Ovarian cancer treatment

INTRODUCTION — Ovarian cancer is the seventh most common cancer among women in the United States, and it occurs most frequently in women who are between 40 and 65 years of age. The lifetime risk of developing ovarian cancer is 1.4 to 1.8 percent for women living in the United States. The following factors increase the risk of ovarian cancer: Being a white person Never being pregnant Early age of menarche (the onset of the menstrual periods) or late age of menopause Family history of ovarian, breast, or endometrial (uterine) cancer Presence of inherited BRCA1 or BRCA2 mutations (See "Patient information: Genetic testing for breast and ovarian cancer") Family history of hereditary nonpolyposis colorectal cancer (HNPCC). Women in families with this trait have up to a 60 percent chance of endometrial cancer and a 10 to 12 percent chance of ovarian cancer [1].

Although there are several different types of cancer that can arise in the ovary, epithelial ovarian cancer (hereafter referred to as ovarian cancer) is the most common, and will be the subject of this review.

SIGNS AND SYMPTOMS — During the early stages of ovarian cancer, symptoms are often vague and ill-defined. They may include pelvic or abdominal discomfort, bloating, difficulty eating, increased abdominal size, urinary symptoms (urgency and frequency), constipation, irregular menstrual cycles, or fatigue.

In some women, ovarian cancer is first suspected when a mass or lump is felt during a routine pelvic (internal) examination. However, a mass is not always detectable in the early stages of ovarian cancer. Furthermore, even when a mass is detected, it does not necessarily indicate the presence of an ovarian cancer, as a number of other conditions (some of which are not cancerous, such as cysts) may also present in a similar way.

Because the initial symptoms are vague and nonspecific, ovarian cancer often goes undetected during its early stages. The majority of women have disease that is at an advanced stage by the time it is diagnosed. At this point, the woman may have more significant symptoms such as abdominal distention (swelling), nausea, or a significant loss of appetite.

DIAGNOSIS — If ovarian cancer is suspected because of symptoms and/or an abnormal physical examination, imaging tests (such as a CT scan or MRI) are usually performed to obtain more information. Although these tests may provide important information about the location and/or extent of a possible cancer, they are insufficient to make the diagnosis of an ovarian cancer.

The only way to diagnose ovarian cancer is to have surgery. During surgery, abnormal areas are examined and a small piece is removed (biopsied).The tissue is then examined with a microscope.

Tumor markers (CA 125) — Prior to surgery, most women with suspected ovarian cancer have a blood test to measure the level of a tumor marker called CA 125. This marker is normally <35>65 U/mL) in 80 percent of women with ovarian cancer, particularly in those with advanced stage disease (see below).

Measurement of levels of CA 125 in the blood (actually the serum, the clear fluid component of the blood) may be useful in one of two ways: as a laboratory test that supports the diagnosis of ovarian cancer, and as a marker of ovarian cancer activity during treatment. Measurement of serum levels of CA 125 prior to surgery provides a baseline value that can be used to monitor the success of treatment (if ovarian cancer is found).

When considering the usefulness of the serum CA 125 concentration as an aid to the diagnosis of ovarian cancer, a number of issues must be kept in mind: Elevated levels of CA 125 may be found in women without ovarian cancer (show table 1). This tumor marker is also elevated in patients with other cancers (eg, endometrial cancer, and certain pancreatic cancers), in a variety of non-cancerous conditions (eg, endometriosis, uterine fibroids, and pelvic inflammatory disease), and in approximately 1 percent of normal healthy women. Thus, CA 125 is not currently recommended as a screening test for ovarian cancer in healthy women. For premenopausal (ie, menstruating) women, CA 125 is less useful as a marker of ovarian cancer, especially when it is increased by only a small amount. Cancer is rare in this age group, and small elevations in serum CA 125 are often not related to the presence of an ovarian cancer. Testing is more useful in postmenopausal women, in whom an elevated value is more likely to indicate the presence of a cancer.

Initial surgery — In a woman suspected of having ovarian cancer (even advanced disease), a procedure called exploratory laparotomy is typically performed. In this procedure, a vertical abdominal incision is made, and the surgeon examines the organs in the pelvis and abdomen for signs of cancer. Any fluid that is found within the abdominal cavity (also referred to as the peritoneal cavity), tissue from the ovary, neighboring lymph nodes, other abdominal organs, and the mesentery (the apron of fat that covers and connects the organs of the abdomen and pelvis), are sampled and sent to the pathology laboratory for testing.

