By Samantha L. Stewart
Sitting at a little kitchen table in Brooklyn, Karen Smith sipped her coffee and flipped through the pages of a well-worn photo album. She paused for a second as one picture in particular grabbed her attention. It was of her-14 months ago-lying in a hospital bed covered in tubes. Her face was pale and there was a pink baseball hat covering her bald head. She sighed a little underneath her breath as she read the slogan on the cap.
It read: ‘F--- Cancer.’
“I had thought I had beat it. I felt so betrayed by my own doctors. They should have told me more,” said Smith, shaking her head side to side.
In 1999, she had been diagnosed with Stage I breast cancer, a very treatable stage of the disease with a strong survival rate. Her doctors were very optimistic that with radiation and a lumpectomy that she would beat the disease.
After successful treatment, her doctor prescribed a powerful cancer treatment drug called Tamoxifen. She was told that this drug would greatly prevent the reoccurrence of her breast cancer. And not wanting another cancer scare, she took the drug upon his advice.
For the next five years took the drug faithfully. And as the doctor predicted, her breast cancer did not return.
But what did happen-and what doctors and scientific researchers had known was a risk of happening-was the development of a deadly side effect from the drug.
In 2008 she was diagnosed with an aggressive form of uterine cancer, much more deadly than her breast cancer.
“The cancer in my uterus was not the breast cancer kind. It was caused by something else. This was far worse,” said Smith.
When she spoke with her new doctors about the uterine cancer, they’d ask her if she had taken Tamoxifen?
“They never said specifically that my cancer was caused by this drug, but they strongly implied it,” said Smith.
To treat this aggressive uterine cancer she had to undergo a painful hysterectomy and rounds of chemotherapy that made her very sick.
Despite these treatments, the uterine cancer metastasized to her lungs. With her body still weak, she began another series of radiation, underwent an operation with a cyberknife, and had two types of chemotherapy every three weeks for six months.
Seeking answers, Karen’s daughter, Lynn, took to the Internet to do some research. Much to both of their dismay, she discovered Tamoxifen can cause uterine cancer, liver cancer, and deadly blood clots in addition to a long list of other strong side effects.
Today she is in remission, but her chances for long-term survival are low.
“I couldn’t believe it,” said Smith. “I never would have taken it if I’d known the risks.”
She is not the only woman to feel this way.
A study published in the Journal of Breast Cancer Research & Treatment in 2009, found that after 632 women were offered Tamoxifen for breast cancer prevention, only 1 percent used it after hearing all the risks. Out of these women, 80 percent cited worries about the side effects as the reason for their refusal to take the drug.
“When the numbers were laid out for women in a way they could clearly understand, they weren’t interested in taking Tamoxifen,” said Dr. Angela Fagerlin, Associate Professor of Internal Medicine at the University of Michigan in a New York Times interview. “They didn’t think the benefits of Tamoxifen outweighed the risks.”
The ‘risk versus the benefit’ of taking Tamoxifen has been largely debated in the scientific community since it was initially approved by the Food and Drug Administration (FDA) in 1977 to treat late-stage breast cancer.
Doctors had long known that the drug can have severe side effects, such as endometrial cancer, liver cancer, blood clots, and cataracts to name a few. However, in clinical trials the drug proved remarkably effective at treating existing breast cancer and preventing reoccurrence. Therefore the FDA determined the benefit to outweigh the risk for women in that category.
The controversy largely arouse when the drug manufacturer AstraZeneca wanted to expand the prescription use of the drug to women who did not already have breast cancer, but were at risk.
This proposal by AstraZeneca met with opposition from independent scientific researchers studying the drug.
“It’s unlikely that a large number of healthy women would ever be persuaded to take Tamoxifen as a breast cancer prevention drug,” Dr. Larry Norton, Deputy Physician-in-Chief for Breast Cancer at Memorial Sloan-Kettering Cancer Center, told the New York Times.
Critics pointed to studies that seemed to demonstrate the risks being too high for women who were otherwise cancer free.
