Expert Panel Dispels Misinformation About Tamoxifen

An expert panel of seven cancer researchers and a patient advocatecame together at the San Antonio Breast Cancer Symposium for aroundtable discussion on tamoxifen (Nolvadex), sponsored by PRR,Inc., publisher of Oncology News International and the journalONCOLOGY.

This report covers the first part of the discussion on therisks of secondary cancers with tamoxifen use. Subsequent reportswill focus on such subjects as the appropriate duration of tamoxifenuse and how to deal with side effects such as hot flashes andvaginal dryness.

SAN ANTONIO--"Tamoxifen is the endocrine therapy of choicefor selected patients with all stages of breast cancer,"V. Craig Jordan, PhD, DSc, of Northwestern University MedicalSchool, said at the outset of the Tamoxifen Roundtable, whichhe moderated. "We've seen clear-cut demonstration of itsbiological efficacy in the clinic and, obviously, some troublesomeside effects as well," he said.

Dr. Jordan's first goal for the panel was to look at tamoxifenuse from the patient's point of view, and to help physicians putthe benefits and side effects into perspective for the patient.

Monica Morrow, MD, also of Northwestern, noted that patients'concerns about tamoxifen have changed over the last 5 years. "Fiveyears ago, most patients' concerns were what I would considerthe primary and appropriate concern, namely, what will tamoxifendo to keep me from dying of breast cancer."

More recently, she said, secondary to adverse publicity surroundingthe Breast Cancer Prevention Trial and the National Surgical AdjuvantBreast and Bowel Project (NSABP) studies, the main issue now amongpatients is side effects, primarily endometrial cancer, but also,to a much lesser extent, liver cancer and, among premenopausalwomen, the misconception that tamoxifen will induce prematuremenopause.

Amy Langer, executive director of NABCO, said that as knowledgeof a drug's benefits increases over the years, so does knowledgeof its side effects, and this is often what the media pick up."When women taking tamoxifen call us with concerns aboutendometrial cancer, we stress the importance of routine gynecologicsurveillance," she said.

C. Kent Osborne, MD, of the University of Texas Health ScienceCenter, San Antonio, said that women may get misinformation notonly from the media but also from physicians, who may not understandthe dual effects of antiestrogens like tamoxifen. "Thesedrugs have beneficial estrogen-agonist properties in some tissuesand antagonist properties in the breast," he said.

Lacking this understanding, some patients and physicians may fear,incorrectly, that tamoxifen will have undesirable antiestrogeniceffects on cholesterol or bone density, or they may overestimatethe risk of endometrial cancer.

He said that the net result of these misunderstandings is thatwomen may stop taking the drug prematurely, in some cases withouttelling their physician (see box at left).

Norman Wolmark, MD, of the Medical College of Pennsylvania/HahnemannUniversity, and chairman of the NSABP, emphasized that "thequestion of endometrial cancers should not be trivialized, andpatients who take tamoxifen need to be apprised of the risk."He added, however, that the risk needs to be placed in perspective.

The NSABP protocol B-14, a randomized prospective trial, attemptedto determine the benefit of tamoxifen in a specific subset ofwomen: those with histologically negative nodes whose tumors wereestrogen-receptor (ER) positive, Dr. Wolmark said.

Ten-year results now indicate that there is an "unequivocaland significant" prolongation of disease-free survival withtamoxifen (68%) vs placebo (57%), he said. Overall survival wasalso increased with tamoxifen use: from 75% for placebo to 78%for tamoxifen, a statistically significant increase.

In the entire trial (1,400 women in each arm), there were only19 cases of endometrial cancer. "Certainly, that is morethan would occur in the general, untreated, age-matched population,"Dr. Wolmark said, but, to put it into perspective, he added thatit is "certainly no more than would occur in women who areover age 50 and receiving estrogen replacement therapy."Overall, he said, the benefits of tamoxifen in this populationfar outweigh the risks.

Cancers Not More Aggressive

The panel also dealt with the fear that endometrial cancer inwomen on tamoxifen is more aggressive, a finding suggested bya review of the Yale-New Haven tumor registry. This report promptedRichard R. Barakat, MD, of Memorial Sloan-Kettering Cancer Center,to review his institution's registry of breast cancer patients,to specifically examine those who subsequently developed cancerof the uterus.

