Laurie Barclay, MD, Sept., 2004

Ovarian cancer originates in tissue exclusive to the ovary, including surface epithelial cells, germ cells, and the sex cord-stromal cells. Most epithelial ovarian tumors are benign, including serous adenomas, mucinous adenomas, and Brenner tumors. Malignant epithelial ovarian carcinomas comprise 85%-90% of all ovarian cancer.

Ovarian cancer accounts for 4% of all female cancers, making it the fifth most common cancer among women, except for non-melanoma skin cancers, and the fourth ranked cause of cancer deaths. Although the incidence of ovarian cancer has decreased since 1991, there will be about 25,580 new cases of ovarian cancer and about 16,090 deaths from ovarian cancer in the U.S. during 2004, according to the American Cancer Society. Lifetime risk of getting ovarian cancer is 1.7%, and lifetime risk of dying from ovarian cancer is 1.0%. These risks are higher in white women than in African American women.

The AJCC/TNM system stages ovarian cancer based on the extent of the primary Tumor (T), the absence or presence of metastasis to nearby lymph Nodes (N), and the absence or presence of distant Metastasis (M). Higher stages represent more widespread disease with worse survival. Cytologic grade ranges from 1 (well differentiated) to 3 (poorly differentiated).

Overall survival in ovarian cancer is about 78% at one year and more than 50% at five years after diagnosis. Five-year survival increases to 95% if ovarian cancer is diagnosed and treated while it is still contained within the ovary (Stage I), but only 29% of all ovarian cancers are found at this early stage. Five-year survival for stage III (pelvic spread) and stage IV (widely metastatic) ovarian cancer is only 15%-20%.

Early symptoms are nonspecific, and may include abdominal swelling, unusual vaginal bleeding, pelvic pressure, back or leg pain, fatigue, dyspareunia, and gastrointestinal symptoms including gas, bloating, poor appetite, constipation, diarrhea, indigestion; and abdominal or pelvic pain.

Regular pelvic examinations may improve the rate of early detection, and women with a very strong family history may be screened with transvaginal sonography. Blood levels of CA-125 (OC-125) are higher in many women with ovarian cancer and may facilitate diagnosis. However, screening tests have not lowered mortality, and they are therefore not recommended for ovarian cancer screening of women not known to be at high risk.

Imaging studies including computed tomography, magnetic resonance imaging, and ultrasound can identify a pelvic mass, but biopsy or ascitic fluid cytology is needed to diagnose cancer. Depending on the extent of disease, biopsy may be obtained via laparoscopy or laparotomy.

The specific cause(s) of ovarian cancer is unknown, but the most significant risk factor is a personal or family history of breast and/or ovarian cancer, and/or BRCA1 and BRCA2 mutations. Other factors which may increase risk include increasing age, high fat diet, nulliparity, infertility or delayed childbirth, using infertility drugs but not becoming pregnant, early age at menarche or late age at menopause, use of talcum powder on the genital area, hereditary nonpolyposis colorectal cancer or syndrome, Caucasian race, and Jewish ancestry. Factors associated with lower risk of ovarian cancer are use of birth control pills, multiparity, breast feeding, tubal ligation, and ovariectomy.

Treatment for ovarian cancer includes surgery, chemotherapy, and radiation therapy. In the U.S., primary treatment usually consists of surgery followed by chemotherapy with a platinum agent such as Carboplatin, and a taxane, typically Taxol. Approximately 70-80% of women achieve clinical remission with this regimen, but ovarian cancer often recurs and is refractory to treatment. Other available chemotherapeutic agents include Topotecan, Doxil, Altretamine (Hexalen), Etoposide (VP-16), Gemcitabine (Gemzar), Vinorelbine (Navelbine), and Capecitabine (Xeloda).

Hormonal therapy includes the anti-estrogen agent Tamoxifen, and Lupron which may have similar effects. Other newer anti-estrogens such as Arimidex and Faslodex have not yet been tested in ovarian cancer.

CenterWatch has identified 21 investigational drugs in various stages of development for ovarian cancer. These include immunotherapeutic agents or vaccines, targeted products evolved from molecular biology, and novel formulations of currently available chemotherapeutics.

