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Researchers Seek to Understand the Mysteries of Uterine Cancer and to Find Better Treatmentsby Sunni Hosemann
Although uterine cancer is the most common gynecologic malignancy in the United States—more common than either cervical or ovarian cancer—fallacies regarding the disease abound. Some women mistakenly believe that their Papanicolaou’s test will screen them for uterine cancer when in fact there is no routine screening test for this disease. Others are unaware that heavier than normal menstrual bleeding and bleeding between periods may be symptoms of uterine cancer. Fortunately, most localized uterine cancers have a high (>90%) cure rate. However, the prognosis is grave for women with metastatic or aggressive forms of uterine cancer. Fewer than 20% of women whose disease has spread into the pelvis will survive five years. “We just don’t have very effective treatments for advanced or recurrent uterine cancers,” said Lois Ramondetta, M.D., an assistant professor in the Department of Gynecologic Oncology at The University of Texas M. D. Anderson Cancer Center. More than 40,000 women in the U.S. will be diagnosed with uterine cancer in 2004. While most women are 60 years or older at diagnosis, 20% to 25% are premenopausal. “For some reason that we don’t yet understand, we are seeing more women with this disease at a younger age, in their 30s and 40s,” noted Anuja Jhingran, M.D., an associate professor in the Division of Radiation Oncology, whose research focuses on gynecologic tumors. “And one of the other mysteries of the disease is that older women [>70 years] have a poorer prognosis than younger women when compared stage-for-stage. This is unlike many other cancers.” To solve the mysteries of uterine cancer and to develop more effective treatments for metastatic and aggressive disease, researchers at M. D. Anderson are investigating new treatment and prevention strategies as well as the disease’s biology. Treatment updates The majority of cancers arising in the uterus are endometrioid adenocarcinomas. These have an excellent prognosis compared to more aggressive types such as uterine sarcomas, papillary serous and clear cell carcinomas, and malignant mixed mullerian tumors. (Serous and clear cell carcinomas—which tend to occur in older women and are often at an advanced stage when found—behave the most aggressively and need to be treated differently than other uterine tumors.) For early-stage endometrial cancers that are considered medically inoperable, radiation therapy is the primary treatment; for all others, total abdominal hysterectomy with bilateral salpingo-oophorectomy and lymph node dissection remains the standard treatment. At M. D. Anderson, some uterine lymph node dissections are performed laparoscopically, with no increased risks and with reduced morbidity. Patients with intermediate- or high-risk uterine tumors may receive adjuvant radiation to the pelvis, depending on the final pathology, to reduce the risk of pelvic or vaginal recurrence. Intensity-modulated radiation therapy, which delivers very focused radiation only to the target area, is a promising new development. “In small studies so far, we have seen much reduced lower bowel toxicity,” said Dr. Jhingran. “This may seem like a small advance, but for women who suffer posttreatment diarrhea, it is a huge improvement in quality of life.” This technique will be part of a large, upcoming Radiation Therapy Oncology Group study. Vaginal cuff radiation is a patient-friendly advance that can be used to treat patients with intermediate-risk disease that has been fully staged or as a boost for patients with high-risk disease that has been treated with external-beam radiation therapy to the pelvis. In this therapy, a tampon-like device called a vaginal dome cylinder is inserted into the vagina where it delivers high-dose radiation. Chemotherapy options with a good chance of cure or palliation are not yet available for patients with uterine cancer. Risk factors for uterine cancer For most women, the lifetime risk of uterine cancer is 3%, but for women with hereditary nonpolyposis colorectal cancer (HNPCC), the lifetime risk jumps to 40%. Obesity is another significant risk factor; the risk of endometrial cancer triples for a woman who is 30 pounds overweight and increases five times for a woman who is 50 pounds overweight. “Of all cancers, endometrial cancer is most strongly linked to obesity,” said Karen Lu, M.D., an assistant professor in the Department of Gynecologic Oncology. “Any obese woman who has irregular periods should have an endometrial biopsy.” Prolonged exposure to unopposed estrogen—either endogenous or exogenous—significantly increases