- © 2003 by American Society of Clinical Oncology
Why Not Start With Thalidomide?
- Address reprint requests to Charles L. Loprinzi, Division of Medical Oncology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905; email: cloprinzi{at}mayo.edu.
THE CASE (AS TOLD BY AN ANONYMOUS PATIENT WITH NEWLY DIAGNOSED MYELOMA)
After several months of unexplained bony aches and pains, the diagnosis of multiple myeloma was finally made in me, a 62-year-old woman. At diagnosis, a pathologic fracture of the left hip was noted, requiring an orthopedic pinning for stabilization.
During the ensuing discussion regarding the natural history of the disease and options for therapy, my husband and I were told about promising results with thalidomide in patients with myeloma who had been failed by almost all other therapies.1,2 An even more recent finding that the drug also seems to work well as initial therapy for myeloma was also discussed.3,4 After clarifying many of my initial concerns about therapeutic options and goals, I was offered a clinical trial in which patients with newly diagnosed myeloma are randomly assigned to receive either high-dose dexamethasone (considered as a standard initial therapy) or high-dose dexamethasone plus thalidomide.
After our initial consultation, my husband and I gleaned information from a variety of sources, including friends, the Internet, and the lay press, many of which extolled the use of thalidomide in patients with multiple myeloma.5,6 Several questions arose. Why, with all of the benefits ascribed to thalidomide, was a randomized trial necessary? Shouldn’t thalidomide just be used upfront, as prominently publicized in the media? Why should a computer decide (like a flip of the coin) whether or not I received thalidomide, given all of the clearcut benefit ascribed to thalidomide in recent studies? As might be expected, these questions generated considerable discussion between my husband, friends, healthcare providers, and me.
With this diagnosis of multiple myeloma, I thus set out on a journey I had not planned to a place that had a language that I had to try to learn. I was reminded of the summer when I took introductory geology at the University of Iowa. In my second year of college, while still learning English, I was trying to learn new geologic terms, pronounce them correctly, understand new concepts, memorize ages, and retain other factual information. At first, it was daunting, but it became familiar with repetition. Hearing the diagnosis of multiple myeloma was very frightening because I saw my life cut short right there. Talking to doctors and learning more about it brought back some calm, because I realized that something could be done about it. Deciding what the treatment should be posed problems in itself, though. Nowadays, the patient is told that she is her own best advocate. But I knew that I would not know as much as my doctor unless I studied medicine.
Therefore, I needed to have faith in my physician and trust that he would decide on the best possible treatment for me. There was a time when people had too much faith in doctors and put them on a pedestal, and oftentimes, patients were disappointed when the professionals turned out to have clay feet. Patients are warned now that they need to look out for themselves. I knew, however, that I still needed to have faith in my doctor and the medical staff, but I was told not to have blind faith. I guess one could call it educated faith. Is that faith though? At any rate, I needed it because I knew I could not rely on the little bit of knowledge I had accumulated on my own.
HERE’S WHAT WE DOCTORS UNDERSTAND AT PRESENT
It is now apparent that thalidomide, a sedative abandoned in the early 1960s because of severe teratogenicity, is an effective agent for the treatment of multiple myeloma.7 Responses are seen even in patients who have failed all other standard therapies, including stem-cell transplantation. Although we still do not fully understand the incidence and severity of the long-term toxicities of thalidomide therapy or the best dose and schedule for clinical use, it is evidently clear from numerous clinical trials that it does provide substantial clinical benefit for approximately one third of patients with advanced myeloma.7 Studies show that the median response duration is approximately 1 year in this setting, with approximately 20% of patients disease-free at 2 years.2
It has recently been hypothesized that long-term results will be better when thalidomide is used as initial therapy. This led investigators at the Mayo Clinic and the M.D. Anderson Cancer Center to study the use of thalidomide as initial therapy for myeloma. In these phase II studies, thalidomide was used as single agent for early-stage asymptomatic myeloma and, in combination with dexamethasone, for symptomatic disease.3,4,8 The results from the two institutions are remarkably similar. As a single agent in early-stage, asymptomatic myeloma, thalidomide reduces tumor burden (measured by monoclonal immunoglobulin level changes) by 50% or more in approximately one third of treated patients. In combination with dexamethasone for symptomatic myeloma, two thirds of patients achieve a 50% reduction in tumor burden. Given the notoriety of thalidomide, the results of these studies were reported widely in print and in the electronic media.5,9
Despite the results described above, what we still do not know is whether the early use of thalidomide in patients with myeloma is actually beneficial for them in the long run. Will this strategy improve overall survival? Does therapy with thalidomide alone in patients with asymptomatic disease delay the need for stem-cell transplantation and other chemotherapy regimens? Will the combination of thalidomide plus dexamethasone be an effective oral alternative to more aggressive intravenous chemotherapy regimens in myeloma such as vincristine, doxorubicin, and dexamethasone? It is possible that early use of this drug may help patient quality and quantity of life? Or, alternatively, is it best to reserve this drug to be used when other more standard therapies have failed?
