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Ovarian epithelial cancer


Table of Contents

GENERAL INFORMATION
CELLULAR CLASSIFICATION
STAGE INFORMATION
Stage I
Stage II
Stage III
Stage IV
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

GENERAL INFORMATION

(Separate summaries containing information on screening for ovarian cancer and prevention of ovarian cancer are also available in PDQ.)

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 levels of evidence summary for more information.

Several malignancies arise from the ovary. However, epithelial carcinoma of the ovary is one of the most common gynecologic malignancies and the fourth 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] The lifetime risk for developing ovarian cancer in patients harboring germ-line mutations in BRCA1 is substantially increased over the general population.[7] Two retrospective studies of patients with germ- line mutations in BRCA1 suggest that these women have improved survival compared to BRCA1 negative women.[8,9][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.[10] 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. Separate summaries containing information on ovarian germ cell tumors and ovarian low malignant potential tumors are also available in PDQ.

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 stage I, 50% in stage II, 74% in stage III, and 73% in stage IV.[11] 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.[12-16] For patients with stage I disease, the most important prognostic factor is grade, followed by dense adherence and large-volume ascites.[17] DNA flow cytometric analysis of stages I and IIA patients may identify a group of high-risk patients.[18] Patients with clear cell histology appear to have a worse prognosis.[19] Patients with a significant component of transitional cell carcinoma appear to have a better prognosis.[20]

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.[21] 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.[22,23]

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.[12] 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.[24,25]

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, Baker TR, Jishi MF, et al.: Familial ovarian cancer: a report of 658 families from the Gilda Radner Familial Ovarian Cancer Registry 1981-1991. Cancer 71(2, Suppl): 582-588, 1993.

  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. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. Thigpen T, Brady MF, Omura GA, et al.: Age as a prognostic factor in ovarian carcinoma. Cancer 71(2, Suppl): 606-614, 1993.

  17. Dembo AJ, Davy M, Stenwig AE: Prognostic factors in patients with stage I epithelial ovarian cancer. Obstetrics and Gynecology 75(2): 263-273, 1990.

  18. Schueler JA, Cornelisse CJ, Hermans J, et al.: Prognostic factors in well-differentiated early-stage epithelial ovarian cancer. Cancer 71(3): 787-795, 1993.

  19. 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.

  20. 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.

  21. Mogensen O: Prognostic value of CA 125 in advanced ovarian cancer. Gynecologic Oncology 44(3): 207-212, 1992.

  22. 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.

  23. 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.

  24. Ozols RF, Young RC: Ovarian cancer. Current Problems in Cancer 11(2): 57-122, 1987.

  25. Cannistra SA: Cancer of the ovary. New England Journal of Medicine 329(21): 1550-1559, 1993.


CELLULAR CLASSIFICATION

A separate summary containing information on ovarian low malignant potential tumors is also available in PDQ.


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 remains to be established. If disease appears to be limited to the ovaries or pelvis, it is essential at laparotomy to examine and biopsy the diaphragm, both paracolic gutters, the pelvic peritoneum, para-aortic and pelvic nodes, and infracolic omentum, and to obtain peritoneal washings.[1]

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 I ovarian cancer is growth limited to the ovaries.

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 II ovarian cancer is growth involving one or both ovaries with pelvic extension.

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.

Different criteria for allotting cases to stages IC and IIC have an impact on diagnosis. In order to evaluate this impact, it would be of value 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 peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes. 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: 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

Stage IV ovarian cancer is growth involving one or both ovaries with distant metastasis. If pleural effusion is present, there must be positive cytologic test results to allot 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): 1534-1540, 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 treatment of ovarian cancer is evolving rapidly. Therefore, all patients with this disease should be considered as candidates for clinical trials. Refer to the separate PDQ summary on ovarian low malignant potential tumors for treatment of "borderline" or "low malignant potential tumors." A separate summary containing information on ovarian germ cell tumors is also available in PDQ.

