INTRODUCTION

There is reason for patients and physicians to question the role of palliative chemotherapy in patients with advanced malignancy. In this unfortunate clinical situation, patients and physicians often turn to palliative care and hospice care in lieu of chemotherapy, which is clearly palliative and offers the prospect of limited effectiveness with unpleasant adverse effects.¹

The important question to be asked is when is it too soon to abandon the prospects for a favorable outcome from investigational therapy. Many authors have concluded that investigational therapy offers such small promise of benefit that it is not worth considering. It is the purpose of this communication to emphasize the potential for investigational therapy; to illustrate it with a description of two real patient experiences; and to encourage physicians not to abandon therapeutic approaches for their patients too soon.

ONE PATIENT'S STORY

Mr X was a 35-year-old successful businessman who developed weakness, went to his physician, and was found to have pancytopenia. A bone marrow examination revealed the diagnosis of hairy cell leukemia. At the time of diagnosis there was no proven therapy for this disease, and the patient was advised to seek palliative care. After considering that option, he searched the country for clinical research that offered investigative therapy for this untreatable, uniformly fatal diagnosis. He found an institution that had just begun clinical trials with a crude preparation of interferon alfa 2a prepared from pooled normal-donor leukocyte Buffy coats infected with Sendai virus and which stimulated the leukocytes to secrete interferon alfa 2a into the supernatant plasma. This was partially purified to yield the product that had less than 1% interferon. Investigators at that institution had decided to conduct a broad phase II clinical trial to study this protein because of its antiproliferative effects in vitro. Mr X traveled to this research institution, enrolled onto the study, and was one of the fortunate ones who achieved a complete remission of his disease. This remission lasted for 9 years, after which the symptoms of hairy cell leukemia returned. At this point, he was advised that interferon was rarely active in patients who had experienced relapse after interferon therapy, that there was no effective therapy for his relapsed leukemia, and that he should consider palliative care.

Because he had enjoyed tremendous success in his family life, social life, and business life during the previous 10 years, he decided that he would again seek investigational therapy. He returned to the major comprehensive cancer center and found that during the 9th year of his remission, a new compound, chlorodeoxyadenosine, had been discovered that seemed to be highly effective for hairy cell leukemia in its early clinical trials. He enrolled onto a phase II confirmatory trial, and once again, he fortunately achieved a complete remission of his disease. This remission lasted for 5 years, and the patient returned to his normal activities.

His disease recurred for a second time. He was again told that the chances of response to either of those agents was now small and that he should consider palliative therapy. Instead, he returned to the clinical research center, where he was offered a second treatment with chlorodeoxyadenosine. During the intervening 5 years, the dosage schedule of the use of this drug had improved, and it was now a highly successful treatment for hairy cell leukemia. He again achieved a complete remission.

His third remission lasted for 6 years, after which he was told that he should consider palliative care for the now-resurgent disease. Having enjoyed 20 years of a return to completely normal life after being advised that he had a hopelessly terminal illness, he was certainly not prepared to accept this route.

He returned to the research center, where he was offered a new investigational treatment, this time with a monoclonal antibody called rituximab, which directed activity against the surface antigen CD20. It had many adverse effects—fever, chills, unpleasantness—which he gladly endured. His disease improved for approximately 1 year but then progressed. At this point, much more experience with rituximab had been obtained, so he returned to the research institution and received a second round of this therapy, which was again successful in controlling his disease. This remission lasted for 2 years.

When his disease recurred for the sixth time, he again refused to accept palliative care and was enrolled onto another investigational therapy, this time with an anti–tumor necrosis factor antibody that had just been developed. This treatment was not successful. At that point, he was offered another treatment with chlorodeoxyadenosine, but on this occasion combined with rituximab. This combination resulted in a complete remission that lasted for 2 years.

For his next relapse, he was treated with a drug that had been discovered during his illness, fludarabine. This caused severe myelosuppression that resulted in Aspergillus pneumonia, which was treated with newly discovered antibiotics. After improving substantially, he discovered an investigational treatment at another research institution using a monoclonal antibody directed against a different surface antigen, CD22. He participated in that clinical trial with a partial remission, which lasted for 6 months. When his disease recurred he found a clinical trial that offered a repeat of interferon therapy, but on this occasion with a new recombinant interferon preparation that had been discovered during his illness. This was not the crude preparation that he received 22 years before, but rather now was in a pegylated formulation, which allowed less frequent administration. Astonishingly, he achieved his 8th complete remission.

While in remission, the patient returned to a completely vigorous life. He went on a hunting trip far away from civilization without transportation, and tragically, developed an infection with a highly invasive bacterium resistant to antibiotics. The patient expired from septicemia less than 24 hours after the diagnosis of this infection. He did not have active hairy cell leukemia at the time of his death, 23 years after he was advised to receive palliative therapy for a uniformly fatal, highly morbid form of leukemia.

A SECOND PATIENT'S STORY

Mr Y was a 44-year-old man with hairy cell leukemia who was treated with 2-chlorodeoxyadenosine while the drug was still experimental and before its success was widely known. After treatment, he returned to his home state. Approximately one week later, the patient's primary care physician called the research center to inform his physician there that the patient was neutropenic, septic, in respiratory failure, and about to die, probably within minutes to hours. In light of his serious condition and his underlying leukemia, a decision had been made by the family, together with the physician, not to resuscitate or ventilate.

