Delivering Chemotherapy to the Liver May Benefit Patients with Metastatic Melanoma

Rising Oropharyngeal Cancer Rates Linked to HPV Infection

A new study provides evidence that human papillomavirus (HPV) infection may be responsible for the rise in incidence of oropharyngeal squamous cell carcinoma (OPSCC), a type of head and neck cancer. The research suggests that if these trends continue, by 2020 HPV-positive OPSCC will likely surpass cervical cancer as the most common HPV-associated cancer in the United States. The findings were published online October 3 in the Journal of Clinical Oncology.

Originally thought to be a single disease, OPSCC is now recognized as two distinct tumor types: HPV-positive and HPV-negative. HPV-negative tumors are associated with tobacco and alcohol use, older age at diagnosis, and a poorer prognosis, whereas HPV-positive cancers have risk factors related to sexual behavior, are diagnosed in younger people, and tend to have better survival rates.

A previous study by the same authors showed that OPSCC diagnoses had been increasing since the early 1970s, even as rates of other oral cancers dropped. “We expected that the oral cancers would decline in incidence,” explained lead author Dr. Anil Chaturvedi of NCI’s Division of Cancer Epidemiology and Genetics, “because cigarette smoking, which is a strong risk factor for these cancers, has declined in the United States. The increasing incidence of oropharyngeal cancers during the same time suggested that there could be another risk factor. We hypothesized that HPV infection could be leading to the rise in oropharyngeal cancer incidence.”

To evaluate the prevalence of HPV in OPSCC tumors over time, the researchers used tissue samples from three registries in the Surveillance, Epidemiology, and End Results Residual Tissue Repository Program. They used several molecular techniques to detect HPV DNA, viral load, and mRNA in 271 OPSCC tumor samples collected between 1984 and 2004.

The prevalence of HPV in tumor samples (as assessed by HPV DNA) surged from 16.3 percent in the second half of the 1980s to 72.7 percent during the early 2000s, the researchers found. “These increases may reflect changes in sexual behavior, including increases in oral sex,” said senior author Dr. Maura Gillison of the Ohio State University in a news release.

The researchers also discovered that the incidence of HPV-positive OPSCC in the population more than doubled between the late 1980s and early 2000s, while that of HPV-negative cancers fell 50 percent.

Patients with HPV-positive OPSCC were more likely than patients with HPV-negative OPSCC to be younger and male, and they had better long-term survival rates (median survival of 131 months, versus 20 months for HPV-negative cancers), especially if they were treated with radiation therapy. But “not everyone with HPV-associated cancers is cured,” said Dr. Arlene Forastiere of the Johns Hopkins University, “and we are seeking to understand the molecular genetics of that [patient] subset.”

These findings are not likely to result in immediate treatment changes for OPSCC patients, but they can enroll in clinical trials specifically studying HPV-positive OPSCC, noted Dr. Forastiere.

Since the majority of the HPV-positive tumors contained HPV type 16 DNA, vaccination against this type prior to exposure—in men and women—also may be beneficial, as no screening techniques currently exist. But studies are needed to evaluate the efficacy and cost-effectiveness of vaccination, Dr. Chaturvedi added.

Hospitalization Following Prostate Biopsy Common in Older Men

Men 65 years of age or older who underwent a prostate biopsy were more likely to be hospitalized for a serious complication within 30 days than men who did not have the procedure, according to a new study. The rate of infectious complications, in particular, has risen substantially in recent years, researchers from the Johns Hopkins University School of Medicine reported online September 22 in the Journal of Urology.

To conduct the study, Dr. Edward Schaeffer and his colleagues analyzed clinical records from 1991 through 2007 for nearly 17,500 Medicare beneficiaries who had had a prostate biopsy and approximately 135,000 male Medicare beneficiaries who had not had a prostate biopsy. The data came from NCI’s Surveillance, Epidemiology, and End Results database.

