previous chemotherapy and subsequent recurrence, the more likely is the response to subsequent chemotherapy. Most patients with recurrent epithelial ovarian cancer require therapy for the remainder of their lives. Because avoidance of toxicity and palliation of symptoms is paramount, single-agent treatment with crossover to other drugs on progression is preferable to using combination therapy.
In addition to retreatment with initially active drugs, several new active agents in platinum- and taxane-resistant epithelial ovarian cancer are available (Table 4). No data suggest that any of the second-line regimens are superior to any of the others. The choice of second-line chemotherapy depends on patient preference, administration schedules, and toxicities.
Response rates ranging from 19% to 40% have been accomplished with platinum,24 paclitaxel,25 topotecan,26 liposomal doxorubicin,27 oral etoposide,28 gemcitabine,29 vinorelbine,30 ifosfamide,31 altretamine,32 and docetaxel33 in patients with recurrent epithelial ovarian cancer. Responses generally are brief (3 to 6 months), but meaningful palliation of symptoms and prolongation of survival has been shown. Objective responses with tamoxifen in platinum-resistant epithelial ovarian cancer have been reported.34
The identification of new active salvage chemotherapeutic agents may allow incorporation of these drugs into front-line chemotherapy with the goal of overcoming resistance and interacting synergistically with other active agents.
Developing three- or four-drug combinations is difficult because of overlapping toxicities and possible use of inadequate doses of each of the drugs. A different approach is under investigation, that is, the use of doublets alternating with one or more other doublets while allowing the administration of a full dose of all of them (i.e., three to four cycles of paclitaxel-platinum followed by three to four cycles of topotecan-oral etoposide or topotecan-germcitabine).35
Novel noncytotoxic drugs targeting specific signaling molecules or the tumor microenvironment include the antibody to HER 2/neu, the p53 gene, matrix metalloproteinase inhibitors, and agents targeting protein kinase C alpha. It is unknown how to best use such agents together with chemotherapy.36
Twenty-one patients with advanced ovarian cancer in complete remission after conventional therapy treated with intraperitoneal radioimmunotherapy using HMFG1-labeled with 90y achieved a survival rate of 78% at more than 10 years.37 Multinational trials are defining the value of intraperitoneal radioimmunotherapy in the management of epithelial ovarian cancer.
Although intraperitoneal chemotherapy in epithelial ovarian cancer as salvage treatment or for consolidation is theoretically attractive, its use should be restricted to research trials.38 Several new treatment strategies are investigating the cause of resistance to cytotoxic agents in ovarian cancer.39
Epithelial ovarian cancer is an active field of investigation. All possible patients should be included in clinical trials to quickly answer the open questions.
Low Malignant Potential Ovarian Tumors
Low malignant potential ovarian tumors represent approximately 10% to 15% of all epithelial ovarian malignancies. The epidemiologic features of women with low malignant potential ovarian tumors are similar to those of women with epithelial ovarian cancer, with the exception of an earlier age onset.40 Management is primarily surgical.
Platinum-based chemotherapy can cause tumor regression.41 Prognostic factors that define women most likely to benefit from adjuvant chemotherapy are unknown. Response to chemotherapy has not shown a survival benefit.41,42
Chemotherapy for Malignant Ovarian Germ Cell Tumors
Malignant ovarian germ cell tumors represent approximately 5% of all ovarian neoplasms. Histologically, they can be divided into dysgerminomatous and nondysgerminomatous ovarian germ cell tumors. The latter group consists of immature teratoma, endodermal sinus tumor, embryonal carcinoma, choriocarcinoma, polyembryoma, and mixed tumors. Known characteristics of these tumors are their presentation at a young age, rapid growth, frequent production of tumor markers (β-human chorionic gonadotropin, α-fetoprotein, lactate dehydrogenase), predilection for hematogenous and lymphatic spread, and, with the exception of dysgerminomas, a predominantly unilateral involvement.
The potential for preservation of the reproductive organs is the result of the development of effective chemotherapy. Current management consists of conservative surgery with adequate surgical staging and surgical cytoreduction of advanced disease followed by adjuvant or primary chemotherapy in most patients.
Nondysgerminomatous Ovarian Germ Cell Malignancies
Postoperative chemotherapy is indicated for all nondysgerminatous malignant ovarian germ cell tumors except those with an adequate surgically staged IA, grade I pure immature teratoma. Various regimens have been used worldwide43,44 (Table 5).