If a diagnosis of ovarian cancer is confirmed by the pathologist, the surgeon then removes as much of the cancerous tissue as possible (this is termed "debulking" or cytoreduction, and is an important first step in the treatment of ovarian cancer). Treatment outcomes are best in women whose debulking surgery removes all visible tumor (termed optimal debulking). This is best performed by a gynecologic oncologist, who has received specialized surgical training.

In most cases, the uterus, both fallopian tubes, and both ovaries are also removed. However, in some young women who wish to preserve their ability to bear children in the future, it may be possible to leave the uterus, one fallopian tube, and one ovary in place if these structures seem to be unaffected by the cancer. The doctor and patient should discuss this option before surgery. If the cancer has spread to other organs, those organs, or affected portions of them, may be removed as well.

In some patients, a less invasive procedure called exploratory laparoscopy may be performed. In this procedure, a flexible tube is inserted through a small incision in the abdomen. A camera located in the tip of the tube allows the surgeon to visualize the contents of the abdomen and pelvis. This less invasive approach may be chosen in a young woman who has a mass that is unlikely to be ovarian cancer. In general, however, the open laparotomy is preferred as it allows the surgeon to more easily and completely visualize the abdominal contents and remove any suspicious masses.

STAGING — Based upon the findings during exploratory surgery, a tumor stage between I and IV is assigned (show table 2). Staging is a means of formally defining the extent and location of any cancer, including ovarian cancer, in order to determine the prognosis (outcome) and appropriate selection of further treatment. In general, the stage designations I, II, III, and IV refer to the location of tumor involvement, while the subdivisions A, B, and C further refine the extent of tumor involvement. A higher stage of disease indicates more extensive tumor involvement.

Stage I and II disease are considered early stage ovarian cancer. For women with stage I disease, tumor involvement is generally limited to one or both ovaries. In stage IA and IB disease, the cancer is limited to one or both or ovaries, and the capsule or membrane covering the ovaries has not been broken by the cancer's growth. In contrast, with stage IC disease, the capsule may have ruptured, or there may be signs suggesting that cancer cells have begun to spread within the pelvis. In stage II disease, other pelvic organs such as the uterus or fallopian tubes are involved with the tumor, and there may be early signs that the cancer has spread beyond the pelvis.

In stage III disease, the cancer is confined to the abdomen and retroperitoneal lymph nodes. In stage IV disease, the cancer has spread to distant sites such as the liver or lungs.

As noted previously, ovarian cancer is uncommonly detected during its early stages. Most women (about 75 percent) have stage III disease at the time the cancer is diagnosed.

TREATMENT OF NEWLY DIAGNOSED OVARIAN CANCER — Treatment focuses on eliminating cancerous tissue and preventing disease recurrence.

Surgery — As noted above, the usual first step in treating ovarian cancer is the removal of as much cancerous tissue as possible at the time of initial surgery. A woman is more likely to have optimal cytoreduction, staging, and a higher cure rate if her initial surgery is performed by a gynecologic oncologist.

For selected women with stage IA and IB disease (show table 1), surgery alone is effective in treating the disease, and no additional therapy is recommended. In almost all other cases, however, chemotherapy is recommended in conjunction with surgery.

Chemotherapy

What is chemotherapy? — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. Chemotherapy works by interfering with the ability of rapidly growing cells (such as cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not rapidly growing, they are not affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues give rise to side effects during treatment.

In general, side effects are more frequent when two or more drugs are administered simultaneously (termed combination chemotherapy, see below), and with higher as compared to lower doses of chemotherapy. Most chemotherapy drugs are administered into the vein, although some agents can be given by mouth. A newer alternative treatment strategy involves giving chemotherapy directly into the abdominal (peritoneal) cavity. This is called intraperitoneal or IP chemotherapy, and is discussed in detail below (see "Intraperitoneal chemotherapy" below).

