Medications

Following surgery, patients (other than those with early-stage, low-grade disease) usually have chemotherapy. Unlike surgery and radiation, which treat the cancerous tumor and the area surrounding it, drug therapy destroys rapidly dividing cells throughout the body, so it is as systemic therapy.

Ovarian cancers are very sensitive to chemotherapy and often respond well initially. Unfortunately, in most cases, ovarian cancer recurs. With treatment advances, however, more than half of women now survive 5 years or longer. Doctors are now approaching this disease as a chronic and potentially long-term illness that requires the folloiwng

• Identifying the disease recurrence as soon as possible
• Administering treatments that are as effective as possible without causing suffering
• Partnering with the patient in determining her own best course

Drugs Used in Chemotherapy

Standard Chemotherapy. The standard initial chemotherapy uses a combination of the following:

• A platinum-based drug, such as carboplatin (Paraplatin) or cisplatin (Platinol). At this time carboplatin is preferred over cisplatin in the combination because carboplatin is as effective as cisplatin but is less toxic and can be administered in a more convenient, outpatient regimen.
• A taxane, such as paclitaxel (Taxol) and docetaxel (Taxotere). Currently paclitaxel is the drug most often used as initial therapy in combination with a platinum drug. Docetaxel, however, is less toxic to the nervous system (but has more adverse effects on blood cell production). Taxotere is now commonly substituted for Taxol.

About 70% of women will experience a response (reduction in tumor size) to paclitaxel-carboplatin chemotherapy. Older women (over age 60) may benefit as much as younger ones from this regimen.

Other drugs that may prove to be useful first-line drugs are gemcitabine and pegylated liposomal doxorubicin (which are discussed below). An important 2006 study indicated that topotecan following paclitaxel-carboplatin therapy is not helpful as a first-line treatment for advanced ovarian cancer. Topetcan did not help prolong survival, and it caused many serious side effects, including anemia and infections.

Chemotherapy Drugs Studied for Relapsed or Refractory Cancer. Unfortunately, some ovarian tumors are resistant to platinum drugs. Even in patients who respond, the disease eventually becomes resistant to the first-line drugs, and the cancer returns. Various approaches for increasing responsiveness to these drugs are being investigated. Investigators are studying two approaches for preventing relapse after remission:

• Developing more effective drug combination regimens to increase initial response rates and duration of the response.
• Developing maintenance drugs to prevent or delay relapse.

Once cancer recurs or continues to progress, several second-line chemotherapies are available or under investigation. The following lists some drugs that are being used, usually as single drugs, for relapsed or refractory cancers:

• Nucleoside analogs, including gemcitabine (Gemzar). In 2006, gemcitabine was approved as a treatment for recurrent ovarian cancer. It is used in combination with carboplatin for women with advanced ovarian cancer that has relapsed at least 6 months after initial therapy.
• Paclitaxel or carboplatin alone or in combination. A landmark study published in the July 2003 Journal of Clinical Oncology, found that extended use of paclitaxel significantly delayed disease progression in women with advanced ovarian cancer.
• Pegylated liposomal doxorubicin (Doxil) is a form of doxorubicin that remains in the bloodstream longer, tends to spare the bone marrow, and moves selectively through the tumor. It is showing promise in clinical trials and also may have fewer toxic effects than standard doxorubicin and other drugs used for ovarian cancer. Studies show that Doxil is very well tolerated with a total response rate of about 20 - 30% in patients with recurrent cancer. This compares favorably with other drugs, such as topotecan, carboplatin, and taxol.
• Topoisomerase I inhibitors, including topotecan (Hycamtin) and irinotecan (Campto).
• Topoisomerase II alpha inhibitors, including etoposide (VePesid).
• Alkaloids, including vinorelbine (Navelbine).
• Hormonal drugs: tamoxifen (Nolvadex) or anastrozole (Arimidex).
• Other drugs. Valspodar and capecitabine (Xeloda) are oral drugs that may help improve response to other drugs, although data are preliminary.

Administration of Chemotherapy

In addition to studying individual drugs in different combinations, investigators are looking for the optimal sequence, dosages and timing of administering them. In general, the typical regimen is as follows:

• Paclitaxel and carboplatin are administered in an outpatient clinic within several weeks of the surgery.
• Each treatment takes about 4 -5 hours to complete.
• It is repeated every 3 weeks for a total of six times. (Each 3-week interval is known as a cycle of chemotherapy.)

Such chemotherapy is usually administered intravenously (by vein). However, an important 2006 study in the New England Journal of Medicine found that patients with stage III ovarian cancer who received intraperitoneal chemotherapy had a significant survival advantage compared with patients who received standard intravenous chemotherapy. (Intraperitoneal chemotherapy involves administering the drugs directly into the abdominal cavity.) Patients in the intraperitoneal group did have more severe side effects than those who had intravenous chemotherapy. Researchers are continuing to investigate ways to reduce these side effects. Another 2006 study noted that intraperitoneal chemotherapy requires careful catheter insertion and maintenance, and that doctors need to be well trained to perform this procedure.

Side Effects of Chemotherapy

Side effects occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment. Some may be long-lasting. In a 2002 study of ovarian cancer survivors, 20% had long-term treatment side effects, such as gynecologic and abdominal problems. Even so, most enjoyed a high quality of life that was comparable to other cancer survivors and peers without a history of cancer.

