General Information

Cellular Classification

Stage Information

Treatment Option Overview

Stage I Ovarian Epithelial Cancer

Stage II Ovarian Epithelial Cancer

Stage III Ovarian Epithelial Cancer

Stage IV Ovarian Epithelial Cancer

Recurrent Ovarian Epithelial Cancer

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GENERAL INFORMATION

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 half of all cases occurring in women over age 65.[1] Approximately 5% to 10% of ovarian cancers are familial and 3 distinct hereditary patterns have been identified: ovarian cancer alone, ovarian and breast cancers, or ovarian and colon cancers.[2] The most important risk factor for ovarian cancer is a family history of a first-degree relative (mother, daughter, or sister) with the disease. The highest risk appears in women with 2 or more first-degree relatives with ovarian cancer.[3] The risk is somewhat less for women with one first-degree and one second-degree (grandmother, aunt) relative 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.[4-6] BRCA2, also responsible for some instances of inherited ovarian and breast cancer, has been mapped by genetic linkage to chromosome 13q12.[7] The lifetime risk for developing ovarian cancer in patients harboring germ-line mutations in BRCA1 is substantially increased over the general population.[8,9] Two retrospective studies of patients with germ-line mutations in BRCA1 suggest that these women have improved survival compared to BRCA1 negative women.[10,11][Level of evidence: 3iiiA] When interpreting these data, it must be considered that 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 patients at increased risk, prophylactic oophorectomy may be considered after the age of 35 if childbearing is complete. However, the benefit of prophylactic oophorectomy has not yet been established. A small percentage of women may develop a primary peritoneal carcinoma, similar in appearance to ovarian cancer, after prophylactic oophorectomy.[12] 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 as high as 24% in patients with stage I disease, 50% in patient with stage II disease, 74% in patients with stage III disease, and 73% in patients with stage IV disease.[13] 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 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, and smaller residual tumor following primary cytoreductive surgery.[14-18] For patients with stage I disease, the most important prognostic factor is grade, followed by dense adherence and large-volume ascites.[19] DNA flow cytometric analysis of stage I and stage IIA patients may identify a group of high-risk patients.[20] Patients with clear cell histology appear to have a worse prognosis.[21] Patients with a significant component of transitional cell carcinoma appear to have a better prognosis.[22]

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 one month after the third course of chemotherapy for patients with stage III or stage IV disease.[23] For patients whose elevated CA 125 normalizes with chemotherapy, more than one subsequent elevated CA 125 is highly predictive of active disease, but this does not mandate immediate therapy.[24,25]

Because ovarian cancer is often asymptomatic in its early stages, most patients have widespread disease at the time of diagnosis. 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 reveals a 5-year survival rate of less than 10% even with platinum-based combination therapy.[14] Nevertheless, early stages of the disease are curable in a high percentage of patients. 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.[26,27]

References:

1. Yancik R: Ovarian cancer: age contrasts in incidence, histology, disease stage at diagnosis, and mortality. Cancer 71(2, Suppl): 517-523, 1993.
2. Lynch HT, Watson P, Lynch JF, et al.: Hereditary ovarian cancer: heterogeneity in age at onset. Cancer 71(2, Suppl): 573-581, 1993.
3. 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. European Journal of Gynaecological Oncology 17(3): 169-176, 1996.
4. 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.
5. Easton DF, Bishop DT, Ford D, et al.: Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. American Journal of Human Genetics 52(4): 678-701, 1993.
6. Steichen-Gersdorf E, Gallion HH, Ford D, et al.: Familial site-specific ovarian cancer is linked to BRCA1 on 17q12-21. American Journal of Human Genetics 55(5): 870-875, 1994.
7. Wooster R, Neuhausen SL, Mangion J, et al.: Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265(5181): 2088-2090, 1994.
8. Easton DF, Ford D, Bishop DT: Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. American Journal of Human Genetics 56(1): 265-271, 1995.
9. Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. New England Journal of Medicine 336(20): 1401-1408, 1997.
10. Rubin SC, Benjamin I, Behbakht K, et al.: Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. New England Journal of Medicine 335(19): 1413-1416, 1996.
11. Aida H, Takakuwa K, Nagata H, et al.: Clinical features of ovarian cancer in Japanese women with germ-line mutations of BRCA1. Clinical Cancer Research 4(1): 235-240, 1998.
12. Piver MS, Jishi MF, Tsukada Y, et al.: Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer. Cancer 71(9): 2751-2755, 1993.
13. Burghardt E, Girardi F, Lahousen M, et al.: Patterns of pelvic and paraaortic lymph node involvement in ovarian cancer. Gynecologic Oncology 40(2): 103-106, 1991.
14. 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. Journal of Clinical Oncology 9(7): 1138-1150, 1991.
15. van Houwelingen JC, ten Bokkel Huinink WW, van der Burg ME, et al.: Predictability of the survival of patients with advanced ovarian cancer. Journal of Clinical Oncology 7(6): 769-773, 1989.
16. 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. European Journal of Cancer 27(11): 1367-1372, 1991.
17. 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. Gynecologic Oncology 47(2): 159-166, 1992.
18. Thigpen T, Brady MF, Omura GA, et al.: Age as a prognostic factor in ovarian carcinoma. Cancer 71(2, Suppl): 606-614, 1993.
19. Dembo AJ, Davy M, Stenwig AE: Prognostic factors in patients with stage I epithelial ovarian cancer. Obstetrics and Gynecology 75(2): 263-273, 1990.
20. Schueler JA, Cornelisse CJ, Hermans J, et al.: Prognostic factors in well-differentiated early-stage epithelial ovarian cancer. Cancer 71(3): 787-795, 1993.
21. 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. New England Journal of Medicine 322(15): 1021-1027, 1990.
22. 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. American Journal of Obstetrics and Gynecology 168(4): 1178-1187, 1993.
23. Mogensen O: Prognostic value of CA 125 in advanced ovarian cancer. Gynecologic Oncology 44(3): 207-212, 1992.
24. Hogberg T, Kagedal B: Long-term follow-up of ovarian cancer with monthly determinations of serum CA 125. Gynecologic Oncology 46(2): 191-198, 1992.
25. 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. Annals of Oncology 7(4): 361-364, 1996.
26. Ozols RF, Young RC: Ovarian cancer. Current Problems in Cancer 11(2): 57-122, 1987.
27. Cannistra SA: Cancer of the ovary. New England Journal of Medicine 329(21): 1550-1559, 1993.

