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National Cancer Institute
Ultima Vez Modificado: 16 de noviembre del 2012
Estimated new cases and deaths from ovarian cancer in the United States in 2012: 1
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.
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.
(Refer to the PDQ® summary on Ovarian Low Malignant Potential Tumor Treatment for more information.)
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
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
|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.|
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.
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.
Treatment options for patients with all stages of ovarian epithelial cancer have consisted of surgery followed by chemotherapy.
Patients diagnosed with stage III and stage IV disease are treated with surgery and chemotherapy; however, the outcome is generally less favorable for patients with stage IV disease. The role of surgery for patients with stage IV disease is unclear, but in most instances, the bulk of the disease is intra-abdominal, and surgical procedures similar to those used in the management of patients with stage III disease are applied. The options for intraperitoneal (IP) regimens are also less likely to apply both practically (as far as inserting an IP catheter at the outset) and theoretically (aimed at destroying microscopic disease in the peritoneal cavity) in patients with stage IV disease.
Surgery has been used as a therapeutic modality and also to adequately stage the disease. Surgery should include total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy and debulking of as much gross tumor as can safely be performed. While primary cytoreductive surgery may not correct for biologic characteristics of the tumor, considerable evidence indicates that the volume of disease left at the completion of the primary surgical procedure is related to patient survival. 1 A literature review showed that patients with optimal cytoreduction had a median survival of 39 months compared with survival of only 17 months in patients with suboptimal residual disease. 1[Level of evidence: 3iA]
Results of a retrospective analysis of 349 patients with postoperative residual masses no larger than 1 cm suggested that patients who present at the outset with large-volume disease and achieve small-volume disease by surgical debulking have poorer outcomes than similar patients who present with small-volume disease. 2 Gradual improvement in survival with decreasing residual tumor volume is likely. Although the association may not be causal, retrospective analyses, including a meta-analysis of patients receiving platinum-based chemotherapy, have found cytoreduction to be an independent prognostic variable for survival. 3 4
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.
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
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.
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).
|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
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