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Tipos de Cancer   /   Cánceres Ginecológicos   /   Cáncer del Ovario   /   Recursos de NCI

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NCI/PDQ® Health professionals: Ovarian Epithelial Cancer Treatment (PDQ®)

Imprima English

National Cancer Institute
Ultima Vez Modificado: 16 de noviembre del 2012

TABLE OF CONTENTS


General Information About Ovarian Epithelial Cancer

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Incidence and Mortality

Estimated new cases and deaths from ovarian cancer in the United States in 2012: 1

  • New cases: 22,280.
  • Deaths: 15,500.

Several malignancies arise from the ovary. Epithelial carcinoma of the ovary is one of the most common gynecologic malignancies and the fifth most frequent cause of cancer death in women, with 50% of all cases occurring in women older than 65 years. 2 Approximately 5% to 10% of ovarian cancers are familial, and three distinct hereditary patterns have been identified: ovarian cancer alone, ovarian and breast cancers, or ovarian and colon cancers. 3 The most important risk factor for ovarian cancer is a family history of a first-degree relative (e.g., mother, daughter, or sister) with the disease. The highest risk appears in women with two or more first-degree relatives with ovarian cancer. 4 The risk is somewhat less for women with one first-degree and one second-degree relative (grandmother or aunt) with ovarian cancer.

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

For women at increased risk, prophylactic oophorectomy may be considered after the age of 35 if childbearing is complete. In a family-based study among women with BRCA1 or BRCA2 mutations, of the 259 women who had undergone bilateral prophylactic oophorectomy, two of them (0.8%) developed subsequent papillary serous peritoneal carcinoma, and six of them (2.8%) had stage I ovarian cancer at the time of surgery. Of the 292 matched controls, 20% who did not have prophylactic surgery developed ovarian cancer. Prophylactic surgery was associated with a higher than 90% reduction in the risk of ovarian cancer (relative risk [RR], 0.04; 95% confidence interval [CI], 0.010.16), with an average follow-up of 9 years; 13 however, family-based studies may be associated with biases resulting from case selection and other factors that may influence the estimate of benefit. 14 (Refer to the Evidence of Benefit section in the PDQ® summary on Ovarian Cancer Prevention for more information.)

After a prophylactic oophorectomy, a small percentage of women may develop a primary peritoneal carcinoma, similar in appearance to ovarian cancer. 15 The prognostic information presented below deals only with epithelial carcinomas. Stromal and germ cell tumors are relatively uncommon and comprise less than 10% of cases. (Refer to the PDQ® summaries on Ovarian Germ Cell Tumor Treatment and Ovarian Low Malignant Potential Tumor Treatment for more information.)

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

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

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

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

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

Case-control studies suggest that BRCA1 and BRCA2 mutation carriers have improved responses to chemotherapy when compared with patients with sporadic epithelial ovarian cancer. This may be the result of a deficient homologous DNA repair mechanism in these tumors, which leads to increased sensitivity to chemotherapy agents. 29 30

Most patients with ovarian cancer have widespread disease at presentation. This may be partly explained by relatively early spread (and implantation) of high-grade papillary serous cancers to the rest of the peritoneal cavity. 31 Conversely, symptoms such as abdominal pain and swelling, gastrointestinal symptoms, and pelvic pain often go unrecognized, leading to delays in diagnosis. Screening procedures such as gynecologic assessment, vaginal ultrasound, and CA 125 assay have had low predictive value in detecting ovarian cancer in women without special risk factors. 32 33 Efforts have been made to enhance physician and patient awareness of the occurrence of these nonspecific symptoms. 34 35 36 37 38 (Refer to the PDQ® summaries on Pain and Gastrointestinal Complications for more information.) As a result of these confounding factors, yearly mortality in ovarian cancer is approximately 65% of the incidence rate. Long-term follow-up of suboptimally debulked stage III and stage IV patients showed a 5-year survival rate of less than 10% with platinum-based combination therapy prior to the current generation of trials including taxanes. 17 By contrast, optimally debulked stage III patients treated with a combination of intravenous taxane and intraperitoneal platinum plus taxane achieved a median survival of 66 months in a Gynecologic Oncology Group trial. 39 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. 40 41 Information about ongoing clinical trials is available from the NCI Web site.