Common side effects include:

• Nausea and vomiting. Drugs known as serotonin antagonists, especially ondansetron (Zofran), can relieve these side effects in nearly all patients given moderate drugs and most patients who take more powerful drugs.
• Diarrhea
• Temporary hair loss
• Weight loss
• Fatigue
• Depression

Serious short- and long-term complications can also occur and may vary depending on the specific drugs used. The following list includes some of these complications and a few of their treatments:

• Anemia. Erythropoietin stimulates red blood cell production and can help reduce or prevent this side effect. It is available as epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). Aranesp stays in the blood longer than epoetin alfa, so fewer injections are needed.
• Increased chance for infection from severe reduction in white blood cells (neutropenia). The addition of a drug called granulocyte colony-stimulating factor (filgrastim and lenograstim) is very helpful in reducing the risk for severe infection in selected patients.
• Liver and kidney damage.
• Abnormal bleeding (thrombocytopenia).
• Allergic reaction, particularly to platinum-based drugs.
• Rarely, secondary cancers such as leukemia.
• Between a quarter and a third of women report problems in concentration, motor function, and memory. These problems may be long-term and may be due to reductions in estrogen levels after treatments.
• Cumulative doses of anthracyclines can damage heart muscles over time and increase the risk for heart failure. An encapsulated form doxorubicin (Myocet, Doxil) may reduce the risk for toxic effects on the heart.
• Taxanes can cause a drop in white blood cells and possible problems in the heart and central nervous system. Allergic reactions can occur. Talking a corticosteroid before taxane administration can help prevent such reactions. Taxane therapy may also cause severe joint and muscle pain in some patients, which is relievable with corticosteroids.

Gauging Success or Detecting Recurrence

Physical Exam and CA-125 Blood Test. During treatment, the effectiveness of the chemotherapy is evaluated primarily with a physical examination and the CA-125 blood test. Falling CA-125 levels indicate effective treatment and persistently elevated levels indicate resistance to the chemotherapy.

Second Look Laparotomy. Second-look laparotomy is sometimes considered after completion of chemotherapy for patients who are participating in clinical trials.

Comparative CT Scans. Another method for evaluating the success of chemotherapy is to compare CT scans of the pelvis and abdomen before and after chemotherapy to check the size of any residual tumors that persisted after the original surgery. CT scanning is not always required, however.

Positron Emission Tomography (PET). At present, PET scans have no proven role in the management of patients with ovarian cancer. More study is needed in order to determine their utility in diagnosing relapsed disease.

Investigational Drugs

Patients with any stage of ovarian cancer are candidates for clinical trials. In addition to testing high-dose or combinations of chemotherapy, drugs with unique actions are being investigated.

HER Dimerization Inihibitors. Pertuzumab (Omnitarg) is the first of a new class of drugs called HER dimerization inhibitors. It is designed to inhibit tumor growth for tumors that express the HER2 receptor protein. Pertuzumab is currently in Phase II trials

Multiple signal transduction regulators (MSTRs). Phenoxodiol is an MSTR that is being developed as a broad-spectrum anti-cancer drug. It is currently being evaluated in Phase II clinical trials, in combination with other drugs such as docetaxel, for its ability to shrink tumors or stop tumor growth in women with ovarian or fallopian cancer who have failed other forms of chemotherapy.

LH-RH Agonists. Luteinizing hormone-releasing hormones (LH-RH) agonists (also called GnRH agonists) include leuprolide (Lupron), goserelin (Zoladex), and deslorelin. These drugs are able to block the release of two major reproductive hormones, and there is some indication that this action may help prevent cell proliferation.

Immunotherapy. Several therapies under investigation use drugs that boost the body's own immune response to specifically attack ovarian cancer cells. To date, they have produced only minor effects. Experimental therapies that are in clinical trials include a vaccinations that use specially designed antibodies (called monoclonal antibodies or MAbs) to boost the immune responses against tumor-associated factors, such as CA125 or HER-2/neu. Vaccines against HERS/neu are also being investigated.

Gene Therapy. Gene therapies generally work in one of two ways:

• One approach involves genes that are used to convert inactive drugs into cancer-fighting drugs.
• The other major approach uses genetic therapies to repair molecular defects that are causing uncontrolled cell proliferation. For example, some investigators are using techniques to deliver a normal p53 gene, which suppresses cancer cell growth, into ovarian cancer cells.

Antiangiogenesis drugs. Angiogenesis, the formation of new blood vessels that feed the growth of a cancerous tumor, is a critical process in the spread of ovarian cancer. Drugs that block this process are under investigation for ovarian cancer. Such drugs include thalidomide, gefinitib (Iressa), and carboxyamido-triazole (CAI).

Aromatase inhibitors. Aromatase inhibitors block aromatase, an enzyme that is a major source of estrogen in many body tissues. The include anastrozole (Arimidex) and letrozole (Femara). A 2002 study suggested they might benefit certain patients who have biologic markers indicating that their cancer cells are sensitive to these drugs.

Retinoids. Laboratory studies have found that retinoids, which are compounds derived from vitamin A, inhibit ovarian cancer cell growth. Certain retinoids, including fenretinide, are being investigated for treating and preventing ovarian cancer.

Epothilones. Epothilones are a new class of anti-cancer drugs that are similar to taxanes (paclitaxel) but are more potent. Currently one of these drugs, called only BMS-247550, is being studied in a late-phase trial for ovarian cancer.