By Monica Zangwill, MD

At first glance you wouldn’t think Tammy Jolly, a 36-year-old from North Carolina, and Nicole Price, a 62-year-old from Billings, Montana, would have much in common. But both have survived cervical cancer, a potentially deadly cancer caused by a common virus. Jolly, only 28 at diagnosis, was 19 years younger than the median age of women with cervical cancer. Price, diagnosed at 56, was nine years over the median age. But both survived the cancer that attacks, as Price says, “one of the most intimate parts of a woman’s body.”

For many, cervical cancer is not on the radar screen like other conditions, such as breast or skin cancer. But the cervix, which resides at the back of the vagina and forms the opening to the uterus, is actually a remarkable and important organ.

The cervix acts like the opening to a drawstring purse. During pregnancy, it stays closed, keeping the growing baby safe inside the womb. During childbirth, it opens and stretches from about the size of a thumb to an opening large enough for the newborn baby to slide through.

Cancer of the cervix occurs when the normal cells of this organ become malignant. Like other cancers, the malignant cells of the cervix can grow, form a tumor and spread throughout the body. Fortunately, cervical cancer is much less common in the United States than it used to be. In fact, cervical cancer mortality has decreased by more than 70 percent over the past 50 years in the United States largely because of early detection with the widespread use of a now common test called the Pap test, or Pap smear, named for George Papanicolaou, MD, who invented the technique in 1928.

Because of the Pap test, which can detect precursor changes in the cervix before cancer appears, only about 10,000 new cases of cervical cancer are diagnosed in American woman each year. Worldwide, however, a half million women still get cervical cancer, particularly in countries without routine screening with the Pap test.

The Pap Test

In a Pap test, a physician gently scrapes the cervix with a brush or swab during a pelvic examination. Laboratory specialists classify any abnormal change that is found by the level of potential danger of becoming cervical cancer.

Infection or inflammation, which can cause changes, may require follow-up Pap tests. Other abnormal changes may require a specialized examination of the cervix called colposcopy, during which a physician views the cervix with a magnifying instrument, taking small biopsies of any suspicious-looking areas.

In 1996, the Food and Drug Administration (FDA) approved a liquid-based test called ThinPrep® Pap test. As opposed to smearing the cells on a slide, ThinPrep involves rinsing the cells into a vial of special liquid. The test is becoming popular because it may pick up more abnormal cells than the traditional slide-based Pap test. Cells can be obscured by blood and mucus with a conventional Pap test, whereas ThinPrep minimizes cell overlap, blood and mucus.

HPV and Cervical Cancer

Doctors now know a virus called human papillomavirus (HPV), transmitted by sexual contact, causes more than 99 percent of cervical cancer cases. Indeed, HPV is so common that 75 percent of sexually active women have been exposed to it at some point.

There are as many as 200 types of HPV, but only 80 have been sequenced to date. And despite such a large number of types, only certain ones are linked to cervical cancer. Specifically, HPV-16 accounts for half of cervical cancer cases, HPV-18 accounts for as many as 12 percent, and HPV-31 and HPV-45 cause about 5 percent of cases.

Fortunately, most women who get HPV, even the types that cause cancer, get over the infection, says Bradley Monk, MD, associate professor at the University of California Irvine Medical Center in Orange. The body can fight the infection and the virus runs its course. In fact, Dr. Monk says, “The vast majority of women with HPV never get cancer.”

Risk factors that may increase the chance of getting cervical cancer, however, include a history of more than four sexual partners, a weakened immune system and smoking, which increases the risk of precursor changes seen on abnormal Pap tests and the risk of developing cervical cancer.

The FDA approved a screening test for HPV in April 2003 for women 30 and older that combines a Pap test with a DNA analysis looking for the subtypes of HPV that may cause cervical cancer.

Many women under 30 will have HPV, but most of them will get over the infection and will not get cancer. The DNA screening, intended to find the persistent and potentially more harmful HPV viruses, has been found to have a 10 to 20 percent greater sensitivity than a single Pap test and has been added to cervical cancer screening guidelines as an adjunct to the Pap test.

An HPV Vaccine

Since we know HPV causes cervical cancer, a vaccine may prevent it. This knowledge has led investigators to work on developing an effective vaccine. “And the data are very good, very compelling,” says Ralph Richart, MD, professor at Columbia University Medical School in New York, who says a vaccine to HPV in the future looks very promising.