OvaRex (oregovamab), in Phase III development by AltaRex/United Therapeutics, is a murine monoclonal antibody binding to specific tumor-associated antigen (CA 125). Clinical trials suggest that OvaRex can induce robust immune responses during quiet periods of the disease, after patients have successfully completed front- line therapy, when there are no approved treatment options. OvaRex has received Orphan Drug Designation and Fast Track status by the U.S. Food and Drug Administration (FDA) for this "watchful waiting" period. It may also be helpful for recurrent disease when given with salvage chemotherapy.

Immune responses to OvaRex include consistent humoral and cytolytic T cell responses, which are associated with higher levels of CA 125, increased time to relapse, and/or prolonged survival in selected groups of patients. The safety profile of OvaRex has been benign in all trials, with no decrease in quality of life compared with placebo. Administration is four to five times yearly as a 20- minute, low-dose (2 mg) IV infusion.

In January 2003, Unither Pharmaceuticals of United Therapeutics began two double-blind phase III trials, IMPACT I & II (IMmunotherapy Pivotal ovArian Cancer Trials), each enrolling 177 patients with stage III/IV ovarian cancer in the "watchful waiting" period, randomized 2:1 active versus placebo. Primary outcome is time to relapse, with secondary outcomes of quality of life, immune response, safety, and survival.

Actimmune, or interferon gamma-1b, is an immune system stimulant in Phase III development by InterMune. This form of interferon is currently marketed in the U.S. for chronic granulomatous disease and severe, malignant osteopetrosis. Interferon gamma-1b is directly toxic to ovarian cancer cells, while enhancing the removal of tumor cells through normal immune mechanisms. In a European trial of 148 women with ovarian cancer, adding interferon gamma-1b to chemotherapy increased the time to disease progression from a median of 17 months to 48 months. An ongoing Phase III clinical trial is testing Actimmune combined with carboplatin and paclitaxel as first-line treatment of ovarian cancer after surgical resection.

Telik is conducting Phase III testing of Telcyta (TLK286), a small molecule targeting tumors that over-express glutathione S-transferase P1-1 (GST P1-1), an enzyme correlated with resistance to commonly used chemotherapeutic agents. When activated by GST P1-1, Telcyta initiates intracellular apoptosis, or programmed cell death. In clinical trials in ovarian, non-small cell lung, breast and colorectal cancer, Telcyta was well- tolerated and produced tumor responses and enhanced survival. The multinational randomized Phase III ASSIST-1 (ASsessment of Survival in Solid Tumors-1) trial, is testing survival with Telcyta, compared with control treatments, in patients with ovarian cancer progressing after platinum-based chemotherapy and one-second line treatment.

Cell Therapeutics is in Phase III development of Xyotax (CT-2103; PG-TXL), or paclitaxel (Taxol) linked to a proprietary biodegradable polyglutamate polymer. The rationale for this novel formulation is to reduce toxicity and improve quality of life by selectively delivering higher and potentially more effective levels of paclitaxel to the tumor. Blood vessels in tumor tissue, but not those in normal tissue, are porous to polyglutamate, allowing Xyotax to be preferentially trapped in the tumor blood vessels. Compared with paclitaxel, lower toxicity, higher efficacy, greater tumor delivery, and twice the maximum tolerated dose for Xyotax is supported in animal models. Because Xyotax is engulfed by tumor cells instead of passively diffusing into them, it bypasses a common mechanism of paclitaxel resistance associated with the multi-drug resistance cell membrane pump.

On July 7, The Gynecologic Oncology Group (GOG) submitted an Investigational New Drug application with the FDA to examine the ability of Xyotax to maintain remission and prolong survival in ovarian cancer. The investigators hope to enroll approximately 1,550 patients with ovarian cancer who have achieved a complete remission following front- line chemotherapy over 18 to 24 months. This trial will compare progression free survival (PFS), overall survival (OS), safety, and quality of life for Xyotax (175 mg/m2), administered over 10 minutes once monthly for 12 months; no maintenance therapy; or paclitaxel (175mg/m2).

