CORRESPONDENCE

Re: Quality of Life in Advanced Prostate Cancer: Results of a Randomized Therapeutic Trial

Jean-François Caubet

Correspondence to: Jean-François Caubet, M.D., 419 Plainfield Ave., Berkeley Heights, NJ 07922 (e-mail: JeanFranc{at}aol.com).

A link between the pharmacology of flutamide and the quality of life (QOL) of patients with metastatic prostate cancer was recently reported (1). In the National Cancer Institute/Southwest Oncology Group INT-0105 trial, better QOL scores were reported in patients receiving orchiectomy plus placebo than in patients receiving orchiectomy plus flutamide. Subjective assessments need, however, to be interpreted in the light of possible confounders of either the causes or the effects. One confounder was discussed—imbalance favoring placebo (1)—but several others need to be explored systematically.

A combined treatment was evaluated (orchiectomy plus flutamide); therefore, any difference observed with orchiectomy can be explained by either flutamide or an interaction between flutamide and orchiectomy. Orchiectomy has a rapid effect on testosterone levels, and it increases cortisol secretion in response to stress (2). The symptoms observed are the result of the addition of flutamide to a situation already producing a rapid androgen deprivation with additional hormonal changes, all occurring to a lesser extent with luteinizing hormone-releasing hormone. This did not translate, however, into a decrease of mental and physical scores, as compared with baseline.

In a randomized, controlled trial, the patients know that they can receive a treatment or a placebo. Their expectations of treatment effects are set, by this uncertainty, between the expected effects of the treatment and the expected effects of no treatment. Expectations are known to influence subjective assessments (3). The subjective assessments of the benefit are underestimated in the treatment arm and overestimated in the placebo arm. This situation minimizes the differences between treatment arms, and a subgroup of patients with side effects may then become the major determinant of how QOL scores compare.

Pain medications and antidepressants represent outcomes of QOL studies. The prostate-specific antigen (PSA) level was decreased more with flutamide than with placebo (4). In such a situation, one may expect less symptomatic medications to be prescribed. These medications can change QOL scores and should be reported.

Withdrawals represent another outcome of QOL studies. In the INT-0105 trial, more withdrawals were observed in the placebo arm. The number of patients returning questionnaires was slightly different at baseline between flutamide and placebo (370 and 367 patients, respectively). The difference increased after 6 months for outcomes such as frequent pain (19 more patients in the flutamide arm), intense pain (18 more patients in the flutamide arm), mental health (17 more patients in the flutamide arm), and distress (16 more patients in the flutamide arm). The status of the missing patients can have an impact on the QOL scores.

A recent publication described symptoms of anxiety and depression in patients with prostate cancer (5) and suggested the use of a questionnaire to detect patients with psychiatric needs. For these patients, flutamide may temporally or definitely be withdrawn. The risk of side effects should, however, be balanced with long-term benefits. A survival advantage of 9% was reported (4), but it may have underestimated the true benefit of flutamide because the model used was not adjusted for prognostic factors. Unadjusted models sometimes underestimate the treatment effects (6) and have a lower predictive value for the individual patient than multivariate models. The benefits of orchiectomy should also be compared with the benefits of luteinizing hormone-releasing hormone, in terms of QOL, risk of osteoporosis, and survival (7).

REFERENCES

1 Moinpour CM, Savage MJ, Troxel A, Lovato LC, Eisenberger M, Veith RW, et al. Quality of life in advanced prostate cancer: results of a randomized therapeutic trial. J Natl Cancer Inst 1998;90:1537-44.[Abstract/Free Full Text]

2 Viau V, Meaney MJ. The inhibitory effect of testosterone on hypothalamic-pituitary-adrenal responses to stress is mediated by the media preoptic area. J Neurosci 1996;16:1866-76.[Abstract]

3 Swartzman LC, Burkell J. Expectations and the placebo effect in clinical drug trials: why we should not turn a blind eye to unblinding, and other cautionary notes. Clin Pharmacol Ther 1998;64:1-7.[Medline]

4 Eisenberger MA, Blumenstein BA, Crawford ED, Miller G, McLeod DG, Loehrer RJ, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 1998;339:1036-42.[Abstract/Free Full Text]