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

Treatment options:

1. Surgery alone is adequate for stage IA and IB (total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy), if tumor is well or moderately well differentiated. 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 further 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. As yet, no randomized trial has demonstrated a survival advantage for one of these approaches over another [6], nor has immediate treatment been shown to prolong life relative to treatment at relapse.[7]

  • intraperitoneal P-32 or radiation therapy [1,6,8]
  • systemic chemotherapy [1,6,7,9,10]
  • 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]

Under clinical evaluation:
1. The Gynecologic Oncology Group is conducting a randomized trial of 3 versus 6 courses of carboplatin plus paclitaxel for selected patients with stages IA-C disease.[13]

2. Two European trials (ICON1 and ACTION) are comparing immediate to delayed platinum-based chemotherapy.

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. 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.

  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. American Journal of Clinical Oncology 11(5): 515-519, 1988.

  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.

  13. Young RC, Gynecologic Oncology Group: Phase III Randomized Study of CBDCA/TAX Administered for 3 vs 6 Courses for Selected Stages IA-C and Stages IIA-C Ovarian Epithelial Cancer (Summary Last Modified 07/98), GOG-157, clinical trial, closed, 05/25/1998.


STAGE II OVARIAN EPITHELIAL CANCER

Treatment options:

Standard:

Surgery (total abdominal hysterectomy and bilateral salpingo-oophorectomy
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 treatment then
include:

1. If minimal postsurgical residual disease (<2 centimeters):
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]

2. If macroscopic postsurgical residual disease (>2 centimeters) remains in
the pelvis, use combination chemotherapy. The following regimens are
commonly used:
TP: paclitaxel (Taxol) + cisplatin or carboplatin [3-8]
CP: cyclophosphamide + cisplatin [9]
CC: cyclophosphamide + carboplatin [10]

A large randomized trial from Norway found equivalent survival rates
with either P-32 administered intraperitoneally or six courses of
cisplatin but a higher complication rate with the P-32.[13]

Under clinical evaluation:
Patients with stage II ovarian cancer are prime candidates for clinical
trials.[14] The Gynecologic Oncology Group study is conducting a randomized
trial of 3 versus 6 courses of carboplatin plus paclitaxel for patients
with stages IIA-C disease.[15] 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.[16]

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.

  15. Young RC, Gynecologic Oncology Group: Phase III Randomized Study of CBDCA/TAX Administered for 3 vs 6 Courses for Selected Stages IA-C and Stages IIA-C Ovarian Epithelial Cancer (Summary Last Modified 07/98), GOG-157, clinical trial, closed, 05/25/1998.

  16. McGuire WP, Rowinsky EK: Old drugs revisited, new drugs, and experimental approaches in ovarian cancer therapy. Seminars in Oncology 18(3): 255-269, 1991.


STAGE III OVARIAN EPITHELIAL CANCER

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 levels of evidence summary for more information.

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

Treatment options:

Standard:

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 2 options
listed below:

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

2. If macroscopic postsurgical residual disease (>1 centimeter): combination chemotherapy. Intravenous paclitaxel (Taxol) plus intravenous cisplatin or intravenous carboplatin is commonly used.[6-12] Combination chemotherapy regimens containing cisplatin 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 cisplatin. 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.[13] 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) stages III and 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%). 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, and reported in abstract form, the relapse-free and overall survival advantages of TP over CP were confirmed.[14,15] 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.[16] Because the 3-hour regimen of paclitaxel is associated with substantial neurotoxicity when given with cisplatin,[14] 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,[15] 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 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).

A second-look laparotomy can be 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. The benefits of the procedure include 1) an avoidance of premature discontinuation of therapy in the presence of persistent disease, 2) termination of therapy in the absence of detectable disease thereby minimizing sequelae of chemotherapy, and 3) accumulation of prognostic information.[19] One study found residual disease to be present at second-look surgery in 92% of patients with CA 125 values between 20 and 35 microns per milliliter. If these results are confirmed, second-look surgery may not be indicated for the determination of residual disease for patients with a value greater than 20 microns per milliliter.[20] However, this operation remains the most sensitive, specific, and accurate method to detect residual disease. In general, a second-look laparotomy should evaluate the same areas that were examined at the time of the initial surgery. When no macroscopic disease is found at the time of second-look surgery, the operative procedure includes an extensive sampling of all possible sites of metastases. It may not be necessary to perform pelvic and para-aortic lymph node sampling at second-look laparotomy if this was done as part of the initial procedure and the lymph nodes were negative.[21] Nevertheless, the disease will recur in approximately 30% to 50% of patients with a pathologic complete response. The risk of recurrence in patients treated with platinum-based combination chemotherapy is directly related to stage, histologic grade, and amount of tumor remaining after the first operation.[22] In cases where residual disease is found, the finding of microscopic disease and lower grade tumor would favor chances for survival.[23]

