Purpose of This PDQ Summary
General Information
Cellular Classification
Stage Information
Stage I and Stage II Ovarian Epithelial Cancer

Current Clinical Trials

Stage III and Stage IV Ovarian Epithelial Cancer

Surgery Treatment Options for Patients With Optimally Cytoreduced Stage III Disease Treatment Options for Patients With Suboptimally Cytoreduced Stage III and Stage IV Disease Current Clinical Trials

Recurrent or Persistent Ovarian Epithelial Cancer

Local Modalities: Surgery and Radiation Therapy Platinum-Sensitive Recurrence Platinum-Refractory or Platinum-Resistant Recurrence Treatment Options for Patients with Recurrent or Persistent Disease Current Clinical Trials

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Changes to This Summary (04/16/2009)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of ovarian epithelial cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board ¹.

Information about the following is included in this summary:

• Genetic characteristics and risk factors.
• Prognostic factors.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system ² in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version ³, written in less technical language, and in Spanish ⁴.

General Information

Note: Separate PDQ summaries on Genetics of Breast and Ovarian Cancer ⁵; Ovarian Cancer Screening ⁶; and Ovarian Cancer Prevention ⁷ are also available. Information on ovarian cancer in children is available in the PDQ summary on Unusual Cancers of Childhood ⁸.

Note: Estimated new cases and deaths from ovarian cancer in the United States in 2008:[1]

• New cases: 21,650.
• Deaths: 15,520.

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 ² 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 65 years.[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.[5-7] 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 of them (0.8%) developed subsequent papillary serous peritoneal carcinoma, and six of them (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 ⁹ section in the PDQ summary on Ovarian Cancer Prevention ⁷ 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 ¹⁰ and Ovarian Low Malignant Potential Tumor Treatment ¹¹ 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:[17-21]

• 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.[30-32] As a result of these confounding factors, 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 showed 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.[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 ¹².

References

1. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. ¹³ Last accessed October 1, 2008. 
   
   
2. Yancik R: Ovarian cancer. Age contrasts in incidence, histology, disease stage at diagnosis, and mortality. Cancer 71 (2 Suppl): 517-23, 1993.  [PUBMED Abstract]
   
   
3. Lynch HT, Watson P, Lynch JF, et al.: Hereditary ovarian cancer. Heterogeneity in age at onset. Cancer 71 (2 Suppl): 573-81, 1993.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
26. Mogensen O: Prognostic value of CA 125 in advanced ovarian cancer. Gynecol Oncol 44 (3): 207-12, 1992.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
30. Goff BA, Mandel L, Muntz HG, et al.: Ovarian carcinoma diagnosis. Cancer 89 (10): 2068-75, 2000.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
32. Smith LH, Morris CR, Yasmeen S, et al.: Ovarian cancer: can we make the clinical diagnosis earlier? Cancer 104 (7): 1398-407, 2005.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
34. Ozols RF, Young RC: Ovarian cancer. Curr Probl Cancer 11 (2): 57-122, 1987 Mar-Apr.  [PUBMED Abstract]
    
    
35. Cannistra SA: Cancer of the ovary. N Engl J Med 329 (21): 1550-9, 1993.  [PUBMED Abstract]
    
    

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 ¹¹ 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.[2-4] 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]

* [Note: 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.

References

1. Hoskins WJ: Surgical staging and cytoreductive surgery of epithelial ovarian cancer. Cancer 71 (4 Suppl): 1534-40, 1993.  [PUBMED Abstract]
   
   
2. Mogensen O: Prognostic value of CA 125 in advanced ovarian cancer. Gynecol Oncol 44 (3): 207-12, 1992.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
8. Shepherd JH: Revised FIGO staging for gynaecological cancer. Br J Obstet Gynaecol 96 (8): 889-92, 1989.  [PUBMED Abstract]
   
   
9. Ovary. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 275-284. 
   
   

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 ² for more information.)