Because of the rarity of these tumors, no randomized clinical trials have been conducted to compare the different regimens. Gershenson and coworkers accomplished a sustained remission in 25 of 26 patients with the bleomycin, etoposide, and cisplatin (BEP) regimen.45 In a GOG study, three courses of adjuvant BEP were administered to patients with completely resected stage I-III tumors. Eighty-nine of 93 patients achieved disease-free survival with a median follow-up of 38.6 months.46 A combination of cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide, and etoposide was administered to 59 newly diagnosed patients. Disease-free and overall survival at 3 years were 86% and 88%, respectively, with acceptable toxicity.47 There is no clear advantage of this regimen over BEP, the current optimal therapy for malignant germ cell tumors.
After tumor removal and thorough surgical staging, three to four courses of BEP is the standard for adjuvant treatment. Patients with higher stages should receive five to six cycles. Patients positive for tumor markers are being treated with two more cycles until after they achieve a status negative for tumor markers.
Platinum-sensitive patients who relapse can be treated with cisplatin and ifosfamide plus either etoposide or vinblastine.48 Platinum-resistant patients can be considered for high-dose chemotherapy (ifosfamide, carboplatin, and etoposide) with autologous bone marrow transplantation or hematopoietic progenitor cell support.49,50
Dysgerminomas of the ovary are the female counterpart of male seminoma. They are among the most radiosensitive and chemosensitive gynecologic malignancies. Preliminary evidence suggests that the fertility potential of patients treated with chemotherapy may be preserved.
In 1991, Williams and associates reported the GOG experience with combination chemotherapy in 20 patients with advanced incompletely resected dysgerminomas. The investigators conclude that probably three to four courses of BEP (see Table 5) is adequate for most women with incompletely resected dysgerminoma, with the possible exception of patients with advanced visceral metastases.51
The GOG is investigating the combination of carboplatin and etoposide in patients with completely resected dysgerminoma. The standard postoperative therapy for dysgerminomas, even with bulky residual disease, is three to four courses of BEP. Radiation can be used as salvage therapy.
Sex Cord Stromal Tumors
Sex cord stromal tumors constitute less than 5% of all ovarian malignancies. The World Health Organization (WHO) classification is shown in Table 6. The most common histologic type (about 70%) is granulosa cell tumor. The mean age at diagnosis is approximately 53 years. Ninety-five percent of cases are diagnosed as stage I. They are low-grade malignancies with a relapse rate of 10% to 30% some 5 to 20 years after the initial diagnosis.
Granulosa stromal cell
Patients with stage III diseases have a 5-year survival rate of only 0% to 22%.52 Potentially useful tumor markers are serum levels of estradiol, testosterone, CA-125, inhibin, and follicle regulatory protein. Cytotoxic chemotherapy usually is administered only to patients with postsurgical residual disease or with recurrent and metastatic disease. The value of adjuvant chemotherapy for stage IA granulosa cell tumors with poor prognostic factors is uncertain. For women with stage IA Sertoli-Leydig cell tumors with poor differentiation or heterologous elements, adjuvant chemotherapy is needed. Optimal chemotherapy of patients with advanced or recurrent ovarian sex cord stromal tumors is uncertain.
Table 7 lists active chemotherapy regimens for advanced ovarian sex cord stromal tumors. A platinum and etoposide combination with or without bleomycin is the current regimen of choice.52,55 There is a need for defining the role of other agents like paclitaxel with the goal of improving response and lowering toxicity.
CR, complete response; PR, partial response
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24. Markman M, Kennedy A, Webster K et al: Evidence a“treatment-free interval of < 6 months” does not equate with clinically defined platinum resistance in ovarian cancer or primary peritoneal carcinoma. J Cancer Res Clin Oncol 124: 326, 1998
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26. 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
27. Muggia FM, Hainsworth JD, Jeffers S et al: Phase II study of liposomal doxorubicin in refractory ovarian cancer: Antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 15: 987, 1997
28. 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. 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
32. Markman M, Blessing JA, Moore D et al: Altrearmine (hexamethylmelamine) in platinum-resistant and platinum-refractory ovarian cancer: A Gynecologic Group phase II trial. Gynecol Oncol 69: 228, 1998
33. Piccart MJ, Gore M, ten Bokkel Huinink W et al: Docetaxel: An active new drug for treatment of advanced epithelial ovarian cancer. J Natl Cancer Inst 87: 676, 1995
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45. Gershenson DM, Morris M, Cungir A et al: Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide, and cisplatin (BEP). J Clin Oncol 8: 715, 1990
46. Williams SD, Liao SY, Ball H et al: Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide and bleomycin: A trial of the Gynecologic Oncology Group. J Clin Oncol 12: 701, 1994
47. Bower M, Fife K, Holden L et al: Salvage therapy in recurrent germ cell cancer: Ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 109: 540, 1988
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50. Margolin BK, Doroshow JH, Ahn C et al: Treatment of germ cell cancer with two cycles of high dose ifosfamide, carboplatin, and etoposide with autologous stem-cell support. J Clin Oncol 14: 263, 1996
55. Homesley HD, 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