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In Defense of Futile Gestures

Stuart H. Bloom

From the Hubert H. Humphrey Cancer Center, Robbinsdale, MN

Corresponding author: Stuart H. Bloom, MD, MS, Minnesota Oncology Hematology, PA, 800 E 28th St, Piper Building, Suite 405, Minneapolis, MN 55407-3799; e-mail stuart.bloom{at}usoncology.com

INTRODUCTION

I bounded into the room, late as usual, and stopped short. There sat Marni Adams, calm, healthy, eyes full of mischief. Her smile came from deep within.

"Did you forget me, Doc?" Tears came to my eyes in response. Forget Marni Adams? Forget the person who showed me the life-affirming benefit of the futile gesture?

INHERITING MARNI

I had originally met Marni a year and a half earlier on weekend hospital rounds. She was in the middle of her third try of induction chemotherapy for a refractory, poor-risk acute myelogenous leukemia that had developed in the setting of essential thrombocythemia. Still, a few months shy of her 50th birthday, she looked surprisingly fit. She and her husband had a hundred questions regarding her disease, prognosis, and plan for treatment that apparently had not been addressed by her primary oncologist, who was a brilliant diagnostician but not known for his patient communication skills. With her chart in my lap, I sat on the edge of her bed, held her hand, and gently told her what I assumed was old information, that her only chance for cure was to get her disease in remission, then send her for an allogeneic peripheral blood stem-cell transplant. However, she was in the middle of her third try at remission, so the chances of this actually happening were pretty low. Absent remission, we could try a clinical trial of a novel agent, troxacitabine, but this would mean she would have to remain in the hospital for perhaps another month, and again, the chances of success were slim. Focusing on her comfort alone, and not actively treating the leukemia at some point, certainly seemed reasonable. I paused, let this all sink in, and wondered about her response.

It was not what I expected. "Would you be my doctor?" she asked. My heart sank. I had just given her extraordinarily bad news. She said all this actually was new information. I doubted that, but maybe after nearly 2 months in the hospital, she was finally ready to begin dealing with everything. And maybe I was the guy to help her do this. Not surprisingly, her primary oncologist had no problem with this arrangement.

My new patient failed her third attempt at inducing a remission. A consultation with a tertiary care referral center recommended a fourth attempt (yes, a fourth), which we tried and, of course, that didn’t work. At that point, no longer a candidate for transplant, they recommended supportive care alone.

Marni, as she always had, still looked great and really had only minimal complications from all the previous chemotherapy. Though she needed regular transfusions, she was delighted to be out of the hospital, going out to lunch with friends, and hanging out with her children. We talked about troxacitabine, although only one of nine patients who received this treatment with refractory acute myeloid leukemia (AML) had a complete response.¹ We decided to go with supportive care alone, although Marni continued to have some trouble not actively treating her leukemia. She asked me how long she could live with this approach. I told her that the longest I’ve seen in her situation was about 1 year, though we would just take it a day at a time. The aim of therapy here was to maximize her quality of life, as well as help her live as long as possible. She heartily endorsed both of these goals.

One month later, still feeling fine, Marni had a change of heart. She just couldn’t live with not doing something to fight her cancer. I felt the chance of any intervention having a meaningful outcome was vanishingly low, and probably futile.² Marni was undeterred. Wasn’t there something, anything, we could try as an outpatient?

IS MORE THERAPY MEDICALLY FUTILE?

While the Oxford English Dictionary defines futility as "incapable of producing results; useless, ineffectual, vain"³; there really is no consensus regarding its meaning in a medical context.^2,4,5 Schneiderman and colleagues proposed that there are two aspects to medical futility: qualitative and quantitative. Qualitative futility is a therapy that sustains permanent coma or dependence on intensive medical treatment, and therefore does not have a meaningful effect on quality of life. A treatment is quantitatively futile if there is an arbitrarily defined chance of benefit of lower than one in 100.⁶

Qualitative futility did not apply to Marni, because far from being in a coma, she was active and vigorous. She still had an implanted catheter, and needed serial transfusions. But she had appropriately gained weight, was pain free, and had decent energy. Any antineoplastic treatment she would get would almost certainly make her feel physically worse. But psychologically she was having understandable difficulty, and though it would come at the cost of the adverse effects of therapy, she made it clear that her mental state would improve with going back on active treatment. I told Marni, when asked, that this was a trade-off I myself would probably not have accepted.

However, more treatment almost certainly was quantitatively futile. After four failed attempts at inducing a remission, I felt the chance that any medical therapy could affect her leukemia, and therefore help her live longer, was vanishingly small. If pressed to quantify, lower than one in 100 was a reasonable guess. I have always believed, as Harnett and Moynihan⁷ suggested in a previous Art of Oncology piece, that continuing toxic therapy in the hope of some response is inadequate medicine. Yet, as Ewer⁸ pointed out, our prognostic acumen is often insufficient to predict which patient will defy statistical odds and improve when, by all subjective and objective criteria, it is beyond the realm of possibility. This thought lingered. Always quick to acknowledge the limitations of my own knowledge, I wondered. Was there a therapy somewhere that could help Marni Adams?

SEARCHING ABSTRACTS

Like most people practicing oncology today, the principles of evidence-based medicine are hard-wired into my system. To stray outside these conventions, would be tantamount to practicing based on anecdote. Although some have suggested the importance of the anecdote,⁹ I have never been among them. During my fellowship, I smugly vowed I would never treat someone based on data that had not been published. In the absence of data, I have always relied on expert opinion. But the mentors with whom I discussed Marni all had the same response: "Hmmm, tough case." No one had an answer outside of supportive care alone. However, the pace of Marni's disease, her easy tolerance of her prior treatments, and her excellent performance status indicated to me that she could probably tolerate further therapy, if the right regimen could be found.

