Ovarian Cancer

Description

Medications

Following surgery, patients other than those with early-stage, low-grade disease usually undergo chemotherapy. Unlike surgery and radiation, which treat the malignant tumor and the area surrounding it, drug therapy destroys rapidly dividing cells throughout the body and so is known 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 five years or longer. Physicians are now approaching this disease as a chronic and potentially long-term illness that requires identifying the disease recurrence as soon as possible, administering treatments that are as effective as possible without causing suffering, and 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 agent, 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 agent. 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.

Approximately 70% of women will experience a response to paclitaxel and carboplatin chemotherapy (i.e., a reduction in tumor size). Older women (over 60) may benefit as much as younger ones from this regimen. Of note, a comparison study in 2002 reported that the use of a platinum-based agent alone was as effective as paclitaxel/platinum agent combination and had lower toxicity. More research is needed to confirm these findings or to discover if specific patients will benefit from the combination compared to the single agent. Other drugs that may prove to be useful first line agent are pegylated liposomal doxorubicin, topotecan, and gemcitabine (which are discussed below.)

Chemotherapy Agents Studied for Relapsed or Refractory Cancer. Unfortunately, some ovarian tumors are resistant to platinum drug. 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 agents 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.
• Develop maintenance drugs to prevent or delay relapse.

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

• 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, Myocet, Caelyx in Canada) is a liposome-encapsulated form of doxorubicin that remains in the blood stream longer, tends to spare the bone marrow, and move selectively through the tumor. It is showing promise in clinical trials and also may have fewer toxic effects than standard doxorubicin and other agents 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 agents such as Topotecan, Carboplatin, and Taxol.
• Topoisomerase I inhibitors, including topotecan (Hycamtin) and irinotecan (Campto).
• Nucleoside analogs, including gemcitabine (Gemzar).
• Topoisomerase II alpha inhibitors, including etoposide (Vepesid).
• Alkaloids, including vinorelbine (Navelbine)
• Hormonal agents: tamoxifen (Nolvadex) or anastrozole (Arimidex).
• Other agents. Valspodar and capecitabine (Xeloda) are oral agents 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 four to five hours to complete.
• It is repeated every three weeks for a total of six times. (Each three-week interval is known as a cycle of chemotherapy.)

Such chemotherapy is usually administered intravenously (by vein).

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% reported that they 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 the following:

• 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. In one study, a combination of dexamethasone (a corticosteroid) with ondansetron taken within 24 hours of chemotherapy achieved either a major or complete reduction in nausea and vomiting.
• Diarrhea.
• Temporary hair loss.
• Weight loss.
• Fatigue.
• Depression.

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

• Anemia. Erythropoetin 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 persists longer in the blood than epoetin alfa and so requires fewer injections.
• 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 agents.
• Rarely, secondary cancers such as leukemia.
• Between a quarter and a third of women report problems in concentration, motor function, and memory, which may be long-term. This effect 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; taking 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 its utility in diagnosing relapsed disease.

Investigative Procedures for Increasing Effectiveness

Intraperitoneal Chemotherapy. With this approach chemotherapy can be instilled directly into the abdominal cavity at higher than standard doses. There is no evidence as yet to suggest that it is superior to intravenous therapy. More work is needed.

Hyperthermia. Researchers are investigating hyperthermia, a technique that heats the patients whole body (whole-body hyperthermia) or the abdominal area (called intraperitoneal hyperthermic therapy). Increasing the temperature enhances the body's response to platinum-based agents without increasing their toxicity. Studies are now under way.

Experimental Agents

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

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 the United States for its availability to shrink tumors or stop tumor growth in women with ovarian or fallopian cancer who have failed other forms of chemotherapy. Pre-clinical study results showed that phenoxodiol restored sensitivity in ovarian cancer cells to both taxane drugs and platinum agents. Combo phenoxodiol with gemcitabine had a comparable response.

LH-RH Agonists. Luteinizing hormone-releasing hormones (LH-RH) agonists (also called GnRH agonists) include leuprolide (Lupron), goserelin (Zoladex), and deslorelin. These agents 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. A number of therapies are under investigation that use agents 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 agents 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 Agents. 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 and 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 be beneficial for certain patients who have biologic markers indicating that their cancer cells are sensitive to these agents.

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

Imatinib. Imatinib (Gleevec) is a new agent that blocks an enzyme called tyrosine kinase. It is proving to be beneficial for some leukemia patients and is now being studied in late-phase trials for ovarian cancer.