Patient information: Ovarian cancer treatment

OVARIAN CANCER OVERVIEW

Ovarian cancer is the seventh most common cancer among women in the United States. 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 [1].

There are several different types of cancer that can arise in the ovary, although epithelial ovarian cancer (referred to as ovarian cancer in this topic) is the most common, and is the subject of this review.

This topic review will cover chemotherapy treatment for ovarian cancer. A separate topic review is available that discusses the diagnosis and staging (including initial surgical staging) of ovarian cancer. (See "Patient information: Ovarian cancer diagnosis and staging".)

TREATMENT OF NEWLY DIAGNOSED OVARIAN CANCER

Treatment of ovarian cancer focuses on eliminating cancerous tissue and preventing the disease from coming back (recurring).

Surgery — The first step in treating ovarian cancer usually involves surgical removal of as much cancerous tissue as possible (called optimal surgical debulking or optimal cytoreduction). Achieving optimal surgical debulking improves the woman's outcome or prognosis and it may also influence the choice of chemotherapy treatment. A woman is more likely to have optimal cytoreduction if her initial surgery is performed by a gynecologic oncologist, a specialist in cancers of the female reproductive system. This topic is addressed elsewhere. (See "Patient information: Ovarian cancer diagnosis and staging".)

CHEMOTHERAPY FOR OVARIAN CANCER

The need for chemotherapy after surgery depends on the disease stage. (See "Patient information: Ovarian cancer diagnosis and staging", section on 'Staging'.)

For selected women with stage IA and IB disease (table 1), surgery alone is effective in treating the disease, and no additional therapy is recommended. In almost all other cases, chemotherapy is recommended in conjunction with surgery. (See "First-line chemotherapy for epithelial ovarian cancer".)

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. Exceptions to this include cells of the bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. These tissues are affected most by chemotherapy, causing the typical side effects (low blood counts, hair loss, etc).

In general, the side effects seen with chemotherapy are more frequent and more severe when two or more drugs are given at the same time (termed combination chemotherapy). However, in most cases, combination therapy is preferred over single agent chemotherapy because it is associated with better outcomes. (See 'Choice of chemotherapy regimen' below.)

Most chemotherapy drugs are given into the vein, although some agents can be given by mouth. A newer treatment strategy for women with optimally debulked stage III ovarian cancer (table 1) 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 (intravenous, intraperitoneal, by mouth), chemotherapy drugs are given in a 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. During this time, patients are closely monitored for signs of drug toxicity and side effects.

Neoadjuvant chemotherapy — In most cases, chemotherapy is given after surgery for ovarian cancer. Occasionally, it is too risky to perform initial surgery because of the extensive nature of the cancer and/or the debilitated condition of the patient. In such cases, chemotherapy may be recommended as a first step in the treatment process; this is referred to as neoadjuvant chemotherapy.

There is controversy as to whether the long-term outcomes in women who are given neoadjuvant chemotherapy before surgery are as favorable as those in women who have aggressive surgery followed by chemotherapy [2]. In general, initial surgery is preferred if, in the opinion of an experienced ovarian cancer surgical team, optimal debulking surgery is possible and the patient can safely tolerate it.

Neoadjuvant chemotherapy is a reasonable approach for women who could not tolerate a lengthy operation and recovery period. In such cases, initial chemotherapy can shrink the tumor and improve a woman's overall medical condition, making her a better candidate for later debulking surgery.

Choice of chemotherapy regimen — 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 chemotherapy regimens that contain these drugs are effective in preventing recurrence of ovarian cancer, and improving a woman's chance of surviving her cancer.

At least three research studies support the superiority of paclitaxel-containing chemotherapy over other combinations that do not contain paclitaxel [3-5]. As a result, 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.

Influence of disease stage on the chemotherapy recommendation — As noted above, the need for chemotherapy after surgery and the type and duration of treatment that is recommended depends on the disease stage.

Stage I disease — After surgery, women with stage IA or IB ovarian cancers (table 1) that appear to be fairly nonaggressive (described as low-grade or grade 1) do well without chemotherapy, and observation alone is a standard approach.