And so, not for the first time in my career, I began searching abstracts. The truth was I already had patients who benefited from therapies only presented in abstract form. A woman the same age as Marni with refractory myeloma received concurrent bortezomib, liposomal doxorubicin, and thalidomide¹⁰ (despite separately receiving all these agents previously), and she lived 1 year longer than I had predicted that she would have, had we not tried the regimen. Three patients with relapsed Hodgkin's disease all had a complete response with an easily tolerated combination of gemcitabine, vinorelbine, and liposomal doxorubicin.¹¹ Still, I told myself, and Marni, not to get our hopes up. I would only consider something that had come from a reputable academic center, had a plausible mechanism of action, and most importantly, was not too toxic.

And, lo and behold, there it was. Abstract 2,798 from the 2005 American Society of Hematology Annual Meeting proceedings described an outpatient regimen of all-trans retinoic acid, valproic acid, and 5-azacytidine given to five patients with refractory AML as part of a pilot study.¹² The patients were similar, although not identical to Marni. The study was from a respected international leukemia group. The rationale for the drugs was reasonable and the adverse effects were minimal. Two of the drugs were pills, the other a subcutaneous injection easily tolerated by 80-year-old patients. And it could all be given as an outpatient. Three of the five patients responded.

"What's the catch?" Marni asked.

"It may not work," I replied. Nonetheless, we got started with the regimen immediately.

RECEIVING FUTILE THERAPY

Marni, as per her norm, tolerated the therapy well. She had some nausea from the all-trans retinoic acid, controlled with ondansetron and prochlorperazine. By the end of the second cycle, her counts began to improve. At the end of the third cycle, I ordered a bone marrow biopsy. Her blast percentage had gone from 67% to 0%. Her cytogenetics were still abnormal, representing minimal residual disease. However, she was now a candidate for an allogeneic transplant. Two more cycles of the regimen followed. She received her transplant 1 year ago. Her most recent bone marrow showed no evidence of leukemia.

WITHOUT A SENSE OF IRONIC FUTILITY

"Those who cannot remember the past," says the filmmaker Errol Morris, "are condemned to repeat it without a sense of ironic futility." As oncologists, we are conditioned to accept that, in advanced cancer, our treatments will ultimately fail our patients, and that in the end, anything we offer will be futile. But the truth is that futility can only be confirmed in retrospect. For the vast majority of patients with refractory AML, more treatment is this setting would absolutely be futile. I hasten to add that, in the future, I will not be offering all patients with refractory AML more and more treatment, outside of a clinical trial. In fact, if I see 10 more patients with refractory AML, the chance that anyone of them would respond the way Marni Adams did is tiny.

However, it apparently isn’t zero.

WITH A SENSE OF IRONIC FUTILITY

Back in her room, Marni and I hugged. She smelled of tobacco. I couldn’t believe it. "When are you going to quit smoking??" I demanded.

"I’ve tried everything," she said sheepishly. "But, it's futile."

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

NOTES

Author's disclosures of potential conflicts of interest and author contributions are found at the end of this article.

REFERENCES

1. Roboz GJ, Giles FJ, Ritchie EK, et al: Phase I/II study of continuous-infusion troxacitabine in refractory acute myeloid leukemia. J Clin Oncol 25:10-15, 2007[Abstract/Free Full Text]

2. Von Gruenigen VE, Daly BJ: Futility: Clinical decisions at the end-of-life in women with ovarian cancer. Gynecol Oncol 97:638-644, 2005[CrossRef][Medline]

3. The Shorter Oxford English Dictionary. London, United Kingdom, Clarendon Press, 1965, pp 765

4. Zucker MB, Zucker HD (eds): Medical Futility and the Evaluation of Life-Sustaining Interventions. Cambridge, United Kingdom, Cambridge University Press, 1997

5. Rodriguez KL, Young AJ: Perceptions of patients on the utility or futility of end-of-life treatment. J Med Ethics 32:444-449, 2006[Abstract/Free Full Text]

6. Schneiderman LJ, Jecker NS, Jonsen AR: Medical futility: Response to critiques. Ann Intern Med 125:669-674, 1996[Abstract/Free Full Text]

7. Harnett PR, Moynihan TJ: "But doctor, what have I got to lose... ?" J Clin Oncol 19:3294-3296, 2001[Free Full Text]

8. Ewer MS: The definition of medical futility: Are we trying to define the wrong term? Heart Lung 30:3-4, 2001[CrossRef][Medline]

9. Enkin MW, Jadad AR: Using anecdotal information in evidence-based health care: Heresy or necessity? Ann Oncol 9:963-966, 1998[Abstract/Free Full Text]

10. Chanan-Khan AA, Miller KC, McCarthy P, et al: A phase II study of velcade, doxil in combination with low-dose thalidomide as salvage therapy for pts with relapsed or refractory multiple myeloma and Waldenstrom's Macroglobulinemia. Blood 104, 2004 (abstr 2421)

11. Bartlett N, Niedzwiecki D, Johnson J, et al: A phase I/II study of gemcitabine, vinorelbine, and liposomal doxorubicin for relapsed Hodgkin's disease. Proc Am Soc Clin Oncol 22:566, 2003 (abstr 2275)

12. Raffoux E, de Labarthe A, Gardin C, et al: Sequential treatment with 5-azacytidine, valproic acid (VPA) and all-trans retinoic acid (ATRA) in pts with high-risk acute myeloid leukemia (AML). Blood 106, 2005 (abstr 2798)

Submitted October 29, 2007; accepted November 12, 2007.

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