Related Summaries

Other PDQ® summaries containing information related to ovarian epithelial cancer include the following:

References:

  1. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online [PUBMED Abstract]
  2. Yancik R: Ovarian cancer. Age contrasts in incidence, histology, disease stage at diagnosis, and mortality. Cancer 71 (2 Suppl): 517-23, 1993. [PUBMED Abstract]
  3. Lynch HT, Watson P, Lynch JF, et al.: Hereditary ovarian cancer. Heterogeneity in age at onset. Cancer 71 (2 Suppl): 573-81, 1993. [PUBMED Abstract]
  4. Piver MS, Goldberg JM, Tsukada Y, et al.: Characteristics of familial ovarian cancer: a report of the first 1,000 families in the Gilda Radner Familial Ovarian Cancer Registry. Eur J Gynaecol Oncol 17 (3): 169-76, 1996. [PUBMED Abstract]
  5. Miki Y, Swensen J, Shattuck-Eidens D, et al.: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266 (5182): 66-71, 1994. [PUBMED Abstract]
  6. Easton DF, Bishop DT, Ford D, et al.: Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet 52 (4): 678-701, 1993. [PUBMED Abstract]
  7. Steichen-Gersdorf E, Gallion HH, Ford D, et al.: Familial site-specific ovarian cancer is linked to BRCA1 on 17q12-21. Am J Hum Genet 55 (5): 870-5, 1994. [PUBMED Abstract]
  8. Wooster R, Neuhausen SL, Mangion J, et al.: Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265 (5181): 2088-90, 1994. [PUBMED Abstract]
  9. Easton DF, Ford D, Bishop DT: Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 56 (1): 265-71, 1995. [PUBMED Abstract]
  10. Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336 (20): 1401-8, 1997. [PUBMED Abstract]
  11. Rubin SC, Benjamin I, Behbakht K, et al.: Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med 335 (19): 1413-6, 1996. [PUBMED Abstract]
  12. Aida H, Takakuwa K, Nagata H, et al.: Clinical features of ovarian cancer in Japanese women with germ-line mutations of BRCA1. Clin Cancer Res 4 (1): 235-40, 1998. [PUBMED Abstract]
  13. Rebbeck TR, Lynch HT, Neuhausen SL, et al.: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346 (21): 1616-22, 2002. [PUBMED Abstract]
  14. Klaren HM, van't Veer LJ, van Leeuwen FE, et al.: Potential for bias in studies on efficacy of prophylactic surgery for BRCA1 and BRCA2 mutation. J Natl Cancer Inst 95 (13): 941-7, 2003. [PUBMED Abstract]
  15. Piver MS, Jishi MF, Tsukada Y, et al.: Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer. A report of the Gilda Radner Familial Ovarian Cancer Registry. Cancer 71 (9): 2751-5, 1993. [PUBMED Abstract]
  16. Burghardt E, Girardi F, Lahousen M, et al.: Patterns of pelvic and paraaortic lymph node involvement in ovarian cancer. Gynecol Oncol 40 (2): 103-6, 1991. [PUBMED Abstract]
  17. Omura GA, Brady MF, Homesley HD, et al.: Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience. J Clin Oncol 9 (7): 1138-50, 1991. [PUBMED Abstract]
  18. van Houwelingen JC, ten Bokkel Huinink WW, van der Burg ME, et al.: Predictability of the survival of patients with advanced ovarian cancer. J Clin Oncol 7 (6): 769-73, 1989. [PUBMED Abstract]
  19. Neijt JP, ten Bokkel Huinink WW, van der Burg ME, et al.: Long-term survival in ovarian cancer. Mature data from The Netherlands Joint Study Group for Ovarian Cancer. Eur J Cancer 27 (11): 1367-72, 1991. [PUBMED Abstract]
  20. Hoskins WJ, Bundy BN, Thigpen JT, et al.: The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 47 (2): 159-66, 1992. [PUBMED Abstract]
