Ovarian Epithelial Cancer

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of ovarian epithelial cancer.

Ovarian Epithelial Cancer

General Information

Note: Separate PDQ summaries on Screening for Ovarian Cancer; Prevention of Ovarian Cancer; and Genetics of Breast and Ovarian Cancer are also available. Information on ovarian cancer in children is available in the PDQ summary on Unusual Cancers of Childhood.

Note: Estimated new cases and deaths from ovarian cancer in the United States in 2007:^1,

• New cases: 22,430.
• Deaths: 15,280.

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Several malignancies arise from the ovary. Epithelial carcinoma of the ovary is one of the most common gynecologic malignancies and the fifth most frequent cause of cancer death in women, with 50% of all cases occurring in women older than age 65.² Approximately 5% to 10% of ovarian cancers are familial and three distinct hereditary patterns have been identified: ovarian cancer alone, ovarian and breast cancers, or ovarian and colon cancers.³ The most important risk factor for ovarian cancer is a family history of a first-degree relative (e.g., mother, daughter, or sister) with the disease. The highest risk appears in women with two or more first-degree relatives with ovarian cancer.⁴ The risk is somewhat less for women with one first-degree and one second-degree relative (grandmother or aunt) with ovarian cancer.

In most families affected with the breast and ovarian cancer syndrome or site-specific ovarian cancer, genetic linkage has been found to the BRCA1 locus on chromosome 17q21.^5,6,7 BRCA2, also responsible for some instances of inherited ovarian and breast cancer, has been mapped by genetic linkage to chromosome 13q12.⁸ The lifetime risk for developing ovarian cancer in patients harboring germline mutations in BRCA1 is substantially increased over the general population.^9,10 Two retrospective studies of patients with germline mutations in BRCA1 suggest that these women have improved survival compared with BRCA1-mutation–negative women.^11,12,[Level of evidence: 3iiiA] The majority of women with a BRCA1 mutation probably have family members with a history of ovarian and/or breast cancer; therefore, these women may have been more vigilant and inclined to participate in cancer screening programs that may have led to earlier detection.

For women at increased risk, prophylactic oophorectomy may be considered after the age of 35 if childbearing is complete. In a family-based study among women with BRCA1 or BRCA2 mutations, of the 259 women who had undergone bilateral prophylactic oophorectomy, two (0.8%) developed subsequent papillary serous peritoneal carcinoma, and six (2.8%) had stage I ovarian cancer at the time of surgery. Of the 292 matched controls, 20% who did not have prophylactic surgery developed ovarian cancer. Prophylactic surgery was associated with a higher than 90% reduction in the risk of ovarian cancer (relative risk [RR] = 0.04; 95% confidence interval [CI], 0.01–0.16), with an average follow-up of 9 years;¹³ however, family-based studies may be associated with biases resulting from case selection and other factors that may influence the estimate of benefit.¹⁴ (Refer to the Evidence of Benefit section in the PDQ summary on Prevention of Ovarian Cancer for more information.) After a prophylactic oophorectomy, a small percentage of women may develop a primary peritoneal carcinoma, similar in appearance to ovarian cancer.¹⁵ The prognostic information presented below deals only with epithelial carcinomas. Stromal and germ cell tumors are relatively uncommon and comprise less than 10% of cases. (Refer to the PDQ summaries on Ovarian Germ Cell Tumor Treatment and Ovarian Low Malignant Potential Tumor Treatment for more information.)

Ovarian cancer usually spreads via local shedding into the peritoneal cavity followed by implantation on the peritoneum and via local invasion of bowel and bladder. The incidence of positive nodes at primary surgery has been reported to be as much as 24% in patients with stage I disease, 50% in patients with stage II disease, 74% in patients with stage III disease, and 73% in patients with stage IV disease.¹⁶ In this study, the pelvic nodes were involved as often as the para-aortic nodes. Tumor cells may also block diaphragmatic lymphatics. The resulting impairment of lymphatic drainage of the peritoneum is thought to play a role in development of ascites in ovarian cancer. Also, transdiaphragmatic spread to the pleura is common.

Prognosis in ovarian cancer is influenced by several factors, but multivariate analyses suggest that the most important favorable factors include:^{17,18,19,20,21,}

• Younger age.
• Good performance status.
• Cell type other than mucinous and clear cell.
• Lower stage.
• Well-differentiated tumor.
• Smaller disease volume prior to any surgical debulking.
• Absence of ascites.
• Smaller residual tumor following primary cytoreductive surgery.

For patients with stage I disease, the most important prognostic factor is grade, followed by dense adherence and large-volume ascites.²² DNA flow cytometric analysis of stage I and stage IIA patients may identify a group of high-risk patients.²³ Patients with clear cell histology appear to have a worse prognosis.²⁴ Patients with a significant component of transitional cell carcinoma appear to have a better prognosis.^25,

Although the ovarian cancer-associated antigen, CA 125, has no prognostic significance when measured at the time of diagnosis, it has a high correlation with survival when measured 1 month after the third course of chemotherapy for patients with stage III or stage IV disease.²⁶ For patients whose elevated CA 125 normalizes with chemotherapy, more than one subsequent elevated CA 125 measurement is highly predictive of active disease, but this does not mandate immediate therapy.^27,28,

Most patients with ovarian cancer have widespread disease at presentation. This may be partly explained by relatively early spread (and implantation) of high grade papillary serous cancers to the rest of the peritoneal cavity.²⁹ Conversely, symptoms such as abdominal pain and swelling, gastrointestinal symptoms, and pelvic pain, often go unrecognized, leading to delays in diagnosis.^30,31,32 Partly as a result of this, yearly mortality in ovarian cancer is approximately 65% of the incidence rate. Long-term follow-up of suboptimally debulked stage III and stage IV patients had a 5-year survival rate of less than 10% with platinum-based combination therapy prior to the current generation of trials including taxanes.¹⁷ By contrast, optimally debulked stage III patients treated with a combination of intravenous taxane and intraperitoneal platinum plus taxane achieved a median survival of 66 months in a Gynecologic Oncology Group trial that accrued patients between 1998 and 2001.³³ Numerous clinical trials are in progress to refine existing therapy and test the value of different approaches to postoperative drug and radiation therapy. Patients with any stage of ovarian cancer are appropriate candidates for clinical trials.^34,35 Information about ongoing clinical trials is available from the NCI Web site.

¹ American Cancer Society.: Cancer Facts and Figures 2007. Atlanta, Ga: American Cancer Society, 2007. Also available online. Last accessed March 5, 2007.

² Yancik R: Ovarian cancer. Age contrasts in incidence, histology, disease stage at diagnosis, and mortality. Cancer 71 (2 Suppl): 517-23, 1993.

³ Lynch HT, Watson P, Lynch JF, et al.: Hereditary ovarian cancer. Heterogeneity in age at onset. Cancer 71 (2 Suppl): 573-81, 1993.

⁴ Piver MS, Goldberg JM, Tsukada Y, et al.: Characteristics of familial ovarian cancer: a report of the first 1,000 families in the Gilda Radner Familial Ovarian Cancer Registry. Eur J Gynaecol Oncol 17 (3): 169-76, 1996.

⁵ Miki Y, Swensen J, Shattuck-Eidens D, et al.: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266 (5182): 66-71, 1994.

⁶ Easton DF, Bishop DT, Ford D, et al.: Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet 52 (4): 678-701, 1993.

⁷ Steichen-Gersdorf E, Gallion HH, Ford D, et al.: Familial site-specific ovarian cancer is linked to BRCA1 on 17q12-21. Am J Hum Genet 55 (5): 870-5, 1994.

⁸ Wooster R, Neuhausen SL, Mangion J, et al.: Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265 (5181): 2088-90, 1994.

⁹ Easton DF, Ford D, Bishop DT: Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 56 (1): 265-71, 1995.

¹⁰ Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336 (20): 1401-8, 1997.