A study by Dr. Gary Williams at the American Heart Foundation found Tamoxifen in animal studies to be “a rip-roaring liver carcinogen, inducing highly aggressive cancer in about 12 percent of rats. Human studies showed a six-fold increase in liver cancer among women taking Tamoxifen more than 2 years.”
In a 1994 Swedish study, breast cancer patients who took Tamoxifen for two to five years were found to have a “six-fold increase in uterine cancer among those taking the drug compared to the women who did not take the drug.” This study forced AstraZeneca-the drug company who makes Tamoxifen-to send letters to over 380,000 physicians across the United States in defense of the drug.
Still, Tamoxifen proved highly effective at stopping reoccurrence of breast cancer. Even though its side effects could cause more deadly aggressive cancers elsewhere in the body.
For this reason, Tamoxifen was largely considered the ‘gold standard’ for treating breast cancer in women who had already been diagnosed, according to the National Cancer Institute (NCI).
The FDA in 1990 approved additional use of the drug in for treating ‘node-negative’ breast cancer patients after determining that “the benefits outweighed the risks for women at risk of reoccurrence.”
By 1998, AstraZeneca applied for another extended license to market the drug to women who were breast cancer-free, but at risk.
Unlike previous requests, this application created an up roar in the scientific community, as researchers largely disagreed on whether the benefits still outweighed the risks when prescribing it to cancer-free women.
The main studies the FDA relied upon to make its decision for expanded ‘prevention’ use were fraught with controversy.
Fraud was uncovered in a NCI sponsored Tamoxifen study conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP). The project’s director, Dr. Bernard Fisher, had been found to falsify data for 99 people enrolled in breast cancer studies with the drug.
Congress investigated these incidents of fraud and stripped Dr. Fisher of his position.
During this time, scientists continued to raise serious questions about the effectiveness of the drug for prevention, the risks, and concerns over public awareness prior to the FDA’s decision to expand the use of the drug.
“There are serious questions as to whether Tamoxifen actually reduced the incidence of breast cancer or merely delayed its onset by treating small undetected tumors,” said Dr. Samuel S. Epstein in a 1998 press release for the Cancer Prevention Coalition.
Citing the NCI-NSABP study, Dr. Epstein stated that the short-term trial on some 13,000 women at ‘high risk of breast cancer’ showed serious and sometimes fatal complications, including uterine cancer and pulmonary embolism.
“Breast cancer was reduced by 1.7%, while the incidence of serious complications was increased by 2.2% in non-hysterectomy women,” said Epstein. “Of great concern is the well documented evidence of short term life-threatening complications, and also risks of delayed fatal complications, evidence for which has been trivialized and suppressed by NCI.”
He also cautioned “the brevity of the trial prevented recognition of other delayed serious health risks.”
Weighing in on the study, Dr. Lynette Dumble, Senior Research Fellow at University of Melbourne called the Tamoxifen study “the medical equivalent of mutilating surgery which prevents a woman from developing breast cancer by cutting off both of her breasts.”
Dr. Dumble brought into question the risk to healthy women volunteering for the trial without fully knowing what risks were involved. As well is questioning what qualifies as a ‘successful result’ in the trial.
“If a woman dies of Tamoxifen-related endometrial or liver cancer, does this count as a Tamoxifen success in preventing breast cancer?” asked Dumble.
Still, the FDA relied on parts of the NCI study during its approval evaluation of the drug’s expanded use for ‘prevention on cancer-free women.’
The FDA discussed its response to the fraudulent activities by NSABP and scientists concerns in a Statement to Congress during the investigation.
“Since NCI was a sponsor of this study, and since the study was properly terminated earlier than originally planned, the manufacturer of Tamoxifen still must finish its examination of the data,” said Dr. Michel A. Friedman, FDA Lead Deputy Commissioner in a statement to Congress.
“The law requires that the FDA must approve drugs on the basis of scientific data showing them to be ‘safe and effective’ for the indication(s) for which they are being considered,” said Friedman. “We have reviewed multiple prior applications based on NCI and NSABP studies, and we are familiar with their research practices and the generally high quality of their research results. The FDA will act as expeditiously as possible.”