In general, regardless of the route by which they are given, chemotherapy drugs are administered in carefully defined sequence and doses over a period of several months. Chemotherapy drugs are usually not administered daily but periodically, in cycles. A cycle of chemotherapy refers to the time it takes to give the treatment and then allow the body to recover from the effects of the medicines. While receiving these medications, patients are closely monitored for signs of drug toxicity and serious side effects. In most cases, chemotherapy is given after surgery.

Neoadjuvant chemotherapy — Occasionally, it is too risky or technically difficult to perform surgery because of the extensive nature of the cancer. In this case, chemotherapy may be recommended as a first step in the treatment process; this is referred to as neoadjuvant therapy. Neoaduvant therapy is often recommended prior to surgery for women with advanced stage ovarian cancer who have a buildup of fluid in the abdominal cavity (called ascites) or evidence of cancer spread to the lungs, liver, or other distant organs. Some women who receive neoadjuvant chemotherapy are able to have surgery at a later date.

In one study, women with spread of tumor outside the pelvis who received carboplatin and paclitaxel neoadjuvant chemotherapy had a longer period before the cancer progressed. These women also lived longer, compared to women who initially had surgery for stage IV disease [2].

Selection of treatment — Among the chemotherapy agents most commonly used in the treatment of ovarian cancer are paclitaxel (Taxol®), and one of the platinum-type agents (carboplatin or cisplatin). Research suggests that these drugs are effective in preventing recurrence of ovarian cancer, and improving a woman's chance of surviving her cancer.

In the United States, combination chemotherapy using intravenous paclitaxel plus carboplatin is commonly used to treat newly diagnosed ovarian cancer. At least three research trials support the superiority of paclitaxel-containing chemotherapy, in contrast to regimens that do not contain paclitaxel [3-5]. The combination of a platinum-type drug (usually carboplatin) and paclitaxel is standard therapy for the first-line treatment of women with ovarian cancer who require chemotherapy. Carboplatin appears to be as effective as cisplatin, and has fewer side effects.

A potentially less toxic alternative is single agent therapy with carboplatin alone, although this approach is more controversial. It is used more often in Europe than in the United States [6].

Intraperitoneal chemotherapy — In contrast to almost all other cancers, ovarian cancer typically does not spread through the bloodstream. Instead, tumor growth is often limited to the abdominal (peritoneal) cavity, even in advanced cases. Because the bulk of cancerous tissue is found within the peritoneum, newer treatment approaches have tried administering chemotherapy directly into this area (called intraperitoneal or IP therapy). The advantage of IP administration is that higher doses of the drugs can be given, compared to the intravenous (IV) route.

IP chemotherapy is administered through a small, soft, flexible catheter, which is placed in the peritoneal cavity The catheter may be left in place for several weeks or months at a time. The catheter is surgically placed into the peritoneum; the procedure can be done in a hospital or clinic setting, and patients are usually able to go home the same day. A helpful website with educational materials about intraperitoneal catheters and IP chemotherapy is available from the Gynecologic Oncology Group (www.gog.org/IPChemoEd/ipchemoed.html) [7]. Benefits — Benefit for administering chemotherapy directly into the abdomen in women with ovarian cancer was suggested in two early trials [8,9]. The question of whether IP chemotherapy is better than intravenous chemotherapy for women with advanced ovarian cancer was the subject of a study that was conducted in several American hospitals [10]. In this study, IP chemotherapy using cisplatin and paclitaxel was given in combination with intravenous paclitaxel, and compared to the standard intravenous regimen of paclitaxel plus cisplatin in women with optimally debulked stage III ovarian cancer (see "Initial surgery" above). Women who received IP chemotherapy had a 16 month longer survival as compared to women who received intravenous chemotherapy only, even though most of them did not receive the entire six courses of IP treatment because of complications. Risks — However, this benefit was counterbalanced by a higher number of treatment-related complications in the IP group. These included both catheter-related complications (infection, blockage or leakage of the catheter) as well as non-catheter-related problems (low white and red blood cell counts, nausea and vomiting, abdominal pain, and neurologic side effects such as numbness and tingling of the fingers and toes). Recommendation for IP chemotherapy — The National Cancer Institute recommends that IP chemotherapy be strongly considered for women who are left with small volume residual tumor after optimal debulking for stage III disease (show table 1). However, at least for the present, a standard intravenous regimen of paclitaxel plus carboplatin is an acceptable alternative to IP therapy for these patients because of toxicity issues. Patients should discuss the risks and benefits of IP versus IV chemotherapy with their physician.