CELLULAR CLASSIFICATION

• 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)
  

STAGE INFORMATION

In addition, invasion of the bladder and bowel needs to be taken into consideration, and a preoperative intravenous pyelogram and barium enema may be useful to evaluate the urinary tract and large bowel.

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 (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging.[8,9]

Stage I

Stage IA: growth limited to one ovary; no ascites. No tumor on the external surface; capsule intact.

Stage IB: growth limited to both ovaries; no ascites. No tumor on the external surfaces; capsules intact.

Stage IC: tumor either stage IA or IB, but with tumor on the surface of one or both ovaries; or with capsule ruptured; or with ascites present containing malignant cells or with positive peritoneal washings.[8]

Stage II

Stage IIA: extension and/or metastases to the uterus and/or tubes.

Stage IIB: extension to other pelvic tissues.

Stage IIC: tumor either stage IIA or stage IIB, but with tumor on the surface of one or both ovaries; or with capsule(s) ruptured; or with ascites present containing malignant cells or with positive peritoneal washings.

Stage III

Stage IIIA: tumor grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces.

Stage IIIB: tumor of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 centimeters in diameter. Nodes negative.

Stage IIIC: abdominal implants greater than 2 centimeters in diameter and/or positive retroperitoneal or inguinal nodes.

Stage IV

References:

1. Hoskins WJ: Surgical staging and cytoreductive surgery of epithelial ovarian cancer. Cancer 71(4, Suppl): 1534-1540, 1993.
2. Mogensen O: Prognostic value of CA 125 in advanced ovarian cancer. Gynecologic Oncology 44(3): 207-212, 1992.
3. Hogberg T, Kagedal B: Long-term follow-up of ovarian cancer with monthly determinations of serum CA 125. Gynecologic Oncology 46(2): 191-198, 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. Annals of Oncology 7(4): 361-364, 1996.
5. Makar AP, Kristensen GB, Bormer OP, et al.: CA 125 measured before second-look laparotomy is an independent prognostic factor for survival in patients with epithelial ovarian cancer. Gynecologic Oncology 45(3): 323-328, 1992.
6. Berek JS, Knapp RC, Malkasian GD, et al.: CA 125 serum levels correlated with second-look operations among ovarian cancer patients. Obstetrics and Gynecology 67(5): 685-689, 1986.
7. Atack DB, Nisker JA, Allen HH, et al.: CA 125 surveillance and second-look laparotomy in ovarian carcinoma. American Journal of Obstetrics and Gynecology 154(2): 287-289, 1986.
8. Shepherd JH: Revised FIGO staging for gynaecological cancer. British Journal of Obstetrics and Gynaecology 96(8): 889-892, 1989.
9. Ovary. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 201-206.

TREATMENT OPTION OVERVIEW

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 OVARIAN EPITHELIAL CANCER

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 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 who have grade I tumors, unilateral salpingo-oophorectomy may not be associated with high risk of recurrence.[2]

2. If the tumor is grade III, densely adherent, or stage IC, the chance of
relapse and subsequent death from ovarian cancer is substantial (up to 20%), although the importance of tumor rupture if it is the only adverse characteristic is not clear.[3-5] Several treatment approaches that have been taken in such patients are listed below.

• intraperitoneal P-32 or radiation therapy [1,6,7]
• systemic chemotherapy [1,6,8-10]
• total abdominal and pelvic radiation therapy [11,12]
• careful observation without immediate treatment in selected patients (watchful waiting)
  

A large randomized trial from Norway found equivalent survival rates with either P-32 administered intraperitoneally or 6 courses of cisplatin, but a higher complication rate with the P-32.[6]

Treatment options under clinical evaluation:

Patients with stage I ovarian cancer are appropriate candidates for clinical trials.

References:

1. Young RC, Brady MF, Walton LA, et al.: Localized ovarian cancer in the elderly: the Gynecologic Oncology Group experience. Cancer 71(2, Suppl): 601-605, 1993.
2. Zanetta G, Chiari S, Rota S, et al.: Conservative surgery for stage I ovarian carcinoma in women of childbearing age. British Journal of Obstetrics and Gynaecology 104(9): 1030-1035, 1997.
3. Dembo AJ, Davy M, Stenwig AE: Prognostic factors in patients with stage I epithelial ovarian cancer. Obstetrics and Gynecology 75(2): 263-273, 1990.
4. Ahmed FY, Wiltshaw E, A'Hern RP, et al.: Natural history and prognosis of untreated stage I epithelial ovarian carcinoma. Journal of Clinical Oncology 14(11): 2968-2975, 1996.
5. Monga M, Carmichael JA, Shelley WE, et al.: Surgery without adjuvant chemotherapy for early epithelial ovarian carcinoma after comprehensive surgical staging. Gynecologic Oncology 43(3): 195-197, 1991.
6. Vergote IB, Vergote-De Vos LN, Abeler VM, et al.: Randomized trial comparing cisplatin with radioactive phosphorus of whole-abdomen irradiation as adjuvant treatment of ovarian cancer. Cancer 69(3): 741-749, 1992.
7. 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. American Journal of Clinical Oncology 11(5): 515-519, 1988.
8. 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). Annals of Oncology 6(9): 887-893, 1995.
9. 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. Gynecologic Oncology 46(3): 357-360, 1992.
10. McGuire WP: Early ovarian cancer: treat now, later, or never? Annals of Oncology 6(9): 865-866, 1995.
11. Martinez A, Schray MF, Howes AE, et al.: Postoperative radiation therapy for epithelial ovarian cancer: the curative role based on a 24-year experience. Journal of Clinical Oncology 3(7): 901-911, 1985.
12. Dembo AJ: Epithelial ovarian cancer: the role of radiotherapy. International Journal of Radiation Oncology, Biology, Physics 22(5): 835-845, 1992.