Treatment options:

1. If the tumor is well differentiated 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%.[3-6] 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.[1,7,9-11]
   • 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 ¹⁴), 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 randomly assigned to adjuvant chemotherapy or observation. Data were reported individually and in pooled form.[12-14]

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 randomizly assigned 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 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.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I ovarian epithelial cancer ¹⁵ and stage II ovarian epithelial cancer ¹⁶. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ¹².

References

1. Young RC, Decker DG, Wharton JT, et al.: Staging laparotomy in early ovarian cancer. JAMA 250 (22): 3072-6, 1983.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
    
    
11. McGuire WP: Early ovarian cancer: treat now, later or never? Ann Oncol 6 (9): 865-6, 1995.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
15. Young RC: Early-stage ovarian cancer: to treat or not to treat. J Natl Cancer Inst 95 (2): 94-5, 2003.  [PUBMED Abstract]
    
    

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 ² for more information.)

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

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 [1-4] 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 (EORTC-55971 ¹⁷) 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.

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).[5] In the 1990s, randomized trials were conducted to evaluate whether the IP route would prove superior to the intravenous 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 ¹⁸, GOG-14 ¹⁹, and GOG-172 ²⁰).[6-8] 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).[8][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 and catheter-related problems.[9] 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 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.[10] In another meta-analysis of seven IP versus IV randomized trials that were conducted by Cancer Care of Ontario, the relative ratio (RR) of progression at 5 years based on the three trials that reported this endpoint was 0.91 (95% confidence interval [CI], 0.85–0.98) and the RR of death at 5 years based on six trials was 0.88 (95% CI, 0.81–0.95).[9]

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.[11][Level of evidence: 1iiB] The GOG-162 ²¹ trial was designed to answer a very similar question but used the then-standard paclitaxel-plus-cisplatin regimen as the chemotherapy.[12] 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

First-line treatment of ovarian cancer is cisplatin, given intravenously, or its second-generation analog, carboplatin, 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 [13-15] for both cisplatin and carboplatin,[16] schedule, [17] and the equivalent results obtained with either of these platinum drugs, usually in combination with cyclophosphamide.[18] With the introduction of the taxane paclitaxel, 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).

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 ²³ 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.
2. The Medical Research Council (MRC-ICON3) ²⁴ study, while having fewer early crossovers, could be interpreted similarly in regard to the impact on survival of sequential treatment.
3. Data from MRC-ICON4 ²⁷ 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 ²⁸).
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,[19-21]
• Noninferiority for carboplatin plus paclitaxel versus carboplatin plus docetaxel,[22] and
• No advantage but increased toxic effects by adding epirubicin to the carboplatin plus paclitaxel doublet.[23]

The GOG-initiated (GOG-0182-ICON5) ²⁹ study, with international collaboration and 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.[24]

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 [25] or radioimmunoconjugate × one cycle [26] following negative reassessment; or IV topotecan × four cycles.[27] 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.[28][Level of evidence: 1iiDiii] Trials to confirm the value of maintenance with taxanes versus observation are being conducted by the GOG.

Treatment options under clinical evaluation:

• IP radioimmunoconjugates, vaccines, and targeted drugs are under clinical evaluation, primarily as consolidation therapy.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III ovarian epithelial cancer ³⁰ and stage IV ovarian epithelial cancer ³¹. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ¹².