¹¹ 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 335 (19): 1413-6, 1996.

¹² Aida H, Takakuwa K, Nagata H, et al.: Clinical features of ovarian cancer in Japanese women with germ-line mutations of BRCA1. Clin Cancer Res 4 (1): 235-40, 1998.

¹³ Rebbeck TR, Lynch HT, Neuhausen SL, et al.: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346 (21): 1616-22, 2002.

¹⁴ Klaren HM, van't Veer LJ, van Leeuwen FE, et al.: Potential for bias in studies on efficacy of prophylactic surgery for BRCA1 and BRCA2 mutation. J Natl Cancer Inst 95 (13): 941-7, 2003.

¹⁵ Piver MS, Jishi MF, Tsukada Y, et al.: Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer. A report of the Gilda Radner Familial Ovarian Cancer Registry. Cancer 71 (9): 2751-5, 1993.

¹⁶ Burghardt E, Girardi F, Lahousen M, et al.: Patterns of pelvic and paraaortic lymph node involvement in ovarian cancer. Gynecol Oncol 40 (2): 103-6, 1991.

¹⁷ 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 9 (7): 1138-50, 1991.

¹⁸ van Houwelingen JC, ten Bokkel Huinink WW, van der Burg ME, et al.: Predictability of the survival of patients with advanced ovarian cancer. J Clin Oncol 7 (6): 769-73, 1989.

¹⁹ 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 27 (11): 1367-72, 1991.

²⁰ Hoskins WJ, Bundy BN, Thigpen JT, et al.: The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 47 (2): 159-66, 1992.

²¹ Thigpen T, Brady MF, Omura GA, et al.: Age as a prognostic factor in ovarian carcinoma. The Gynecologic Oncology Group experience. Cancer 71 (2 Suppl): 606-14, 1993.

²² Dembo AJ, Davy M, Stenwig AE, et al.: Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol 75 (2): 263-73, 1990.

²³ Schueler JA, Cornelisse CJ, Hermans J, et al.: Prognostic factors in well-differentiated early-stage epithelial ovarian cancer. Cancer 71 (3): 787-95, 1993.

²⁴ Young RC, Walton LA, 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 322 (15): 1021-7, 1990.

²⁵ Gershenson DM, Silva EG, Mitchell MF, et al.: Transitional cell carcinoma of the ovary: a matched control study of advanced-stage patients treated with cisplatin-based chemotherapy. Am J Obstet Gynecol 168 (4): 1178-85; discussion 1185-7, 1993.

²⁶ Mogensen O: Prognostic value of CA 125 in advanced ovarian cancer. Gynecol Oncol 44 (3): 207-12, 1992.

²⁷ Högberg T, Kågedal B: Long-term follow-up of ovarian cancer with monthly determinations of serum CA 125. Gynecol Oncol 46 (2): 191-8, 1992.

²⁸ Rustin GJ, Nelstrop AE, Tuxen MK, et al.: Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study. Ann Oncol 7 (4): 361-4, 1996.

²⁹ Hogg R, Friedlander M: Biology of epithelial ovarian cancer: implications for screening women at high genetic risk. J Clin Oncol 22 (7): 1315-27, 2004.

³⁰ Goff BA, Mandel L, Muntz HG, et al.: Ovarian carcinoma diagnosis. Cancer 89 (10): 2068-75, 2000.

³¹ Friedman GD, Skilling JS, Udaltsova NV, et al.: Early symptoms of ovarian cancer: a case-control study without recall bias. Fam Pract 22 (5): 548-53, 2005.

³² Smith LH, Morris CR, Yasmeen S, et al.: Ovarian cancer: can we make the clinical diagnosis earlier? Cancer 104 (7): 1398-407, 2005.

³³ Armstrong DK, Bundy B, Wenzel L, et al.: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354 (1): 34-43, 2006.

³⁴ Ozols RF, Young RC: Ovarian cancer. Curr Probl Cancer 11 (2): 57-122, 1987 Mar-Apr.

³⁵ Cannistra SA: Cancer of the ovary. N Engl J Med 329 (21): 1550-9, 1993.

Cellular Classification

The following is a list of ovarian epithelial cancer histologic classifications.

• Serous cystomas:
  • Serous benign cystadenomas.
  • Serous cystadenomas with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low potential or borderline malignancy).
  • Serous cystadenocarcinomas.
• Mucinous cystomas:
  • Mucinous benign cystadenomas.
  • Mucinous cystadenomas with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low potential or borderline malignancy).
  • Mucinous cystadenocarcinomas.
• Endometrioid tumors (similar to adenocarcinomas in the endometrium):
  • Endometrioid benign cysts.
  • Endometrioid tumors with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low malignant potential or borderline malignancy).
  • Endometrioid adenocarcinomas.
• Clear cell (mesonephroid) tumors:
  • Benign clear cell tumors.
  • Clear cell tumors with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low malignant potential or borderline malignancy).
  • Clear cell cystadenocarcinomas.
• Unclassified tumors that cannot be allotted to one of the above groups.
• No histology.
• Other malignant tumors (malignant tumors other than those of the common epithelial types are not to be included with the categories listed above).

(Refer to the PDQ summary on Ovarian Low Malignant Potential Tumor Treatment for more information.)

Stage Information

In the absence of extra-abdominal metastatic disease, definitive staging of ovarian cancer requires laparotomy. The role of surgery in patients with stage IV disease and extra-abdominal disease is yet to be established. If disease appears to be limited to the ovaries or pelvis, it is essential at laparotomy to examine and biopsy or to obtain cytologic brushings of the diaphragm, both paracolic gutters, the pelvic peritoneum, para-aortic and pelvic nodes, and infracolic omentum, and to obtain peritoneal washings.^1,

The serum CA 125 level is valuable in the follow-up and restaging of patients who have elevated CA 125 levels at the time of diagnosis.^2,3,4 While an elevated CA 125 level indicates a high probability of epithelial ovarian cancer, a negative CA 125 level cannot be used to exclude the presence of residual disease.⁵ CA 125 levels can also be elevated in other malignancies and benign gynecologic problems such as endometriosis, and CA 125 levels should be used with a histologic diagnosis of epithelial ovarian cancer.^6,7,

The Federation Internationale de Gynecologie et d’Obstetrique and the American Joint Committee on Cancer have designated staging.^8,9,

Stage I

Stage I ovarian cancer is limited to the ovaries.

• Stage IA: Tumor limited to one ovary; capsule intact, no tumor on ovarian surface. No malignant cells in ascites or peritoneal washings.*
• Stage IB: Tumor limited to both ovaries; capsules intact, no tumor on ovarian surface. No malignant cells in ascites or peritoneal washings.*
• Stage IC: Tumor limited to one or both ovaries with any of the following: capsule ruptured, tumor on ovarian surface, malignant cells in ascites or peritoneal washings.^8,

*The term, malignant ascites, is not classified. The presence of ascites does not affect staging unless malignant cells are present.

Stage II

Stage II ovarian cancer is tumor involving one or both ovaries with pelvic extension and/or implants.

• Stage IIA: Extension and/or implants on the uterus and/or fallopian tubes. No malignant cells in ascites or peritoneal washings.
• Stage IIB: Extension to and/or implants on other pelvic tissues. No malignant cells in ascites or peritoneal washings.
• Stage IIC: Pelvic extension and/or implants (stage IIA or stage IIB) with malignant cells in ascites or peritoneal washings.

Different criteria for allotting cases to stage IC and stage IIC have an impact on diagnosis. To assess this impact, of value would be to know if rupture of the capsule was (1) spontaneous or (2) caused by the surgeon; and, if the source of malignant cells detected was (1) peritoneal washings or (2) ascites.

Stage III

Stage III ovarian cancer is tumor involving one or both ovaries with microscopically confirmed peritoneal implants outside the pelvis. Superficial liver metastasis equals stage III. Tumor is limited to the true pelvis but with histologically verified malignant extension to small bowel or omentum.