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,[24,25] while others report survival benefit for those left with microscopic disease only.[26] 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.[27-29]

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.[30-32] 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.[33] Patients who have a surgically proven favorable response to second-line IP chemotherapy do have a significant survival benefit.[34] 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 IV paclitaxel, and the toxic effect profile was acceptable. Phase II studies are planned by the Gynecologic Oncology Group.[35] The use of intraperitoneal radioactive phosphate after negative second-look surgery does not appear to increase overall or disease-free survival rates.[36]

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.[31]

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. Advanced Ovarian Cancer Trialists' Group: Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. British Journal of Cancer 78(11): 1479-1487, 1998.

  14. Piccart MJ, Bertelsen K, Stuart G, et al.: Is cisplatin-paclitaxel (P-T) the standard in first-line treatment of advanced ovarian cancer (Ov Ca)? The EORTC-GCCG, NOCOVA, NCI-C and Scottish intergroup experience. Proceedings of the American Society of Clinical Oncology 16: 1258A, 352a, 1997.

  15. Stuart G, Bertelsen K, Mangioni C, et al.: Updated analysis shows a highly significant improved overall survival (OS) for cisplatin-paclitaxel as first line treatment of advanced ovarian cancer: mature results of the EORTC-GCCG, NOCOVA, NCIC CTG and Scottish Intergroup trial. Proceedings of the American Society of Clinical Oncology 17: 1394A, 361a, 1998.

  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: 1395A, 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. Podratz KC, Cliby WA: Second-look surgery in the management of epithelial ovarian carcinoma. Gynecologic Oncology 55(3, Part 2): S128-S133, 1994.

  20. Gallion HH, Hunter JE, van Nagell JR, et al.: The prognostic implications of low serum CA 125 levels prior to the second-look operation for stage III and IV epithelial ovarian cancer. Gynecologic Oncology 46(1): 29-32, 1992.

  21. Goldberg GL, Scheiner J, Friedman A, et al.: Lymph node sampling in patients with epithelial ovarian carcinoma. Gynecologic Oncology 47(2): 143-145, 1992.

  22. Rubin SC, Hoskins WJ, Saigo PE, et al.: Prognostic factors for recurrence following negative second-look laparotomy in ovarian cancer patients treated with platinum-based chemotherapy. Gynecologic Oncology 42(2): 137-141, 1991.

  23. Miller DS, Spirtos NM, Ballon SC, et al.: Critical reassessment of second-look exploratory laparotomy for epithelial ovarian carcinoma: minimal diagnostic and therapeutic value in patients with persistent cancer. Cancer 69(2): 502-510, 1992.

  24. Bertelsen K: Tumor reduction surgery and long-term survival in advanced ovarian cancer: a DACOVA study. Gynecologic Oncology 38(2): 203-209, 1990.

  25. 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.

  26. 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.

  27. Williams L: The role of secondary cytoreductive surgery in epithelial ovarian malignancies. Oncology (Huntington NY) 6(8): 25-32, 1992.

  28. Potter ME: Secondary cytoreduction in ovarian cancer: pro or con? Gynecologic Oncology 51(1): 131-135, 1993.

  29. Carson LF, Rubin SC: Secondary cytoreduction - thoughts on the "pro" side. Gynecologic Oncology 51(1): 127-130, 1993.

  30. 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.

  31. 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.

  32. 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.

  33. Markman M: Intraperitoneal chemotherapy. Seminars in Oncology 18(3): 248-254, 1991.

  34. 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.

  35. 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.

  36. 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

Treatment options:

Standard:

Intravenous paclitaxel (Taxol) plus intravenous cisplatin or intravenous
carboplatin is commonly used.[1-7] 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) stages III and 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, and reported
in abstract form, the relapse-free and overall survival advantages of
TP over CP were confirmed.[8,9] 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.[10] 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,[11] and in a meta-analysis,[9] 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.

Under clinical evaluation:
Although many patients with stage IV disease undergo cytoreductive surgery,
whether this improves survival has not been established.[12]

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, Stuart G, et al.: Is cisplatin-paclitaxel (P-T) the standard in first-line treatment of advanced ovarian cancer (Ov Ca)? The EORTC-GCCG, NOCOVA, NCI-C and Scottish intergroup experience. Proceedings of the American Society of Clinical Oncology 16: 1258A, 352a, 1997.