STAGE II OVARIAN EPITHELIAL CANCER

Surgery should include total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy and tumor debulking to remove all or most of the tumor. If there is no clinically apparent disease outside of the pelvis and systemic therapy is contemplated, additional staging procedures, while possibly influencing choice of therapy, may not influence survival.[1] If there is no clinical residual disease, the undersurface of the diaphragm should be visualized and biopsied and the abdominal peritoneum sampled; selective pelvic and para-aortic node sampling is required. The options for further treatment include:

1. If minimal postsurgical residual disease (<2 centimeters) remains: systemic
chemotherapy: [2]

TP: paclitaxel (Taxol) + cisplatin or carboplatin [3-8]
CP: cyclophosphamide + cisplatin [9]
CC: cyclophosphamide + carboplatin [10]
total abdominal and pelvic radiation therapy (only if there is no macroscopic upper abdominal disease, and minimal residual pelvic disease is <0.5 centimeters) [11,12]
intraperitoneal P-32 radiation therapy is less frequently used (only if residual tumor is <1 millimeter).[2] This option is associated with a significant number of late bowel complications.[13]

TP: paclitaxel (Taxol) + cisplatin or carboplatin [3-8]
CP: cyclophosphamide + cisplatin [9]
CC: cyclophosphamide + carboplatin [10]

Treatment options under clinical evaluation:

Patients with stage II ovarian cancer are appropriate candidates for clinical trials.[14]

References:

1. Potter ME, Partridge EE, Hatch KD, et al.: Primary surgical therapy of ovarian cancer: how much and when. Gynecologic Oncology 40(3): 195-200, 1991.
2. 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. New England Journal of Medicine 322(15): 1021-1027, 1990.
3. McGuire WP, Rowinsky EK, Rosenshein NB, et al.: Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Annals of Internal Medicine 111(4): 273-279, 1989.
4. 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. Journal of Clinical Oncology 10(11): 1748-1753, 1992.
5. Thigpen T, Blessing J, Ball H, et al.: Phase II trial of taxol as second-line therapy for ovarian carcinoma: a Gynecologic Oncology Group study. Proceedings of the American Society of Clinical Oncology 9: A-604, 156, 1990.
6. Kohn EC, Sarosy G, Bicher A, et al.: Dose-intense Taxol: high response rate in patients with platinum-resistant recurrent ovarian cancer. Journal of the National Cancer Institute 86(1): 18-24, 1994.
7. 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. Journal of Clinical Oncology 11(12): 2405-2410, 1993.
8. Trimble EL, Arbuck SG, McGuire WP: Options for primary chemotherapy of epithelial ovarian cancer: taxanes. Gynecologic Oncology 55(3, Part 2): S114-S121, 1994.
9. Decker DG, Fleming TR, Malkasian GD, et al.: Cyclophosphamide plus cis-platinum in combination: treatment program for stage III or IV ovarian carcinoma. Obstetrics and Gynecology 60(4): 481-487, 1982.
10. Trask C, Silverstone A, Ash CM, et al.: A randomized trial of carboplatin versus iproplatin in untreated advanced ovarian cancer. Journal of Clinical Oncology 9(7): 1131-1137, 1991.
11. Martinez A, Schray MF, Howes AE, et al.: Postoperative radiation therapy for epithelial ovarian cancer: the curative role based on a 24-year experience. Journal of Clinical Oncology 3(7): 901-911, 1985.
12. Dembo AJ: Epithelial ovarian cancer: the role of radiotherapy. International Journal of Radiation Oncology, Biology, Physics 22(5): 835-845, 1992.
13. Vergote IB, Vergote-De Vos LN, Abeler VM, et al.: Randomized trial comparing cisplatin with radioactive phosphorus of whole-abdomen irradiation as adjuvant treatment of ovarian cancer. Cancer 69(3): 741-749, 1992.
14. Young RC: Initial therapy for early ovarian carcinoma. Cancer 60(8, Suppl): 2042-2049, 1987.

STAGE III OVARIAN EPITHELIAL CANCER

Clinical trials exploring improvements in eradicating residual disease are appropriate to consider as the first option for patients with stage III disease.

Standard treatment options:

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, there is considerable evidence 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 median survival of 39 months compared with survival of only 17 months in patients with suboptimal residual disease.[1] However, results of a retrospective analysis of 349 patients with postoperative residual masses less than or equal to 1 centimeter suggested that patients who present 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] It is nevertheless likely that there is gradual improvement in survival with decreasing residual tumor volume. In a retrospective analysis, patients whose tumor volume was reduced to less than 2 centimeters had significantly improved survival when compared with those patients with greater than 2 centimeters residual disease.[3]

A randomized trial demonstrated a median survival advantage of 8 months with the use of intraperitoneal versus intravenous cisplatin in combination with cyclophosphamide in patients with no individual nodules measuring greater than 2 centimeters.[4][Level of evidence: IiiA] However, intraperitoneal therapy is not advised in patients who have significant intraabdominal adhesions at the conclusion of their exploratory laparotomy for surgical staging because adhesions may limit the distribution of the chemotherapy within the abdomen after infusion of the intraperitoneal catheter. Further studies of primary intraperitoneal chemotherapy with regimens including paclitaxel are needed to define the role of this method of administration. However, there is as yet no randomized study proving that radical surgical procedures, including peritoneal stripping and bowel resection for the purpose of complete cytoreduction, improve survival.[5] Surgery should be followed by one of the options listed below:

1. If minimal postsurgical residual disease (<1 centimeter) remains:
combination chemotherapy. Intravenous paclitaxel (Taxol) plus intravenous cisplatin or intravenous carboplatin is commonly used.[6-12]

2. If macroscopic postsurgical residual disease (>1 centimeter) remains:
combination chemotherapy. Intravenous paclitaxel (Taxol) plus intravenous cisplatin or intravenous carboplatin is commonly used.[6-13] Combination chemotherapy regimens containing platinum have been shown to produce higher response rates and, in some studies, have produced a statistically significant prolongation of survival compared to drug regimens without platinum. A meta-analysis addressing this comparison in 1,400 patients revealed a strong trend in favor of platinum-containing combinations with respect to response, but not survival.[14] Some have argued that single-agent cisplatin is equally effective and less toxic than platinum-containing combinations. This meta-analysis, however, suggests that the combination confers a 15% survival advantage out to the eighth year over the use of single-agent platinum.

The Gynecologic Oncology Group (GOG) has conducted a randomized, phase III clinical trial comparing paclitaxel and cisplatin (TP) with cyclophosphamide and cisplatin (CP) in suboptimally debulked (>1 centimeter residual mass) stage III and stage IV patients who had no prior chemotherapy.[6] There was a statistically significant improvement in the clinical response rate in the TP arm (73%) versus the CP arm (60%). Median survival was also significantly better in the TP arm (24 months versus 38 months; P=0.001). Differences in surgically documented complete response were not statistically significant (20% for CP and 26% for TP). Further, in a European-Canadian trial carried out in patients with both optimally and sub-optimally debulked tumors the relapse-free and overall survival advantages of TP over CP were confirmed,[13] and were seen in both groups of patients (i.e., those with large-bulk and low-bulk disease). This outcome advantage for the paclitaxel-based regimen was preserved despite the fact that many patients randomized to the initial non-paclitaxel regimen were treated at recurrence (clinical) with paclitaxel.

Another randomized trial that compared paclitaxel (135 mg/m2) combined with cisplatin (75 mg/m2) with paclitaxel monotherapy (200 mg/m2) given over 24 hours or cisplatin monotherapy (100 mg/m2) found equivalent survival for all 3 regimens. Paclitaxel monotherapy was inferior in response rate and progression-free interval while cisplatin monotherapy was associated with significant neurotoxicity.[15]

In the European-Canadian study, paclitaxel was administered over a more convenient 3 hours at a dose of 175 milligrams per square meter. This dose and schedule were previously found to be equivalent to a dose of 135 milligrams per square meter over 24 hours in terms of response and disease-free survival in patients with advanced disease.[16] Because the 3-hour regimen of paclitaxel is associated with substantial neurotoxicity when given with cisplatin,[13] carboplatin has frequently been substituted for cisplatin in this regimen. Clinical trials assessing the efficacy of this substitution are in progress. Initial reports indicate no loss of efficacy,[17] and in a meta-analysis,[13] carboplatin was found to be as effective as cisplatin alone and in combination. Thus, many investigators consider the 3-hour regimen of paclitaxel plus carboplatin (AUC 5-7) to be an acceptable alternative to the GOG regimen of paclitaxel and cisplatin as the preferred initial chemotherapy for patients with ovarian cancer.

A prospective randomized trial demonstrated a survival benefit for interval surgical debulking in patients with stage IIb through stage IV ovarian epithelial cancer.[18] In this trial, patients with ovarian cancer who underwent primary cytoreductive surgery and were left with a greater than 1 centimeter residual tumor burden were evaluated after 3 cycles of cisplatin and cyclophosphamide chemotherapy. Patients with a clinical response or stable disease were randomized either to undergo an exploratory laparotomy for interval surgical debulking or to not undergo surgery prior to receiving 3 additional cycles of cisplatin and cyclophosphamide. Overall, a survival advantage was demonstrated for patients who underwent interval debulking surgery. When stratified on the basis of the size of residual disease at the conclusion of the interval cytoreductive surgery, patients who had residual disease of less than 1 centimeter on exploratory laparotomy (median survival 41.6 months) and those who were able to achieve optimal status (defined as residual disease <1 centimeter; median survival 26.6 months) as a result of the interval cytoreductive surgery, survived significantly longer than patients with greater than 1 centimeter residual disease (median survival 19.4 months) and those on the no interval surgery arm (median survival 20.0 months).

Second-look laparotomies have been considered after completion of chemotherapy for those stage III patients who have a computed tomographic scan not suggestive of residual active disease, who are clinically without evidence of disease, and whose CA 125 is normal. There are no data to show that therapeutic decisions based upon results of this procedure alter outcomes for the patient. In a large non-randomized trial, there was no survival advantage in patients who received a second-look operation as compared to those who did not [19] and the only randomized trial, albeit statistically underpowered, was negative.[20]

Approximately one third of patients found to have macroscopic tumor at second-look surgery achieve complete cytoreduction resulting in microscopic residual disease, approximately one third achieve partial debulking resulting in optimal residual disease, and the remainder are left with bulky tumors. The value of secondary tumor reduction at the time of second-look laparotomy is controversial. Some have reported improved survival in patients who achieve optimal secondary debulking,[21,22] while others report survival benefit for those left with microscopic disease only.[23] Whether the survival benefit of complete secondary cytoreduction is a function of the surgical debulking or a reflection of the characteristics of the tumor that permits complete cytoreduction is not known.[24-26]

