Ovarian Cancer

WHAT IS OVARIAN CANCER?

Ovarian epithelial cancer is a disease in which malignant (cancer) cells form in the tissue covering the ovary.

The ovaries are a pair of organs in the female reproductive system. They are located in the pelvis, one on each side of the uterus (the hollow, pear-shaped organ where a fetus grows). Each ovary is about the size and shape of an almond. The ovaries produce eggs and female hormones (chemicals that control the way certain cells or organs function).

Several malignancies arise from the ovary. Epithelial carcinoma of the ovary is one of the most common gynecologic malignancies and the fifth most frequent cause of cancer death in women, with half of all cases occurring in women over age 65.



WHAT ARE RISK FACTORS OF OVARIAN CANCER?

Women who have a family history of ovarian cancer are at an increased risk of developing ovarian cancer.

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. 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. BRCA2, also responsible for some instances of inherited ovarian and breast cancer, has been mapped by genetic linkage to chromosome 13q12. The lifetime risk for developing ovarian cancer in patients harboring germline mutations in BRCA1 is substantially increased over the general population. Two retrospective studies of patients with germline mutations in BRCA1 suggest that these women have improved survival compared to BRCA1 negative women. 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.

Some ovarian cancers are caused by inherited gene mutations (changes).

The genes in cells carry the hereditary information that is received from a person’s parents. Hereditary ovarian cancer makes up approximately 5% to 10% of all cases of ovarian cancer. Three hereditary patterns have been identified: ovarian cancer alone, ovarian and breast cancers, and ovarian and colon cancers.

Women with an increased risk of ovarian cancer may consider surgery to prevent it.

Some women who have an increased risk of ovarian cancer may choose to have a prophylactic oophorectomy (the removal of healthy ovaries so that cancer cannot grow in them). It is not known if this procedure prevents ovarian cancer.



HOW TO DETECT OVARIAN CANCER?

Ovarian cancer is hard to detect (find) early because usually there are no symptoms.

Some women who have early stage ovarian cancer may have symptoms such as vague gastrointestinal (GI) discomfort, pressure in the pelvis, pain, swelling of the abdomen, and shortness of breath. Most of the time, there are no symptoms or they are very mild. By the time symptoms do appear, the cancer is usually advanced.

Tests that examine the ovaries, pelvic area, blood, and ovarian tissue are used to detect (find) and diagnose ovarian cancer.

The following tests and procedures may be used:

Pelvic exam: An exam of the vagina, cervix, uterus, fallopian tubes, ovaries, and rectum. The doctor or nurse inserts one or two lubricated, gloved fingers of one hand into the vagina and the other hand is placed over the lower abdomen to feel the size, shape, and position of the uterus and ovaries. A speculum is also inserted into the vagina and the doctor or nurse looks at the vagina and cervix for signs of disease. A Pap test or Pap smear of the cervix is usually done. The doctor or nurse also inserts a lubricated, gloved finger into the rectum to feel for lumps or abnormal areas.
Ultrasound: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.
CA 125 assay: A test that measures the level of CA 125 in the blood. CA 125 is a substance released by cells into the bloodstream. An increased CA 125 level is sometimes a sign of cancer or other condition.
Barium enema(lower GI series): A series of x-rays of the lower gastrointestinal tract. A liquid that contains barium (a silver-white metallic compound) is put into the rectum. The barium coats the lower gastrointestinal tract and x-rays are taken. This procedure is also called a lower GI series.
Intravenous pyelogram (IVP): A series of x-rays of the kidneys, ureters, and bladder to find out if cancer is present in these organs. A contrast dye is injected into a vein. As the contrast dye moves through the kidneys, ureters, and bladder, x-rays are taken to see if there are any blockages.
CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
Biopsy: The removal of cells or tissues so they can be viewed under a microscope to check for signs of cancer. The tissue is removed in a procedure called a laparotomy (a surgical incision made in the wall of the abdomen).


WHAT IS STAGE OF OVARIAL CANCER?

The Federation Internationale de Gynecologie et d’Obstetrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging. The stage of classifications is helpful for making therapy and determing prognosis.

Stage I

Stage I ovarian cancer is limited to the ovaries.

Stage IA: Tumor limited to 1 ovary; capsule intact, no tumor on ovarian surface. No malignant cells in ascites or peritoneal washings.
Stage IB: Tumor limited to both ovaries; capsules intact, no tumor on ovarian surface. No malignant cells in ascites or peritoneal washings.*
Stage IC: Tumor limited to 1 or both ovaries with any of the following: capsule ruptured, tumor on ovarian surface, malignant cells in ascites or peritoneal washings.
Stage II

Stage II ovarian cancer is tumor involving 1 or both ovaries with pelvic extension and/or implants.