Overall, 6.9 percent of men who had a biopsy were hospitalized within 30 days of their first biopsy. By comparison, only 2.9 percent of the men in the control group were hospitalized within 30 days of a randomly selected date. Men who had had a prostate biopsy had a more than 2.5-fold increased risk of hospitalization for a serious bacterial infection and a more than eightfold increased risk of a complication unrelated to a bacterial infection.

Among men who had a biopsy, rates of hospitalization for reasons unrelated to infection remained relatively stable during the study period, Dr. Schaeffer noted, but rates of hospitalization for infection-related complications rose sharply from 2000 to 2007. The finding seems to confirm what urologists around the country have reported anecdotally: A growing number of men are developing antibiotic-resistant infections following a prostate biopsy.

“Two decades ago we didn’t have problems with resistant organisms,” Dr. Schaeffer said. The available evidence suggests that it may be a growing problem, he continued, “and we have to do a better job of controlling it.”

Men about to undergo a prostate biopsy typically receive antibiotics to prevent infections. The Johns Hopkins research team is working with researchers at the Northwestern University Feinberg School of Medicine to investigate whether pre-biopsy testing for antibiotic-resistant bacterial strains can reduce infection rates. They have also launched a study of infection rates in men with low-risk prostate cancer enrolled in the active surveillance program at Johns Hopkins, who undergo periodic prostate biopsies.

More than one million Medicare beneficiaries undergo prostate biopsies annually, in most cases as a result of screening for prostate cancer, the study authors noted. Had similar findings been seen in a randomized clinical trial, they added, 1 of every 24 patients who underwent a prostate biopsy would be hospitalized for a complication within 30 days.

“Although prostate biopsy is often considered a benign procedure,” the researchers wrote, “these findings highlight the importance of individualized assessment of the risk-to-benefit ratio of this potentially risky procedure.” Clinicians should discuss the potential for complications with patients considering prostate biopsy, they concluded.

Study Examines Sex Differences in Screening Colonoscopy Findings

A large study in Austria has shown that the prevalence of abnormal growths detected in screening colonoscopies is higher in men than in women at all ages. The study results, reported September 28 in JAMA, suggest that the optimal age for an initial screening colonoscopy may differ for men and women.

In many countries, including the United States and Austria, guidelines recommend screening for colorectal cancer (CRC) starting at age 50 for men and women of average risk. Colonoscopy is used to find and remove precancerous growths known as polyps or adenomas, especially advanced adenomas (AAs). Colonoscopy also can detect CRC at an earlier stage, when it is generally more treatable.

“This study is important…but it’s not a reason to change screening recommendations in the United States. It’s one report, and the implications for people in the United States aren’t clear,” said Dr. Stephen Taplin, a cancer screening expert and chief of the Process of Care Research Branch in NCI’s Division of Cancer Control and Population Sciences. 

The study, led by Dr. Monika Ferlitsch of the Medical University of Vienna, analyzed findings from 44,350 participants in a national screening colonoscopy program from 2007 to 2010. Women made up 51 percent of the study population, and the median ages were 60.7 years for women and 60.6 years for men.

Dr. Ferlitsch and her colleagues found that the rates of adenomas, AAs, and CRC detected by colonoscopy were higher in men than in women at all ages, with men having twice the risk of CRC detected by colonoscopy as women. The prevalence of AAs detected was similar between men 45 to 49 years of age and women 55 to 59 years of age. The average number of patients who had to be screened to detect adenomas, AAs, or CRC was significantly higher in women than men.

“There is interest in the wider community of people working on disease screening to think about individualizing recommendations based on more than age,” Dr. Taplin noted. “This study is beginning to push the envelope of research” in that area, he said.

However, Dr. Taplin added, the study findings “need to be replicated in other populations, including those that are more diverse and have different dietary habits than in Austria.” He noted that U.S. SEER cancer statistics show CRC rates only one-third higher in men than women.

Dr. Taplin added that NCI is launching a multicenter research program called PROSPR that will include studies of the benefits and risks of cancer screening in people with different risk profiles in community practice settings in the United States.

