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Work continues to define stem cell role in breast cancer treatment
After bad publicity and recent news that a researcher lied about results, Aetna pulled the plug on coverage.
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Investigational treatments are not usually made eligible for reimbursement by insurance companies, even when initial clinical findings appear promising. Autologous stem-cell transplantation with high-dose chemotherapy for breast cancer was unique among unproven protocols because its advocates fought for reimbursement before researchers knew whether the method was effective.
Many clinicians have said it may not work and at least one major insurance company has decided to halt coverage of the controversial procedure. At the time this issue went to press, others were still willing to pay, but with recent news that the only positive clinical study finding on the technique was falsified, referrals for the procedure might disappear entirely.
Brief history
By the mid-1990s, following a series of courtroom defeats and mounting pressure from patients’ rights groups, insurance companies reluctantly agreed to reimburse for autologous stem cell transplantation in the treatment of breast cancer.
The most recent clinical data, however, suggests autologous stem cell support with high-dose chemotherapy holds less promise than once thought. While its advocates defend it as a valid therapeutic option with tremendous potential, phase 3 trials have shown it may be no more effective than the current standard of care. Although companies are still willing to cover the procedure, fewer doctors are referring their patients for treatment.
Some clinicians say the procedure still may offer breast cancer patients their best shot at prolonged survival and argue that it is too early to know for certain whether the treatments work; others say researchers should focus efforts elsewhere.
The controversy surrounding high-dose chemotherapy and stem cell transplantation for breast cancer boiled over at last year’s meeting of the American Society of Clinical Oncology (ASCO), in Atlanta, where four papers presented during the plenary session reported mediocre early results. A smaller study, presented in a general poster session, showed an overall benefit in the high-dose regimen. Later, however, an audit team sent to investigate those results found the team’s leader may have lied about the outcomes, which suggests that none of the studies actually proved the technique offers any therapeutic benefit.
Taken together, the studies presented at ASCO were among the largest randomized, phase 3 trials to compare high-dose chemotherapy regimens and stem cell support with more standard doses.
“The crescendo took place at ASCO,” explained Samuel Silver, MD, PhD, of the University of Michigan Cancer Center in Ann Arbor. “Months prior to the meeting there was a lot of speculation as to what the results would be. It had percolated out that the abstracts were negative.”
Amidst rumors that the trial results were worse than expected, ASCO did something unprecedented: it posted the abstracts on its web site a month prior to the meeting, with an explanation stating that although the results appeared negative in most of the studies, the information contained in them was only preliminary. The organization hoped that its caveat would prevent a public-arena debate on whether the treatment works, knowing any verdict might be premature.
“With that statement, ASCO basically wanted to put these abstracts into context,” Silver said. “I think a lot of people got the idea that the results were released too early, and feared that the insurance companies were going to withdraw payment because of the negativity. This was a snap-shot to tell scientists what was going on and not intended to redefine policy. Nevertheless, the rank-and-file oncologists sitting in the audience saw these results and said ‘Even if it works, it’s not going to be a home run.’”
Two of the five studies presented examined the use of high-dose chemotherapy in metastatic breast cancer, and three investigated its role in treating very high-risk primary breast cancer — breast cancer that has spread to 10 or more axillary lymph nodes.
All of the studies indicated that high-dose chemotherapy with bone marrow or stem cell transplant and standard, lower doses of chemotherapy result in equivalent survival. High-dose chemotherapy is statistically superior in one study.
In the largest singular study of its kind, Edward A. Stadtmauer, MD, and his colleagues at the Eastern Cooperative Oncology Group and the University of Pennsylvania Cancer Center, found that high-dose chemotherapy with stem-cell transplant in the treatment of responding metastatic breast cancer has shown no significant difference in overall survival or lethal toxicity when compared with conventional-dose maintenance chemotherapy.
Stadtmauer’s trial, which began in December 1990, was designed to compare overall survival, time to treatment failure and toxicity in women with metastatic breast cancer whose disease was not responding to chemotherapy.
One hundred one patients received high-dose chemotherapy/stem cell transplant regimen, and 83 received maintenance chemotherapy. The median follow-up time was 37 months. Three-year survival for patients in the stem-cell group was 32%. The survival rate at three years in the maintenance chemotherapy group was 38%.