5 Roth AJ, Kornblith AB, Batel-Copel L, Peabody E, Scher HI, Holland JC. Rapid screening for psychologic distress in men with prostate carcinoma: a pilot study. Cancer 1998;82:1904-8.[Medline]

6 Hauck WW, Anderson S, Marcus SM. Should we adjust for covariates in nonlinear regression analyses of randomized trials? Control Clin Trials 1998;19:249-56.[Medline]

7 Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma [published erratum appears in N Engl J Med 1989;321:1420]. N Engl J Med 1989;321:419-24.[Abstract]


 

RESPONSE

Carol M. Moinpour, Andrea Troxel, Laura C. Lovato, Mario Eisenberger, Brent A. Blumenstein, E. David Crawford

Affiliations of authors: C. M. Moinpour, L. C. Lovato, Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA; A. Troxel, Columbia Presbyterian Cancer Center, New York, NY; M. Eisenberger, The Johns Hopkins University School of Medicine, Baltimore, MD; B. A. Blumenstein, American College of Surgeons, Chicago, IL; E. D. Crawford, University of Colorado, Denver.

Correspondence to: Carol M. Moinpour, Ph.D., Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N./MP 557, Box 19024, Seattle, WA 98109-1024.

Dr. Caubet first notes that the treatment arms in the quality-of-life (QOL) sample were not balanced with respect to extent of disease. In the article, we reported this, but we also noted that extent of disease was included in all longitudinal analyses and did not change our conclusions.

Dr. Caubet is correct in noting that average scores for physical and emotional functioning did not worsen significantly over the 6-month assessment period for either arm. However, we did report that the emotional functioning of patients receiving orchiectomy plus placebo improved more over this 6-month period than did that of patients receiving orchiectomy plus flutamide. That is, additional treatment with flutamide appeared to confer less improvement when compared with orchiectomy alone.

By administering follow-up treatment to orchiectomy in a double-blind manner, the Southwest Oncology Group/INT-0105 trial employed the most rigorous possible experimental design for a clinical trial. A very intricate clinical trial is required to address Dr. Caubet's suggestion that a patient's perception of which treatment he is receiving can affect his report of QOL.

Dr. Caubet's suggestion that, with decreasing PSA levels, supportive care medication would be reduced seems unlikely. One would not expect a physician to reduce symptom-relieving medications (e.g., analgesics) based solely on PSA levels alone, particularly if the patient still complained about the symptom. This hypothesis could not be examined in INT-0105 or in most clinical trials with this patient population. Dr. Caubet is correct in suggesting that both pain reports and analgesic use reflect effects of treatment on the patient's pain status. However, data do not support that both are necessarily required. A study of patients with metastatic prostate cancer found that reports of pain and analgesic use changed in the same direction (1) and reports of pain and analgesic use for transplant patients with oral mucositis were highly positively correlated (2).

Missing data in QOL assessments present a formidable problem to statisticians. It certainly is the case that analyses in the presence of non-ignorable missing data (i.e., where the reason is associated with the health or QOL outcome) can result in spurious conclusions, usually overestimating QOL. We examined plots of data from patients who had missing data for health-related versus non-health-related reasons to see if there was a tendency for the patients with the poorest QOL to drop out. However, as reported in our article, the pattern of dropping out did not show this problem.

Dr. Caubet's speculation about the possibility of the survival effect size being underestimated touches on a controversial issue in the analysis of data from clinical trials, and he fails to mention the increased likelihood of misleading results when covariates are added to statistical models built on the data from randomized trials.

Finally, Dr. Caubet suggested that physicians might incorporate screening for emotional dysfunction as part of routine care for patients with prostate cancer. We believe that our emotional functioning data support the need for more systematic monitoring of the patient's mental health when hormonal treatments such as flutamide are administered. Such data would certainly help inform the benefits and trade-offs associated with hormonal treatment for prostate cancer.

REFERENCES

1 Collins C, Eary JF, Donaldson G, Vernon C, Bush NE, Petersdorf S, et al. Samarium-153-EDTMP in bone metastases of hormone refractory prostate carcinoma: a phase I/II trial. J Nucl Med 1993;34:1839-44.[Abstract]

2 Donaldson GW. The determining role of theory in measurement practice. In: Chapman CR, Loeser JD, editors. Advances in pain research and therapy: issues in pain measurement. Vol. 12. New York (NY): Raven Press; 1989. p. 17-35.



             
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