References

1. Hoskins WJ: Surgical staging and cytoreductive surgery of epithelial ovarian cancer. Cancer 71 (4 Suppl): 1534-40, 1993.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
5. 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.  [PUBMED Abstract]
   
   
6. 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.  [PUBMED Abstract]
   
   
7. 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.  [PUBMED Abstract]
   
   
8. Armstrong DK, Bundy B, Wenzel L, et al.: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354 (1): 34-43, 2006.  [PUBMED Abstract]
   
   
9. Elit L, Oliver TK, Covens A, et al.: Intraperitoneal chemotherapy in the first-line treatment of women with stage III epithelial ovarian cancer: a systematic review with metaanalyses. Cancer 109 (4): 692-702, 2007.  [PUBMED Abstract]
   
   
10. Jaaback K, Johnson N: Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev (1): CD005340, 2006.  [PUBMED Abstract]
    
    
11. 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.  [PUBMED Abstract]
    
    
12. 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.  [PUBMED Abstract]
    
    
13. 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.  [PUBMED Abstract]
    
    
14. Markman M: Intraperitoneal chemotherapy. Semin Oncol 18 (3): 248-54, 1991.  [PUBMED Abstract]
    
    
15. 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.  [PUBMED Abstract]
    
    
16. 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.  [PUBMED Abstract]
    
    
17. 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.  [PUBMED Abstract]
    
    
18. 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.  [PUBMED Abstract]
    
    
19. 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.  [PUBMED Abstract]
    
    
20. 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.  [PUBMED Abstract]
    
    
21. 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.  [PUBMED Abstract]
    
    
22. 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.  [PUBMED Abstract]
    
    
23. 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.  [PUBMED Abstract]
    
    
24. 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. 
    
    
25. 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.  [PUBMED Abstract]
    
    
26. 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.  [PUBMED Abstract]
    
    
27. 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.  [PUBMED Abstract]
    
    
28. 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.  [PUBMED Abstract]
    
    

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 ² for more information.)

Cytoreduction is often employed,[1] but such intervention only now is being studied in the setting of a randomized clinical trial (GOG-0213 ³²). The role of radiation therapy in patients with recurrent ovarian cancer has not been defined.

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—cisplatin or carboplatin— 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 generally deemed toxic and not sufficiently useful to be part of the treatment plan.

Carboplatin was approved in 1987 for the treatment of patients with ovarian cancer whose disease recurred after treatment with cisplatin, based on improved survival with etoposide or 5-fluorouracil.[7] In a randomized phase II trial of paclitaxel, a currently used second-line drug, the cisplatin-containing combination of cisplatin plus doxorubicin plus cyclophosphamide (CAP) yielded a superior survival outcome. This, and subsequent studies (see Table 2 ²⁸), have reinforced using carboplatin as the treatment core for patients with platinum-sensitive recurrences. Cisplatin is occasionally used, particularly in combination with other drugs, because of its lesser myelosuppression, but this advantage over carboplatin is counterbalanced by its greater intolerance. Oxaliplatin, initially introduced with the hope that it would overcome platinum resistance, has activity mostly in platinum-sensitive patients [8] but has not been compared with carboplatin alone or in combinations. With all platinums, outcome is generally better the longer the initial interval without recurrence from the initial platinum-containing regimens.[9] Therefore, on occasion, patients with platinum-sensitive recurrences relapsing within 1 year have been included in trials of nonplatinum drugs. In one such trial, comparing the pegylated liposomal doxorubicin (PLD) to topotecan, the subset of patients who were platinum sensitive had better outcomes with either drug (and in particular with PLD) relative to the platinum-resistant cohort.[10]

Several randomized trials have addressed whether the use of a platinum in combination is superior to single agents (see Table 2 ²⁸). 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 controls 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). 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.[6][Level of evidence: 1iiA][3] The AGO had previously compared the combination of epirubicin plus carboplatin to carboplatin alone and had not found significant differences in outcome.

Another trial by European and Canadian groups compared gemcitabine plus carboplatin to carboplatin. The PFS of 8.6 months with the combination was significantly superior to 5.8 months for the carboplatin alone (HR = .72; 95% CI, 0.58–0.90; P = .003). The study was not powered to detect significant differences in OS, and the median survival for both arms was 18 months (HR = 0.96; CI, 0.75–1.23; P = .73).[5]

Accordingly, because of this randomized experience, carboplatin plus paclitaxel is considered the standard regimen for platinum-sensitive recurrence in the absence of residual neurotoxicity. The GOG-0213 ³² trial will be comparing this regimen to the experimental arm that adds bevacizumab to carboplatin plus paclitaxel.