This review identified 23 patients who received tamoxifen anddeveloped endometrial cancer after a breast cancer diagnosis,Dr. Barakat said. The results showed that 75% to 80% of the endometrialcancers in the tamoxifen group were low-grade, stage I, highlycurable lesions, a distribution similar to that seen in the 50breast cancer patients from the Memorial Sloan-Kettering registrywho had developed endometrial cancer but had not taken tamoxifen.

Dr. Wolmark, commenting on the NSABP experience, said that thereis no evidence that the endometrial cancers found in women ontamoxifen are different from those that develop in patients whodo not receive tamoxifen, with the majority of such lesions beinglow grade and confined.

"That's not to say there won't be deaths resulting from endometrialcancer that develops while taking tamoxifen," he pointedout, "but we have not seen anything unique about endometrialcancers that occur in tamoxifen patients, relative to histology,distribution, or level of aggressiveness."

Dr. Jordan added that he and his Northwestern colleague, Dr. VasiliosAssikis, recently published a review of international data showing,essentially, that the grade and stage of endometrial cancers associatedwith tamoxifen use are in exactly the same proportions as thoseseen in SEER data throughout the United States.

"So I think it is fair to say that all of the evidence thatwe have available to us now has been contrary to that single reportfrom the Yale-New Haven database published in the Journal of ClinicalOncology," he said.

Dr. Wolmark also pointed out that the NSABP data have shown noincreased incidence of gastrointestinal or hepatic cancers, evenwith 10 years of tamoxifen use.

Dr. Jordan emphasized that the increased risks of liver cancerare based largely on animal data that, if translated into humandoses, would be the equivalent of a 14-year-old female taking80 tamoxifen tablets daily until age 45 or 50.

A 15-year review of the British Columbia tumor registry involvingmore than 27,000 breast cancer patients, many of whom had receivedtamoxifen, found 24 cases of gallbladder common duct cancer andfive cases of liver disease, "very similar to what we'veseen in the population at large," said Joseph Ragaz, MD,of the Vancouver Cancer Centre.

He proposed a series of case-control studies on secondary malignanciesusing combined data, adjusted for age and follow-up, from numerouscancer center registries. Such studies could determine more accuratelywhether tamoxifen is implicated in these cancers.

Ms. Langer pointed out that tamoxifen has been associated withliver abnormalities in some women and asked the other panel membersto comment.

Dr. Osborne responded that such findings were rare in his experienceand have had no clinically important ramifications. "I havenot had a case where I've had to stop tamoxifen because of liverfunction abnormalities," he said, adding that with almostany drug, there will be patients who cannot tolerate the agentbecause of elevated liver function tests.

Dr. Wolmark noted that the incidence of liver function abnormalitiesin tamox-ifen patients must be compared with those of patientson placebo. In the NSABP studies, he said, "we have not seena difference between tamoxifen and placebo relative to liver dysfunctionas measured by the standard liver function tests."

Should Patients Worry About 'Fatty Liver'?

In a Q&A session at the tamoxifen roundtable (see story above),a patient advocate from the Alamo Breast Cancer Foundation, SanAntonio, asked about the development of "fatty livers"in women on tamoxifen, and described two women who had stoppedtaking tamoxifen because of this finding.

Dr. Norman Wolmark, of the NSABP, responded that his group hasnot seen the phenomenon of fatty replacement of the liver as aresult of tamoxifen treatment. "We've just not seen any changein the liver configuration," he said.

A physician from the audience described fatty liver as a benigncondition that is "quite common if you look for it,"particularly in women who are obese or have mild diabetes.

Breast cancer patients taking tamoxifen are closely monitoredfor possible metastases, the physician said, including CT scansof the abdomen. In reading these scans, the radiologist may notea fatty liver.

"That's actually reassuring to the oncologist and the patientbecause it does not represent metastatic disease, and it's nota problem that progresses to chronic liver disease," he said."It frequently goes away with time, with weight loss, orwith diabetes control."

Dr. Craig Jordan, who moderated the panel, said that this illustrateshow misconceptions within the patient population can lead to potentiallyserious consequences, such as stopping a drug that will providesurvival benefits.