Another concern is toxicity. How much additional toxicity does thalidomide add to therapy with dexamethasone alone? How does the improvement in response rate compare to the added toxicity? The bottom line is that although thalidomide is a promising drug for initial therapy of myeloma, additional evidence regarding its true value is needed from randomized trials, such as the one offered to this patient.
DISCUSSION
Hype Versus Truth
There are many examples where the initial hype with new oncologic therapies have not borne out to really represent the truth. One example of this, dating back a century or so, concerns the use of radical mastectomy, first proposed by Dr Halsted in the early part of the last century, as an effective surgical means of treating breast cancer. Back when one of us was in medical school, which really wasn’t that long ago, an experienced surgeon was extolling the virtues of radical mastectomy and couldn’t understand why these young whippersnapper surgeons were suggesting that something less aggressive (ie, a modified radical mastectomy) might be just as good as a radical mastectomy. Had not, this experienced surgeon went on to say, Halsted clearly proven that a radical mastectomy was the right way to go and something less than that would lead to diminished patient survival? Nonetheless, it is now well appreciated that this assertion was wrong, and that less-aggressive surgery is preferred.10,11
Similarly, many will recall that interferon was on the front page of a prominent lay newsmagazine approximately 20 years ago. How much do we hear about interferon now in terms of a cure-all for cancer? Likewise, interleukin-2, approximately a decade ago, graced the front pages of lay newsmagazines. Again, how much do we presently hear about interleukin-2 as a cure-all for cancer now?
In many situations, the initial enthusiasm about new therapies is based on uncontrolled trials, generally tempered at a later date by results from randomized controlled trials. For example, at one time, considerable enthusiasm ensued based on phase II trials for several aggressive chemotherapy regimens to treat diffuse large-cell lymphoma. Survival rates in these uncontrolled studies were reported to be much better than had been reported with standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. In fact, leaders of the United States oncology community at the time stated that “ProMACE-MOPP [prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide–mechlorethamine, vincristine, procarbazine, and prednisone] combination chemotherapy represents a substantial improvement in the treatment of diffuse aggressive lymphomas as compared with previously used regimens.”12 Nonetheless, a subsequently completed large randomized trial found that such regimens were more toxic than CHOP with no added benefit, thereby proving that the initial enthusiasm was hype, not truth.13
Finally, a valuable lesson can be learned from thalidomide itself. This drug was first marketed in the late 1950s, in more than 40 countries, as a sedative.7 At the time it was introduced, adequate safety testing for use in pregnancy had not been conducted. For almost 5 years, the drug was hyped to be one of the safest sedatives around and proved very effective for pregnancy-related morning sickness. Unfortunately, thalidomide turned out to be a severe teratogen and affected over 10,000 infants worldwide. At that time, the United States Food and Drug Administration was concerned about thalidomide-induced peripheral neuropathy, and it did not approve thalidomide for clinical use in this country. This is an important reason why the United States Food and Drug Administration takes time to evaluate new drugs carefully for safety before making them available for widespread clinical use. This example also illustrates how initial hype about the safety and efficacy of a drug may turn out to be gravely misleading.
Societal Versus Individual Perspectives
From a societal perspective, the best choice of therapy for a patient with newly diagnosed myeloma (and for that matter, most other incurable cancers) would be participation in a peer-reviewed and approved clinical trial, if available. This is the best way for cancer therapy to advance and bring benefits to future patients and to society as a whole. There is not much debate here.
What about from an individual perspective? The same argument could clearly be made that it is most reasonable, from an individual conservative perspective, to go with the randomized clinical trial because we just don’t know the benefits of thalidomide in this situation. Nonetheless, this is a free country, and there are some people who wish to take a gambling perspective as opposed to a more conservative perspective.
Are Randomized Trials Always Needed?