Other advocates raised concerns about the public’s awareness and information disclosing the risks involved in taking Tamoxifen versus the potential benefits. For women already diagnosed, the decision may be clearer. But for healthy women merely at risk of breast cancer, not understanding the possible consequences of taking the drug could prove fatal.
“We just don’t know enough now to change the label and tell the women of America that Tamoxifen can be used to prevent breast cancer,” said Cynthia Pearson, Executive Director of National Women’s Health Network to the FDA advisory committee.
“Do you really think that every busy primary care doctor and gynecologist in America has the time go over the risks? I don’t think so. Women already have quite a high concern about the likelihood of being diagnosed with breast cancer. If we add FDA approval to this, we are giving the manufacturer a green light to start direct to consumer advertising,” said Pearson.
Despite these concerns, the FDA did approve the drug for expanded prevention use in 1998. Representing an additional 30 million users in the United States and a 36 billion dollar annual windfall for the drug company AstraZeneca.
By 2002, over 4.5 million prescriptions for Tamoxifen had been written, according to IMS Health, a company that tracks the drug industry.
During this time, Adverse Reaction Reports were coming in to the FDA regarding incidents of a new uterine cancer type in Tamoxifen patients. After 159 previously unseen uterine cancer sarcoma reports came in, FDA Medical Reviewer Dr. Susan Honig began an investigation as to the extent of this additional cancer risk.
Later that year, the FDA added a ‘Black Box” warning on the label of Tamoxifen. Warning of newly identified risk of uterine sarcoma, a new form of uterine cancer not previously seen when using Tamoxifen.
In the mid-2000’s the first long term studies of Tamoxifen for ‘prevention’ use were published. The studies demonstrated mixed results.
In response to the ongoing new studies being published, the FDA recently issued the following statement: “The FDA continues to monitor post-marketing safety but Tamoxifen has been on the market for many years and large numbers of women have participated in ‘prevention’ and adjuvant trials. No changes to the risk benefit assessment are expected.”
But changes in the risk benefit assessment have been seen despite this stance by the FDA.
Several studies indicated that Tamoxifen began to lose its effectiveness after 5 years of use. The same studies showed major side effects dramatically increased at year 5 as well.
One study, the Royal Marsden Trial, followed 2,494 women who were taking Tamoxifen and at risk of developing breast cancer. The 20-year follow up results were released in 2007.
The findings of the 20-year Marsden study indicated that Tamoxifen does not statistically prevent the risk ER-positive breast cancer. But continued to show the drug significantly lowering the recurrence of breast cancer in women previously diagnosed.
This trial also looked specifically at adverse reactions to the drug, specifically endometrial abnormalities and cancer in women in the control group. Out of 111 women examined for evidence of uterine changes after using the drug, all of the subjects had increased cell growth. 39 percent had evidence of abnormal cells, 16 percent had abnormal cell growth, and 8 percent had polyps.
The Marsden trial also found that the longer a woman took Tamoxifen, the greater the risk.
Similarly, the City of Hope Trial studied 35 women who had endometrial changes on Tamoxifen. Of those, 23 developed polyps, and 11 underwent hysterectomies.
Since then, warning labels on the drug have been revised more than 20 times to include stronger warnings and additional risks to a woman’s health.
“Prior to and after the approval of the breast cancer risk reduction indication, FDA worked to ensure that patients and physicians had accurate information on the risks and benefits of Tamoxifen so that they could make informed decisions about whether to take or prescribe the drug. As part of this effort a boxed warning was added and a Medication Guide approved,” said Erica V. Jefferson, FDA spokesperson at its Office of Public Affairs.
Critics have questioned the effectiveness of these label warnings, regardless of the constant revisions.
“People are frightened by these labels and the fact is that a huge list of potential side effects is written primarily to defend the company legally with no indication of prevalence,” said Dr. Iona Heath of the Royal College of General Practitioners in the United Kingdom. “They are not contextualized in any sort of way about how likely that is to happen to you and that information actually is available.”