Delivering Chemotherapy to the Liver May Benefit Patients with Metastatic Melanoma

For patients with melanoma of the eye (ocular or uveal melanoma) that has spread to the liver, a new technique may delay the progression of the disease better than current treatments, new research suggests. The technique, called percutaneous hepatic perfusion, delivers chemotherapy directly to the liver, sparing other parts of the body from the drug’s effects.

Ocular melanoma frequently spreads to the liver, and because there are no effective treatments, most patients die within several months. 

“This is the first treatment to show a clinical benefit in patients with liver metastases from ocular melanoma,” said Dr. James Pingpank of the University of Pittsburgh Cancer Institute in a news release. He presented results from a study testing the approach—sometimes called regional chemotherapy—last week at the European Multidisciplinary Cancer Congress in Stockholm, Sweden.

In the phase III clinical trial, 93 patients were randomly assigned to receive regional chemotherapy or the best alternative therapy, as chosen by the investigator. The median time before disease progressed in the liver was 8.1 months among those who received regional chemotherapy, compared with 1.6 months for those in the control group.

The study, which began at NCI and was expanded to nine other U.S. medical centers, also showed a benefit in median overall progression-free survival: 6.1 months in the regional chemotherapy group versus 1.6 months in the control group. Most patients retained 80 percent or more of their daily functional status and returned to full performance once therapy was completed, said Dr. Pingpank.

Patients who initially received the best alternative care were allowed to cross over and receive regional chemotherapy if the disease continued to progress. “These patients were able to achieve a benefit from regional chemotherapy even after their earlier treatment,” said Dr. Marybeth Hughes of NCI’s Center for Cancer Research, who co-led the trial.

To deliver the drug, melphalan, doctors use an intra-arterial catheter, inserted through the skin to deliver drugs to the liver, capture the flow of blood from the liver, and then remove the drugs from the blood before it returns to the rest of the body. The technique avoids the complications of major surgery and can be repeated if necessary.

“We see this as a frontline therapy for patients with this disease,” said Dr. Pingpank in the news release. He noted, however, that applying a regional therapy to patients with metastatic disease can be controversial, especially if there is a high risk for metastases elsewhere in the body.

A similar approach could potentially be used for other cancers that have spread to the liver. At the meeting, Dr. Pingpank and his colleagues reported positive results from a phase II study of percutaneous hepatic perfusion for patients with metastatic neuroendocrine tumors.

The device used to deliver and filter the melphalan has been approved in Europe for use in all malignant liver tumors, whereas approval is pending in the United States for melanoma only, the researchers said.

Smoking Cessation Drug Proves Effective in Single-Center Trial

In a single-center randomized controlled trial, the smoking cessation drug cytisine was more effective than a placebo at helping participants abstain from smoking. Results from the trial, conducted at the Maria Sklodowska-Curie Memorial Cancer Center in Warsaw, Poland, appeared in the September 29 issue of the New England Journal of Medicine.

Cytisine binds to the alpha-4 beta-2 nicotinic acetylcholine receptor, which has been implicated in nicotine dependence and is the primary target for the smoking cessation drug varenicline. Cytisine has been available for more than 40 years as a smoking cessation aid in some eastern European countries, although results from animal studies have suggested that cytisine might have limited efficacy in humans.

The research team randomly assigned 740 participants to receive cytisine or a placebo for 25 days. All study participants received a minimal amount of counseling. Twelve months after the end of treatment, 31 participants in the cytisine group and 9 in the placebo group remained smoke-free, an abstinence rate of 8.4 percent versus 2.4 percent. Smoking abstinence was verified by measuring the carbon monoxide concentration in exhaled breath.

Cytisine resulted in more gastrointestinal adverse events than did placebo, but rates of other adverse events and death were similar in the two groups. The rates of discontinuation or dose reduction were also similar with cytisine and placebo.

“Combining cytisine with more intensive behavioral support may result in higher absolute quit rates,” wrote the authors, “and it is possible that efficacy could be improved by a longer regimen.” They also noted that the lower cost of cytisine as compared with that of other smoking-cessation drugs “may make it an attractive treatment option for smokers in low-income and middle-income countries.”