Maintenance or consolidation chemotherapy — The high likelihood of cancer recurrence after initial chemotherapy has led to efforts to improve outcomes by increasing either the duration and/or the intensity of chemotherapy. There are no data to support a benefit from increasing the chemotherapy dose.

Increasing the duration of first-line chemotherapy may delay cancer progression. This was illustrated in a study of 277 women with stage III or IV ovarian cancer who had achieved a complete response to first-line intravenous chemotherapy [11]. Women who were given 12 additional months of paclitaxel alone had a seven month delay in disease progression compared to those who only received three months of continued paclitaxel [12]. However, whether more women were cured by the longer course of chemotherapy is not clear. Moreover, this benefit was achieved at the cost of more treatment-related side effects with longer treatment.

Because of these issues, some experts regard these results as inconclusive. Nevertheless, the issue of maintenance chemotherapy should be discussed with your physician.

PROGNOSIS — A number of factors influence the success of treatment for ovarian cancer. Treatment tends to be more successful when the cancer is diagnosed at an early stage and at a younger age (below the age of 67). One of the most important factors influencing the outcome of treatment is the amount of tumor that remains after the initial surgery. This is the reason why the goal of the initial exploration is to remove as much of the cancerous tissue as possible.

At the end of treatment, a patient is considered to have a complete response if the physical examination is normal, there is no evidence of disease on radiologic studies (such as a CT scan), and the serum CA 125 level is normal. However, even when all of these criteria are met, microscopic amounts of residual cancer can still be present. In some women, surgery (termed a second look laparotomy) may be performed to more conclusively evaluate the response to treatment. The benefit of second look surgery is controversial, and it is not routinely recommended for all women.

Even when a complete response is obtained (as determined by physical examination, x-ray studies, or second look surgery), ovarian cancer can recur at a later time. The likelihood of tumor recurrence is highest in women with more advanced stage disease at diagnosis, particularly if the debulking surgery was unable to remove all visible tumor. Recurrence of ovarian cancer may be suggested by the development of new symptoms, a rising level of serum CA 125, or new areas of abnormality seen on CT scan. Any of these findings may prompt a reevaluation for disease recurrence. Further treatment may not necessarily be recommended for an isolated rise in the serum CA 125 if symptoms are absent and CT scans show no new growth.

SECOND-LINE TREATMENT — Women with recurrent ovarian cancer and those who do not respond well to initial chemotherapy are candidates for further chemotherapy (often called "second-line chemotherapy").

Chemotherapy — The choice of chemotherapy agents for second-line treatment depends on whether, and how well, the patient responded to first-line treatment with paclitaxel and one of the platinum-type agents. If a good response was obtained that lasted for at least six months, the same or a similar regimen may be used again. Research has shown that such patients may obtain a good response with a second course of a platinum agent plus paclitaxel. In fact, if the initial response lasted longer than 24 months, up to one-fourth of patients may achieve a complete response to second-line chemotherapy.

For women who have relapse at least six months following initial treatment who have persistent neurologic side effects related to prior paclitaxel and a platinum agent, an alternative regimen includes the combination of gemcitabine plus carboplatin [13].

If a patient did not respond well to first-line therapy with paclitaxel and a platinum agent or if she relapses within six months of completing such therapy, a different non-platinum-containing regimen may be considered. Usually, a single drug rather than combination chemotherapy is recommended in these patients. A variety of agents may be considered, including docetaxel, oral etoposide, liposomal doxorubicin, topotecan, gemcitabine, vinorelbine, ifosfamide, leucovorin-modulated 5-fluorouracil, and tamoxifen.

Molecularly targeted therapy — A different type of therapy, referred to as molecularly targeted therapy, may also be of benefit. The drug bevacizumab (Avastin®) binds a protein called vascular endothelial growth factor (VEGF). VEGF is involved in the development of a blood supply within a growing cancer; this blood supply is essential for the tumor to grow and spread. Avastin enhances the antitumor effect of other anticancer drugs, and is used in combination chemotherapy regimens for the treatment of metastatic colorectal, breast, non-small cell lung, and renal cell cancer.