  21. Thigpen T, Brady MF, Omura GA, et al.: Age as a prognostic factor in ovarian carcinoma. The Gynecologic Oncology Group experience. Cancer 71 (2 Suppl): 606-14, 1993. [PUBMED Abstract]
  22. Dembo AJ, Davy M, Stenwig AE, et al.: Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol 75 (2): 263-73, 1990. [PUBMED Abstract]
  23. Schueler JA, Cornelisse CJ, Hermans J, et al.: Prognostic factors in well-differentiated early-stage epithelial ovarian cancer. Cancer 71 (3): 787-95, 1993. [PUBMED Abstract]
  24. Young RC, Walton LA, Ellenberg SS, et al.: Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials. N Engl J Med 322 (15): 1021-7, 1990. [PUBMED Abstract]
  25. Gershenson DM, Silva EG, Mitchell MF, et al.: Transitional cell carcinoma of the ovary: a matched control study of advanced-stage patients treated with cisplatin-based chemotherapy. Am J Obstet Gynecol 168 (4): 1178-85; discussion 1185-7, 1993. [PUBMED Abstract]
  26. Mogensen O: Prognostic value of CA 125 in advanced ovarian cancer. Gynecol Oncol 44 (3): 207-12, 1992. [PUBMED Abstract]
  27. Hígberg T, Kígedal B: Long-term follow-up of ovarian cancer with monthly determinations of serum CA 125. Gynecol Oncol 46 (2): 191-8, 1992. [PUBMED Abstract]
  28. Rustin GJ, Nelstrop AE, Tuxen MK, et al.: Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study. Ann Oncol 7 (4): 361-4, 1996. [PUBMED Abstract]
  29. Vencken PM, Kriege M, Hoogwerf D, et al.: Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients. Ann Oncol 22 (6): 1346-52, 2011. [PUBMED Abstract]
  30. Safra T, Borgato L, Nicoletto MO, et al.: BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin. Mol Cancer Ther 10 (10): 2000-7, 2011. [PUBMED Abstract]
  31. Hogg R, Friedlander M: Biology of epithelial ovarian cancer: implications for screening women at high genetic risk. J Clin Oncol 22 (7): 1315-27, 2004. [PUBMED Abstract]
  32. Partridge E, Kreimer AR, Greenlee RT, et al.: Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol 113 (4): 775-82, 2009. [PUBMED Abstract]
  33. van Nagell JR Jr, Miller RW, DeSimone CP, et al.: Long-term survival of women with epithelial ovarian cancer detected by ultrasonographic screening. Obstet Gynecol 118 (6): 1212-21, 2011. [PUBMED Abstract]
  34. Goff BA, Mandel L, Muntz HG, et al.: Ovarian carcinoma diagnosis. Cancer 89 (10): 2068-75, 2000. [PUBMED Abstract]
  35. Friedman GD, Skilling JS, Udaltsova NV, et al.: Early symptoms of ovarian cancer: a case-control study without recall bias. Fam Pract 22 (5): 548-53, 2005. [PUBMED Abstract]
  36. Smith LH, Morris CR, Yasmeen S, et al.: Ovarian cancer: can we make the clinical diagnosis earlier? Cancer 104 (7): 1398-407, 2005. [PUBMED Abstract]
  37. Goff BA, Mandel LS, Melancon CH, et al.: Frequency of symptoms of ovarian cancer in women presenting to primary care clinics. JAMA 291 (22): 2705-12, 2004. [PUBMED Abstract]
  38. Goff BA, Mandel LS, Drescher CW, et al.: Development of an ovarian cancer symptom index: possibilities for earlier detection. Cancer 109 (2): 221-7, 2007. [PUBMED Abstract]
  39. Armstrong DK, Bundy B, Wenzel L, et al.: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354 (1): 34-43, 2006. [PUBMED Abstract]
  40. Ozols RF, Young RC: Ovarian cancer. Curr Probl Cancer 11 (2): 57-122, 1987 Mar-Apr. [PUBMED Abstract]
  41. Cannistra SA: Cancer of the ovary. N Engl J Med 329 (21): 1550-9, 1993. [PUBMED Abstract]