Dr. Michele Bloch, acting branch chief of NCI’s Tobacco Control Research Branch, noted, “The combination of cytisine with behavioral strategies is promising and worthy of further investigation.”

Lasers in Cancer Treatment

1. What is laser light?

   The term “laser” stands for light amplification by stimulated emission of radiation. Ordinary light, such as that from a light bulb, has many wavelengths and spreads in all directions. Laser light, on the other hand, has a specific wavelength. It is focused in a narrow beam and creates a very high-intensity light. This powerful beam of light may be used to cut through steel or to shape diamonds. Because lasers can focus very accurately on tiny areas, they can also be used for very precise surgical work or for cutting through tissue (in place of a scalpel).

2. What is laser therapy, and how is it used in cancer treatment?

   Laser therapy uses high-intensity light to treat cancer and other illnesses. Lasers can be used to shrink or destroy tumors or precancerous growths. Lasers are most commonly used to treat superficial cancers (cancers on the surface of the body or the lining of internal organs) such as basal cell skin cancer and the very early stages of some cancers, such as cervical, penile, vaginal, vulvar, and non-small cell lung cancer.

   Lasers also may be used to relieve certain symptoms of cancer, such as bleeding or obstruction. For example, lasers can be used to shrink or destroy a tumor that is blocking a patient’s trachea (windpipe) or esophagus. Lasers also can be used to remove colon polyps or tumors that are blocking the colon or stomach.

   Laser therapy can be used alone, but most often it is combined with other treatments, such as surgery, chemotherapy, or radiation therapy. In addition, lasers can seal nerve endings to reduce pain after surgery and seal lymph vessels to reduce swelling and limit the spread of tumor cells. 

3. How is laser therapy given to the patient?

   Laser therapy is often given through a flexible endoscope (a thin, lighted tube used to look at tissues inside the body). The endoscope is fitted with optical fibers (thin fibers that transmit light). It is inserted through an opening in the body, such as the mouth, nose, anus, or vagina. Laser light is then precisely aimed to cut or destroy a tumor.

   Laser-induced interstitial thermotherapy (LITT), or interstitial laser photocoagulation, also uses lasers to treat some cancers. LITT is similar to a cancer treatment called hyperthermia, which uses heat to shrink tumors by damaging or killing cancer cells. (More information about hyperthermia is available in the NCI fact sheet Hyperthermia in Cancer Treatment.) During LITT, an optical fiber is inserted into a tumor. Laser light at the tip of the fiber raises the temperature of the tumor cells and damages or destroys them. LITT is sometimes used to shrink tumors in the liver.

   Photodynamic therapy (PDT) is another type of cancer treatment that uses lasers. In PDT, a certain drug, called a photosensitizer or photosensitizing agent, is injected into a patient and absorbed by cells all over the patient’s body. After a couple of days, the agent is found mostly in cancer cells. Laser light is then used to activate the agent and destroy cancer cells. Because the photosensitizer makes the skin and eyes sensitive to light afterwards, patients are advised to avoid direct sunlight and bright indoor light during that time. (More information about PDT is available in the NCI fact sheet Photodynamic Therapy for Cancer.)

4. What types of lasers are used in cancer treatment?

   Three types of lasers are used to treat cancer: carbon dioxide (CO₂) lasers, argon lasers, and neodymium:yttrium-aluminum-garnet (Nd:YAG) lasers. Each of these can shrink or destroy tumors and can be used with endoscopes.

   CO₂ and argon lasers can cut the skin’s surface without going into deeper layers. Thus, they can be used to remove superficial cancers, such as skin cancer. In contrast, the Nd:YAG laser is more commonly applied through an endoscope to treat internal organs, such as the uterus, esophagus, and colon.

   Nd:YAG laser light can also travel through optical fibers into specific areas of the body during LITT. Argon lasers are often used to activate the drugs used in PDT. 