• Stage IIIA: Microscopic peritoneal metastasis beyond pelvis (no macroscopic tumor).
• Stage IIIB: Macroscopic peritoneal metastasis beyond pelvis 2 cm or less in greatest dimension.
• Stage IIIC: Peritoneal metastasis beyond pelvis more than 2 cm in greatest dimension and/or regional lymph node metastasis.

Stage IV

Stage IV ovarian cancer is tumor involving one or both ovaries with distant metastasis. If pleural effusion is present, positive cytologic test results must exist to designate a case to stage IV. Parenchymal liver metastasis equals stage IV.

¹ Hoskins WJ: Surgical staging and cytoreductive surgery of epithelial ovarian cancer. Cancer 71 (4 Suppl): 1534-40, 1993.

² Mogensen O: Prognostic value of CA 125 in advanced ovarian cancer. Gynecol Oncol 44 (3): 207-12, 1992.

³ Högberg T, Kågedal B: Long-term follow-up of ovarian cancer with monthly determinations of serum CA 125. Gynecol Oncol 46 (2): 191-8, 1992.

⁴ Rustin GJ, Nelstrop AE, Tuxen MK, et al.: Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study. Ann Oncol 7 (4): 361-4, 1996.

⁵ Makar AP, Kristensen GB, Børmer OP, et al.: CA 125 measured before second-look laparotomy is an independent prognostic factor for survival in patients with epithelial ovarian cancer. Gynecol Oncol 45 (3): 323-8, 1992.

⁶ Berek JS, Knapp RC, Malkasian GD, et al.: CA 125 serum levels correlated with second-look operations among ovarian cancer patients. Obstet Gynecol 67 (5): 685-9, 1986.

⁷ Atack DB, Nisker JA, Allen HH, et al.: CA 125 surveillance and second-look laparotomy in ovarian carcinoma. Am J Obstet Gynecol 154 (2): 287-9, 1986.

⁸ Shepherd JH: Revised FIGO staging for gynaecological cancer. Br J Obstet Gynaecol 96 (8): 889-92, 1989.

⁹ Ovary. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 275-284.

Treatment Option Overview

The treatment of ovarian cancer is evolving rapidly. Therefore, all patients with this disease are appropriate candidates for clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

Stage I and Stage II Ovarian Epithelial Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Treatment options:

1. If the tumor is well- or moderately well differentiated, total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy is adequate for patients with stage IA and stage IB disease. The undersurface of the diaphragm should be visualized and biopsied; pelvic and abdominal peritoneal biopsies and pelvic and para-aortic lymph node biopsies are required and peritoneal washings should be obtained routinely.¹ In selected patients who desire childbearing and have grade I tumors, unilateral salpingo-oophorectomy may be associated with a low risk of recurrence.^2,
2. If the tumor is grade III, densely adherent, or stage IC, the chance of relapse and death from ovarian cancer is as much as 30%.^3,4,5,6 Clinical trials evaluating the following treatment approaches have been performed:
   • Intraperitoneal P-32 or radiation therapy.^1,7,8,
   • Systemic chemotherapy based on platinums alone or in combination with alkylating agents.^1,7,9,10,11,
   • Systemic chemotherapy based on platinums with paclitaxel.

In two large European trials, European Organisation for Research and Treatment of Cancer–Adjuvant ChemoTherapy in Ovarian Neoplasm (EORTC–ACTION) and International Collaborative Ovarian Neoplasm (ICON1), patients with stage IA and stage IB (grades II and III), all stage IC and stage II, and all stage I and stage IIA clear-cell carcinoma were randomized to adjuvant chemotherapy or observation. Data were reported individually and in pooled form.^12,13,14

The EORTC–ACTION trial required four cycles or more of carboplatin or cisplatin-based chemotherapy as treatment. Although surgical staging criteria were monitored, inadequate staging was not an exclusion criterion. Recurrence-free survival (RFS) was improved in the adjuvant chemotherapy arm (hazard ratio [HR] = 0.63; P = .02), but overall survival (OS) was not affected (HR = 0.69; 95% confidence interval [CI], 0.44–1.08; P = .10). OS was improved by chemotherapy in the subset of patients with inadequate surgical staging.

The ICON1 trial randomized patients to six cycles of single-agent carboplatin or cisplatin or platinum-based chemotherapy (usually cyclophosphamide, doxorubicin, and cisplatin) versus observation and had similar entry criteria to the EORTC–ACTION trial, but the ICON1 trial did not monitor whether adequate surgical staging was performed. Both RFS and OS were significantly improved: 5-year survival figures were 79% with adjuvant chemotherapy versus 70% without adjuvant chemotherapy.

The pooled data from both studies, which were completed in January 2000, indicate significant improvement in RFS (HR = 0.64; 95% CI, 0.50–0.82; P = .001) and OS (HR = 0.67; 95% CI, 0.50–0.90; P = .008). These pooled data provide for an OS at 5 years of 82% with chemotherapy and 74% with observation, with a 95% CI in the difference of 2% to 12%. An accompanying editorial emphasizes that the focus of subsequent trials must be to identify patients who do not require additional therapy among the early ovarian cancer subset.^15,[Level of evidence: 1iA]. Optimal staging is one way to better identify these patients. Except for the most favorable subset (patients with stage IA well-differentiated disease), Gynecologic Oncology Group (GOG) trials and the evidence above, which is based on double-blinded, randomized controlled trials with total mortality endpoints, support treatment with cisplatin, carboplatin, and paclitaxel (in the United States).

In future trials, the Ovarian Committee of the GOG has opted to include patients with stage II disease in advanced ovarian cancer trials and not to include further study of patients with stage I disease at this time. Information about ongoing clinical trials is available from the NCI Web site.

¹ Young RC, Decker DG, Wharton JT, et al.: Staging laparotomy in early ovarian cancer. JAMA 250 (22): 3072-6, 1983.

² Zanetta G, Chiari S, Rota S, et al.: Conservative surgery for stage I ovarian carcinoma in women of childbearing age. Br J Obstet Gynaecol 104 (9): 1030-5, 1997.

³ Dembo AJ, Davy M, Stenwig AE, et al.: Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol 75 (2): 263-73, 1990.

⁴ Ahmed FY, Wiltshaw E, A'Hern RP, et al.: Natural history and prognosis of untreated stage I epithelial ovarian carcinoma. J Clin Oncol 14 (11): 2968-75, 1996.

⁵ Monga M, Carmichael JA, Shelley WE, et al.: Surgery without adjuvant chemotherapy for early epithelial ovarian carcinoma after comprehensive surgical staging. Gynecol Oncol 43 (3): 195-7, 1991.

⁶ Kolomainen DF, A'Hern R, Coxon FY, et al.: Can patients with relapsed, previously untreated, stage I epithelial ovarian cancer be successfully treated with salvage therapy? J Clin Oncol 21 (16): 3113-8, 2003.

⁷ Vergote IB, Vergote-De Vos LN, Abeler VM, et al.: Randomized trial comparing cisplatin with radioactive phosphorus or whole-abdomen irradiation as adjuvant treatment of ovarian cancer. Cancer 69 (3): 741-9, 1992.

⁸ Piver MS, Lele SB, 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 11 (5): 515-9, 1988.

⁹ Bolis G, Colombo N, Pecorelli S, et al.: Adjuvant treatment for early epithelial ovarian cancer: results of two randomised clinical trials comparing cisplatin to no further treatment or chromic phosphate (32P). G.I.C.O.G.: Gruppo Interregionale Collaborativo in Ginecologia Oncologica. Ann Oncol 6 (9): 887-93, 1995.

¹⁰ Piver MS, Malfetano J, Baker TR, et al.: Five-year survival for stage IC or stage I grade 3 epithelial ovarian cancer treated with cisplatin-based chemotherapy. Gynecol Oncol 46 (3): 357-60, 1992.