Since there are no controlled clinical trials that demonstrate a survival advantage for the second-look operation, the operation should only be performed by surgeons trained in gynecologic oncology either as part of a clinical trial or where second-line therapy is available. Some reports suggest a role for intraperitoneal chemotherapy to treat patients with advanced ovarian cancer.[27-29] Surgically defined complete response rates have been documented in approximately 25% to 35% of patients with small-volume residual persistent disease who have received a variety of intraperitoneal (IP) regimens.[30] Patients who have a surgically proven favorable response to second-line IP chemotherapy do have a significant survival benefit.[31] However, a randomized trial will be necessary to determine whether IP therapy has a survival advantage over alternative second-line therapies. A phase I trial of IP paclitaxel (Taxol) has reported a major pharmacologic advantage for the drug. Plasma levels of paclitaxel were similar to those achieved with intravenous paclitaxel, and the toxic effect profile was acceptable. Phase II studies are planned by the GOG.[32] The use of intraperitoneal radioactive phosphate after negative second-look surgery does not appear to increase overall or disease-free survival rates.[33]

For patients who responded to first-line intravenous cisplatin-based chemotherapy and responded to second-line intraperitoneal chemotherapy, the 5-year survival in one study was 60% from time of initial diagnosis. For patients who responded to first-line chemotherapy but had no response to intraperitoneal chemotherapy, the 5-year survival was 17%. No patient without a response to either treatment survived 5 years.[28]

References:

1. Hoskins WJ: Surgical staging and cytoreductive surgery of epithelial ovarian cancer. Cancer 71(4, Suppl): 1534-1540, 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. Gynecologic Oncology 47(2): 159-166, 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. American Journal of Obstetrics and Gynecology 170(4): 974-980, 1994.
4. Alberts DS, Liu PY, Hannigan EV, et al.: Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. New England Journal of Medicine 335(26): 1950-1955, 1996.
5. Potter ME, Partridge EE, Hatch KD, et al.: Primary surgical therapy of ovarian cancer: how much and when. Gynecologic Oncology 40(3): 195-200, 1991.
6. McGuire WP, Hoskins WJ, Brady MF, et al.: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. New England Journal of Medicine 334(1): 1-6, 1996.
7. McGuire WP, Rowinsky EK, Rosenshein NB, et al.: Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Annals of Internal Medicine 111(4): 273-279, 1989.
8. 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. Journal of Clinical Oncology 10(11): 1748-1753, 1992.
9. Thigpen T, Blessing J, Ball H, et al.: Phase II trial of taxol as second-line therapy for ovarian carcinoma: a Gynecologic Oncology Group study. Proceedings of the American Society of Clinical Oncology 9: A-604, 156, 1990.
10. Kohn EC, Sarosy G, Bicher A, et al.: Dose-intense Taxol: high response rate in patients with platinum-resistant recurrent ovarian cancer. Journal of the National Cancer Institute 86(1): 18-24, 1994.
11. 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. Journal of Clinical Oncology 11(12): 2405-2410, 1993.
12. Trimble EL, Arbuck SG, McGuire WP: Options for primary chemotherapy of epithelial ovarian cancer: taxanes. Gynecologic Oncology 55(3, Part 2): S114-S121, 1994.
13. 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. Journal of the National Cancer Institute 92(9): 699-708, 2000.
14. Aabo K, Adams M, Adnitt P, et al.: Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists' Group. British Journal of Cancer 78(11): 1479-1487, 1998.
15. Muggia FM, Braly PS, Brady MF, et al.: Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a Gynecologic Oncology Group study. Journal of Clinical Oncology 18(1): 106-115, 2000.
16. Connelly E, Markman M, Kennedy A, et al.: Paclitaxel delivered as a 3-hr infusion with cisplatin in patients with gynecologic cancers: unexpected incidence of neurotoxicity. Gynecologic Oncology 62(2): 166-168, 1996.
17. du Bois A, Richter B, et al. for the AGO Study Group: Cisplatin/paclitaxel vs carboplatin/paclitaxel as 1st-line treatment in ovarian cancer. Proceedings of the American Society of Clinical Oncology 17: A1395, 361a, 1998.
18. 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. New England Journal of Medicine 332(10): 629-634, 1995.
19. Ozols RF, Bundy BN, Fowler J, et al.: Randomized phase III study of cisplatin (CIS)/paclitaxel (PAC) versus carboplatin (CARBO)/PAC in optimal stage III epithelial ovarian cancer (OC): a Gynecologic Oncology Group trial (GOG 158). Proceedings of the American Society of Clinical Oncology 18: A-1373, 356a, 1999.
20. Nicoletto MO, Tumolo S, Talamini R, et al.: Surgical second look in ovarian cancer: a randomized study in patients with laparoscopic complete remission--a Northeastern Oncology Cooperative Group-Ovarian Cancer Cooperative Group study. Journal of Clinical Oncology 15(3): 994-999, 1997.
21. Bertelsen K: Tumor reduction surgery and long-term survival in advanced ovarian cancer: a DACOVA study. Gynecologic Oncology 38(2): 203-209, 1990.
22. Podczaski E, Manetta A, Kaminski P, et al.: Survival of patients with ovarian epithelial carcinomas after second-look laparotomy. Gynecologic Oncology 36(1): 43-47, 1990.
23. 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. Gynecologic Oncology 34(3): 365-371, 1989.
24. Williams L: The role of secondary cytoreductive surgery in epithelial ovarian malignancies. Oncology (Huntington NY) 6(8): 25-32, 1992.
25. Potter ME: Secondary cytoreduction in ovarian cancer: pro or con? Gynecologic Oncology 51(1): 131-135, 1993.
26. Carson LF, Rubin SC: Secondary cytoreduction - thoughts on the "pro" side. Gynecologic Oncology 51(1): 127-130, 1993.
27. Markman M, Hakes T, Reichman B, et al.: Intraperitoneal cisplatin and cytarabine in the treatment of refractory or recurrent ovarian carcinoma. Journal of Clinical Oncology 9(2): 204-210, 1991.
28. Piver MS, Recio FO, Baker TR, et al.: Evaluation of survival after second-line intraperitoneal cisplatin-based chemotherapy for advanced ovarian cancer. Cancer 73(6): 1693-1698, 1994.
29. Howell SB, Kirmani S, McClay EF, et al.: Intraperitoneal cisplatin-based chemotherapy for ovarian carcinoma. Seminars in Oncology 18(1, Suppl 3): 5-10, 1991.
30. Markman M: Intraperitoneal chemotherapy. Seminars in Oncology 18(3): 248-254, 1991.
31. 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. Journal of Clinical Oncology 10(9): 1479-1484, 1992.
32. Markman M, Rowinsky E, Hakes T, et al.: Phase I trial of intraperitoneal taxol: a Gynecologic Oncology Group study. Journal of Clinical Oncology 10(9): 1485-1491, 1992.
33. Vergote IB, Winderen M, De Vos LN, et al.: Intraperitoneal radioactive phosphorus therapy in ovarian carcinoma: analysis of 313 patients treated primarily or at second-look laparotomy. Cancer 71(7): 2250-2260, 1993.

