Patient information: First-line medical treatment of epithelial ovarian cancer (Beyond the Basics)

OVARIAN CANCER OVERVIEW

Ovarian cancer is the ninth most common of all types of cancer and the second most common cancer of the reproductive organs among women in the United States [1]. The average age at diagnosis of ovarian cancer is 63 years-old [2]. The lifetime risk of developing ovarian cancer is approximately 1.4 percent.

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. Separate topic reviews are available that discusses the diagnosis and staging (including initial surgical staging) of ovarian cancer. (See "Patient information: Ovarian cancer diagnosis and staging (Beyond the Basics)".)

DO I NEED CHEMOTHERAPY?

After ovarian cancer is removed with surgery, there is still a risk that cancer cells remain and may return or spread to other parts of the body. Chemotherapy is given after surgery to destroy these cells and improves the chance of curing ovarian cancer and decreases the risk of dying of ovarian cancer. The need for chemotherapy depends on the disease stage, which is determined at the time of surgery. In general, chemotherapy is recommended for all newly diagnosed patients except in the case of selected women with stage IA or IB disease (also called “early stage disease”). For women diagnosed with early stage disease, surgery alone is effective, and no additional therapy is recommended. (See "Patient information: Ovarian cancer diagnosis and staging (Beyond the Basics)", section on 'Staging'.)

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 as affected by chemotherapy. Exceptions to this include rapidly dividing cells such as bone marrow (where the blood cells are produced), hair, and lining of the gastrointestinal tract; thus chemotherapy results in side effects such as low blood counts and hair loss.

What types of chemotherapy are used? — Among the chemotherapy agents most commonly used in the treatment of ovarian cancer are taxanes (paclitaxel or docetaxel) and platinum agents (carboplatin or cisplatin). Studies have demonstrated that platinum and taxane-containing chemotherapy improves the survival of women with ovarian cancer over other types of regimens. As a result, the combination of a platinum-type drug (usually carboplatin) and a taxane (typically paclitaxel) is a standard chemotherapy regimen.

How is chemotherapy administered? — Most chemotherapy drugs is given into the vein (intravenously or IV). However, for women with optimally resected stage III disease, another treatment strategy involves giving a combination of chemotherapy both IV and directly into the abdominal (peritoneal) cavity, called intraperitoneal (IP) chemotherapy (IV/IP treatment).

In general, regardless of the route administered (intravenously or intraperitoneally), 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.

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 and aggressiveness of the tumor (also referred to as the “grade” of the tumor). (See "Patient information: Ovarian cancer diagnosis and staging (Beyond the Basics)", section on 'Staging'.)

Stage I — After surgery, most women with stage IA or IB ovarian cancers (ie, cancers limited to the ovary) do well without chemotherapy, and observation alone is a standard approach. Women with aggressive (grade 2 or 3) stage IA or IB ovarian cancers and all women with stage IC ovarian cancer should receive chemotherapy after surgery using paclitaxel and carboplatin. Treatment usually begins within two to six weeks after surgery. Each cycle of chemotherapy is given over three weeks for a total of six cycles. However, the optimal duration of chemotherapy for women with stage I ovarian cancer remains controversial. 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.

Stage II — All women with stage II disease (ie, outside the ovary but confined to the pelvis) require chemotherapy after surgery. Most oncologists administer six cycles of intravenous paclitaxel plus carboplatin. Some clinicians also use a combination of intraperitoneal and intravenous chemotherapy for women with stage II disease, but there is no evidence that the benefits of IV/IP treatment in women with stage II ovarian cancer is more beneficial than standard administration of IV chemotherapy alone.

Stage III — All women with stage III disease (ie, abdominal involvement) require chemotherapy after surgery. In the United States, the standard course of chemotherapy can be given in different methods:

• Six cycles of paclitaxel plus carboplatin given on day 1 of a 21-day cycle. This treatment approach has been a standard approach for many years. Some studies suggest that adding another drug, bevacizumab (given every three weeks during chemotherapy and then for one year after), to this regimen may postpone relapse. No data to date have shown that adding bevacizumab improves overall survival.
• Six cycles of carboplatin on day 1 with paclitaxel on days 1, 8, and 15 of a 21-day cycle. This “dose-dense” treatment approach is preferred by some clinicians based upon one randomized trial that showed an improvement over time to relapse and overall survival when compared with every 21 day paclitaxel plus carboplatin. However, “dose-dense” chemotherapy is associated with more toxicity than every 21-day administration.
• Six cycles of a combination of intravenous (IV) and intraperitoneal (IP) chemotherapy. In this 21-day schedule, cisplatin is given IP on day 1, paclitaxel on day 1 or day 2 as an IV infusion, and then paclitaxel is given IP on day 8. This IV/IP regimen is preferred by some clinicians based upon several randomized trials that have shown an improvement in time to relapse and overall survival when compared with IV therapy alone. However, IV/IP chemotherapy requires placement of an IP catheter (either during the initial surgery or as a second outpatient surgical procedure) and is associated with significant toxicity, which many patients cannot tolerate.

Stage IV — All women with stage IV disease (ie, commonly involving the lungs or liver) require chemotherapy. Women who present with stage IV ovarian cancer cannot be cured. Instead, the chemotherapy is given to control cancer growth. In this case, carboplatin and paclitaxel are typically administered as long as the chemotherapy is tolerated and a benefit is seen. This may require more than six cycles of chemotherapy.  