5. What are the advantages of laser therapy?

   Lasers are more precise than standard surgical tools (scalpels), so they do less damage to normal tissues. As a result, patients usually have less pain, bleeding, swelling, and scarring. With laser therapy, operations are usually shorter. In fact, laser therapy can often be done on an outpatient basis. It takes less time for patients to heal after laser surgery, and they are less likely to get infections. Patients should consult with their health care provider about whether laser therapy is appropriate for them. 

6. What are the disadvantages of laser therapy?

   Laser therapy also has several limitations. Surgeons must have specialized training before they can do laser therapy, and strict safety precautions must be followed. Laser therapy is expensive and requires bulky equipment. In addition, the effects of laser therapy may not last long, so doctors may have to repeat the treatment for a patient to get the full benefit. 

7. What does the future hold for laser therapy?

   In clinical trials (research studies), doctors are using lasers to treat cancers of the brain and prostate, among others. To learn more about clinical trials, call NCI’s Cancer Information Service at 1–800–4–CANCER or visit the clinical trials page of NCI’s Web site.

Diethylstilbestrol (DES) and Cancer

1. What is DES?

   Diethylstilbestrol (DES) is a synthetic form of the female hormone estrogen. It was prescribed to pregnant women between 1940 and 1971 to prevent miscarriage, premature labor, and related complications of pregnancy (1). The use of DES declined after studies in the 1950s showed that it was not effective in preventing these problems.

   In 1971, researchers linked prenatal (before birth) DES exposure to a type of cancer of the cervix and vagina called clear cell adenocarcinoma in a small group of women (2). Soon after, the Food and Drug Administration (FDA) notified physicians throughout the country that DES should not be prescribed to pregnant women (3). The drug continued to be prescribed to pregnant women in Europe until 1978 (4).

   DES is now known to be an endocrine-disrupting chemical, one of a number of substances that interfere with the endocrine system to cause cancer, birth defects, and other developmental abnormalities. The effects of endocrine-disrupting chemicals are most severe when exposure occurs during fetal development.  

2. What is the cancer risk of women who were exposed to DES before birth?

   The daughters of women who used DES while pregnant—commonly called DES daughters—have about 40 times the risk of developing clear cell adenocarcinoma of the lower genital tract than unexposed women. However, this type of cancer is still rare; approximately 1 in 1,000 DES daughters develops it.

   The first DES daughters who were diagnosed with clear cell adenocarcinoma were very young at the time of their diagnoses (2). Subsequent research has shown that the risk of developing this disease remains elevated as women age into their 40s (5).

   DES daughters have an increased risk of developing abnormal cells in the cervix and the vagina that are precursors of cancer (dysplasia, cervical intraepithelial neoplasia, and squamous intraepithelial lesions) (6). These abnormal cells resemble cancer cells, but they do not invade nearby healthy tissue and are not cancer. They may develop into cancer, however, if left untreated. Scientists estimated that DES-exposed daughters were 2.2 times more likely to have these abnormal cell changes in the cervix than unexposed women. Approximately 4 percent of DES daughters developed these conditions because of their exposure (7). It has been recommended that DES daughters have a yearly Pap test and pelvic exam to check for abnormal cells (6).

   DES daughters may also have a slightly increased risk of breast cancer after age 40. A 2006 study from the United States suggested that, overall, breast cancer risk is not increased in DES daughters, but that, after age 40, DES daughters have approximately twice the risk of breast cancer as unexposed women of the same age and with similar risk factors (8). However, a 2010 study from Europe found no difference in breast cancer risk between DES daughters and unexposed women and no difference in overall cancer risk (5). A 2011 study found that about 2 percent of a large cohort of DES daughters has developed breast cancer due to their exposure (7).

   DES daughters should be aware of these health risks, share their medical history with their doctors, and get regular physical examinations. 

3. Do DES daughters have problems with fertility and pregnancy?

   Several studies have found increased risks of premature birth, miscarriage, and ectopic pregnancy associated with DES exposure. An analysis of updated data published in 2011 is outlined in the table below.