STAGE IV OVARIAN EPITHELIAL CANCER

Intravenous paclitaxel (Taxol) plus intravenous cisplatin or intravenous carboplatin is commonly used.[1-8] The Gynecologic Oncology Group (GOG) has conducted a randomized, phase III clinical trial comparing paclitaxel and cisplatin (TP) with cyclophosphamide and cisplatin (CP) in suboptimally debulked (>1 centimeter residual mass) stage III and stage IV patients who had no prior chemotherapy.[1] There was a statistically significant improvement in the clinical response rate in the TP arm (73%) versus the CP arm (60%). Differences in surgically documented complete response were not statistically significant (20% for CP and 26% for TP). Median survival was also significantly better in the TP arm (24 months versus 38 months; p=0.001). Further, in a European-Canadian trial carried out in patients with both optimally and sub-optimally debulked tumors the relapse-free and overall survival advantages of TP over CP were confirmed,[8] and was seen in both groups of patients (i.e., those with large-bulk and low-bulk disease). Of note, however, was an apparent significant increase in incidence and severity of peripheral neurotoxicity by increasing the dose and shortening the infusion duration of paclitaxel. However, paclitaxel was administered over a more convenient 3 hours at a dose of 175 milligrams per square meter. This dose and schedule were previously found to be equivalent to a dose of 135 milligrams per square meter over 24 hours in terms of response and disease-free survival in patients with advanced disease.[9] Because the 3-hour regimen of paclitaxel is associated with substantial neurotoxicity when given with cisplatin,[8] carboplatin has frequently been substituted for cisplatin in this regimen. Clinical trials assessing the efficacy of this substitution are in progress. Initial reports indicate no loss of efficacy,[10] and in a meta-analysis,[8] carboplatin was found to be as effective as cisplatin alone and in combination. Thus, many investigators consider the 3-hour regimen of paclitaxel plus carboplatin (AUC 5-7) to be an acceptable alternative to the GOG regimen of paclitaxel and cisplatin as the preferred initial chemotherapy for patients with ovarian cancer.

Treatment options under clinical evaluation:

Although many patients with stage IV disease undergo cytoreductive surgery, whether this improves survival has not been established.[11]

References:

1. McGuire WP, Hoskins WJ, Brady MF, et al.: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. New England Journal of Medicine 334(1): 1-6, 1996.
2. McGuire WP, Rowinsky EK, Rosenshein NB, et al.: Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Annals of Internal Medicine 111(4): 273-279, 1989.
3. 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. Journal of Clinical Oncology 10(11): 1748-1753, 1992.
4. Thigpen T, Blessing J, Ball H, et al.: Phase II trial of taxol as second-line therapy for ovarian carcinoma: a Gynecologic Oncology Group study. Proceedings of the American Society of Clinical Oncology 9: A-604, 156, 1990.
5. Kohn EC, Sarosy G, Bicher A, et al.: Dose-intense Taxol: high response rate in patients with platinum-resistant recurrent ovarian cancer. Journal of the National Cancer Institute 86(1): 18-24, 1994.
6. 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. Journal of Clinical Oncology 11(12): 2405-2410, 1993.
7. Trimble EL, Arbuck SG, McGuire WP: Options for primary chemotherapy of epithelial ovarian cancer: taxanes. Gynecologic Oncology 55(3, Part 2): S114-S121, 1994.
8. 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. Journal of the National Cancer Institute 92(9): 699-708, 2000.
9. Connelly E, Markman M, Kennedy A, et al.: Paclitaxel delivered as a 3-hr infusion with cisplatin in patients with gynecologic cancers: unexpected incidence of neurotoxicity. Gynecologic Oncology 62(2): 166-168, 1996.
10. du Bois A, Richter B, et al. for the AGO Study Group: Cisplatin/paclitaxel vs carboplatin/paclitaxel as 1st-line treatment in ovarian cancer. Proceedings of the American Society of Clinical Oncology 17: A1395, 361a, 1998.
11. Goodman HM, Harlow BL, Sheets EE, et al.: The role of cytoreductive surgery in the management of stage IV epithelial ovarian carcinoma. Gynecologic Oncology 46(3): 367-371, 1992.