The early, remarkable results with 2-chlorodeoxyadenosine were reported to the local physician with the strong recommendation that the patient be intubated electively in the next few minutes and be treated aggressively with antibiotics. The physician expressed dismay at the aggressive course of action suggested, as he felt that enough was enough. Nevertheless, he discussed the circumstances with the patient and the family, and they requested immediate intubation, which he arranged. Five days later, the primary care physician called back to report that the patient's neutrophil count had increased the day before and that the patient was extubated that morning. The patient attained a complete remission without additional treatment and returned to the research clinic for check-ups for the next 10 years, after which he chose to be followed exclusively at home. He has not relapsed and remains well, working full time.

PERSPECTIVES

We all live our lives in the future. We base most of our decisions on experiences of the past, but we have limited ability to envision the potential for major changes in the future. Consider the enormous change in outlook for patients who have coronary artery disease, where mortality from this disease has declined more than 30% in a decade. In many fields of medicine there is continuing progress, improvement, and opportunities, and as physicians in advising our patients, we have to be prepared for success. When patients receive hopeless diagnoses, it is important for the physician to discuss palliative care,¹ but it is equally important—and perhaps more so—for the physician to be knowledgeable about, and to discuss frankly and positively with the patient, the options for participating in clinical research at major research centers where new therapies are being developed.

Many patients are advised that participation in early clinical trials has a record of a low frequency of benefit, perhaps 3%. Is 3% too low a probability of success to participate in such trials? The answer is that for the 3% it was certainly worthwhile, particularly for those patients who have long-term benefit. Furthermore, benefit rates from even the earliest experimental trials in the most dismal setting—advanced, refractory cancer—may have been underestimated. Indeed, a meta-analysis showed that the complete and partial remission rate for phase I cancer trials was 10.6% among almost 12,000 patients, with approximately a 44% benefit rate if less than partial remission and disease stabilization were included.^2,3

One of the authors (E.J.F.) has been a physician involved in caring for cancer patients with diagnoses of terminal illnesses for more than 50 years and has personally cared for hundreds of patients who have had dramatic, life-altering benefits from investigational therapies. This physician has assisted in caring for the first patient with metastatic choriocarcinoma to be treated with high-dose methotrexate, a patient who is still alive today 50 years after her initial diagnosis, and has cared for children with acute lymphoblastic leukemia who, rather than going to palliative care, engaged in clinical trials that have not only benefited them, but have transformed a uniformly fatal illness 70 years ago to one that is now 85% curable. The important point to be made is that one must be cautious in discarding the possibility of investigational therapy.

The distinction between palliative care and participating in investigational therapeutic protocols is the issue of hope. A move to palliative care requires that the individual accept a state of hopelessness. Many patients turn to unproven remedies to restore hope. In the case of investigational therapeutics, the patient is willing to participate in a process that offers not only hope for the patient as an individual, but makes a substantial contribution to the body of knowledge that will benefit patients in the future. Therefore, though there may be a point at which continuing therapy is unrealistic, or when the comfort offered from palliative care is preferable, it is crucial to acknowledge how difficult it is for anyone to know when a patient reaches this point. Breakthroughs, by definition, imply successful treatment in a situation that was previously considered hopeless.

Meriting discussion in this regard is the issue of who should decide when enough is enough or too soon is too soon. Clearly, some people do not want to be debilitated by adverse effects or inconveniences associated with therapy, even if it extends life. Others may want every last possible chance, given that ongoing treatment offers hope regardless of the chances of response, and the presence of hope may improve their quality of life. In conclusion, there are clearly patients for whom enough is enough, and others for whom too soon is too soon. However, distinguishing between the two is subjective and complex. This topic warrants additional study, including examinations regarding the financial costs of each approach.

EDITOR'S NOTE

A commentary by Schapira et al (pp 307-308) accompanies this article.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Razelle Kurzrock, AstraZeneca (C), Centocor (C), Maxygen (C) Stock Ownership: None Honoraria: Razelle Kurzrock, AstraZeneca, Genentech, Imclone, Johnson & Johnson, Maxygen, Pharmion Research Funding: Razelle Kurzrock, Abraxis, Amgen, AmpliMed, Antigenics, AstraZeneca, Bayer, Bristol-Myers Squibb, Callisto Pharmaceuticals, Centocor, Concordia Pharmaceuticals, CuraGen, Eisai, Eli Lilly, Enzon Pharmaceuticals, Exelixis, Genentech, GlaxoSmithKline, GloboMax, Hoffmann-La Roche, Kinex Pharmaceuticals, Merck, MGI Pharmaceuticals, Metastatix, Myriad Genetics, Nereus Pharmaceuticals, Novartis, Pfizer, Pharmacyclics, Pharmion, Phoenix Biotech, Reata Pharmaceuticals, Taiho Pharmaceuticals, VioQuest Pharmaceuticals, ZIOPHARM Oncology Expert Testimony: None Other Remuneration: None