What are the side effects of treatment? — Chemotherapy can cause side effects during and after treatment. The type and severity of these side effects depends upon which chemotherapy drugs are used and how they are administered. Side effects that occur during chemotherapy are usually temporary and reversible. The most common side effects are nausea, vomiting, mouth soreness, temporary lowering of the blood counts, and hair loss.

Bevacizumab can cause side effects that are different from those caused by chemotherapy. Common side effects include new or worsening hypertension, nose bleeds, dizziness, headache, and delayed wound healing. Women with ovarian cancer who receive bevacizumab may have a slightly increased risk of bowel perforation during treatment. Patients with preexisting tumor involvement of the gastrointestinal tract (eg, bowel obstruction or bowel wall thickening) or history of inflammatory bowel disease appear to be at greatest risk for this complication. Although initial studies suggested that this was relatively common, subsequent studies suggest that the overall risk is 7 percent or less.

SPECIAL CONSIDERATIONS

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. Initial or neoadjuvant chemotherapy can shrink the tumor and improve a woman's overall medical condition, making her a better candidate for later debulking surgery.

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 the tumor marker 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. Though optimal surveillance strategy is not defined, our approach is similar to the guidelines from the National Comprehensive Cancer Network (NCCN):

• Office visits with pelvic examination every two to four months for two years, then every six months for three years, then annually.
• Periodic blood tests for CA-125 and/or HE4 at the discretion of your physician. A rise in the level of blood tumor markers such as these is often the earliest sign of an ovarian cancer recurrence. However, the benefit of detecting and treating a recurrence based on elevations in tumor makers alone, before there are any signs or symptoms of recurrence, has been questioned. (See 'Signs of recurrence' below.)
• Chest X-ray and chest/abdomen/pelvic CT scan are reserved for patients with any abnormalities on history, exam, or blood test.

Signs of recurrence — Even women with a complete response to initial therapy 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 one of the tumor markers (CA-125 or HE4), symptoms (often abdominal pain or bloating with or without back pain), or clinical signs (bloating or a pelvic mass).

In the past, treatment for recurrent ovarian cancer was sometimes recommended based on rising levels of tumor markers alone, instead of waiting until symptoms developed. However, a large study showed no survival benefit of starting chemotherapy based on a high level of CA-125 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.

DIAGNOSIS OF RECURRENT 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. The choice of chemotherapy agents for second-line treatment depends upon whether and how well, the patient responded to first-line treatment, current symptoms, time elapsed from last treatment, and long term side-effects from previous chemotherapies.

Platinum-sensitive ovarian cancer — If a woman had a complete response, and the response lasted for at least six months, she is considered to have “platinum-sensitive” cancer and re-treatment with platinum-based chemotherapy is usually recommended. Studies show that a repeat response to chemotherapy is possible with platinum-based re-treatment. In fact, if the initial response lasted longer than 24 months, up to one-fourth of patients will have a complete response to re-treatment with platinum. Suitable regimens include carboplatin with either a taxane, gemcitabine, or pegylated liposomal doxorubicin. The addition of bevacizumab to the combination of carboplatin and gemcitabine in particular was associated with an improvement in both response rate and time to progression in a large randomized trial.

Studies in carefully selected patients have also demonstrated a benefit to repeat surgical treatment, particularly if the tissue can be easily removed and the woman has been free of disease recurrence for more than 6 to 12 months. Thus, repeat surgical treatment may be an option.

Platinum-resistant ovarian cancer — If a woman has persistent or non-responsive ovarian cancer despite first-line therapy with paclitaxel and a platinum agent, or if she relapses within six months of completing such therapy, she is considered to have “platinum-resistant” cancer. In this case, treatment with a single chemotherapy agent is recommended as combination chemotherapy has not improved either response rates or survival, but is associated with an increased risk of toxicity. A variety of agents may be considered, including pegylated liposomal doxorubicin, topotecan, docetaxel, oral etoposide, gemcitabine, vinorelbine, ifosfamide, leucovorin-modulated 5-fluorouracil, bevacizumab, and tamoxifen.

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. Patients should strongly consider enrollment on a trial and available studies should be discussed with your physician. Read about clinical trials at:

• www.cancer.gov/clinicaltrials/learning/
• www.cancer.gov/clinicaltrials/
• 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.

This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient information: Ovarian cancer (The Basics)
Patient information: Ovarian cysts (The Basics)
Patient information: Ovarian cancer screening (The Basics)
Patient information: Preserving fertility after cancer treatment in women (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient information: Ovarian cancer diagnosis and staging (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis
Serum biomarkers for evaluation of an adnexal mass for epithelial carcinoma of the ovary, fallopian tube, or peritoneum
Screening for ovarian cancer
Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-resistant disease
Epithelial ovarian cancer: Pathology
First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tubal, and peritoneal cancer
Epithelial ovarian cancer: Initial surgical management
Early detection of epithelial ovarian cancer: Role of symptom recognition
Adjuvant therapy of early stage (stage I and II) epithelial ovarian, fallopian tubal, or peritoneal cancer
Surgery for recurrent epithelial ovarian cancer
Epithelial ovarian cancer: Second look surgery

The following organizations also provide reliable health information:

• 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)