New Methods of Diagnosis and Treatment May Offer Longer Survival in Ovarian Cancer Cancer Patients

WASHINGTON—New diagnostic tests and effective second-line chemotherapeutic agents may transform ovarian cancer from a certain killer into a chronic disease capable of being managed with medications that are easy to administer, provide good quality of life, and reliably quash recurrences of disease, said Patricia Goldman and Agustin Garcia, MD.

Ms. Goldman, president of the Ovarian Cancer National Alliance, and Dr. Garcia, a medical oncologist at the Kenneth Norris, Jr., Comprehensive Cancer Center, University of Southern California, Los Angeles, spoke during a telephone briefing preceding the annual conference of the Ovarian Cancer National Alliance.

 “Because of the development of tests that catch ovarian cancer earlier and new drugs for treating recurrences, women with ovarian cancer will be surviving beyond the time that was anticipated, and they will be able to lead full and active lives,” Ms. Goldman said.

Dr. Garcia added, “There are many new drugs that are being developed as pills; so in the future a woman may not even have to go to her doctor’s office or into the hospital for chemotherapy to treat disease recurrences. She may be able to pick up a prescription for two or three chemotherapeutic drugs, take some pills once a day, and that’s it.”

Standard chemotherapy for ovarian cancer, which involves paclitaxel (Taxol) and cisplatin (Platinol) or carboplatin (Paraplatin), can shrink tumors in about 80% of women. The life expectancy following treatment, nevertheless, is only about 3 years, because the disease most commonly is diagnosed at an advanced stage.

Ovarian tumors, particularly those that arise between the vagina and rectum, frequently escape detection with routine pelvic or rectal examination. Blood testing for CA 125 signals the presence of ovarian cancer in as many as 80% of women with stage III or IV disease, but only about 50% of women with stage I disease.

Two promising new diagnostic tests are being evaluated in an ongoing multicenter clinical trial that will enroll 5,000 women at high risk for ovarian cancer and 1,000 women with newly diagnosed disease.

The first is a blood test that screens for the presence of lysophospholipic acid (LPA), a recently discovered marker for ovarian cancer that may be related to the process of angiogenesis in malignant tumors. An initial clinical trial conducted by the Cleveland Clinic involved 48 women with ovarian cancer and approximately 100 controls (healthy women or women with other kinds of tumors). The results indicated that LPA might detect early ovarian cancer, Dr. Garcia said.

“LPA appears to be elevated in women with early ovarian cancer, so the hope is that LPA will be like PSA for prostate cancer in men. It will be elevated in women with an early form of the disease that can be cured with current therapy in 90% of cases,” he said.

The second diagnostic strategy involves “Pap smear” sampling of the ovaries to obtain cells for pathologic analysis. This is done by ultrasound-guided, needle-directed brushing of the surface of the ovary. If the “Pap smear” for the ovaries proves to be able to detect ovarian tumors as well as its counterpart detects cervical cancer, it might be done as a screening measure in every woman every 4 or 5 years, Dr. Garcia suggested.

The Pap smear strategy is being assessed in a study headed by David A. Fishman, MD, of the Robert H. Lurie Cancer Center, Northwestern University. Dr. Fishman is also involved in the development of LPA, in collaboration with Atairgin Technologies, Irvine, Ca.

New Chemotherapies

Newer chemotherapeutic drugs, such as topotecan (Hycamtin) and liposomal doxorubicin (Doxil), have been effective in the treatment of women after the first recurrence of ovarian cancer. In a European trial conducted about 5 years ago, topotecan was as effective as paclitaxel in treating women whose cancer recurred after a course of platinum-based therapy, he said.

Liposomal doxorubicin elicited one complete and eight partial clinical responses in 35 women who failed to respond to platinum and paclitaxel. Seven of the responses were durable; they were confirmed in two consecutive CT scans, he said.

Liposomal doxorubicin also produced a median disease-free survival of 5.7 months, and an overall median survival of 11 months with minimal side effects (J Clin Oncol 15:987-993, 1997).

A trial comparing the liposomal form of doxorubicin and topotecan indicated that the two drugs had nearly identical efficacy, although liposomal doxorubicin produced fewer serious side effects, Dr. Garcia said.

Some of the chemotherapeutic drugs that are being developed for the treatment of ovarian cancer, such as liposomal doxorubicin, have fewer side effects than paclitaxel and the platinums. Because liposomal doxorubicin is encased in microscopic packets of fat, the drug does not exert its effect until it passes into malignant tumors from the blood vessels that feed them. As a result, the liposomal form of doxorubicin causes little or no hair loss, nausea, or vomiting and only slight myelosuppression.

He noted that these newer anticancer drugs will not immediately replace conventional platinum-based therapy for ovarian cancer. “It will take some time before we can disregard platinum because platinum is a very effective drug,” he said. “So in the next few years, we will be adding new drugs to the treatment of ovarian cancer. We may add gemcitabine [Gemzar], which has very few side effects, to current paclitaxel and platinum regimens.”

Newer treatment regimens may be given sequentially, he said. “A patient may receive four cycles of topotecan and cisplatin, then four cycles of paclitaxel and carboplatin. So the patient will get multiple drugs as initial therapy but with manageable side effects,” he said.

An international clinical study will be assessing whether some of today’s second-line chemotherapeutic drugs can move to the front lines of ovarian cancer treatment, Dr. Garcia said. The study will be randomizing between 5,000 and 6,000 women to several treatment arms: conventional carboplatin/paclitaxel vs gemcitabine; carboplatin/paclitaxel vs liposomal doxorubicin; four cycles of carboplatin/topotecan followed by four cycles of carboplatin/paclitaxel; four cycles of carboplatin/gemcitabine followed by four cycles of carboplatin/paclitaxel.

Other Treatment Approaches

Ovarian cancer also may be amenable to other treatment approaches, such as gene therapy and antiangiogenesis drugs. Gene therapy for the treatment of some malignancies has been hampered because the immune system destroys intravenously administered gene vectors.

“Ovarian cancer tends to be limited to the abdominal cavity. It may respond to gene therapy that is administered directly to the abdominal cavity through a catheter because the gene therapy would not need to get into the bloodstream to arrive at a tumor,” Dr. Garcia pointed out.

Antiangiogenesis drugs may prevent further growth of tumors in women who still have ovarian cancer after surgery to decrease tumor volume and chemotherapy. “Antiangiogenesis drugs might not destroy ovarian cancer or completely cure a patient, but they could be one of the ways of making ovarian cancer a chronic disease,” Dr. Garcia said. For example, in diseases such as hypertension, patients take a nontoxic medication to prevent spikes of high blood pressure. “In the future, antiangiogenesis drugs may be given to women who are in remission from ovarian cancer to prevent the cancer from coming back,” he said.

At present, women who have achieved complete remission of ovarian cancer are being randomized to receive either gene therapy or no treatment in phase III clinical trials. Antiangiogenesis drugs are currently in phase I/II trials of ovarian cancer, and some will enter phase III trials in the near future, Dr. Garcia said.