   Fertility Problems in DES Daughters (7)
   Fertility Complication	Hazard Ratio	Percent Cumulative Risk* to Age 45, DES-exposed Women	Percent Cumulative Risk* to Age 45, Unexposed Women
   Premature delivery	4.68	53.3	17.8
   Stillbirth	2.45	8.9	2.6
   Neonatal death	8.12	7.8	0.6
   Ectopic pregnancy	3.72	14.6	2.9
   Miscarriage (second trimester)	3.77	16.4	1.7
   Preeclampsia	1.42	26.4	13.7
   Infertility	2.37	33.3	15.5

   *The total risk (probability) that a certain problem will occur.

   Some studies suggest that the increased risk of infertility is mainly due to uterine or fallopian tube problems (9).  

4. What other health problems might DES daughters have?

   Concerns have been raised that DES daughters may have problems with their immune system. However, research thus far suggests that DES daughters do not have an increased risk of autoimmune diseases. Researchers found no difference in the rates of lupus, rheumatoid arthritis, optic neuritis, and idiopathic thrombocytopenia purpura between DES-exposed and unexposed women (10).

   Studies examining the risk of depression among DES daughters have had conflicting results. One study found a 40 percent increase in risk of depression, whereas another found no increased risk for these women (11, 12). A study published in 2003 found little support for the possibility that prenatal exposure to DES influences certain psychological and sexual characteristics of adult men and women, such as the likelihood of ever having been married, age at first sexual intercourse, number of sexual partners, and having had a same-sex sexual partner in adulthood (12).

   DES daughters have more than twice the risk of early menopause (menopause that begins before age 45) as unexposed women. Scientists estimate that 3 percent of DES-exposed women have experienced early menopause due to their exposure to DES (7). 

5. What health problems might DES-exposed sons have?

   Some studies have found that men whose mothers used DES during pregnancy have an increased risk of testicular abnormalities, including undescended testicles or development of cysts in the epididymis (13). There is also some evidence of increased risks of inflammation or infection of the testicles (13).

   Whether DES-exposed sons have increased risks of testicular or prostate cancer is unclear; studies to date have produced mixed results. As the cohort of these men gets older, more data will be available to help answer this question.

   Research has shown that men who were exposed to DES through their mothers do not have an increased risk of infertility, even when they have genital abnormalities (13). 

6. What health problems might women who took DES during pregnancy have?

   Women who used DES themselves have a slightly increased risk of breast cancer—approximately 30 percent higher than that of women who did not take DES (14). Women who used DES also have a 30 percent higher risk of death from breast cancer than unexposed women (15). This risk has been found to be stable over time—that is, it does not increase as the mothers become older (16). No evidence exists to suggest that women who took DES are at higher risk for any other type of cancer (4). 

7. What health problems might DES-exposed grandchildren have?

   Researchers are also studying possible health effects among women and men who are the children of DES daughters. These groups are called DES granddaughters and DES grandsons, or the third generation. Researchers are studying these groups because studies in animal models suggest that DES may cause DNA changes (i.e., altered patterns of methylation) in mice exposed to the chemical during early development (17). These changes can be heritable and have the potential to affect subsequent generations.

   A comparison of the results of DES granddaughters’ pelvic exams with those of their mothers’ first pelvic exams found none of the changes that had been associated with prenatal DES exposure in their mothers (9). However, another analysis showed that DES granddaughters began their menstrual periods later and were more likely to have menstrual irregularities than other women of the same age. The data also suggested that infertility was greater among DES granddaughters, and that they tended to have fewer live births (18). However, this association is based on small numbers of events and was not statistically significant. Researchers will continue to follow these women to study the risk of infertility.

   Recent studies have found that DES granddaughters and DES grandsons may have a slightly higher risk of cancer (19) and birth defects (20), including hypospadias in DES grandsons (21). However, because each of these associations is based on small numbers of events, researchers will continue to study these groups to clarify the findings. 