Compared with standard paclitaxel, Xyotax appears to be superior at enhancing the effectiveness of chemotherapy and radiation without sensitizing normal tissue, including skin, hair follicles, and the gastrointestinal tract, to radiation.

A similar product designed to reduce toxicity and drug resistance and improve bioavailability of a standard chemotherapeutic is Aroplatin, in Phase II development by Antigenics. This liposomal formulation of a third- generation platinum product is similar to oxaliplatin, which was recently approved for colorectal cancer. In laboratory studies, Aroplatin demonstrates considerable antitumor activity via a mechanism different from current platinum-based chemotherapeutics.

Karenitecin BNP1350 (Highly Lipophilic Camptothecin) is in Phase II development by BioNumerik Pharmaceuticals. Although camptothecins have broad anticancer activity, their toxicity profile limits their use. Karenitecins, which contain silicon, are designed to lower toxicity and drug resistance, and have demonstrated very high potency and broad activity in preclinical studies against human ovarian cancer.

Genaera is carrying out Phase II testing of squalamine (MSI-1246), a systemically administered anti-angiogenic drug. This aminosterol compound isolated from the dogfish shark inhibits salt and acid regulating pumps on endothelial cells. It has multiple mechanisms of action, including blockade of vascular endothelial growth factor (VEGF) and other angiogenic growth factors, cytoskeleton and integrin expression.

Omnitarg (Pertuzumab) is a recombinant humanized monoclonal antibody in Phase II development by Roche. Although 0mnitarg is in some ways similar to Herceptin, it targets a different extracellular region of the HER-2 tyrosine kinase receptor. Omnitarg is the first in the new class of HER dimerization inhibitors, which block the ability of the HER2 receptor to partner with other HER receptor family members (HER1/EGFR, HER3, and HER4), thereby inhibiting cancer cell signaling and ultimately causing cancer cell growth inhibition and death.

Phenoxodiol, in Phase II development by Marshall Edwards (Novogen Limited) is a multiple signal transduction regulator (MSTR) targeting sphingosine kinase. It was derived from genistein, a naturally occurring plant isoflavone with modest anti-cancer activity, but it was altered to enhance the antineoplastic effect through apoptosis. By binding to the tNOX (NADH oxidase) protein receptor, phenoxodiol stops production of anti-apoptotic proteins and activates proteolytic caspases which digest the cancer cell. The intravenous formulation of phenoxodiol is being tested in ovarian cancer, where it may be useful as monotherapy or work synergistically with chemotherapeutic agents such as cisplatin, carboplatin, taxanes and gemcitabine.

MGI Pharma (MGI-114) is in Phase II testing of Irofulven, an acylfulvene which binds to DNA and protein to inhibit replication and cell division. It has activity against a broad range of multi-drug resistant tumor cell lines and DNA-repair deficient cell lines, and clinical trials suggest activity against refractory tumors, as well as synergism with other agents. Dose-escalation trials are determining the maximum tolerated dose for irofulven when combined with approved chemotherapeutic agents such as gemcitabine, docetaxel, cisplatin, and capecitabine. Toxicity is similar to that of available agents and includes bone marrow suppression, nausea, vomiting, fatigue, and visual disturbances.

Orathecin (rubitecan, RF-2000), in Phase II development by SuperGen, is an oral inhibitor of the topoisomerase I enzyme, which interferes with cell replication by preventing DNA from unwinding. Adverse effects include mild-to-moderate hematological toxicities, low-grade cystitis, and some gastrointestinal symptoms.

A unique immunological approach to ovarian cancer is ACA 125, an anti-idiotypic antibody imitating the natural antigen CA 125. CellControl Biomedical Laboratories has completed Phase I/II testing of this agent, which enables the immune system to recognize CA-125 positive cancer cells as foreign and to attack and destroy them.

Molecular biology targeting specific proteins, immunologic enhancers including directed antibodies, and novel formulations for enhanced bioavailability of standard chemotherapeutic agents provide new weapons in the therapeutic arsenal against ovarian cancer. This disease poses unique challenges in that it typically is discovered in more advanced stages, and patients may initially respond to therapy only to relapse later. New, effective agents in the pipeline targeting this "watchful waiting" period should therefore prove to be particularly useful in enhancing survival.