Avastin is an active agent in the treated of ovarian cancer, and it may be considered for women with platinum-resistant ovarian cancer, either alone or in combination with chemotherapy. However, a major problem is the risk of bowel perforations during treatment (approximately 10 percent in two reports [14,15]). Patients with preexisting tumor involvement of the GI tract (eg, obstruction or bowel wall thickening) appear to be at greater risk for this complication [15].

Timing of second-line therapy — An area of major controversy is the optimal timing of second-line therapy. Immediate treatment is reasonable for women with a symptomatic recurrence, with the specific goal of palliation (improvement) of symptoms. In contrast, the optimal timing of second-line therapy in women who are asymptomatic, but who have either a rising level of the tumor marker CA 125 or an abnormal CT scan, is uncertain.

Some experts believe that treatment should be delayed or deferred until the woman has symptoms because therapy is unlikely to result in a cure. Others argue that women with a smaller volume of disease have a better response to chemotherapy, and that responders almost always do better than nonresponders.

Recommendation — One approach to recurrent ovarian cancer takes into account the response to first-line therapy, and the duration of the recurrence-free interval. Immediate therapy at initial discovery of recurrence could be considered for women with disease who responded well to initial platinum-containing chemotherapy and who had a recurrence-free interval of longer than 24 months. Response rates up to 60 percent and average survival durations as long as two years have been reported in such women [16]. In contrast, response rates are relatively low and survival durations are short in women who have disease that is resistant to chemotherapy (ie, an incomplete response to first-line chemotherapy and/or a recurrence-free interval of 12 months or less). In such patients, treatment could be reasonably deferred until actual masses are observed on CT scans or symptoms develop. A rising serum CA 125 concentration would indicate the likelihood of progressive disease and the need for further evaluation.

Surgery — In some cases, surgery may also be beneficial, particularly if the tissue can be easily removed and the patient has been free of disease recurrence for more than 6 to 12 months. Surgery can also be helpful in relieving symptoms and discomfort caused by the growth of cancerous tumors.

CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/


OVARIAN CANCER SCREENING — A screening test is one that is able to detect a disease, such as a precancer or cancer in the early stages, when it is most likely to respond to treatment. An example of a commonly used screening test is the Pap smear, which is used to detect cervical precancers and cancers. A screening test must be both sensitive and specific, meaning that it is able to accurately identify most people with a specific condition and avoids mistakenly identifying people who do not have the condition. This is especially important for ovarian cancer, since a positive screening test usually requires surgery to obtain a biopsy.

High risk family history — Women who have a high-risk family history of ovarian or breast cancer should meet with a genetic counselor to discuss genetic testing for BRCA1 and BRCA2. Characteristics of a high risk family history are described in table 3 (show table 3). Genetic testing and management after a positive or negative genetic test result are discussed in a separate topic review. (See "Patient information: Genetic testing for breast and ovarian cancer").

Family history of ovarian cancer — Women with a family history of ovarian cancer but who do not meet the criteria for a high-risk family history should discuss their individual risk factors (age, number of children, and history of oral contraceptive pill use) with a healthcare provider. A woman is said to have a family history if she has one first degree relative (eg, mother, sister) or two second-degree relatives (eg, grandmother, aunt) with ovarian cancer.

Screening for ovarian cancer in this group has not proven to prevent death related to ovarian cancer. In addition, there are potential risks of screening, including the need for surgery if screening is positive. However, selected postmenopausal women with a family history of ovarian cancer may benefit from screening. An optimal screening strategy for this group has not yet been defined; one screening approach includes an annual CA 125 blood test; transvaginal ultrasound is recommended if the CA 125 level is above 30 U/mL.

Trials are currently underway to better identify the risks and benefits of screening low and high-risk women, and also to determine the most accurate combination of screening tests.

Average risk women — Women with an "average risk" of ovarian cancer include those with no history of ovarian cancer or BRCA mutation in a first or second degree relative (mother, sister, grandmother, aunt). Screening for ovarian cancer is not recommended in average risk women because of the increased risk of an inaccurate result.

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information

website ofthe American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The Women's Cancer Network

(www.wcn.org)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
Gynecologic Oncology Group

(www.gog.org/gynecologiccancerinformation.html)
National Cancer Institute

1-800-4-CANCER
(www.cancer.gov)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
National Ovarian Cancer Coalition

(www.ovarian.org)



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