¹¹ McGuire WP: Early ovarian cancer: treat now, later or never? Ann Oncol 6 (9): 865-6, 1995.

¹² Trimbos JB, Parmar M, Vergote I, et al.: International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 95 (2): 105-12, 2003.

¹³ Trimbos JB, Vergote I, Bolis G, et al.: Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial. J Natl Cancer Inst 95 (2): 113-25, 2003.

¹⁴ Colombo N, Guthrie D, Chiari S, et al.: International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. J Natl Cancer Inst 95 (2): 125-32, 2003.

¹⁵ Young RC: Early-stage ovarian cancer: to treat or not to treat. J Natl Cancer Inst 95 (2): 94-5, 2003.

Stage III and Stage IV Ovarian Epithelial Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Treatment options for patients with all stages of ovarian epithelial cancer have consisted of surgery followed by chemotherapy.

Surgery

Patients diagnosed with stage III and stage IV disease are treated with surgery and chemotherapy; however, the outcome is generally less favorable for patients with stage IV disease. The role of surgery for patients with stage IV disease is unclear, but in most instances, the bulk of the disease is intra-abdominal, and surgical procedures similar to those used in the management of patients with stage III disease are applied. The options for intraperitoneal (IP) regimens are also less likely to apply both practically (as far as inserting an IP catheter at the outset) and theoretically (aimed at destroying microscopic disease in the peritoneal cavity) in patients with stage IV disease.

Surgery has been used as a therapeutic modality and also to adequately stage the disease. Surgery should include total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy and debulking of as much gross tumor as can safely be performed. While primary cytoreductive surgery may not correct for biologic characteristics of the tumor, considerable evidence indicates that the volume of disease left at the completion of the primary surgical procedure is related to patient survival.¹ A literature review showed that patients with optimal cytoreduction had a median survival of 39 months compared with survival of only 17 months in patients with suboptimal residual disease.^1,[Level of evidence: 3iA] Results of a retrospective analysis of 349 patients with postoperative residual masses no larger than 1 cm suggested that patients who present at the outset with large-volume disease and achieve small-volume disease by surgical debulking have poorer outcomes than similar patients who present with small-volume disease.² Gradual improvement in survival with decreasing residual tumor volume is likely. Although the association may not be causal, retrospective analyses, including a meta-analysis of patients receiving platinum-based chemotherapy, have found cytoreduction to be an independent prognostic variable for survival.^3,4

For the past 3 decades, the Gynecologic Oncology Group (GOG) has conducted separate trials for women whose disease has been optimally cytoreduced (most recently defined as ≤1 cm residuum) and for those who had suboptimal cytoreductions (>1 cm residuum). The extent of residual disease following the initial surgery is a determinant of outcome in most series ^1,2,3,4 and has been used in the design of clinical trials, particularly by the GOG.

On the basis of these findings, the standard treatment approaches are subdivided into:

1. Treatment options for patients with optimally cytoreduced stage III disease.
2. Treatment options for patients with suboptimally cytoreduced stage III and stage IV disease.

Rarely, and mostly because of operative risks, it is preferable to treat patients with several cycles of chemotherapy before interval debulking surgery. The European Organisation for the Research and Treatment of Cancer (EORTC) Gynecological Cancer Group, together with the National Cancer Institute of Canada, has initiated a randomized clinical trial to determine whether neoadjuvant chemotherapy followed by such interval debulking surgery will be as effective as primary debulking surgery in some or all patients with stage IIIC and stage IV disease.^5,

Treatment Options for Patients With Optimally Cytoreduced Stage III Disease

Intraperitoneal chemotherapy

The pharmacologic basis for the delivery of anticancer drugs by the IP route was established in the late 1970s and early 1980s. When several drugs were studied, mostly in the setting of minimal residual disease at reassessment after patients had received their initial chemotherapy, cisplatin alone and in combination received the most attention. Favorable outcomes from IP cisplatin were most often seen when tumors had shown responsiveness to platinums and with small-volume tumors (usually defined as tumors <1 cm).⁶ In the 1990s, randomized trials were conducted to evaluate whether the IP route would prove superior to the IV route. IP cisplatin was the common denominator of these randomized trials.

The use of IP cisplatin as part of the initial up-front approach in patients with stage III optimally debulked ovarian cancer is supported principally by the results of three randomized clinical trials (GOG-104, GOG-14, and GOG-172).^7,8,9 These studies tested the role of IP drugs (IP cisplatin in all three studies and IP paclitaxel in the last study) against the standard IV regimen. In the three studies, superior progression-free survival (PFS) and overall survival (OS) favoring the IP arm was documented. Specifically, the most recent study, GOG-172, resulted in a median survival rate of 66 months for patients on the IP arm versus 50 months for patients who received IV administration of cisplatin and paclitaxel (P = .03).^9,[Level of evidence:1iiA] Toxic effects were greater in the IP arm, contributed to in large part by the cisplatin dose per cycle (100 mg/m2) and by sensory neuropathy from the additional IP as well as from the IV administration of paclitaxel. The rate of completion of six cycles of treatment was also less frequent in the IP arm (42% vs. 83%) because of the toxic effects. Notwithstanding these problems, IP therapy for patients with optimally debulked ovarian cancer is receiving wider adoption, and efforts are under way by the GOG to examine some modifications of the IP regimen used in GOG-172 to improve its tolerability (e.g., to reduce by at least 25% the total 3-hour amount of cisplatin given; a shift from the less practical 24-hour IV administration of paclitaxel to a 3-hour IV administration). A clinical alert was issued by the National Cancer Institute so physicians not familiar with the technique may refer patients to appropriate centers.¹⁰ A Cochrane-sponsored meta-analysis of all randomized IP versus IV trials shows a hazard ratio of 0.79 for disease-free survival and 0.79 for OS, favoring the IP arms.¹¹

Treatment Options for Patients With Suboptimally Cytoreduced Stage III and Stage IV Disease

Cytoreductive surgery

The value of interval cytoreductive surgery has been the subject of two large phase III trials. In the first study, performed by the EORTC, patients subjected to debulking after four cycles of cyclophosphamide and cisplatin (with additional cycles given later) had an improved survival rate compared with patients who completed six cycles of this chemotherapy without surgery.^12,[Level of evidence: 1iiB] A trial by the GOG (GOG-162 ^13,) was designed to answer a very similar question but used the then-standard paclitaxel-plus-cisplatin regimen as the chemotherapy.¹⁴ This trial did not demonstrate any advantage from the use of interval cytoreductive surgery. The divergence of results may be caused by the efficacy of the chemotherapy obscuring any effects of interval cytoreduction, the wider use of maximal surgical effort at the time of diagnosis by U.S. gynecologic oncologists, or unknown factors. Although many patients with stage IV disease also undergo cytoreductive surgery at diagnosis, whether this improves survival has not been established.

Systemic chemotherapy

Since the approval of cisplatin, the was approved in 1979, first-line treatment of ovarian cancer has consisted of this drug being given intravenously or its second-generation analog, carboplatin, being given either alone or in combination with other drugs. Clinical response rates from these drugs regularly exceed 60%, and median time-to-recurrence usually exceeds 1 year in this subset of suboptimally debulked women. Trials by various cooperative groups in the subsequent 2 decades addressed issues of optimal dose-intensity ^15,16,17 for both cisplatin and carboplatin,¹⁸ schedule, ¹⁹ and the equivalent results obtained with either of these platinum drugs, usually in combination with cyclophosphamide.²⁰ With the introduction of the taxane paclitaxel in the early 1990s, two trials confirmed the superiority of cisplatin combined with paclitaxel to the previous standard of cisplatin plus cyclophosphamide; however, two trials that compared the agent with either cisplatin or carboplatin as a single agent failed to confirm such superiority in all outcome parameters (i.e., response, time-to-progression, and survival) (see Table 1).