Clinical recurrences that take place within 6 months of completion of a platinum-containing regimen are considered platinum-refractory or platinum-resistant recurrences. Anthracyclines (particularly when formulated as PLD), taxanes, topotecan, and gemcitabine are used as single agents for these recurrences based on activity and their favorable therapeutic indices relative to agents listed in Table 3 ³⁴. The long list underscores the marginal benefit, if any, generally conveyed by these agents. Patients with platinum-resistant disease should be encouraged to enter clinical trials.

Treatment with paclitaxel historically provided the first agent with consistent activity in patients with platinum-refractory or platinum-resistant recurrences.[11-15] Subsequently, randomized studies have indicated that the use of topotecan achieved results that were comparable to those achieved with paclitaxel.[16] Topotecan was compared with pegylated liposomal doxorubicin in a randomized trial of 474 patients and demonstrated similar response rates, PFS, and OS at the time of the initial report, contributed primarily by the platinum-resistant subsets.[17]

Drugs used to treat platinum-refractory or platinum-resistant recurrence:

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.[16,18-20] Objective responses are reported in patients with platinum-refractory disease. Substantial myelosuppression follows administration. Other toxic effects include nausea, vomiting, alopecia, and asthenia. A number of schedules and oral formulations are under evaluation.



2. PLD. 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.[21] Liposomal doxorubicin and topotecan have been compared in a randomized trial of 474 patients with recurrent ovarian cancer.[17] 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.[17][Level of evidence: 1iiA] Survival was longer for the patients with platinum-sensitive disease who received liposomal doxorubicin.[10]



3. Docetaxel. This drug has shown activity in paclitaxel-pretreated patients and is a reasonable alternative to weekly paclitaxel in the recurrent setting.[22]



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.[23-25] A randomized trial of gemcitabine versus PLD showed noninferiority and no advantage in therapeutic index of one drug over the other.[26]



5. Paclitaxel. Patients generally received paclitaxel in front-line induction regimens. Retreatment with paclitaxel, particularly in weekly schedules, indicates an activity comparable to those of the preceding drugs. If there is residual neuropathy upon recurrence, this may shift the choice of treatment towards other agents. 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.[16]



6. Bevacizumab. Three phase II studies have shown activity for this antibody to vascular endothelial growth factor (VEGF). The first study, GOG-0170D ³⁵, included 62 patients who had received only one or two prior treatments (these last patients had received one additional platinum-based regimen because of an initial interval of 12 months or greater after first-line regimens and also had to have a performance status of 0 or 1).[27] Patients received a dose of 15 mg/kg every 21 days; there were two complete responses and 11 partial responses, a median PFS of 4.7 months, and an OS of 17 months. This activity was noted in both platinum-sensitive and platinum-resistant subsets. The second study only included patients with platinum-resistant disease using an identical dose schedule, but the study was stopped because five of 44 patients experienced bowel perforations, one of them fatal; seven partial responses had been observed.[28] This increased risk of bowel perforations was associated with three or more prior treatments.[29-31][Level of evidence: 3iiiDii] The third study (CCC-PHII-45 ³⁶) included 70 patients who received 50 mg of oral cyclophosphamide daily, in addition to bevacizumab (10 mg/kg every 2 weeks); 17 partial responses were observed and four patients had intestinal perforations.[32] Studies by the Gynecologic Oncology Group are evaluating the efficacy of the drug added to the intial treatment and at first recurrence in the platinum-resistant setting.

Other drugs used to treat platinum-refractory or platinum-resistant recurrence

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

1. Secondary cytoreduction has been advocated, but it remains controversial.[1] The GOG-0213 ³² trial, actived in 2008, is attempting to define its role.