Some people may say that randomized trials are not always needed and that sometimes they are unethical when there is obviously a better therapy to be given. As alluded to above, however, there are multiple times when these randomized trials do demonstrate that the older, more conservative therapy is the right one. A recent example with hormone replacement therapy (HRT) is one of the most stunning reminders of the importance of randomized trials. In this case, numerous uncontrolled studies virtually proved the benefit of HRT for the prevention of coronary disease. Yet the results of a recently completed large randomized trial proved that HRT may actually be harmful.14
Nonetheless, in oncology, there are rare situations where randomized trials are not necessary. One such example of this deals with the treatment of germ cell cancers. In this instance, in the 1970s, new therapies with platinum-based chemotherapy regimens were able to clearly cure many patients, when previously this had not been nearly so prevalent.15 A randomized trial in this situation should never haven been, and never was, performed. A more recent example is shown with the use of imatinib mesylate (Gleevec; Novartis, East Hanover, NJ) for gastrointestinal stromal cell tumors.16 Unfortunately, these situations, where the new therapy is clearly beneficial by a large degree, are relatively rare.
Choices and Implications for the Patient in This Situation
It seems that there are three potential choices for the patient in the situation described in the beginning of this article. One choice is to enroll onto the randomized clinical trial. In this situation, she may be randomly assigned to receive thalidomide, something that the patient and spouse are really hoping to receive (and society may learn something). By proceeding along this route, however, a risk clearly is taken that she will not be randomly assigned to get the thalidomide, but she could take comfort in the fact that the benefit of thalidomide as initial therapy is not yet established.
The second option for this patient is for her to take thalidomide off study. This may cause some troubles with insurance reimbursement, but some patients may wish to bear this risk. It also raises some ethical concerns for the physician in terms of prescribing promising but yet unproven therapy. Moreover, this approach does not allow for societal learning, and the patient may be getting a therapy that may not be more beneficial than standard therapy, or worse, may prove to have decreased efficacy and/or excessive toxicity.
A final option, one that hopefully not many choose, is for this patient to enter the clinical trial hoping to be randomly assigned to the thalidomide plus dexamethasone arm but withdraw from the trial if she is randomly assigned to the dexamethasone-alone arm. This situation might have been avoided if the study offered to her had been designed as a double-blind, placebo-controlled trial.
How Can the Oncologist Help the Patient Make a Right Decision?
Explaining the benefits of making the right decision in this situation can be time consuming and difficult to say the least. How do we really know that this new therapy, one that is touted so much, is not beneficial? Why can’t the patient and doctor make a choice and get thalidomide when it sounds so promising? Are physicians, who have an additional role as clinical investigators, able to act primarily as the patient advocate and provide unbiased recommendations to their patients? Are they not likely to benefit from an academic standpoint by leading, participating, and accruing to high quality, high-profile research trials? Is there not a conflict of interest in these situations, one less publicized but one that may be more important than the financial conflicts that have been the subject of much discussion? Should the oncologist primarily consider the best interest of the patient or the best interest of science and society?
The answers to these questions can be tough. It is vital that these issues should be considered when the randomized trial is being designed. The single most important consideration in the design of randomized trials is that the investigators truly not know which of the comparison arms is better. There should be genuine uncertainty and, at the same time, hope that the results of the trials will improve patient care. In rare situations in which one arm is clearly better, randomized trials are not ethical. In this present case regarding thalidomide, clearly no one can be sure which of the two arms will come out the winner. Although there is a high likelihood that the combination of thalidomide plus dexamethasone may have higher response rates, it is quite likely that there is significant added toxicity with the combination, such as excessive deep vein thrombosis or neuropathy. Secondly, the oncologist should always consider the best interests of the patient. Merely because the patient meets eligibility criteria for a trial does not mean that participating in that clinical trial is the best treatment option for that patient. Eligibility criteria should be considered as minimum requirements. The decision on whether offering the trial is in the best interest of the patient should be in conjunction with using the eligibility criteria to ensure that the patient meets the minimum parameters. As Dr William J. Mayo once put it in a speech to the graduating class of Rush Medical College, “the best interest of the patient is the only interest to be considered.”17 Finally, the oncologist should be willing to take the time to discuss all available options and help the patient make an informed decision in a noncoercive fashion. This way, the patient feels like part of the decision-making process and is less likely to drop out of the study if she doesn’t receive the randomized study arm she desired or when things do not go well.
Conclusion
During the 2 weeks from diagnosis until systemic therapy was to be initiated (with the patient having undergone her hip pinning during this time), there were multiple discussions regarding these issues. During these discussions, a draft of the present essay was developed, in an effort to get some of the discussion items down in writing for mutual study and reflection. Additionally, the patient and her husband came across a local resident from their hometown that had received thalidomide as initial therapy for multiple myeloma but did not respond to this therapy. In the end, this patient decided to participate in the randomized trial and was, by chance, randomly assigned to the combination arm of thalidomide plus dexamethasone.
Acknowledgments
We thank the anonymous patient whose input helped in the development of this piece.
- Received March 19, 2003.
- Accepted March 19, 2003.