Table 1. Paclitaxel/Platinum Combinations Versus Comparator Arms in Trials

TrialTreatment RegimensNo. of Patients % Early CrossoverProgression-free Survival (mo) Overall Survival (mo)AUC = area under the curve; h = hour; mo = month*Statistically inferior result (P < .001–< .05).GOG-132 ^21,Paclitaxel (135 mg/m2, 24 h) and cisplatin (75 mg/m2)20122%14.2 26.6 Cisplatin (100 mg/m2)20040%16.430.2Paclitaxel (200 mg/m2, 24 h)21323%11.2*26MRC-ICON3 ^22,Paclitaxel (175 mg/m2, 3 h) and carboplatin AUC 647823%17.336.1Carboplatin AUC 6 94325%16.135.4Paclitaxel (175 mg/m2, 3 h) and carboplatin AUC 6 23223%1740Cyclophosphamide (750 mg/m2) and doxorubicin (75 mg/m2) and cisplatin (75 mg/m2) 42120%1740GOG-111^23,Paclitaxel (135 mg/m2, 24 h) and cisplatin (75 mg/m2)184None1838Cyclophosphamide (750 mg/m2) and cisplatin (75 mg/m2)202None13*24*OV-10^24,Paclitaxel (175 mg/m2, 3 h) and cisplatin (75 mg/m2)162None15.535.6Cyclophosphamide (750 mg/m2) and cisplatin (75 mg/m2)1614%11.5*25.8*

Nevertheless, for patients with ovarian cancer, the combination of cisplatin or carboplatin and paclitaxel has been used as the initial treatment (defined as induction chemotherapy) for a number of reasons:

1. GOG-132 was regarded by many as showing that sequential treatment of cisplatin and paclitaxel was equivalent to the combination because many patients crossed over before progression; moreover, the cisplatin only arm was more toxic because it utilized a 100 mg/m2 dose.^21,
2. The Medical Research Council (MRC)-ICON3 study, while having fewer early crossovers, could be interpreted similarly in regard to the impact on survival of sequential treatment.^22,
3. Data from MRC-ICON4 have shown a survival advantage for patients treated with the combination treatment regimen versus those treated with single-agent carboplatin upon recurrence (see Table 2).
4. In past trials, single-agent platinums were not superior to platinum combined with an alkylating agent; therefore, the explanation of a detrimental effect of cyclophosphamide is unlikely.

Since the adoption of the platinum-plus-taxane combination as the standard nearly worldwide, clinical trials have demonstrated:

• noninferiority for carboplatin plus paclitaxel versus cisplatin plus paclitaxel,^23,24,25,
• noninferiority for carboplatin plus paclitaxel versus carboplatin plus docetaxel,²⁶ and
• no advantage but increased toxic effects by adding epirubicin to the carboplatin plus paclitaxel doublet.^27,

A study started by the GOG with international collaboration, currently published in abstract form, compared the carboplatin-plus-paclitaxel standard to two carboplatin-containing sequential doublets (one with topotecan and one with gemcitabine) followed by carboplatin plus paclitaxel, and to two triplets including either pegylated liposomal doxorubicin or gemcitabine with the standard doublet. No differences have emerged.^28,

Consolidation and/or maintenance therapy

In an effort to improve on the modest results achieved in suboptimally debulked patients (in contrast to those achieved after optimal cytoreduction and IP therapy), trials of consolidation and/or maintenance therapy have been carried out. Presently, none of the treatments given after the initial induction have been shown to improve survival: IP cisplatin × four cycles ²⁹ or radioimmunoconjugate × one cycle ³⁰ following negative reassessment; or IV topotecan × four cycles.³¹ However, the SWOG/GOG study comparing 3 versus 12 doses of monthly paclitaxel given every 4 weeks following a clinically defined complete response at the time of completion of platinum/paclitaxel induction was stopped early because of a very significant difference in PFS.^32,[Level of evidence:1iiDii] Trials to confirm the value of maintenance with taxanes versus observation are currently being conducted by the GOG.

Treatment options under clinical evaluation:

• IP radioimmunoconjugates, vaccines, and targeted drugs are under clinical evaluation, primarily as consolidation therapy. Information about ongoing clinical trials is available from the NCI Web site.

¹ Hoskins WJ: Surgical staging and cytoreductive surgery of epithelial ovarian cancer. Cancer 71 (4 Suppl): 1534-40, 1993.

² Hoskins WJ, Bundy BN, Thigpen JT, et al.: The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 47 (2): 159-66, 1992.

³ Hoskins WJ, McGuire WP, Brady MF, et al.: The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol 170 (4): 974-9; discussion 979-80, 1994.

⁴ Bristow RE, Tomacruz RS, Armstrong DK, et al.: Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 20 (5): 1248-59, 2002.

⁵ Vergote IB, European Organization for Research and Treatment of Cancer: Phase III Randomized Study of Neoadjuvant Chemotherapy Followed By Interval Debulking Surgery Versus Upfront Cytoreductive Surgery Followed By Chemotherapy With or Without Interval Debulking Surgery in Patients With Stage IIIC or IV Ovarian Epithelial, Peritoneal, or Fallopian Tube Cancer, EORTC-55971, Clinical trial, Closed.

⁶ Howell SB, 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 5 (10): 1607-12, 1987.

⁷ 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 335 (26): 1950-5, 1996.

⁸ 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 intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 19 (4): 1001-7, 2001.

⁹ Armstrong DK, Bundy B, Wenzel L, et al.: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354 (1): 34-43, 2006.

¹⁰ National Cancer Institute.: NCI Clinical Announcement on Intraperitoneal Chemotherapy for Ovarian Cancer (January 5, 2006). Rockville, Md: Cancer Therapy Evaluation Program, NCI, 2006 Available online. Last accessed April 26, 2006.

¹¹ Jaaback K, Johnson N: Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev (1): CD005340, 2006.

¹² van der Burg ME, van Lent M, Buyse M, et al.: The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med 332 (10): 629-34, 1995.

¹³ Spriggs DR, Gynecologic Oncology Group: Phase III Randomized Study of 24 Hour Versus 96 Hour Infusion of Paclitaxel With Cisplatin in Patients With Suboptimal Stage III or IV Ovarian Epithelial Cancer or Primary Peritoneal Cancer (Summary Last Modified 10/2000), GOG-162, Clinical trial, Closed.

¹⁴ Goodman HM, Harlow BL, Sheets EE, et al.: The role of cytoreductive surgery in the management of stage IV epithelial ovarian carcinoma. Gynecol Oncol 46 (3): 367-71, 1992.

¹⁵ Markman M, Reichman B, Hakes T, et al.: Impact on survival of surgically defined favorable responses to salvage intraperitoneal chemotherapy in small-volume residual ovarian cancer. J Clin Oncol 10 (9): 1479-84, 1992.

¹⁶ Markman M: Intraperitoneal chemotherapy. Semin Oncol 18 (3): 248-54, 1991.

¹⁷ Levin L, Simon R, Hryniuk W: Importance of multiagent chemotherapy regimens in ovarian carcinoma: dose intensity analysis. J Natl Cancer Inst 85 (21): 1732-42, 1993.

¹⁸ 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 13 (7): 1589-99, 1995.

¹⁹ Bolis G, Favalli G, Danese S, et al.: Weekly cisplatin given for 2 months versus cisplatin plus cyclophosphamide given for 5 months after cytoreductive surgery for advanced ovarian cancer. J Clin Oncol 15 (5): 1938-44, 1997.

²⁰ Alberts DS, Green S, Hannigan EV, et al.: Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer. J Clin Oncol 10 (5): 706-17, 1992.

²¹ Muggia FM, Gynecologic Oncology Group: Phase III Randomized Study of CDDP vs TAX vs CDDP/TAX in Patients with Suboptimal Stage III/IV Ovarian Epithelial Carcinoma, GOG-132, Clinical trial, Completed.