A randomized Scandinavian study of women with high-risk breast cancer, conducted by Jonas Bergh, MD, PhD, and the Scandinavian Breast Cancer Study Group, also found there is no overall benefit to high-dose chemotherapy with bone marrow or stem cell support vs. those who received chemotherapy doses tailored to blood counts.
Intergroup Study
During the same session, William Peters, MD, PhD, in the U.S. Intergroup Study Group, presented his groups’ results. In a study of 783 patients with primary breast cancer that had spread to 10 or more lymph nodes under the arm, patients were randomized to receive either high-dose chemotherapy (cyclophosphamide, cisplatin and carmustine) with bone marrow and peripheral blood stem cell support, or intermediate-dose chemotherapy using the same drugs at doses that could be safely administered without bone marrow and peripheral blood stem cell support.
The early results of trial indicated that a patient receiving the high-dose therapy with stem cell support has about a 68% chance of living without breast cancer at three years, compared with a 64% chance for a patient receiving the intermediate-dose therapy.
Currently, Peters said both groups of patients in his study are doing well. A little more than 70% of his patients with 10 or more nodes are alive and free of disease after five years.
“The data is substantially better than any other study in the field,” he said. “This is a strategy that we should build upon, not a study that we should discard because in someone’s mind it didn’t live up to expectations that they had set for it.”
South African Study
One study, a 154-patient trial conducted in South Africa, claimed high-dose chemotherapy is effective in the treatment of primary breast cancer, but auditors later discovered the team falsified its results by tampering with control-patient data.
Researchers hoped to prove that the protocol increased survival rates and lowered relapse rates among women who received high-dose chemotherapy and stem cell support, compared to women receiving standard dose chemotherapy. The study was led by Werner Bezwoda, PhD of the University of Witwatersrand Medical School in Johannesburg.
The University of Witwatersrand Medical School is now investigating Bezwoda for scientific misconduct for lying about the trial results. In a letter to his colleagues, Bezwoda acknowledged that he “committed a serious breach of scientific honesty and integrity.” Bezwoda has since resigned his position at University.
As a result of this news, Aetna, the nation’s largest heath insurance company, has decided it will not longer cover the procedure, except for those patients currently enrolled in federally sponsored investigations. Other insurers are still willing to pay, but for how long is uncertain.
Wait and see
Gabriel N. Hortobagyi, MD, of the department of breast oncology at the M.D. Anderson Cancer Center in Houston does not support the regular use of high-dose chemotherapy and stem cell support in the treatment of breast cancer, but said that the therapy still may have potential.
“One interpretation of this data is that a strategy which uses standard-dose induction followed by high-dose chemotherapy consolidation and stem cell support does not work in either metastatic or high-risk breast cancer, but a more complex assessment of the data would suggest that that interpretation is probably not completely true,” Hortobagyi said.
Hortobagyi, who occasionally refers patients to a stem cell support clinical trial, notes that in Peters’ study there was a decrease in the number of relapses or recurrences with high-dose therapy as compared with standard therapy, but cautions that any interpretation of those finding be tempered with the knowledge that the decrease in the number relapses was matched by an increase in the number of toxic deaths.
“So, while there may be a conceptual advance in treatment strategy, there was no net gain. Do I think there is any place for high dose therapy with stem cell support now? No. Regarding its future application, I will reserve judgement,” he said.
Keeping it in context
Peters would like his other colleagues to follow Hortobagyi’s example and wait and see.
“One cannot take any singular set of results and try to draw a conclusion from them,” Peters said. “When we presented the data, we knew we were 3 years too early to have defined a disease-free survival difference between the three groups. We did this because there was information in our study that would be useful to patients in helping them define alternatives.”
In retrospect, Peters said the decision to present his data early was probably not a good one.
“I regret the result of going early, but I don’t regret actually doing it,” he said.
“I was persuaded to go early with the data by some of the women’s advocates who pointed out that it would be valuable to have data for women presented in the appropriate venue to help them in facing a difficult circumstance. Unfortunately, the media reduced everything to a four-word headline, and some complicated issues that attended four separate studies, which were quite different in their respective characters were lost,” he said.