a woman’s risk of uterine cancer. This includes obese women, those treated with hormone replacement therapy consisting of estrogen without progesterone, and women who have had an early menarche (before age 12) or late menopause (after age 52). According to a recent National Surgical Adjuvant Bowel and Breast Project (NSABP) trial, uterine cancer developed in some users of tamoxifen. However, this is not a reason to discontinue its use, said Dr. Ramondetta, because the benefits of preventing recurrent breast cancer outweigh the increased risk of endometrial cancer. In the NSABP trial, all cases of endometrial cancer were low grade and early stage (i.e., curable) and occurred in patients who had used tamoxifen for more than five years. Other risk factors are hypertension, diabetes type 1 and type 2, hypothyroidism, and nulliparity. Women with a family history of uterine cancer or a personal history of breast or colon cancer are considered to be at higher risk than women in the general population. Monitoring and reducing risk Because there is no recommended routine screening test for uterine cancers, all women should be queried by their gynecologists about unusual menstrual bleeding, irregular periods, or spotting, and women at high risk should be advised to report any unusual bleeding. Women who have HNPCC or a family history of uterine cancer should start being monitored between ages 25 and 35 years, with an annual pelvic examination, transvaginal ultrasonography, and endometrial biopsy. No large studies have produced guidelines for reducing or managing the risk of uterine cancer, but both surgical and medical options are available. Prophylactic surgery—a total hysterectomy and salpingo-oophorectomy—is recommended for women with confirmed HNPCC who have completed childbearing or who are in their mid- to late 40s. For others, chemoprevention is an option that may be of interest; oral contraceptives and progestins have been shown to reduce uterine cancer risk. A National Cancer Institute (NCI) trial available at M. D. Anderson and two other sites will compare the effectiveness of contraceptive agents LoOvral and Depo-Provera in preventing uterine cancer. The question of how best to monitor women who are being treated with tamoxifen remains unanswered. “At M. D. Anderson, we do not routinely screen women treated with tamoxifen who are asymptomatic,” said Dr. Ramondetta. “We only recommend endometrial biopsy for those who have vaginal bleeding.” In addition, because of the submucosal edema that can develop in patients taking this medication, many experts recommend that a transvaginal ultrasound measurement of 8 mm—rather than the 5-mm criterion used for other endometrial biopsies—be used to determine whether a patient should undergo biopsy. New research The NCI recently awarded a Specialized Programs of Research Excellence (SPORE) grant—the first ever for uterine cancer—to researchers at M. D. Anderson, who plan to answer some of the many questions about this disease and its treatment. “We will study prevention, novel treatments, and gain a better knowledge of the biology of the disease with this funding,” said Dr. Lu. The group is looking at new hormonal therapies, including mifepristone (RU486), as well as new combinations of radiation therapy and chemotherapy. One crucial area of research that will be investigated is the molecular aspect of this disease. “We know that 75% of uterine cancers have a good prognosis and can be cured by surgery and/or radiation therapy,” said Russell Broaddus, M.D., Ph.D., an assistant professor in the Division of Pathology. But for patients with aggressive variants, the outlook is poor. “We want to know more about aggressive versus nonaggressive types of this disease,” Dr. Broaddus said. He noted that uterine cancer, unlike many other cancers, is not just an oncology problem; lipid metabolism, insulin biochemistry, and hormones also play a crucial role. “We must understand the endocrine and biochemical aspects,” he said. Therefore, oncologists, endocrinologists, internists, obesity specialists, and pharmacologists, among others, will contribute to the uterine cancer studies. In addition to receiving funding from the SPORE grant, researchers from M. D. Anderson’s Uterine Cancer Research Program will also receive proceeds from sales of the cookbook From Home Plate to Your Plate, which was created by the wives of Houston Astros baseball players to benefit uterine cancer research. Thanks to these contributions, researchers may finally have the resources they need to defeat this disease. For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789. Other articles in OncoLog, October 2004 issue:
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