Recently a study showed encouraging results of a test vaccine. In the study, which followed 2,391 young women (aged 16 to 23), half the subjects were randomly assigned to get a new vaccine against HPV-16, while the other half got placebo shots. The vaccine was made from the outer coating of the virus and did not contain any DNA that might initiate cancerous tumors.

The investigators followed the women for four years and periodically evaluated them with Pap tests, colposcopy and HPV tests. At the trial’s end, only seven of the women who got the vaccine got HPV-16, while 111 of the women in the placebo group did. Of the HPV-infected women in the placebo group, 12 had abnormal changes on their Pap tests compared to none of the seven HPV-infected women in the vaccine group. These results showed the vaccine was almost 100 percent effective in preventing HPV-16–related cervical precancers. Studies are currently under way testing vaccines that work against other cancer-causing types of HPV, including HPV-6, -11 and -18.

Merck & Co., Inc., one of the companies developing an HPV vaccine, is currently conducting a phase III trial of a multivalent vaccine that targets the four most common HPV types that infect women—16, 18, 6 and 11. Kelley Dougherty, director of public affairs at Merck, says the HPV-16 vaccine will not continue into development in order to make way for the multivalent.

“We are filing for licensure for the multivalent in the second half of 2005,” she says. “Ideally, the vaccine would be administered when people are most susceptible, which would be prior to sexual debut. Early adolescence would be best case, but these details are all yet to be determined.”

Other vaccines in development include Cervarix and ZYC101a.

Trends in Treating Cervical Cancer

Jolly, who got regular Pap tests in her early 20s, took antibiotics several times when the results were abnormal. But in 1996 she saw a gynecologic specialist for a biopsy after her Pap test was again abnormal. When the biopsy results showed cancer, Jolly was shocked. “I thought it was going to be certain death,” she says. But because the cancer was confined to her cervix, she only needed surgery.

Surgical therapy alone is usually all that’s necessary to treat the earliest stages of cervical cancer (see sidebar). Surgeons use a procedure called conization to remove cancer cells from women who have stage 0 cervical cancer, also called carcinoma in situ or cervical dysplasia, which occurs when cancer cells are found only on the superficial layers of the cervix.

During conization the gynecologic surgeon cuts out a small cone-shaped piece of the cervix containing the abnormal cells with a laser, a surgical knife or a LEEP (loop electrosurgical excision procedure), which uses a thin wire heated by electricity to remove the malignant cells.

Doctors treat other early-stage cervical cancers like 1A, 1B and 2A (when the cancer is found only in the cervix) with a hysterectomy. Very small cancers can be removed by a “simple” hysterectomy, which involves only removing the uterus and cervix. Larger cancers may require a “radical” hysterectomy to remove the uterus and cervix, the upper part of the vagina and the connective tissues that keep the uterus in place. Five-year survival rates for these early-stage cancers range from 70 to 100 percent. Jolly underwent a radical hysterectomy in 1996 and has not had a recurrence of her disease.

Radiation therapy, also an effective treatment option for some stage 1 and 2A cervical cancers, involves external beam therapy to the pelvis or brachytherapy, where a radioactive source is placed inside the vagina.

“Brachytherapy allows you to give intense doses of radiation to just small areas in the pelvis,” says J. Tate Thigpen, MD, professor at the University of Mississippi. But, like conventional chemotherapy, radiation therapy can cause damage to abnormal and normal parts of the body, he says. Radiation therapy can expose the ovaries to radiation, causing them to stop functioning. Radiation therapy can also cause vaginal dryness and scarring that may make sexual relations uncomfortable.

Sexuality and Fertility

Issues of sexuality and fertility become essential in deciding how to treat cervical cancer, and women should understand the side effects of various treatments to help them decide. A satisfying sexual life is possible after cervical cancer and open communication with physicians, spouses or partners can facilitate this goal.

A hysterectomy with removal of the ovaries may result in menopausal symptoms such as hot flashes, dry skin, dry vagina and lowered libido. In addition, radiation to the pelvic area can cause the vagina to become narrower.
Debra Thaler-DeMers, RN, OCN, an oncology nurse at Stanford University Hospital and Clinics, addresses issues of cancer and sexuality in workshops around the country. She has worked with patients about sexuality issues for 13 years and says women want to find someone willing to address the issue of sexuality with them.