Cellular Classification of Ovarian Epithelial Cancer

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

  • Serous cystomas:
    • Serous benign cystadenomas.
    • Serous cystadenomas with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low potential or borderline malignancy).
    • Serous cystadenocarcinomas.

  • Mucinous cystomas:
    • Mucinous benign cystadenomas.
    • Mucinous cystadenomas with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low potential or borderline malignancy).
    • Mucinous cystadenocarcinomas.

  • Endometrioid tumors (similar to adenocarcinomas in the endometrium):
    • Endometrioid benign cysts.
    • Endometrioid tumors with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low malignant potential or borderline malignancy).
    • Endometrioid adenocarcinomas.

  • Clear cell (mesonephroid) tumors:
    • Benign clear cell tumors.
    • Clear cell tumors with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low malignant potential or borderline malignancy).
    • Clear cell cystadenocarcinomas.

  • Unclassified tumors that cannot be allotted to one of the above groups.
  • No histology.
  • Other malignant tumors (malignant tumors other than those of the common epithelial types are not to be included with the categories listed above).

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


Stage Information for Ovarian Epithelial Cancer

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

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


Definitions: FIGO

The Féderation Internationale de Gynécologie et d'Obstétrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging to define ovarian epithelial cancer; the FIGO system is most commonly used. 8 9


Table 1. Carcinoma of the Ovarya

aAdapted from FIGO Committee on Gynecologic Oncology.bIn order to evaluate the impact on prognosis of the different criteria for allotting cases to stage Ic or IIc, it would be of value to know if rupture of the capsule was spontaneous, or caused by the surgeon; and if the source of malignant cells detected was peritoneal washings, or ascites.
Stage   
I  Growth limited to the ovaries. 
Ia  Growth limited to one ovary; no ascites present containing malignant cells. No tumor on the external surface; capsule intact. 
Ib  Growth limited to both ovaries; no ascites present containing malignant cells. No tumor on the external surfaces; capsules intact. 
Icb  Tumor either stage Ia or Ib, but with tumor on surface of one or both ovaries, or with capsule ruptured, or with ascites present containing malignant cells, or with positive peritoneal washings. 
II  Growth involving one or both ovaries with pelvic extension. 
IIa  Extension and/or metastases to the uterus and/or tubes. 
IIb  Extension to other pelvic tissues. 
IIcb  Tumor either stage IIa or IIb, but with tumor on surface of one or both ovaries, or with capsule(s) ruptured, or with ascites present containing malignant cells, or with positive peritoneal washings. 
III  Tumor involving one or both ovaries with histologically confirmed peritoneal implants outside the pelvis and/or positive regional lymph nodes. Superficial liver metastases equals stage III. Tumor is limited to the true pelvis, but with histologically proven malignant extension to small bowel or omentum. 
IIIa  Tumor grossly limited to the true pelvis, with negative nodes, but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces, or histologic proven extension to small bowel or mesentery. 
IIIb  Tumor of one or both ovaries with histologically confirmed implants, peritoneal metastasis of abdominal peritoneal surfaces, none exceeding 2 cm in diameter; nodes are negative. 
IIIc  Peritoneal metastasis beyond the pelvis >2 cm in diameter and/or positive regional lymph nodes. 
IV  Growth involving one or both ovaries with distant metastases. If pleural effusion is present, there must be positive cytology to allot a case to stage IV. Parenchymal liver metastasis equals stage IV. 
8 
 

References:

  1. Hoskins WJ: Surgical staging and cytoreductive surgery of epithelial ovarian cancer. Cancer 71 (4 Suppl): 1534-40, 1993. [PUBMED Abstract]
  2. Mogensen O: Prognostic value of CA 125 in advanced ovarian cancer. Gynecol Oncol 44 (3): 207-12, 1992. [PUBMED Abstract]
  3. Hígberg T, Kígedal B: Long-term follow-up of ovarian cancer with monthly determinations of serum CA 125. Gynecol Oncol 46 (2): 191-8, 1992. [PUBMED Abstract]
  4. Rustin GJ, Nelstrop AE, Tuxen MK, et al.: Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study. Ann Oncol 7 (4): 361-4, 1996. [PUBMED Abstract]
  5. Makar AP, Kristensen GB, Bírmer OP, et al.: CA 125 measured before second-look laparotomy is an independent prognostic factor for survival in patients with epithelial ovarian cancer. Gynecol Oncol 45 (3): 323-8, 1992. [PUBMED Abstract]
  6. Berek JS, Knapp RC, Malkasian GD, et al.: CA 125 serum levels correlated with second-look operations among ovarian cancer patients. Obstet Gynecol 67 (5): 685-9, 1986. [PUBMED Abstract]
  7. Atack DB, Nisker JA, Allen HH, et al.: CA 125 surveillance and second-look laparotomy in ovarian carcinoma. Am J Obstet Gynecol 154 (2): 287-9, 1986. [PUBMED Abstract]
  8. FIGO Committee on Gynecologic Oncology.: Current FIGO staging for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia. Int J Gynaecol Obstet 105 (1): 3-4, 2009. [PUBMED Abstract]
  9. Ovary and primary peritoneal carcinoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 419-28. [PUBMED Abstract]


Stage I and Stage II Ovarian Epithelial Cancer Treatment

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Treatment options:

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

In two large European trials, European Organization for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm (EORTC-ACTION) and International Collaborative Ovarian Neoplasm (MRC-ICON1 [NCT00002477]), patients with stage IA and stage IB (grades II and III), all stage IC and stage II, and all stage I and stage IIA clear cell carcinoma were randomly assigned to adjuvant chemotherapy or observation. Data were reported individually and in pooled form. 12 13 14

The EORTC-ACTION trial required at least four cycles of carboplatin or cisplatin-based chemotherapy as treatment. Although surgical staging criteria were monitored, inadequate staging was not an exclusion criterion. Recurrence-free survival (RFS) was improved in the adjuvant chemotherapy arm (hazard ratio [HR], 0.63; P = .02), but overall survival (OS) was not affected (HR, 0.69; 95% confidence interval [CI], 0.441.08; P = .10). OS was improved by chemotherapy in the subset of patients with inadequate surgical staging.

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

The pooled data from both studies indicated significant improvement in RFS (HR, 0.64; 95% CI, 0.500.82; P = .001) and OS (HR, 0.67; 95% CI, 0.500.90; P = .008). These pooled data provided for an OS at 5 years of 82% with chemotherapy and 74% with observation, with a 95% CI in the difference of 2% to 12%. An accompanying editorial emphasized that the focus of subsequent trials must be to identify patients who do not require additional therapy among the early ovarian cancer subset. 15[Level of evidence: 1iA] Optimal staging is one way to better identify these patients. Except for the most favorable subset (patients with stage IA well-differentiated disease), Gynecologic Oncology Group (GOG) trials, and the evidence above, which is based on double-blinded, randomized controlled trials with total mortality endpoints, support treatment with cisplatin, carboplatin, and paclitaxel (in the United States).

In future trials, the Ovarian Committee of the GOG has opted to include patients with stage II disease in advanced ovarian cancer trials and not to include further study of patients with stage I disease at this time.