Fewer treatment referrals
Despite the less-than-encouraging findings, insurance companies did not, to the surprise of some, back away from their promise to reimburse for the procedures. Following presentation of the papers, it was the medical community that appeared to lose interest as the number of referrals for treatment dropped precipitously. One company which aids physicians in establishing local transplant centers reported a 66% decrease in business after the ASCO meeting.
“In the month between the time abstracts went up on the web and the ASCO meeting, it really went down,” said Peters, who runs his hospital’s stem cell clinic. “There was unimpeded negative press out there and the referral rate went to virtually zero. I can’t speak for the other centers, but I expect it to come back to pre-ASCO levels, because the truth is, there isn’t much else out there.”
Peters said several third-party payers contacted him after the ASCO meeting to discuss the papers and what they would mean to future referrals.
“The insurance companies had noticed that the referral rates had gone way down and they didn’t think the data was all that bad and urged us to continue doing research in the area,” he said.
Richard Watt, MD, medical director of United Resource Networks (URN), a Minneapolis-based transplant benefit management service provider, said he saw a moderate decrease in the number of referrals for high-dose chemotherapy with stem cell support after ASCO.
For now, UnitedHealth Group, URN’s parent, will continue to reimburse patients for the procedure. After Bezwoda’s announcement and Aetna’s decision, company officials said that they believe the use of stem cell support in combination with high-dose chemotherapy is decision that should be left to patients and their physicians. Yet, even before the South African scandal, some clinicians said they felt the same way.
“It would be foolish for the insurance companies to go back to the reasoning of the early 1990s and withdraw payment,” Silver said. “Patients would go back to court to fight for reimbursement, and they would likely win. By no longer referring patients, the referring oncologists accomplished a goal of the insurance companies.”
Silver said large phase 3 trials involving hundreds of randomized patients would be necessary for clinicians in any number to reconsider this option.
Peters has planned three.
One of the studies is in patients with four or more positive nodes and is designed to compare high-dose therapy to standard dose therapy. Another will compare up-front vs. adjuvant therapy plus transplant in metastatic disease, and a third will compare two different regimens anchored to CPB-therapy, but will look at a single versus double transplant in an inflammatory disease.
In addition to scientific inquiry, two external factors may be driving the continued research into stem cell support, even though initial findings failed to sustain widespread interest. The first is the economic implication of abandoning research, and the second is the perceived need to make medical progress in a high-profile disease.
Since insurance companies agreed to reimburse health providers for the procedure, a cottage industry has developed around it. Additionally, women’s health advocates are focusing a great deal of attention on breast cancer.
“Patients with metastatic breast cancer do not do well, and therefore the oncology community was more than willing to accept relatively poor data to support the illusion that we were making progress,” Hortobagyi said.
Peters agrees that the external issues surrounding the use of stem cell support in breast cancer makes it more controversial than it might otherwise be.
“It is a high-profile, expensive therapy, with a for-profit angle, and as a result, everyone saw in the data what they wanted to see,” he said.
For Your Information:
- Peters WP. A prospective, randomized comparison of two doses of combination alkyating agents as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes: preliminary results of CALGB 9082/SWOG 9114/NCIC MA-13. Abstract #2.
- Bezwoda WR. Randomized, controlled trial of high dose chemotherapy vs. standard dose chemotherapy for high risk, surgically treated, primary breast cancer. Abstract #4.
- Jonas Bergh, et al. Results from a randomized adjuvant breast cancer study with high dose chemotherapy with CTCb supported by autologous bone marrow stem cells versus dose escalated and tailored FEC therapy. Abstract #3.
- Stadtmauer EA. Phase III Randomized trial of high-dose chemotherapy and stem cell support shows no difference in overall survival or severe toxicity compared to maintenance chemotherapy with cyclophosphomide, methotrexate and 5-fluorouracil for women with metastatic breast cancer who are responding to conventional induction chemotherapy: the Philadelphia Intergroup Study. Abstract #1.
- Lotz J-P. High-dose chemotherapy with hematopoietic stem cells transplantation for metastatic breast cancer : results of the French protocol PEGASE 04. #161. All presented at ASCO, May 15-18, 1999. Atlanta.