²² Harper PG, Medical Research Council Clinical Trials Unit: Phase III Randomized Study of TAX/CBDCA vs CBDCA or CAP (CTX/DOX/CDDP) for Advanced Ovarian Cancer, MRC-ICON3, Clinical trial, Closed.

²³ du Bois A, Lück HJ, Meier W, et al.: A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 95 (17): 1320-9, 2003.

²⁴ Neijt JP, Engelholm SA, Tuxen MK, et al.: Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol 18 (17): 3084-92, 2000.

²⁵ 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 Gynecologic Oncology Group study. J Clin Oncol 21 (17): 3194-200, 2003.

²⁶ Vasey PA, Jayson GC, Gordon A, et al.: Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst 96 (22): 1682-91, 2004.

²⁷ Kristensen GB, Vergote I, Stuart G, et al.: First-line treatment of ovarian cancer FIGO stages IIb-IV with paclitaxel/epirubicin/carboplatin versus paclitaxel/carboplatin. Int J Gynecol Cancer 13 (Suppl 2): 172-7, 2003 Nov-Dec.

²⁸ Bookman MA: GOGO182-ICON5: 5-arm phase III randomized trial of paclitaxel and carboplatin vs combinations with gemcitabine, PEG-lipososomal doxorubicin, or topotecan in patients with advanced-stage epithelial ovarian or primary peritoneal carcinoma. [Abstract] J Clin Oncol 24 (Suppl 18): A-5002, 256s, 2006.

²⁹ 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 92 (9): 699-708, 2000.

³⁰ Verheijen RH, Massuger LF, Benigno BB, et al.: Phase III trial of intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody in patients with epithelial ovarian cancer after a surgically defined complete remission. J Clin Oncol 24 (4): 571-8, 2006.

³¹ Pfisterer J, Weber B, Reuss A, et al.: Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a gynecologic cancer intergroup trial of the AGO-OVAR and GINECO. J Natl Cancer Inst 98 (15): 1036-45, 2006.

³² 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 (13): 2460-5, 2003.

Recurrent or Persistent Ovarian Epithelial Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Surgery

Cytoreduction is often employed,¹ but such intervention has not been studied in the setting of a randomized clinical trial.

Systemic treatment options for patients with recurrent disease are subdivided as follows:

1. Platinum-sensitive recurrence: for patients whose disease recurs more than 6 months after cessation of the induction (usually retreated with a platinum and referred to as potentially platinum sensitive).
2. Platinum-refractory or platinum-resistant recurrence: for patients who progress prior to cessation of induction (platinum refractory) or within 6 months after cessation (platinum resistant); in these patients, platinums are deemed not useful.

Considerably higher response rates and response durations are achievable at retreatment with platinums alone or in combination when the disease is potentially platinum sensitive rather than when it is platinum resistant.

Platinum-sensitive recurrence

A small randomized study showed a significant difference in response rates and in duration of response in favor of a platinum-containing regimen over paclitaxel.² Several larger randomized trials have addressed whether the use of a platinum in combination is superior to single agents (see Table 2). A platinum-plus-paclitaxel combination yielded a superior outcome in terms of response rates, progression-free survival (PFS), and overall survival (OS) in comparison to carboplatin as a single agent or other platinum-containing combinations as control in an analysis of data analyzing jointly the results of three trials performed by the Medical Research Council/Arbeitsgemeinschaft Gynaekologische Onkologie (MRC/AGO) and ICON investigators (known as ICON4). These trials differed with respect to platinum-free interval, number of prior regimens allowed, and whether exposure to a prior taxane was required. Platinum plus paclitaxel was compared to several control regimens, though 71% used carboplatin as a single agent in the control, and 80% used carboplatin plus paclitaxel. Prolonged PFS (hazard ratio [HR] = 0.76; 95% confidence interval [CI], 0.66–0.89; P = .004) and overall survival (HR = 0.82; 95% CI, 0.69–0.97; P = .023) were improved in the platinum-plus-paclitaxel arm.^3,[Level of evidence: 1iiA]

Table 2. Platinums and Platinum-based Drug Combinations Studied in Second-line Randomized Trials

Drug regimen ComparatorComments Cisplatin + doxorubicin + cyclophosphamidePaclitaxel Combination superior survival and PFS.^4,Carboplatin + epirubicinCarboplatin No difference in PFS and OS.^5,Carboplatin + gemcitabine Carboplatin Combination superior PFS; not powered to determine OS differences.^6,Cisplatin or carboplatin + paclitaxelSingle platinums or nontaxane combinations Combination with paclitaxel superior in PFS, OS. See text above.^3,

The combination of carboplatin plus epirubicin has also been tested in randomized trials, but a survival advantage has not been observed for the combination versus carboplatin alone. Carboplatin plus pegylated liposomal doxorubicin has been studied in phase II trials but the results are only available in abstract form.⁷ While platinum plus taxane is considered the standard option for a platinum-sensitive recurrence, particularly in the absence of residual neurotoxicity, the superior results might have as readily been achieved with this combination by using the single agents given sequentially, or with any of the combinations shown in Table 2.

Platinum-refractory or platinum-resistant recurrence

For patients with platinum-refractory or platinum-resistant disease, the drugs listed in Group 1 (below) constitute the currently preferred treatment options based on stronger evidence of single-agent activity and/or a more favorable therapeutic index than the drugs listed in Group 2.

Treatment with paclitaxel historically provided the first agent with consistent activity in patients with platinum-refractory or platinum-resistant recurrences.^8,9,10,11,12 Subsequently, randomized studies have indicated that the use of topotecan achieved results that were comparable to those achieved with paclitaxel.¹³ More recently, topotecan was compared with pegylated liposomal doxorubicin in a randomized trial of 474 patients, nearly 50% of whom had platinum-sensitive disease, and demonstrated similar response rates, PFS, and OS at the time of the initial report.¹⁴

Treatment Options With Group 1 Drugs

1. Topotecan. In phase II studies, topotecan administered intravenously on days 1 to 5 of a 21-day cycle yielded objective response rates ranging from 13% to 16.3% and other outcomes that were equivalent or superior to paclitaxel.^15,16,17 Objective responses are reported in patients with platinum-refractory disease. Substantial myelosuppression follows administration. Other toxic effects include nausea, vomiting, alopecia, and asthenia.
2. Pegylated liposomal doxorubicin. A phase II study of encapsulated doxorubicin given intravenously once every 21 to 28 days demonstrated one complete response and eight partial responses in 35 patients with platinum-refractory or paclitaxel-refractory disease (response rate = 25.7%). In general, liposomal doxorubicin has few acute side effects other than hypersensitivity. The most frequent toxic effects are usually observed after the first cycle and are more pronounced following dose rates exceeding 10 mg/m2 per week and include stomatitis and hand-foot syndrome. Neutropenia and nausea are minimal, and alopecia rarely occurs.^18,

   Liposomal doxorubicin and topotecan have been compared in a randomized trial of 474 patients with recurrent ovarian cancer.¹⁴ Response rates (19.7% vs. 17.0%, P = .390), PFS (16.1 weeks vs. 17.0 weeks; P = .095), and OS (60 weeks vs. 56.7 weeks, P = .341) did not differ significantly between the liposomal doxorubicin and topotecan arms, respectively.^14,[Level of evidence: 1iiA] Survival was longer for the patients with platinum-sensitive disease who received liposomal doxorubicin.^19,

3. Docetaxel. This drug has shown activity in paclitaxel-pretreated patients and is a reasonable alternative to weekly paclitaxel in the recurrent setting.²⁰
4. Gemcitabine. Several phase II trials of gemcitabine as a single agent administered intravenously on days 1, 8, and 15 of a 28-day cycle have been reported. The response rate ranges from 13% to 19% in evaluable patients. Responses have been observed in patients whose disease is platinum refractory and/or paclitaxel refractory as well as in patients with bulky disease. Leukopenia, anemia, and thrombocytopenia are the most common toxic effects. Many patients report transient flu-like symptoms and a rash following drug administration. Other toxic effects, including nausea, are usually mild.^21,22,23
5. Paclitaxel. In a phase III study, 235 patients who did not respond to initial treatment with a platinum-based regimen but who had not previously received paclitaxel or topotecan, were randomly assigned to receive either topotecan as a 30-minute infusion daily for 5 days every 21 days or paclitaxel as a 3-hour infusion every 21 days. The overall objective response rate was 20.5% for those patients who were randomly assigned to treatment with topotecan and 13.2% for those patients who were randomly assigned to treatment with paclitaxel (P = .138). Both groups experienced myelosuppression and gastrointestinal toxic effects. Nausea and vomiting, fatigue, and infection were observed more commonly following treatment with topotecan, whereas alopecia, arthralgia, myalgia, and neuropathy were observed more commonly following paclitaxel.^13,

Treatment Options With Group 2 Drugs

(This group includes drugs that are not fully confirmed to have activity in a platinum-resistant setting, have a less desirable therapeutic index, and do not have a level of evidence higher than 3iiiDiii.)