With pharmaceutical sales being the 3rd most profitable economic activity in the UK after tourism and finance, European drug regulators have also expressed concern about these drug-warning labels.
“Patients clearly wish to be informed about their condition but find it difficult to obtain independent specialist information,” stated a 2005 report to the United Kingdom House of Commons Health Committee. “At the heart of the problem may be the trend for the pharmaceutical industry to become ever more driven by its marketing force.”
In response to these criticisms, AstraZeneca representatives have appeared before the FDA and European regulators to defend their labels and the information given to the public.
“The majority of enquiries about our medicines that come directly from patients and their care providers cannot be fully answered because this would be construed as an ‘illegal promotion’ of a prescription-only medication to the public,” AstraZeneca said in a statement to the UK House of Commons Health Committee in 2005.
“At present, patients can find out more information about the safe use of Tamoxifen from the Internet then they can from the company who discovered it,” said AstraZeneca’s representative.
The UK Health Committee also raised concerns about the accuracy of risk-reports, used to determine what goes on the labels, especially in light of the United States NCI-NSABP Tamoxifen trial with fraudulent misrepresentation of its results.
“We were informed of several high profile cases of suppression of trial results, of selective publication strategies and ghost-writing. The suppression of negative clinical trial findings leads to a body of evidence that does not reflect the true risk: benefit profile of the medicine in question.”
As resistance to label expansion in Europe and troublesome reports have come out as to Tamoxifen’s downside, AstraZeneca has experienced decreased profits in both the US and world market.
This revenue decline is partly attributable to new drugs on the market that appear to have less severe side effects, the introduction of generics, and health care reforms in the US.
In 2011 AstraZeneca reported revenue losses of more than $350 million from generic competition as well as the impact of government intervention in the markets. In 3rd Quarter SEC filings, it reported its US revenue down 5 percent and its Western European revenue down 15% due to generic competition.
“It was once the drug to beat,” said Sophia Walker, Senior Oncology Market Analyst at IHS Financial in the United Kingdom. “In 2002 it lost its patent protection and it suffered a sharp decline. Sales were anywhere from ½ billion to a billion pre-2002. Now they are hovering around 900 million. It’s been a huge drop.”
To counter this revenue decline, AstraZeneca sought to expand label use in countries such as Japan, Canada, Australia, and New Zealand to include ‘preventative’ treatment. Especially as its strategy to expand label use ran into resistance by drug regulators in Western Europe.
“It’s approved in the UK for treatment only-not prevention,” said Walker.
“Neither of the early results from the two initial long-term European Tamoxifen chemoprevention trials-Italian Trial and the Royal Marsden Trial-showed a reduction in breast cancer incidence,” said Walker. “Now focus of cancer prevention in Europe has turned to newer generation-patent protected-drugs.”
Competition by other drug companies like Novartis, with the new generation breast cancer prevention drug ‘Femara,’ are getting the upper hand in the UK Market and have been pushed for approval in the US.
A study published in The Lancet Oncology Journal compared the effectiveness of Femara versus Tamoxifen. The results demonstrated Femara outperforming Tamoxifen after 5 years and with fewer deadly side effects.
Some of Femara’s side effects included bone fractures, increased cholesterol, and possible increased risk of heart disease. Still it was not as effective as Tamoxifen at preventing recurrences of breast cancer from 1 to 5 years after diagnoses.
The study published in The Lancet was funded by Novartis, the manufacturer of Femara.
The next generation of cancer prevention drugs are in varying research and development stages. Until an adequate replacement for Tamoxifen is found, women at risk of breast cancer will have to make the decision whether this controversial drug is right for them.
As for Karen Smith, her chance to make that informed decision has passed. But she does have a word of advice for any woman facing that big decision.
“Take someone with you to the doctor, ask everything. Don’t be afraid to be obnoxious about asking. Don’t leave until your questions are fully answered. It’s your life at stake and your risks to take. If I had done that the pictures in this old photo album would look very different today.
And that hat would say ‘F--- Tamoxifen.’”