Current Clinical Trials

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

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

References:

  1. Young RC, Decker DG, Wharton JT, et al.: Staging laparotomy in early ovarian cancer. JAMA 250 (22): 3072-6, 1983. [PUBMED Abstract]
  2. Zanetta G, Chiari S, Rota S, et al.: Conservative surgery for stage I ovarian carcinoma in women of childbearing age. Br J Obstet Gynaecol 104 (9): 1030-5, 1997. [PUBMED Abstract]
  3. Dembo AJ, Davy M, Stenwig AE, et al.: Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol 75 (2): 263-73, 1990. [PUBMED Abstract]
  4. Ahmed FY, Wiltshaw E, A'Hern RP, et al.: Natural history and prognosis of untreated stage I epithelial ovarian carcinoma. J Clin Oncol 14 (11): 2968-75, 1996. [PUBMED Abstract]
  5. Monga M, Carmichael JA, Shelley WE, et al.: Surgery without adjuvant chemotherapy for early epithelial ovarian carcinoma after comprehensive surgical staging. Gynecol Oncol 43 (3): 195-7, 1991. [PUBMED Abstract]
  6. Kolomainen DF, A'Hern R, Coxon FY, et al.: Can patients with relapsed, previously untreated, stage I epithelial ovarian cancer be successfully treated with salvage therapy? J Clin Oncol 21 (16): 3113-8, 2003. [PUBMED Abstract]
  7. Vergote IB, Vergote-De Vos LN, Abeler VM, et al.: Randomized trial comparing cisplatin with radioactive phosphorus or whole-abdomen irradiation as adjuvant treatment of ovarian cancer. Cancer 69 (3): 741-9, 1992. [PUBMED Abstract]
  8. Piver MS, Lele SB, Bakshi S, et al.: Five and ten year estimated survival and disease-free rates after intraperitoneal chromic phosphate; stage I ovarian adenocarcinoma. Am J Clin Oncol 11 (5): 515-9, 1988. [PUBMED Abstract]
  9. Bolis G, Colombo N, Pecorelli S, et al.: Adjuvant treatment for early epithelial ovarian cancer: results of two randomised clinical trials comparing cisplatin to no further treatment or chromic phosphate (32P). G.I.C.O.G.: Gruppo Interregionale Collaborativo in Ginecologia Oncologica. Ann Oncol 6 (9): 887-93, 1995. [PUBMED Abstract]
  10. Piver MS, Malfetano J, Baker TR, et al.: Five-year survival for stage IC or stage I grade 3 epithelial ovarian cancer treated with cisplatin-based chemotherapy. Gynecol Oncol 46 (3): 357-60, 1992. [PUBMED Abstract]
  11. McGuire WP: Early ovarian cancer: treat now, later or never? Ann Oncol 6 (9): 865-6, 1995. [PUBMED Abstract]
  12. Trimbos JB, Parmar M, Vergote I, et al.: International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 95 (2): 105-12, 2003. [PUBMED Abstract]
  13. Trimbos JB, Vergote I, Bolis G, et al.: Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial. J Natl Cancer Inst 95 (2): 113-25, 2003. [PUBMED Abstract]
  14. Colombo N, Guthrie D, Chiari S, et al.: International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. J Natl Cancer Inst 95 (2): 125-32, 2003. [PUBMED Abstract]
  15. Young RC: Early-stage ovarian cancer: to treat or not to treat. J Natl Cancer Inst 95 (2): 94-5, 2003. [PUBMED Abstract]


Stage III and Stage IV Ovarian Epithelial Cancer Treatment

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


Surgery

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

Surgery has been used as a therapeutic modality and also to adequately stage the disease. Surgery should include total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy and debulking of as much gross tumor as can safely be performed. While primary cytoreductive surgery may not correct for biologic characteristics of the tumor, considerable evidence indicates that the volume of disease left at the completion of the primary surgical procedure is related to patient survival. 1 A literature review showed that patients with optimal cytoreduction had a median survival of 39 months compared with survival of only 17 months in patients with suboptimal residual disease. 1[Level of evidence: 3iA]