1. Etoposide. Oral low doses of etoposide have generated response rates from 6% to 26%. Studies have not determined efficacy relative to other drugs.^24,25,26,27,
2. Alkylating drugs (i.e., cyclophosphamide, ifosfamide, melphalan, Treosulfan, and thioTepa). Ifosfamide has shown modest activity in patients with epithelial ovarian cancer, including disease that is platinum refractory. A GOG study demonstrated 3 clinical complete responses and 5 partial responses (overall response rate was 20%) in 41 evaluable patients whose disease was either refractory to platinum or had relapsed following platinum-based chemotherapy.²⁸ Toxic effects include myelosuppression, nephrotoxicity, hemorrhagic cystitis, and toxic encephalopathy. Other phase II studies confirm the activity of ifosfamide in patients with epithelial ovarian cancer. In 1 phase II study, 7 objective responses were observed in 52 patients (objective response rate was 13.5%). Of the seven patients who responded, five had tumors that were platinum refractory.²⁹ Data on other alkylating drugs are mostly from the preplatinum era or from outside the United States.
3. Hexamethylmelamine (HMM, altretamine). Several reports of orally administered HMM as salvage chemotherapy after failure of cisplatin-based combination regimens are encouraging.^{30,31,32,33,34} Response rates in platinum-resistant patients are 12% to 14%. Mild to moderate toxic effects and peripheral neuropathy are often observed following treatment with HMM.
4. Irinotecan. Most trials with this topoisomerase I inhibitor derivative of camptothecin have been conducted in Japan. Some activity, particularly against clear cell carcinoma, has been claimed.
5. Oxaliplatin. In a phase II randomized study, this platinum analog showed activity similar to that seen with paclitaxel; however, there was little activity in the platinum-resistant setting.^35,36 Combinations with pegylated liposomal doxorubicin, however, are well tolerated and active.
6. Vinorelbine. This vinca derivative has shown activity in some series but only modest activity in the platinum-resistant setting.³⁷ Aggravation of intestinal hypomotility (ileus) and need for a central line further inhibit its use.
7. Fluorouracil and capecitabine. In patients with platinum-resistant recurrent disease, an objective response rate of 10% to 17% has been reported.^38,39,
8. Tamoxifen. Some patients will respond to tamoxifen. In one study, 18% of patients responded to a dose of 20 mg twice daily.⁴⁰ A response is more likely in patients with detectable levels of cytoplasmic estrogen receptor on their tumors.

Summary of treatment options

1. For patients with platinum-sensitive disease (i.e., a minimum of 5–12 months between completion of a platinum-based regimen and the development of recurrent disease), retreatment with cisplatin or carboplatin should be considered.^41,42,
2. For patients with platinum-refractory or resistant disease (i.e., disease that has progressed while on a platinum-based regimen or has recurred within 6 months of completion of a platinum-based regimen), treatment with paclitaxel, liposomal doxorubicin, docetaxel, topotecan, or gemcitabine should be considered.⁴³ Other drugs listed above have also had some claims of antitumor activity.
3. No studies have clearly demonstrated that secondary cytoreduction confers a survival advantage, and its role remains controversial; however, 100 patients with recurrent or progressive disease after standard cytoreduction and platinum-based chemotherapy were re-explored.^44,45 The 61 patients who had successful cytoreduction (greatest residual tumor diameter <2 cm) had a statistically significant prolongation of survival.¹ Multivariate analyses revealed the cytoreduction to be the most important variable influencing survival. Whether the success of cytoreduction is related to the biologic nature of the tumor is not known.

   When disease-related symptoms can be abrogated, surgical intervention may improve the quality of life, such as the reversal of small or large bowel obstruction. Palliation, however, is rarely achieved when there are multiple areas of partial or complete obstruction, when the transit time is prolonged as a result of diffuse peritoneal carcinomatosis, or when anatomy requires a bypass that results in the short bowel syndrome.^44,

4. Other agents shown to have activity in phase II trials:
   • Gemcitabine.
   • Fluorouracil and leucovorin.
   • Tamoxifen.
   • Etoposide.
   • Ifosfamide.
   • Hexamethylmelamine (HMM).
   • Capecitabine.^46,
   • Bevacizumab. Although phase II studies have shown single-agent activity for this antibody to vascular endothelial growth factor (VEGF), bowel perforations have occurred, primarily in patients who had partial bowel obstruction.^47,48,
5. Drug combinations. Pilot studies have reported tolerance and activity for combinations of doxorubicin plus topotecan, gemcitabine plus doxorubicin, oxaliplatin plus topotecan, oxaliplatin plus doxorubicin, and a number of other combinations with drugs listed above. There is no evidence that drug combinations are superior to single agents in the platinum-resistant setting.
6. A number of tyrosine kinase inhibitors alone and in combination with Group 1 drugs. A number of pilot studies with erlotinib, lapatinib, sunitinib, imatinib, sorafenib, and additional VEGF small-molecule inhibitors are under way.

¹ Hoskins WJ, Rubin SC, Dulaney E, et al.: Influence of secondary cytoreduction at the time of second-look laparotomy on the survival of patients with epithelial ovarian carcinoma. Gynecol Oncol 34 (3): 365-71, 1989.

² Bolis G, Parazzini F, Scarfone G, et al.: Paclitaxel vs epidoxorubicin plus paclitaxel as second-line therapy for platinum-refractory and -resistant ovarian cancer. Gynecol Oncol 72 (1): 60-4, 1999.

³ Parmar MK, Ledermann JA, Colombo N, et al.: Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 361 (9375): 2099-106, 2003.

⁴ Cantù MG, 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 first-line platinum-based regimens. J Clin Oncol 20 (5): 1232-7, 2002.

⁵ Bolis G, Scarfone G, Giardina G, et al.: Carboplatin alone vs carboplatin plus epidoxorubicin as second-line therapy for cisplatin- or carboplatin-sensitive ovarian cancer. Gynecol Oncol 81 (1): 3-9, 2001.

⁶ Pfisterer J, Vergote I, Du Bois A, et al.: Combination therapy with gemcitabine and carboplatin in recurrent ovarian cancer. Int J Gynecol Cancer 15 (Suppl 1): 36-41, 2005 May-Jun.

⁷ Weber, B, Mayer F, Bougnoux P, et al.: What is the best chemotherapy regimen in recurrent or advanced endometrial carcinoma? Preliminary results. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-1819, 2003.

⁸ Kohn EC, Sarosy G, Bicher A, et al.: Dose-intense taxol: high response rate in patients with platinum-resistant recurrent ovarian cancer. J Natl Cancer Inst 86 (1): 18-24, 1994.

⁹ McGuire WP, Rowinsky EK, Rosenshein NB, et al.: Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 111 (4): 273-9, 1989.