In contrast, women with higher grade (grade 2 or 3), stage IA or IB ovarian cancers, and all women with stage IC ovarian cancer (regardless of the grade or level of aggressiveness) are usually advised to have adjuvant chemotherapy. The standard regimen includes a platinum-based combination such as paclitaxel and carboplatin. Each cycle is given over three weeks and treatment usually begins within two to six weeks after surgery.

The optimal duration of postsurgery chemotherapy for women with stage I ovarian cancer remains controversial. Some experts recommend six cycles (18 weeks of therapy) while others recommend three. Many oncologists recommend individualizing the number of cycles (with a minimum of three) based upon patient risk factors and how well the woman is tolerating the chemotherapy.

A potentially less toxic alternative to combination therapy is single agent therapy with carboplatin alone [6]. This approach is more often used in Europe, and is considered controversial in the United States.

Stage II — Women with stage II disease have a prognosis that is slightly worse than those with stage I disease, but better than those with stage III or IV disease. Although there are few trials validating this approach, many groups suggest the use of six cycles of intravenous paclitaxel plus carboplatin, similar to the regimen used for women with stage III/IV disease.

An acceptable alternative is to use a combination of intraperitoneal and intravenous chemotherapy (see 'Intraperitoneal chemotherapy' below. However, the use of IP chemotherapy after surgery for stage II ovarian cancer is controversial since the data supporting this treatment was derived from studies of women with stage III disease.

Stage III to IV disease — In the United States, the standard course of chemotherapy after surgical debulking for stage III or IV ovarian cancer includes six cycles of paclitaxel plus carboplatin. Each cycle given over three weeks and treatment usually begins within two to six weeks after surgery. However, the preferred treatment for all patients is enrollment in a clinical trial. (See 'Clinical trials' below.)

A potentially less toxic alternative to combination therapy is single agent therapy with carboplatin alone [6]. This approach is more often used in Europe, and is considered controversial in the United States.

Women with optimally debulked stage III disease should also consider the use of intraperitoneal chemotherapy as a component of their chemotherapy (see 'Intraperitoneal chemotherapy' below.

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 peritoneal cavity, newer treatment approaches give chemotherapy directly into this body cavity, an approach that is called intraperitoneal or IP chemotherapy. The advantage of IP therapy compared to the intravenous (IV) route is that higher doses of the drugs can be given directly to the areas at highest risk for tumor involvement.

IP chemotherapy is administered through a small, soft, flexible catheter, which is surgically placed in the peritoneal cavity, often at the time of the initial debulking surgery. The procedure can also be done as a separate procedure in a hospital or clinic setting; patients are usually able to go home the same day.

The IP catheter can be safely left in place for several months at a time. A website with educational materials about intraperitoneal catheters and IP chemotherapy is available from the Gynecologic Oncology Group (www.gog.org/IPChemoEd/ipchemoed.html).

• Benefits — A study conducted in several American hospitals examined the benefit of giving IP versus IV chemotherapy in women with advanced ovarian cancer [7]. In the study, IP chemotherapy (cisplatin and paclitaxel) was given in combination with intravenous paclitaxel and compared to the standard regimen of all IV treatment with paclitaxel plus cisplatin. Participants included women with optimally debulked stage III ovarian cancer (see 'Surgery' above. Women who were given IP chemotherapy had a 16 month longer survival as compared to women who were given all of their chemotherapy IV, even though most of the women did not take the entire six courses of IP treatment because of side effects.
• Risks — The benefit of IP chemotherapy is counterbalanced by a higher number of treatment-related side effects. These include 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). Successful management of these complications (and therefore, avoidance of unnecessary treatment delays or discontinuation) is most likely in centers that are experienced in the use of IP chemotherapy.
• Recommendation for IP chemotherapy — The National Cancer Institute recommends that IP chemotherapy be strongly considered for women with stage III ovarian cancer who are left with a small amount of tumor after optimal debulking (table 1). However, at least for the present, a standard regimen of intravenous paclitaxel plus carboplatin is an acceptable alternative to IP therapy 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 ovarian cancer recurrence after initial surgery and chemotherapy has led to efforts to improve outcomes by increasing either the intensity and/or the duration of chemotherapy. In general, research studies do not support any benefit from increasing the chemotherapy dose (ie, high-dose chemotherapy, sometimes referred to as a "bone marrow transplant").