Results of a retrospective analysis of 349 patients with postoperative residual masses no larger than 1 cm suggested that patients who present at the outset with large-volume disease and achieve small-volume disease by surgical debulking have poorer outcomes than similar patients who present with small-volume disease. 2 Gradual improvement in survival with decreasing residual tumor volume is likely. Although the association may not be causal, retrospective analyses, including a meta-analysis of patients receiving platinum-based chemotherapy, have found cytoreduction to be an independent prognostic variable for survival. 3 4

A study led by the European Organization for the Research and Treatment of Cancer (EORTC) Gynecological Cancer Group, together with the National Cancer Institute of Canada (NCIC) Clinical Trials Group (EORTC-55971 [NCT00003636]) between 1998 and 2006 included 670 women with stage IIIC and IV ovarian, tubal, and primary peritoneal cancers. 5 The women were randomly assigned to primary debulking surgery followed by at least six courses of platinum-based chemotherapy or to three courses of neoadjuvant platinum-based chemotherapy followed by so-called interval debulking surgery, and at least three more courses of platinum-based chemotherapy. Methods included efforts to ensure accuracy of diagnosis (vis-í-vis peritoneal carcinomatosis of gastrointestinal origin) and stratification by largest preoperative tumor size (excluding ovaries) (<5 cm, >5 cm10 cm, >10 cm20 cm, or >20 cm). Other stratification factors were for institution, method of biopsy (i.e., image-guided, laparoscopy, laparotomy, or fine-needle aspiration), and tumor stage (i.e., stages IIIC or IV). The primary endpoint of the study was overall survival (OS), with primary debulking surgery considered the standard.

Median OS for the primary debulking surgery was 29 months, compared with 30 months for patients assigned to neoadjuvant chemotherapy. The hazard ratio (HR) for death in the group assigned to neoadjuvant chemotherapy followed by interval debulking, as compared with the group assigned to primary debulking surgery followed by chemotherapy, was 0.98 (90% confidence interval [CI], 0.841.13; P = .01 for noninferiority). 5[Level of evidence: 1iiA] Perioperative and postoperative morbidity and mortality were higher in the primary-surgery group (7.4% severe hemorrhage and 2.5% deaths, contrasting with 4.1% severe hemorrhage and 0.7% deaths in the neoadjuvant group). The strongest independent predictor of prolonged survival was the absence of residual tumor after surgery. The subset of patients achieving optimal cytoreduction (1 cm residuum) whether after primary debulking surgery or after neoadjuvant chemotherapy followed by interval debulking surgery had the best median OS.

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

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

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


Treatment Options for Patients With Optimally Cytoreduced Stage III Disease


IP chemotherapy

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

The use of IP cisplatin as part of the initial up-front approach in patients with stage III optimally debulked ovarian cancer is supported principally by the results of three randomized clinical trials (SWOG-8501, GOG-0114, and GOG-0172). 7 8 9 These studies tested the role of IP drugs (IP cisplatin in all three studies and IP paclitaxel in the last study) against the standard IV regimen. In the three studies, superior progression-free survival (PFS) and OS favoring the IP arm was documented. Specifically, the most recent study, GOG-0172, resulted in a median survival rate of 66 months for patients on the IP arm versus 50 months for patients who received IV administration of cisplatin and paclitaxel (P = .03). 9[Level of evidence:1iiA] Toxic effects were greater in the IP arm, contributed to in large part by the cisplatin dose per cycle (100 mg/m2) and by sensory neuropathy from the additional IP as well as from the IV administration of paclitaxel. The rate of completion of six cycles of treatment was also less frequent in the IP arm (42% vs. 83%) because of the toxic effects and catheter-related problems. 10