¹⁰ Einzig AI, Wiernik PH, Sasloff J, et al.: Phase II study and long-term follow-up of patients treated with taxol for advanced ovarian adenocarcinoma. J Clin Oncol 10 (11): 1748-53, 1992.

¹¹ Thigpen JT, Blessing JA, Ball H, et al.: Phase II trial of paclitaxel in patients with progressive ovarian carcinoma after platinum-based chemotherapy: a Gynecologic Oncology Group study. J Clin Oncol 12 (9): 1748-53, 1994.

¹² Trimble EL, Adams JD, Vena D, et al.: Paclitaxel for platinum-refractory ovarian cancer: results from the first 1,000 patients registered to National Cancer Institute Treatment Referral Center 9103. J Clin Oncol 11 (12): 2405-10, 1993.

¹³ ten Bokkel Huinink W, Gore M, Carmichael J, et al.: Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 15 (6): 2183-93, 1997.

¹⁴ 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 (14): 3312-22, 2001.

¹⁵ Kudelka AP, Tresukosol D, Edwards CL, et al.: Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol 14 (5): 1552-7, 1996.

¹⁶ Creemers GJ, 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 14 (12): 3056-61, 1996.

¹⁷ Bookman MA, Malmström 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 16 (10): 3345-52, 1998.

¹⁸ 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 (3): 987-93, 1997.

¹⁹ Gordon AN, Tonda M, Sun S, et al.: Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol 95 (1): 1-8, 2004.

²⁰ Berkenblit A, Seiden MV, Matulonis UA, et al.: A phase II trial of weekly docetaxel in patients with platinum-resistant epithelial ovarian, primary peritoneal serous cancer, or fallopian tube cancer. Gynecol Oncol 95 (3): 624-31, 2004.

²¹ Friedlander M, Millward MJ, Bell D, et al.: A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer. Ann Oncol 9 (12): 1343-5, 1998.

²² Lund B, Hansen OP, Theilade K, et al.: Phase II study of gemcitabine (2',2'-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 86 (20): 1530-3, 1994.

²³ Shapiro JD, Millward MJ, Rischin D, et al.: Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. Gynecol Oncol 63 (1): 89-93, 1996.

²⁴ 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 119 (1): 55-7, 1992.

²⁵ Hoskins PJ, Swenerton KD: Oral etoposide is active against platinum-resistant epithelial ovarian cancer. J Clin Oncol 12 (1): 60-3, 1994.

²⁶ Seymour MT, Mansi JL, Gallagher CJ, et al.: Protracted oral etoposide in epithelial ovarian cancer: a phase II study in patients with relapsed or platinum-resistant disease. Br J Cancer 69 (1): 191-5, 1994.

²⁷ 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 (2): 405-10, 1998.

²⁸ Sutton GP, Blessing JA, Homesley HD, et al.: Phase II trial of ifosfamide and mesna in advanced ovarian carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 7 (11): 1672-6, 1989.

²⁹ 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 10 (2): 243-8, 1992.

³⁰ Rosen GF, Lurain JR, Newton M: Hexamethylmelamine in ovarian cancer after failure of cisplatin-based multiple-agent chemotherapy. Gynecol Oncol 27 (2): 173-9, 1987.

³¹ Manetta A, MacNeill C, Lyter JA, et al.: Hexamethylmelamine as a single second-line agent in ovarian cancer. Gynecol Oncol 36 (1): 93-6, 1990.

³² Moore DH, Fowler WC Jr, Jones CP, et al.: Hexamethylmelamine chemotherapy for persistent or recurrent epithelial ovarian cancer. Am J Obstet Gynecol 165 (3): 573-6, 1991.

³³ Vergote I, Himmelmann A, Frankendal B, et al.: Hexamethylmelamine as second-line therapy in platin-resistant ovarian cancer. Gynecol Oncol 47 (3): 282-6, 1992.

³⁴ Hauge MD, Long HJ, Hartmann LC, et al.: Phase II trial of intravenous hexamethylmelamine in patients with advanced ovarian cancer. Invest New Drugs 10 (4): 299-301, 1992.

³⁵ Piccart MJ, Green JA, Lacave AJ, et al.: Oxaliplatin or paclitaxel in patients with platinum-pretreated advanced ovarian cancer: A randomized phase II study of the European Organization for Research and Treatment of Cancer Gynecology Group. J Clin Oncol 18 (6): 1193-202, 2000.

³⁶ Fracasso PM, Blessing JA, Morgan MA, et al.: Phase II study of oxaliplatin in platinum-resistant and refractory ovarian cancer: a gynecologic group study. J Clin Oncol 21 (15): 2856-9, 2003.

³⁷ George MJ, Heron JF, Kerbrat P, et al.: Navelbine in advanced ovarian epithelial cancer: a study of the French oncology centers. Semin Oncol 16 (2 Suppl 4): 30-2, 1989.

³⁸ Reed E, Jacob J, Ozols RF, et al.: 5-Fluorouracil (5-FU) and leucovorin in platinum-refractory advanced stage ovarian carcinoma. Gynecol Oncol 46 (3): 326-9, 1992.

³⁹ Look KY, Muss HB, Blessing JA, et al.: A phase II trial of 5-fluorouracil and high-dose leucovorin in recurrent epithelial ovarian carcinoma. A Gynecologic Oncology Group Study. Am J Clin Oncol 18 (1): 19-22, 1995.

⁴⁰ Hatch KD, Beecham JB, Blessing JA, et al.: Responsiveness of patients with advanced ovarian carcinoma to tamoxifen. A Gynecologic Oncology Group study of second-line therapy in 105 patients. Cancer 68 (2): 269-71, 1991.

⁴¹ Markman M, Rothman R, Hakes T, et al.: Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 9 (3): 389-93, 1991.

⁴² Eisenhauer EA, Swenerton KD, Sturgeon JF, et al.: Carboplatin therapy for recurrent ovarian carcinoma: National Cancer Institute of Canada experience and a review of the literature. In: Carboplatin (JM-8): Current Perspectives and Future Directions. Philadelphia, PA: W.B. Saunders Company, 1990, pp 133-140.

⁴³ Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, 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 12 (12): 2654-66, 1994.

⁴⁴ Segna RA, Dottino PR, Mandeli JP, et al.: Secondary cytoreduction for ovarian cancer following cisplatin therapy. J Clin Oncol 11 (3): 434-9, 1993.

⁴⁵ Morris M, Gershenson DM, Wharton JT, et al.: Secondary cytoreductive surgery for recurrent epithelial ovarian cancer. Gynecol Oncol 34 (3): 334-8, 1989.

⁴⁶ Vasey PA, McMahon L, Paul J, et al.: A phase II trial of capecitabine (Xeloda) in recurrent ovarian cancer. Br J Cancer 89 (10): 1843-8, 2003.

⁴⁷ Monk BJ, Han E, Josephs-Cowan CA, et al.: Salvage bevacizumab (rhuMAB VEGF)-based therapy after multiple prior cytotoxic regimens in advanced refractory epithelial ovarian cancer. Gynecol Oncol 102 (2): 140-4, 2006.

⁴⁸ Aghajanian C: The role of bevacizumab in ovarian cancer--an evolving story. Gynecol Oncol 102 (2): 131-3, 2006.

Changes to This Summary (03/08/2007)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information

Updated statistics with estimated new cases and deaths for 2007 (cited American Cancer Society as reference 1).

More Information

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database.
  • Full description of the NCI PDQ database.

Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment
  • Treatment options for adult cancers.
• PDQ® Cancer Information Summaries: Pediatric Treatment
  • Treatment options for childhood cancers.
• PDQ® Cancer Information Summaries: Supportive Care
  • Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.
• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)
  • Tests or procedures that detect specific types of cancer.
• PDQ® Cancer Information Summaries: Prevention
  • Risk factors and methods to increase chances of preventing specific types of cancer.
• PDQ® Cancer Information Summaries: Genetics
  • Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.
• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine
  • Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237) .