The value of giving "maintenance" chemotherapy after the woman achieves a complete response to first-line chemotherapy has been debated. In an early study, women who were given 12 additional months of paclitaxel alone had a 7 month delay in disease progression compared to those who were given 3 additional months [8]. However, this study did not prove that more women were cured by the longer course of chemotherapy. In addition, the benefit of the seven month delay was achieved at the cost of additional chemotherapy side effects.

Furthermore, a preliminary report of a second study, the Italian After-6 protocol, failed to show any benefit for a shorter course (6 rather than 12 months) of maintenance paclitaxel in women who obtained a complete response after surgery and six cycles of paclitaxel and carboplatin [9]. Compared to observation alone, maintenance therapy did not reduce the risk of disease relapse or improve survival.

In view of these results, the use of maintenance chemotherapy is not common, although the concept of improved overall survival is being tested in a clinical trial (GOG 212, find more information at www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=422427&version=patient).

SURVEILLANCE AFTER OVARIAN CANCER TREATMENT

At the end of treatment (both surgery and chemotherapy), a woman is considered to have a "complete response" if her physical examination is normal, there is no evidence of cancer on imaging studies (such as a CT scan), and the blood levels of CA-125 are normal. However, even when all of these criteria are met, microscopic amounts of residual cancer (ie, not visible on imaging studies) can still be present. Growth of these microscopic tumor cells is probably responsible for tumor recurrence at a later date.

To monitor for the possibility of recurrent ovarian cancer, follow-up blood tests, physical examinations, and imaging tests are recommended for at least five years after treatment ends. The optimal surveillance strategy is not defined, although guidelines from the National Comprehensive Cancer Network (NCCN) are as follows [10]:

• Office visits every two to four months for two years, then every six months for three years, then annually.
• Periodic blood tests for CA-125, although this may be changing. While a rise in the CA-125 level is often the earliest sign of an ovarian cancer recurrence, the benefit of detecting and treating a recurrence based on CA-125 alone, before there are any signs or symptoms of recurrence, has been questioned. (See 'Signs of recurrence' below.)

• Pelvic examination, chest x-ray, and chest/abdomen/pelvic CT scan if there are any abnormalities on the blood test or examination.

Signs of recurrence — Even women who have a complete response to initial therapy (as determined by physical examination, x-ray studies, and/or second look surgery) can have a recurrence of ovarian cancer at a later time. The likelihood of a tumor recurrence is highest in women with more advanced stage disease at diagnosis, particularly if the initial debulking surgery was unable to remove all visible tumor.

The earliest evidence of recurrent ovarian cancer can be indicated by a rising blood level of CA-125, followed later by symptoms (often abdominal pain or bloating with or without back pain). In the past, treatment for recurrent ovarian cancer was sometimes recommended based on a high CA-125 level alone, instead of waiting until symptoms developed.

However, studies have shown that there is no survival benefit of starting chemotherapy based on a high level of CA-125 alone, and that quality of life may be improved by waiting until there are symptoms or signs of ovarian cancer recurrence. You should talk to your healthcare provider for more information about this issue. (See "Medical treatment for relapsed epithelial ovarian cancer".)

SECOND-LINE TREATMENT OF OVARIAN CANCER

Women with recurrent ovarian cancer following an initial complete response, and those who do not respond well to initial chemotherapy are candidates for further chemotherapy, often called second-line chemotherapy.

Choice of chemotherapy regimen — The choice of chemotherapy agents for second-line treatment depends upon whether, and how well, the patient responded to first-line treatment with paclitaxel and either carboplatin or cisplatin. If the woman had a complete response, and the response lasted for at least six to 12 months, research has shown that a good response is possible with a second course of the same regimen. In fact, if the initial response lasted longer than 24 months, up to one-fourth of patients will have a complete response to retreatment with the same regimen.