8. How can people find out if they took DES during pregnancy or were exposed to DES in utero?

   It is estimated that 5 to 10 million Americans—pregnant women and the children born to them—were exposed to DES between 1940 and 1971 (4). DES was given widely to pregnant women between 1940 and 1971 to prevent complications during pregnancy. DES was provided under many different product names and also in various forms, such as pills, creams, and vaginal suppositories (6). The table below includes examples of products that contained DES.

   DES Product Names
   Nonsteroidal Estrogens
   Benzestrol	Estrosyn	Restrol
   Chlorotrianisene	Fonatol Gynben Gyneben	Stil-Rol
   Comestrol	Hexestrol	Stilbal Stilbestrol
   Cyren A.	Hexoestrol	Stilbestronate
   Cyren B.	Hi-Bestrol	Stilbetin
   Delvinal	Menocrin	Stilbinol
   DES	Meprane	Stilboestroform
   Desplex	Mestilbol	Silboestrol
   Dibestil	Microest	Stilboestrol DP
   Diestryl	Methallenestril Mikarol	Stilestrate
   Dienostrol	Mikarol Forti	Stilpalmitate
   Dienoestrol	Milestrol	Stilphostrol
   Diethylsteilbestrol dipalmitate	Monomestrol	Stilronate
   Diethylstilbestrol diphosphate	Neo-Oestranol I	Stilrone
   Diethylstilbestrol dipropionate	Neo-Oestranol II	Stils
   Diethylstilbenediol	Nulabort	Synestrin
   Digestil	Oestrogenine	Synestrol
   Dinestrol	Oestromenin	Synthosestrin
   Domestrol	Oestromon	Tace
   Estilben	Orestol	Vallestril
   Estrobene	Pabestrol D	Willestrol
   Estrobene DP	Palestrol
   Nonsteroidal Estrogen-Androgen Combinations
   Amperone	Teserene
   Di-Erone	Tylandril
   Estan	Tylostereone
   Metystil
   Nonsteroidal Estrogen-Progesterone Combinations
   Progravidium
   Vaginal Cream Suppositories with Nonsteroidal Estrogens
   AVC Cream with Dienestrol
   Dienestrol Cream

   Women who think they used DES during pregnancy, or people who think that their mother used DES during pregnancy, can try contacting the physician or institution where they received their care to request a review of their medical records. If any pills were taken during pregnancy, obstetrical records could be checked to determine the name of the drug.

   However, finding medical records after a long period of time can be difficult. If the doctor has retired or died, another doctor may have taken over the practice as well as the records. The county medical society or health department may know where the records have been stored. Some pharmacies keep records for a long time and can be contacted regarding prescription dispensing information. Military medical records are kept for 25 years. In most cases, however, it may be impossible to determine whether DES was used.  

9. What should DES-exposed daughters do?

   Women who know or believe they were exposed to DES before birth should be aware of the health effects of DES and inform their doctor about their possible exposure. It has been recommended that exposed women have an annual medical examination to check for the adverse health effects of DES (6). A thorough examination may include the following:

   • Pelvic examination

   • Pap test and colposcopy—A routine cervical Pap test is not adequate for DES daughters. The Pap test must gather cells from the cervix and the vagina. It is also good for a clinician to see the cervix and vaginal walls. They may use a colposcope to follow-up if there are any abnormal findings.

   • Biopsy

   • Breast examinations—It is recommended that DES daughters continue to rigorously follow the routine breast cancer screening recommendations for their age group. The NCI fact sheet Mammograms includes information about these guidelines. 

10. What should DES-exposed mothers do?

    A woman who took DES while pregnant or who suspects she may have taken it should inform her doctor. She should try to learn the dosage, when the medication was started, and how it was used. She also should inform her children who were exposed before birth so that this information can be included in their medical records.

    It is recommended that DES-exposed mothers have regular breast cancer screenings and yearly medical checkups that include a pelvic examination and a Pap test. 