  9. Stuart G, Bertelsen K, Mangioni C, et al.: Updated analysis shows a highly significant improved overall survival (OS) for cisplatin-paclitaxel as first line treatment of advanced ovarian cancer: mature results of the EORTC-GCCG, NOCOVA, NCIC CTG and Scottish Intergroup trial. Proceedings of the American Society of Clinical Oncology 17: 1394A, 361a, 1998.

  10. 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.

  11. 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: 1395A, 361a, 1998.

  12. 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

It is important to determine the interval between the completion of therapy with cisplatin or carboplatin and the development of recurrent disease. Patients who have had a significant response to cisplatin or carboplatin may respond to treatment with one of these agents; the likelihood that a patient will respond increases as the length of time since the patient was last treated increases.[1] Intraperitoneal therapy should be reserved for those patients with low-volume disease with no single nodule greater than 1 centimeter.

For patients who are 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 who are platinum sensitive and those who are 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. Refer to PDQ or to CancerNet (http://cancernet.nci.nih.gov) for information on clinical trials for patients with ovarian epithelial cancer.

Treatment options:

Under clinical evaluation:

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. In this population, salvage therapy with cisplatin or carboplatin with ifosfamide is associated with a response rate of 25% to 56%.[1,8-10]

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.[11]

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.[12,13] The 61 patients who had successful cytoreduction (greatest residual tumor diameter <2 centimeters) had a statistically significant prolongation of survival.[14] 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.[12]

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: A Gynecologic Oncology Group trial [15] has suggested that
ifosfamide may be useful in the salvage setting in ovarian carcinoma.
In that study there were 3 clinical complete responses and 5
clinical partial responses (overall response rate 20%) in 41 evaluable
patients who were either refractory to cisplatin or who relapsed after
receiving cisplatin-based chemotherapy. Two additional studies reported
a 12% objective response rate in patients with platinum-refractory
disease.[10,16] Complications included renal tubular dysfunction,
myelosuppression, hemorrhagic cystitis, and toxic encephalopathy.

Hexamethylmelamine (HMM): There have been several encouraging reports
of orally-administered HMM as salvage chemotherapy after failure of
cisplatin-based combination regimens.[17-21] 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.[22]

5-FU and leucovorin: In platinum-resistant recurrent disease, an
objective response rate of 10% to 17% has been reported.[23,24]

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.[25-28]

Some reports suggest a potential role for intraperitoneal chemotherapy to
treat patients with advanced ovarian cancer.[29,30] 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.[31] 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.[32] 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. Refer to PDQ or to CancerNet
(http://cancernet.nci.nih.gov) for information on clinical trials for
patients with ovarian epithelial cancer.

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. Reed E, Janik J, Bookman MA, et al.: High-dose carboplatin and recombinant granulocyte-macrophage colony-stimulating factor in advanced-stage recurrent ovarian cancer. Journal of Clinical Oncology 11(11): 2118-2126, 1993.

  10. Lorusso V, Catino A, Leone B, et al.: Carboplatin plus ifosfamide as salvage treatment of epithelial ovarian cancer: a pilot study. Journal of Clinical Oncology 11(10): 1952-1956, 1993.

  11. 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.

  12. 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.

  13. Morris M, Gershenson DM, Wharton JT, et al.: Secondary cytoreductive surgery for recurrent epithelial ovarian cancer. Gynecologic Oncology 34(3): 334-338, 1989.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  21. 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.

  22. 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.

  23. 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.

  24. 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.

  25. 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.

  26. Hoskins PJ, Swenerton KD: Oral etoposide is active against platinum-resistant epithelial ovarian cancer. Journal of Clinical Oncology 12(1): 60-63, 1994.

  27. 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.

  28. Rose PG, Blessing JA, Mayer AR, et al.: Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study. Journal of Clinical Oncology 16(2): 405-410, 1998.

  29. 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.

  30. 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.

  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. McGuire WP, Rowinsky EK: Old drugs revisited, new drugs, and experimental approaches in ovarian cancer therapy. Seminars in Oncology 18(3): 255-269, 1991.

Date Last Modified: 10/1999



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