Alternately, a regimen including carboplatin with either gemcitabine or pegylated liposomal doxorubicin (PLD) may be used. Women who have symptoms of nerve damage (neuropathy) are ideal candidates for one of these regimens.

If the woman 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 cases. A variety of agents may be considered, including pegylated liposomal doxorubicin, topotecan, docetaxel, oral etoposide, gemcitabine, vinorelbine, ifosfamide, leucovorin-modulated 5-fluorouracil, or tamoxifen.

Molecularly targeted therapy — A different type of therapy altogether, referred to as molecularly-targeted therapy, may also be of benefit for second-line therapy. The drug bevacizumab (Avastin®) interacts with 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. Bevacizumab interferes with the blood supply of the tumor by interacting with VEGF, causing the tumors to shrink. Bevacizumab also enhances the antitumor effect of conventional chemotherapy drugs, and is used in combination chemotherapy regimens for the treatment of other advanced tumors, such as colorectal, breast, lung, and renal cell cancer.

Bevacizumab is effective for the treatment 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 with this drug is the risk of bowel perforations during treatment. Patients with preexisting tumor involvement of the gastrointestinal tract (eg, bowel obstruction or bowel wall thickening) appear to be at greatest risk for this complication. However, the overall risk is estimated to be 7 percent or less.

Surgery — In some cases, surgery may also be beneficial for women with recurrent ovarian cancer, particularly if the tissue can be easily removed and the woman 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.

END OF LIFE CARE

In some women with ovarian cancer, the disease cannot be cured. Deciding when to stop treating the cancer can be difficult, and should involve the patient, family, friends, and the healthcare team.

Ending cancer treatment does not mean ending care for the patient. Hospice care is frequently recommended when a person is unlikely to live longer than six months. Hospice care involves treatment of all aspects of a patient and family's needs, including the physical (eg, pain relief), psychological, social, and spiritual aspects of suffering. This care may be given at home or in a nursing home or hospice facility, and usually involves multiple care providers, including a physician, registered nurse, nursing aide, a chaplain or religious leader, a social worker, and volunteers.

These providers work together to meet the patient and family's needs and significantly reduce their suffering. For more information about hospice, see www.hospicenet.org. (See "Hospice: Philosophy of care and appropriate utilization".)

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/

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 people 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.uptodate.com/patients). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

Some of the most pertinent include:

Patient Level Information:
Patient information: Ovarian cancer diagnosis and staging

Professional Level Information:
Adenocarcinoma of unknown primary site
Adjuvant therapy of early stage ovarian cancer
Differential diagnosis of the adnexal mass
Epithelial ovarian cancer: Clinical manifestations, diagnostic evaluation, staging, and histopathology
Epithelial ovarian cancer: Initial surgical management
Epithelial ovarian cancer: Pathogenesis, epidemiology, and risk factors
Epithelial ovarian cancer: Second look surgery
First-line chemotherapy for epithelial ovarian cancer
Genetic counseling and psychosocial issues in women with an inherited predisposition to breast and ovarian cancer
Genetic testing for breast and ovarian cancer
Management of intraperitoneal chemotherapy for treatment of ovarian cancer
Management of ovarian cancer in pregnant women
Medical treatment for relapsed epithelial ovarian cancer
Options for women with a genetic predisposition to breast and ovarian cancer
Ovarian germ cell tumors: Pathology, clinical manifestations, and diagnosis
Ovarian tumors of low malignant potential
Overview of genetics in breast and ovarian cancer
Risk reducing salpingo-oophorectomy in women at high risk of epithelial ovarian cancer
Screening for ovarian cancer
Surgery for recurrent epithelial ovarian cancer
Hospice: Philosophy of care and appropriate utilization

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.

• American Society of Clinical Oncology

       (www.cancer.net/portal/site/patient)

• The Women's Cancer Network

      (www.wcn.org)

• National Comprehensive Cancer Network

      (www.nccn.com)

• 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)

Patient Support — There are a number of online forums where patients can find information and support from other people with similar conditions.

• About.com Cancer Forum

      (http://cancer.about.com/forum)

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