Stage IIA: Extension and/or implants on the uterus and/or fallopian tubes. No malignant cells in ascites or peritoneal washings.
Stage IIB: Extension to and/or implants on other pelvic tissues. No malignant cells in ascites or peritoneal washings.
Stage IIC: Pelvic extension and/or implants (stage IIA or IIB) with malignant cells in ascites or peritoneal washings.
Stage III

Stage III ovarian cancer is tumor involving 1 or both ovaries with microscopically confirmed peritoneal implants outside the pelvis. Superficial liver metastasis equals stage III. Tumor is limited to the true pelvis but with histologically verified malignant extension to small bowel or omentum.

Stage IIIA: Microscopic peritoneal metastasis beyond pelvis (no macroscopic tumor).
Stage IIIB: Macroscopic peritoneal metastasis beyond pelvis 2 cm or less in greatest dimension.
Stage IIIC: Peritoneal metastasis beyond pelvis more than 2 cm in greatest dimension and/or regional lymph node metastasis.
Stage IV

Stage IV ovarian cancer is tumor involving 1 or both ovaries with distant metastasis. If pleural effusion is present, there must be positive cytologic test results to designate a case to stage IV. Parenchymal liver metastasis equals stage IV.



HOW TO TREAT OVARIAL CANCER?

Stage I Ovarian Epithelial Cancer

Standard treatment options

If the tumor is well or moderately well differentiated, total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy is adequate for patients with stage IA and IB disease.
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. Several treatment approaches that have been taken in such patients are listed below.
Intraperitoneal P-32 or radiation therapy.
Systemic chemotherapy.
Total abdominal and pelvic radiation therapy.
Careful observation without immediate treatment in selected patients (watchful waiting).
As yet, no randomized trial has demonstrated a survival advantage for one of these approaches over another, nor has immediate treatment been shown to prolong life relative to treatment at relapse.

Stage II Ovarian Epithelial Cancer

Standard treatment options

Surgery should include total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy and tumor debulking to remove all or most of the tumor. If there is no clinically apparent disease outside of the pelvis and systemic therapy is contemplated, additional staging procedures, while possibly influencing choice of therapy, may not influence survival. The options for further treatment include:

If minimal postsurgical residual disease (<1 cm) remains, systemic chemotherapy:
TP: paclitaxel (Taxol) + cisplatin or carboplatin.
CP: cyclophosphamide + cisplatin.
CC: cyclophosphamide + carboplatin.
Total abdominal and pelvic radiation therapy (only if there is no macroscopic upper abdominal disease, and minimal residual pelvic disease is <0.5 cm).
Intraperitoneal P-32 radiation therapy is less frequently used (only if residual tumor is <1 mm). This option is associated with a significant number of late bowel complications.
If macroscopic postsurgical residual disease (>2 cm) remains in the pelvis, combination chemotherapy should be used. The following regimens are commonly used:
TP.
CP
CC.
Stage III and IV Ovarian Epithelial Cancer

The same observations concerning surgery and chemotherapy pertain to patients with stage III or IV disease; however, the outcome of patients with stage IV disease is somewhat less favorable. 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 similar surgical procedures are applied as in the management of stage III patients. Also, the options for intraperitoneal (IP) regimens are less likely to apply both practically (as far as inserting an IP catheter at the outset) and theoretically (aimed towards destroying microscopic disease in the peritoneal cavity).

Standard treatment options

Surgery

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.

Surgery has a role in reassessment to determine the extent of residual disease, if any, following the initial (induction) chemotherapy.

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 remainders are left with bulky tumors. Some have reported improved survival in patients who achieve optimal secondary debulking, while others report survival benefit for those left with microscopic disease only. 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. Since there are no controlled clinical trials that demonstrate a survival advantage for the second-look operation, it is often performed either as part of a clinical trial or when a prescribed second-line therapy is being tested. Finally, reassessment surgery has been linked to the introduction of IP catheters, in order to test the pharmacologically derived concept of IP consolidation with drugs delivered directly into the peritoneal cavity. A number of IP regimens have been tested, and phase III trials have provided support for the validity of this concept.

Intraperitoneal regimens

A pharmacologic advantage for this route possibly resulting in an improved outcome pertains only to the minimal or no residual disease setting. Therefore, the extent of residual disease after the initial surgery or at reassessment has been used to guide the development of these treatment strategies. Early reports suggested a role for IP chemotherapy by demonstrating surgically defined complete response rates and prolonged survival in approximately 25% to 35% of patients with small-volume residual persistent disease after a variety of IP regimens. Outcome was particularly favorable in patients defined as platinum-sensitive, a feature indicative of a greater overall responsiveness to other treatments as well.