RECURRENT OVARIAN EPITHELIAL CANCER

For patients whose disease is platinum refractory (i.e., with disease that has progressed while on a platinum regimen or that has recurred shortly after completion of a platinum-containing regimen), treatment with paclitaxel (Taxol) should be considered. The response rate to paclitaxel in patients with recurrent ovarian cancer ranges from 21% to 48%.[2-6] Responses have been observed in patients whose disease is platinum sensitive and those whose disease is platinum refractory. The primary toxic effect is reversible neutropenia; other rare toxic effects include anaphylactoid reactions (thought to be due to the Cremophor vehicle and/or rapid intravenous administration), cardiac arrhythmias, and peripheral neuropathy. An overall response rate of 53% has been demonstrated in patients with recurrent ovarian cancer treated with paclitaxel and cisplatin.[7] Whether the use of combination therapy is superior to the use of these agents in sequence is unknown. Information about ongoing clinical trials is available from the NCI (Http: //cancer.gov/clinical_trials).

Standard 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), re-treatment with cisplatin or carboplatin should be considered.[1,8]

2. For patients with platinum-refractory disease (i.e., disease that has
progressed while on a platinum-based regimen or has recurred shortly after completion of a platinum-based regimen), treatment with paclitaxel (Taxol) should be considered. In a salvage setting, 3-hour infusions are safe, less myelotoxic, and equally effective.[9]

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 reexplored.[10,11] The 61 patients who had successful cytoreduction (greatest residual tumor diameter <2 centimeters) had a statistically significant prolongation of survival.[12] 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. However, palliation is rarely achieved when there are multiple areas of partial or complete obstruction, when the transit time is prolonged due to diffuse peritoneal carcinomatosis, or when anatomy requires a bypass that results in the short bowel syndrome.[10]

4. Salvage chemotherapy. Drug combinations have not been demonstrated to
improve response rate or survival in drug resistant ovarian cancer. Several single agents have been shown to have activity in refractory ovarian cancer and should be considered:

Ifosfamide: Ifosfamide has shown modest activity in patients with epithelial ovarian cancer, including disease that is platinum-refractory. A Gynecologic Oncology Group study demonstrated 3 clinical complete responses and 5 partial responses (overall response rate was 20%) in 41 evaluable patients who were either refractory to platinum or who had relapsed following platinum-based chemotherapy.[13] 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 one phase II study, 7 objective responses were observed in 52 patients (objective response rate was 13.5%). Of the 7 patients who responded, 5 had tumors that were platinum-refractory.[14]

Hexamethylmelamine (HMM): There have been several encouraging reports of orally-administered HMM as salvage chemotherapy after failure of cisplatin-based combination regimens.[15-19] Response rates in platinum-resistant patients are 12% to 14%. Mild to moderate toxic effects and peripheral neuropathy are observed following treatment with HMM but are manageable.

Tamoxifen: Some patients (18%) will respond to tamoxifen (20 milligrams twice daily). A response is more likely in patients with detectable levels of cytoplasmic estrogen receptor on their tumors.[20]

5-FU and leucovorin: In platinum-resistant recurrent disease, an objective response rate of 10% to 17% has been reported.[21,22]

Etoposide: Oral low doses have generated response rates from 6% to 26%. Additional studies are necessary to determine efficacy, but the toxic effect profile is favorable in comparison with many other salvage therapies.[23-26]

Liposomal doxorubicin: A phase II study of encapsulated doxorubicin given intravenously once every 21 to 28 days demonstrated 1 complete response and 8 partial responses in 35 patients with platinum- or paclitaxel-refractory disease (RR=25.7%). In general, liposomal doxorubicin is well tolerated. The most frequent toxic effects, which are more pronounced following higher doses or when liposomal doxorubicin is given every 3 weeks, include neutropenia, stomatitis, and hand-foot syndrome. Oral and cutaneous toxic effects completely resolve within 5 weeks of drug administration. Nausea is minimal and alopecia rarely occurs.[27]

Gemcitabine: Gemcitabine, a pyrimidine antimetabolite with similarities to cytosine arabinoside, has shown activity in patients with recurrent ovarian cancer. 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 who are platinum- 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 following drug administration. Other toxic effects, including nausea, are usually mild. Regrowth of hair lost during previous chemotherapy has been reported following treatment with gemcitabine.[28-30]

Topotecan: Topotecan, a topoisomerase I inhibitor, has been extensively evaluated as a single agent in patients with recurrent epithelial ovarian cancer. In phase II studies of topotecan administered intravenously on days 1 to 5 of a 21-day cycle, objective response rates ranging from 13% to 16.3% have been reported.[31-33] Objective responses are reported in patients with platinum-refractory disease. Substantial myelosuppression follows administration. Other toxic effects include nausea, vomiting, alopecia, and, rarely, asthenia.

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 randomized 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 randomized 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.[34]

Liposomal doxorubicin and topotecan have been compared in a randomized trial of 474 patients with recurrent ovarian cancer.[35] Response rates (19.7% versus 17.0%, p=.390), progression-free survival (16.1 weeks versus 17.0 weeks; p=.095), and overall survival (60 weeks versus 56.7 weeks, p=.341) did not differ significantly between the liposomal doxorubicin and topotecan arms, respectively.[35][Level of evidence: 1iiA]

Some reports suggest a potential role for intraperitoneal chemotherapy to treat patients with advanced ovarian cancer.[36,37] Surgically defined complete response occurs in about 30% of patients who have low-volume disease at initiation of therapy (no nodule >0.5 centimeter). This surgical complete response may have a favorable impact on survival.[38] Other clinical trials including high-dose chemotherapy with autologous bone marrow transplant, and the use of other agents to reduce the dose-limiting toxic effect of platinum compounds, are underway.[39] Patients with platinum-refractory ovarian cancer who have not responded to paclitaxel (Taxol) may be candidates for phase I and II clinical trials evaluating new anticancer drugs and biological therapies. Information about ongoing clinical trials is available from the NCI (Http: //cancer.gov/clinical_trials).