11. What should DES-exposed sons do?

    Men whose mothers took DES while pregnant should inform their physician of their exposure and be examined periodically. Although the risk of developing testicular cancer among DES-exposed sons is unclear, males with undescended or unusually small testicles have an increased risk of testicular cancer whether or not they were exposed to DES. 

12. Is it safe for DES daughters to use hormone replacement therapy?

    Each woman should discuss this question with her doctor. Studies have not shown that hormone replacement therapy is unsafe for DES daughters. However, some doctors believe that DES daughters should avoid these medications because they contain estrogen (22). 

13. What is the focus of current research on DES exposure?

    In 1992, NCI, together with collaborators at five research centers, began a long-term study of individuals exposed to DES, the DES Follow-up Study. Participants were initially drawn from eight different medical centers and consisted of five individual cohorts of people. In order for the study findings to be valid, enrollment in the study is limited to participants who have been part of existing cohorts. It is not currently possible for the DES Follow-up Study to accept new participants.

    Researchers continue to study DES daughters as they move into their menopausal years. The cancer risks for exposed sons are also being studied to determine whether they differ from those for unexposed men. In addition, researchers are studying possible health effects on the grandchildren of mothers who were exposed to DES during pregnancy (also called third-generation daughters or DES granddaughters) (6).

    The National Institute of Environmental Health Sciences (NIEHS) is leading laboratory studies to investigate DES exposure and its effects on health. NIEHS researchers developed a rodent model of prenatal DES exposure that has been useful in replicating and predicting adverse health effects in prenatally exposed men and women. This experimental model has been used worldwide to study mechanisms involved in DES-related toxicity and the adverse effects of less potent environmental estrogens. 

14. Where can DES-exposed people get additional information?

    Resources for people who were exposed to DES include the following:

    Organization:	National Cancer Institute DES Follow-up Study
    Web site:	http://www.desfollowupstudy.org

    Since 1992, the NCI, in collaboration with research centers throughout the United States, has been conducting the DES Follow-up Study of more than 21,000 mothers, daughters, and sons, to better understand the long-term health effects of exposure to DES.

    Organization:	Registry for Research on Hormonal Transplacental Carcinogenesis (Clear Cell Cancer Registry)
    Address:	The University of Chicago Department of Obstetrics and Gynecology MC 2050 5841 South Maryland Avenue Chicago, IL 60637
    Telephone:	773–702–6671
    Fax:	773–834–2341
    E-mail:	danderso1@babies.bsd.uchicago.edu
    Web site:	http://obgyn.bsd.uchicago.edu/registry.html

    The Registry for Research on Hormonal Transplacental Carcinogenesis (also called the Clear Cell Cancer Registry) is a worldwide registry for individuals diagnosed with clear cell adenocarcinoma of the vagina and/or cervix. Staff members also answer questions from the public. 

Selected References 

1. Professional and Public Relations Committee of the DESAD (Diethylstilbestrol and Adenosis) Project of the Division of Cancer Control and Rehabilitation. Exposure in utero to diethylstilbestrol and related synthetic hormones. Association with vaginal and cervical cancers and other abnormalities. JAMA 1976; 236(10):1107–1109. [PubMed Abstract] 

2. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. The New England Journal of Medicine 1971; 284(15):878–881. [PubMed Abstract] 

3. FDA Drug Bulletin: Diethylstilbestrol contraindicated in pregnancy. California Medicine 1972; 116(2):85–86. [PubMed Abstract] 

4. Giusti RM, Iwamoto K, Hatch EE. Diethylstilbestrol revisited: a review of the long-term health effects. Annals of Internal Medicine 1995; 122(10):778–788. [PubMed Abstract] 

5. Verloop J, van Leeuwen FE, Helmerhorst TJ, van Boven HH, Rookus MA. Cancer risk in DES daughters. Cancer Causes and Control 2010; 21(7):999–1007. [PubMed Abstract] 

6. Rubin MM. Antenatal exposure to DES: lessons learned…future concerns. Obstetrical and Gynecological Survey 2007; 62(8):548–555. [PubMed Abstract] 

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