Notwithstanding these problems, IP therapy for patients with optimally debulked ovarian cancer is receiving wider adoption, and efforts are under way by the GOG to examine some modifications of the IP regimen used in GOG-0172 to improve its tolerability (e.g., to reduce by 25% the total 3-hour amount of cisplatin given; a shift from the less practical 24-hour IV administration of paclitaxel to a 3-hour IV administration). A Cochrane-sponsored meta-analysis of all randomized IP versus IV trials shows an HR of 0.79 for disease-free survival and 0.79 for OS, favoring the IP arms. 11 In another meta-analysis of seven IP versus IV randomized trials that were conducted by Cancer Care of Ontario, the relative ratio (RR) of progression at 5 years based on the three trials that reported this endpoint was 0.91 (95% CI, 0.850.98) and the RR of death at 5 years based on six trials was 0.88 (95% CI, 0.810.95). 10


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


Cytoreductive surgery

The value of interval cytoreductive surgery has been the subject of two large phase III trials. In the first study, performed by the EORTC, patients subjected to debulking after four cycles of cyclophosphamide and cisplatin (with additional cycles given later) had an improved survival rate compared with patients who completed six cycles of this chemotherapy without surgery. 12[Level of evidence: 1iiB] The GOG-0162 trial was designed to answer a very similar question but used the then-standard paclitaxel-plus-cisplatin regimen as the chemotherapy. 13 This trial did not demonstrate any advantage from the use of interval cytoreductive surgery. The divergence of results may be caused by the efficacy of the chemotherapy obscuring any effects of interval cytoreduction, the wider use of maximal surgical effort at the time of diagnosis by U.S. gynecologic oncologists, or unknown factors. Although many patients with stage IV disease also undergo cytoreductive surgery at diagnosis, whether this improves survival has not been established.


Systemic chemotherapy

First-line treatment of ovarian cancer is cisplatin, given IV, or its second-generation analog, carboplatin, given either alone or in combination with other drugs. Clinical response rates from these drugs regularly exceed 60%, and median time-to-recurrence usually exceeds 1 year in this subset of suboptimally debulked women. Trials by various cooperative groups in the subsequent 2 decades addressed issues of optimal dose-intensity 14 15 16 for both cisplatin and carboplatin, 17 schedule, 18 and the equivalent results obtained with either of these platinum drugs, usually in combination with cyclophosphamide. 19 With the introduction of the taxane paclitaxel, two trials confirmed the superiority of cisplatin combined with paclitaxel to the previous standard of cisplatin plus cyclophosphamide; however, two trials that compared the agent with either cisplatin or carboplatin as a single agent failed to confirm such superiority in all outcome parameters (i.e., response, time-to-progression, and survival) (see Table 2).


Table 2. Paclitaxel/Platinum Combinations Versus Comparator Arms in Trials

aStatistically inferior result (P < .001< .05).
Trial  Treatment Regimens  No. of Patients  % Early Crossover  Progression-free Survival (mo)  Overall Survival (mo) 
GOG-132  Paclitaxel (135 mg/m2, 24 h) and cisplatin (75 mg/m2)  201  22%  14.2   26.6  
Cisplatin (100 mg/m2)  200  40%  16.4  30.2 
Paclitaxel (200 mg/m2, 24 h)  213  23%  11.2a  26 
MRC-ICON3  Paclitaxel (175 mg/m2, 3 h) and carboplatin AUC 6  478  23%  17.3  36.1 
Carboplatin AUC 6   943  25%  16.1  35.4 
Paclitaxel (175 mg/m2, 3 h) and carboplatin AUC 6   232  23%  17  40 
Cyclophosphamide (500 mg/m2) and doxorubicin (50 mg/m2) and cisplatin (50 mg/m2)   421  20%  17  40 
GOG-111  Paclitaxel (135 mg/m2, 24 h) and cisplatin (75 mg/m2)  184  None  18  38 
Cyclophosphamide (750 mg/m2) and cisplatin (75 mg/m2)  202  None  13a  24a 
EORTC-55931  Paclitaxel (175 mg/m

OncoLink I wish u knew...

Dr. Giantonio discusses the importance of oncology clinical trials and clarifies some myths about studies. Read more.

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