References:

1. Markman M, Rothman R, Hakes T, et al.: Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. Journal of Clinical Oncology 9(3): 389-393, 1991.
2. Kohn EC, Sarosy G, Bicher A, et al.: Dose-intense Taxol: high response rate in patients with platinum-resistant recurrent ovarian cancer. Journal of the National Cancer Institute 86(1): 18-24, 1994.
3. McGuire WP, Rowinsky EK, Rosenshein NB, et al.: Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Annals of Internal Medicine 111(4): 273-279, 1989.
4. 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. Journal of Clinical Oncology 10(11): 1748-1753, 1992.
5. 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. Journal of Clinical Oncology 12(9): 1748-1753, 1994.
6. 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. Journal of Clinical Oncology 11(12): 2405-2410, 1993.
7. Goldberg JM, Piver MS, Hempling RE, et al.: Paclitaxel and cisplatin combination chemotherapy in recurrent epithelial ovarian cancer. Gynecologic Oncology 63(3): 312-317, 1996.
8. 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.
9. 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. Journal of Clinical Oncology 12(12): 2654-2666, 1994.
10. Segna RA, Dottino PR, Mandeli JP, et al.: Secondary cytoreduction for ovarian cancer following cisplatin therapy. Journal of Clinical Oncology 11(3): 434-439, 1993.
11. Morris M, Gershenson DM, Wharton JT, et al.: Secondary cytoreductive surgery for recurrent epithelial ovarian cancer. Gynecologic Oncology 34(3): 334-338, 1989.
12. 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. Gynecologic Oncology 34(3): 365-371, 1989.
13. Sutton GP, Blessing JA, Homesley HD, et al.: Phase II trial of ifosfamide and mesna in advanced ovarian carcinoma: a Gynecologic Oncology Group study. Journal of Clinical Oncology 7(11): 1672-1676, 1989.
14. Markman M, Hakes T, Reichman B, et al.: Ifosfamide and mesna in previously treated advanced epithelial ovarian cancer: activity in platinum-resistant disease. Journal of Clinical Oncology 10(2): 243-248, 1992.
15. Rosen GF, Lurain JR, Newton M: Hexamethylmelamine in ovarian cancer after failure of cisplatin-based multiple-agent chemotherapy. Gynecologic Oncology 27(2): 173-179, 1987.
16. Manetta A, MacNeill C, Lyter JA, et al.: Hexamethylmelamine as a single second-line agent in ovarian cancer. Gynecologic Oncology 36(1): 93-96, 1990.
17. Moore DH, Fowler WC, Jones CP, et al.: Hexamethylmelamine chemotherapy for persistent or recurrent epithelial ovarian cancer. American Journal of Obstetrics and Gynecology 165(3): 573-576, 1991.
18. Vergote I, Himmelmann A, Frankendal B, et al.: Hexamethylmelamine as second-line therapy in platin-resistant ovarian cancer. Gynecologic Oncology 47(3): 282-286, 1992.
19. Hauge MD, Long HJ, Hartmann LC, et al.: Phase II trial of intravenous hexamethylmelamine in patients with advanced ovarian cancer. Investigational New Drugs 10(4): 299-301, 1992.
20. 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): 269-271, 1991.
21. Reed E, Jacob J, Ozols RF, et al.: 5-Fluorouracil (5-FU) and leucovorin in platinum-refractory advanced stage ovarian carcinoma. Gynecologic Oncology 46(3): 326-329, 1992.
22. Look KY, Muss HM, 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. American Journal of Clinical Oncology 18(1): 19-22, 1995.
23. 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. Journal of Cancer Research and Clinical Oncology 119(1): 55-57, 1992.
24. Hoskins PJ, Swenerton KD: Oral etoposide is active against platinum-resistant epithelial ovarian cancer. Journal of Clinical Oncology 12(1): 60-63, 1994.
25. 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. British Journal of Cancer 69(1): 191-195, 1994.
26. 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. Journal of Clinical Oncology 16(2): 405-410, 1998.
27. Muggia FM, Hainsworth JD, Jeffers S, et al.: Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. Journal of Clinical Oncology 15(3): 987-993, 1997.
28. Friedlander M, Millward MJ, Bell D, et al.: A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer. Annals of Oncology 9(12): 1343-1345, 1998.
29. Lund B, Hansen OP, Theilade K, et al.: Phase II study of gemcitabine (2',2'-difluorodeoxycytidine) in previously treated ovarian cancer patients. Journal of the National Cancer Institute 86(20): 1530-1533, 1994.
30. Shapiro JD, Millward MJ, Rischin D, et al.: Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. Gynecologic Oncology 63(1): 89-93, 1996.
31. Kudelka AP, Tresukosol D, Edwards CL, et al.: Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. Journal of Clinical Oncology 14(5): 1552-1557, 1996.
32. 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. Journal of Clinical Oncology 14(12): 3056-3061, 1996.
33. Bookman MA, Malmstrom 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. Journal of Clinical Oncology 16(10): 3345-3352, 1998.
34. ten Bokkel Huinink W, Gore M, Carmichael J, et al.: Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. Journal of Clinical Oncology 15(6): 2183-2193, 1997.
35. Gordon AN, Fleagle JT, Guthrie D, et al.: Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. Journal of Clinical Oncology 19(14): 3312-3322, 2001.
36. Markman M, Hakes T, Reichman B, et al.: Intraperitoneal cisplatin and cytarabine in the treatment of refractory or recurrent ovarian carcinoma. Journal of Clinical Oncology 9(2): 204-210, 1991.
37. Markman M, Rowinsky E, Hakes T, et al.: Phase I trial of intraperitoneal taxol: a Gynecologic Oncology Group study. Journal of Clinical Oncology 10(9): 1485-1491, 1992.
38. 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. Journal of Clinical Oncology 10(9): 1479-1484, 1992.
39. McGuire WP, Rowinsky EK: Old drugs revisited, new drugs, and experimental approaches in ovarian cancer therapy. Seminars in Oncology 18(3): 255-269, 1991.

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