2. 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 a platinum or platinum-containing combination, such as carboplatin, should be considered (see Table 2 ²⁸).



3. For patients with platinum-refractory or platinum-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), clinical trials should be considered. For patients who are not entering a trial, treatment with one of the drugs listed above ³⁴ should be considered.



4. Other agents that have shown activity in phase II trials are listed in Table 3 ³⁴ and may also be used alone or in combination with other drugs, but such treatments are best done in prospective trials.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent ovarian epithelial cancer ³⁸. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ¹².

References

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.  [PUBMED Abstract]
   
   
2. Ferrero JM, Weber B, Geay JF, et al.: Second-line chemotherapy with pegylated liposomal doxorubicin and carboplatin is highly effective in patients with advanced ovarian cancer in late relapse: a GINECO phase II trial. Ann Oncol 18 (2): 263-8, 2007.  [PUBMED Abstract]
   
   
3. 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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
5. Pfisterer J, Plante M, Vergote I, et al.: Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 24 (29): 4699-707, 2006.  [PUBMED Abstract]
   
   
6. 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.  [PUBMED Abstract]
   
   
7. Muggia FM: Overview of carboplatin: replacing, complementing, and extending the therapeutic horizons of cisplatin. Semin Oncol 16 (2 Suppl 5): 7-13, 1989.  [PUBMED Abstract]
   
   
8. 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.  [PUBMED Abstract]
   
   
9. Markman M, Markman J, Webster K, et al.: Duration of response to second-line, platinum-based chemotherapy for ovarian cancer: implications for patient management and clinical trial design. J Clin Oncol 22 (15): 3120-5, 2004.  [PUBMED Abstract]
   
   
10. 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.  [PUBMED Abstract]
    
    
11. 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.  [PUBMED Abstract]
    
    
12. 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.  [PUBMED Abstract]
    
    
13. 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.  [PUBMED Abstract]
    
    
14. 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.  [PUBMED Abstract]
    
    
15. 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.  [PUBMED Abstract]
    
    
16. 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.  [PUBMED Abstract]
    
    
17. 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.  [PUBMED Abstract]
    
    
18. 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.  [PUBMED Abstract]
    
    
19. 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.  [PUBMED Abstract]
    
    
20. 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.  [PUBMED Abstract]
    
    
21. 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.  [PUBMED Abstract]
    
    
22. 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.  [PUBMED Abstract]
    
    
23. 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.  [PUBMED Abstract]
    
    
24. 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.  [PUBMED Abstract]
    
    
25. 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.  [PUBMED Abstract]
    
    
26. Mutch DG, Orlando M, Goss T, et al.: Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol 25 (19): 2811-8, 2007.  [PUBMED Abstract]
    
    
27. Burger RA, Sill MW, Monk BJ, et al.: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol 25 (33): 5165-71, 2007.  [PUBMED Abstract]
    
    
28. Cannistra SA, Matulonis UA, Penson RT, et al.: Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 25 (33): 5180-6, 2007.  [PUBMED Abstract]
    
    
29. 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.  [PUBMED Abstract]
    
    
30. 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.  [PUBMED Abstract]
    
    
31. Kaye SB: Bevacizumab for the treatment of epithelial ovarian cancer: will this be its finest hour? J Clin Oncol 25 (33): 5150-2, 2007.  [PUBMED Abstract]
    
    
32. Garcia AA, Hirte H, Fleming G, et al.: Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 26 (1): 76-82, 2008.  [PUBMED Abstract]
    
    

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  Full description of the NCI PDQ database.

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Glossary Terms

Randomized, controlled, double-blinded clinical trial with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Randomized, controlled, nonblinded clinical trial with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Randomized, controlled, nonblinded clinical trial with cause-specific mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Randomized, controlled, nonblinded clinical trial with progression-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Population-based, consecutive case series with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with total disease-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with tumor response rate as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.