The use of IP cisplatin as part of the initial up-front approach in stage III optimally-debulked ovarian cancer is supported by the results of 3 randomized clinical trials. These studies tested the role of IP drugs (IP cisplatin in all 3 studies, and IP paclitaxel in the last study) versus the standard IV regimen. In all 3 studies superior progression-free survival was documented favoring the IP arm, and in the 2 fully reported to date, the overall survival was also significantly better in the IP arm.

Chemotherapy options

First-line chemotherapy has been built on 2 premises supported by retrospective analyses and consecutive clinical trials by cooperative groups:

Platinum compounds, up to an “optimal dose-intensity,” represent the core of the treatment (e.g., platinum-based chemotherapy). Clinical trials escalating the drug to 100 mg/m2 every 3 weeks did not support an advantage over 50 mg/m2 every 3 weeks, and adopted 75 mg/m2 as the standard. Similarly for carboplatin, a large retrospective study suggested improved outcome up to a target area under the curve (AUC) of 5, and then a plateau in effectiveness in spite of increasing drug exposure.
Cisplatin and carboplatin yield equivalent results. Several clinical trials supporting the introduction of carboplatin into the clinic demonstrated it yielded similar results in ovarian cancer as cisplatin.
Specifically, treatments that have been advocated and tested fall within the following categories:

Lengthening the number of cycles of the induction platinum-based chemotherapy (however, a single-institution randomized trial of 5 versus 10 cycles was negative). Continuing paclitaxel once a complete clinical response to induction chemotherapy has been achieved. Monthly paclitaxel after a clinical complete response, given for 12 months, has demonstrated a statistically significant advantage in progression-free survival (median 28 months) for these patients over those receiving paclitaxel for only 3 months (median progression-free survival = 21 months). This study of 206 patients was terminated early and is unlikely to be informative with respect to overall survival. Whether to provide maintenance treatment, as given in this study, or to treat upon progression is still uncertain. Moreover, maintenance paclitaxel is associated with increased neuropathy (>25%).
Integrating other active drugs.
Consolidation with high-dose chemotherapy, whether in complete remission or after positive reassessment. Encouraging results from high-dose chemotherapy series and bone-marrow and stem cell autotransplants have been reported. However, the reported benefit appeared confined to patients with platinum-sensitive and small-volume tumors – a situation associated with median survivals that exceed 3 years, often with standard measures alone.
Treatment options under clinical evaluation:

Chemotherapy. Trials are ongoing integrating active drugs in induction, consolidation, or maintenance regimens, added to or following initial carboplatin-based or cisplatin-based treatments.
Other treatments. IP radioimmunoconjugates, vaccines, and targeted drugs are under clinical evaluation, primarily as consolidation therapy
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. Other platinum agents, such as oxaliplatin, have activity and could be considered. Intraperitoneal (IP) therapy is usually not given beyond consolidation, but could be considered for those patients with low-volume disease and no single nodule greater than 1 cm.

For patients whose disease is platinum-refractory (i.e., with disease that has progressed while on a platinum regimen or that has recurred shortly after completion of a platinum-containing regimen), treatment with paclitaxel (Taxol) historically provided the first agent with consistent activity in these patients and should be considered. Responses have been observed in patients whose disease is platinum-sensitive and those whose disease is platinum-refractory. The primary toxic effect is reversible neutropenia; other rare toxic effects include anaphylactoid reactions (thought to be due to the Cremophor vehicle and/or rapid intravenous administration), cardiac arrhythmias, and peripheral neuropathy. The overall response rate is higher in patients with recurrent ovarian cancer treated with paclitaxel and carboplatin or cisplatin.

Several randomized trials have addressed whether the use of combination therapy is superior to single agents, and the outcome of one of these studies has been published. Overall, in comparison to nonpaclitaxel-containing platinum-based treatment (carboplatin alone in 71%), the use of a platinum-containing regimen with paclitaxel (carboplatin + paclitaxel in 80%) resulted in a prolonged progression-free survival (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.66-0.89, P=.0004; difference at 1 year 10% [50% versus 40%] CI 4% to 15%). Survival was also improved on the carboplatin plus paclitaxel-containing arm (HR 0.82; 95% CI 0.69-0.97; P=.023; difference at 2 years 7% [57% versus 50%] CI 1% to 12%).

Standard treatment options

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.
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 should be considered. In a salvage setting, 3-hour infusions are safe, less myelotoxic, and equally effective.
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 re-explored. The 61 patients who had successful cytoreduction (greatest residual tumor diameter <2 cm) had a statistically significant prolongation of survival. 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.