“There is a tremendous amount of relief that someone is willing to talk to them,” she says. “They have no idea there are ways to address their issues. We talk about sexual aids, lubricants and other things that are available. I send them to websites such as www.goodvibes.com, where they find books and other educational information as well as sexual aids.”

Thaler-DeMers says one of the biggest issues after surgery is painful intercourse, which can be discouraging to both partners. It may take time to regain the pleasure of intimacy.

“The surgery means they may have a shortened vagina. It is easily remedied by having the woman on top or from the side so the penis is not against where the cervix was. They also need to use a lot of lubrication.”

For women going through treatment, loss of libido is an issue because of hormone changes and being tired and anemic, Thaler-DeMers says. For this issue, she tells patients and their partners to focus less on the sexual act and more on building intimacy and communication. “Do things together. Take a bubble bath. Talk about feelings. Intimacy isn’t just sex.”

Regarding fertility, women with stage 1 disease who want to get pregnant in the future have the option of having a conization that removes only the cancerous tumor and not the whole cervix.

Fertility issues can be considered, says Dr. Monk, even for women with slightly larger tumors. A new surgical procedure, called radical trachelectomy, removes only the cervix and leaves the uterus, thus providing hope for women with slightly larger tumors who want to get pregnant.

Concepts in Chemotherapy

Price had not undergone a Pap test in about eight years when she saw a doctor for a routine physical for a new job. Although she was menopausal, she had noticed occasional vaginal bleeding—the most common symptom of invasive cervical cancer. Early cervical cancer and precursor changes of the cervix seen on Pap tests, however, may not cause any symptoms.

In February 1998, Price was diagnosed with cervical cancer and underwent surgery shortly after diagnosis. “But in surgery,” she says, “I had a positive lymph node that was outside the cervix.” Price’s cancer had spread to nodes in her groin.

Recommended treatment for larger tumors and cancer that has spread outside the cervix includes radiation and chemotherapy. In 1999, five large trials showed that combining chemotherapy with radiation for women with cervical cancer resulted in longer survival time than treating them with radiation alone. Combining radiation treatment and chemotherapy is the current standard therapy for women with stage 2B to stage 4 disease or any woman with cervical cancer requiring radiation for treatment, says Dr. Monk.

“The chemotherapy given with radiation is cisplatin,” says Dr. Monk. “It’s given weekly during the radiation.” Platinol® (cisplatin) is a platinum-based drug that kills malignant cells by interfering with the cancer cell’s DNA, preventing the cells from multiplying. Common side effects of cisplatin include nausea, vomiting and a metallic taste in the mouth.

Recently, several clinical studies have looked at combining two chemotherapy drugs as treatment for women with advanced or recurrent cervical cancer. “Three randomized trials suggest an advantage for three different two-drug regimens as opposed to just a single-drug regimen,” says Dr. Thigpen. The two-drug combinations, also called “doublets” that were tested against cisplatin alone were: cisplatin and ifosfamide, cisplatin and Taxol® (paclitaxel) and cisplatin and Hycamtin® (topotecan).

A recent phase III study reported in the Journal of Clinical Oncology tested cisplatin with and without Taxol and found the combination regimen was superior to cisplatin alone, resulting in a higher response rate and longer progression-free survival.

The combination of Hycamtin and cisplatin may be even more effective. Hycamtin kills cancer cells by causing breaks in the cells’ DNA. In February 2004, a clinical study reported encouraging news of a comparison of cisplatin with or without Hycamtin in women with advanced cervical cancer or whose cervical cancer came back after previous treatment. Women who took the combination treatment survived longer and reported no difference in their quality of life as compared to women who took cisplatin alone.

Dr. Thigpen and his colleagues in the Gynecologic Oncology Group are planning to run a randomized trial comparing several doublet chemotherapies for the treatment of cervical cancer. “So we’ll find out which doublet regimen is the best of the group,” he says. Other chemotherapy drugs that may be used to treat cervical cancer include Gemzar® (gemcitabine), Navelbine® (vinorelbine) and Camptosar® (irinotecan). These are usually given for late-stage or recurrent cervical cancer.

Investigators are currently attacking cervical cancer from all sides. From early detection with Pap test to preventing it with vaccines to treating it with new combination chemotherapy regimens, modern medicine may conquer cervical cancer in the future.

Jolly and Price now have remarkably similar aims for their futures: helping other women successfully fight cancer. Jolly’s advice echoes Price’s goals and the work of researchers making inroads to beat cervical cancer. “Keep an open mind and keep positive,” says Jolly.