Other salvage chemotherapy, including several single agents that have been shown to have activity in refractory ovarian cancer, should be considered:
Liposomal doxorubicin: A phase II study of encapsulated doxorubicin given intravenously once every 21 to 28 days demonstrated 1 complete response and 8 partial responses in 35 patients with platinum-refractory or paclitaxel-refractory disease (relative risk = 25.7%). In general, liposomal doxorubicin is well tolerated. The most frequent toxic effects, which are more pronounced following higher doses or when liposomal doxorubicin is given every 3 weeks, include neutropenia, stomatitis, and hand-foot syndrome. Oral and cutaneous toxic effects completely resolve within 5 weeks of drug administration. Nausea is minimal and alopecia rarely occurs.
Topotecan: A topoisomerase I inhibitor, topotecan has been extensively evaluated as a single agent in patients with recurrent epithelial ovarian cancer. In phase II studies of topotecan administered intravenously on days 1 to 5 of a 21-day cycle, objective response rates ranging from 13% to 16.3% have been reported. Objective responses are reported in patients with platinum-refractory disease. Substantial myelosuppression follows administration. Other toxic effects include nausea, vomiting, alopecia, and, rarely, asthenia.
Liposomal doxorubicin and topotecan have been compared in a randomized trial of 474 patients with recurrent ovarian cancer. Response rates (19.7% versus 17.0%, P=.390), progression-free survival (16.1 weeks versus 17.0 weeks; P=.095), and overall survival (60 weeks versus 56.7 weeks, P=.341) did not differ significantly between the liposomal doxorubicin and topotecan arms, respectively.
Gemcitabine: A pyrimidine antimetabolite with similarities to cytosine arabinoside, gemcitabine has shown activity in patients with recurrent ovarian cancer. The response rate ranges from 13% to 19% in evaluable patients. Responses have been observed in patients who are platinum-refractory and/or paclitaxel-refractory as well as in patients with bulky disease.
Fluorouracil and leucovorin: In platinum-resistant recurrent disease, an objective response rate of 10% to 17% has been reported.
Tamoxifen: Some patients (18%) will respond to tamoxifen (20 mg twice daily). A response is more likely in patients with detectable levels of cytoplasmic estrogen receptor on their tumors.
Etoposide: Oral low doses have generated response rates from 6% to 26%.
Ifosfamide: Modest activity has been demonstrated in patients with epithelial ovarian cancer, including disease that is platinum-refractory.
Hexamethylmelamine (HMM): There have been several encouraging reports of orally-administered HMM as salvage chemotherapy after failure of cisplatin-based combination regimens. Response rates in platinum-resistant patients are 12% to 14%.
Some reports suggest a potential role for IP chemotherapy to treat patients with advanced ovarian cancer. Surgically defined complete response occurs in about 30% of patients who have low-volume disease at initiation of therapy (no nodule >0.5 cm). This surgical complete response may have a favorable impact on survival.



NOVAL THERAPIES

High-dose chemotherapy with stem cell transplant

There is evidence that high-dose chemotherapy with stem cell(or bone marrow) transplantation is superior to conventional chemotherapy in relapsed ovarian cancer.

Cryoablation:Percutaneous cryoablation may be used for unresectable ovarial cancer due to patient performance or disease factor.This is a mini-invational therapy and less damage to patient.

Dendritic cell vaccine: Immunomodality is helpful to control ovarial cancer.One such approach uses bone marrow-derived dendritic cells (DCs), phenotypically distinct and very potent antigen-presenting cells, to present tumour-associated antigens (TAAgs) and, thereby, generate tumour-specific immunity. Many observations have led to clinical trials designed to investigate the immunological and clinical effects of Ag-pulsed DCs administered as a therapeutic vaccine to patients with cancer. Although current DC-based vaccination methods are cumbersome and complex, promising preliminary results from clinical trials in patients with ovarial cancer,malignant lymphoma, melanoma, and prostate cancer suggest that immuno-therapeutic strategies, that take advantage of the unique properties of DCs, may ultimately prove both efficacious and widely applicable treatment in patients with cancer.



HOW IS PROGNOSIS OF OVARIAL CANCER?

Ovarian cancer usually spreads via local shedding into the peritoneal cavity followed by implantation on the peritoneum, and via local invasion of bowel and bladder. The incidence of positive nodes at primary surgery has been reported as high as 24% in patients with stage I disease, 50% in patients with stage II disease, 74% in patients with stage III disease, and 73% in patients with stage IV disease.

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.
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. DNA flow cytometric analysis of stage I and stage IIA patients may identify a group of high-risk patients. Patients with clear cell histology appear to have a worse prognosis. Patients with a significant component of transitional cell carcinoma appear to have a better prognosis..

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. For patients whose elevated CA 125 normalizes with chemotherapy, more than 1 subsequent elevated CA 125 measurement is highly predictive of active disease, but this does not mandate immediate therapy.