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Originally published as JCO Early Release 10.1200/JCO.2005.04.4388 on October 30 2006 © 2006 American Society of Clinical Oncology.
Whose Opinion Counts?
Mayo Clinic, College of Medicine, Rochester, MN This issue of the Journal of Clinical Oncology publishes the results of two studies examining the role of palifermin for the prevention of chemotherapy-induced oral mucositis.1,2 Stiff et al1 report on the results from a randomized trial comparing palifermin with placebo for reducing mucositis in patients receiving high-dose chemotherapy. While the primary results of this trial were recently reported,3 the Stiff et al article is an extension of the previous report, whereby the authors provide data from patient-completed questionnaires, comparing them with "clinician's assessment of oral mucositis using the objective scales."1 The results reported in this article are in concert with the recent US Food and Drug Administration approval of this drug. This report supports that palifermin is useful for preventing mucositis, to a clinically important degree, in patients that are receiving high-dose chemotherapy with a propensity to cause substantial mucositis, such as the chemotherapy regimen used in this trial. This is a move forward from the viewpoint of a 2003 editorial in the Journal entitled "Keratinocyte growth factor: Not yet ready for prime time."4 The second article provides a balanced report of a relatively small randomized, double-blinded, placebo-controlled trial of the same drug, trying to prevent mucositis induced by bolus fluorouracil plus leucovorin.2 This study did demonstrate biologic activity of palifermin, with decreased mucositis in the treated group. Nonetheless, the results from this individual study are not likely to change clinical practice for several reasons, including the small study size, the decreased use of the bolus fluorouracil plus leucovorin regimen in clinical practice, the availability of oral cryotherapy, not used in this trial,5,6 and the costs of the therapy. The remainder of this editorial will address two issues raised in the Stiff et al article1: utilization of patient-completed questionnaire data and the propensity to blame assessment measures and clinical trial methodology for negative results when it is more likely to be related to the lack of efficacy of the agent being tested. Patient-Completed Questionnaire Data It should be no surprise that virtually identical results were seen with the patient-completed data reported in the Stiff et al article compared with that which was previously reported with clinician-reported data.3 The authors concluded that their article provided "evidence that a patient's self assessment instrument... may serve as an attractive tool to assess oral mucositis severity... ."1 While the tone of the article is that this concept is new, this editorial proposes that this idea is old news, not new news. Several previous trials evaluating interventions to potentially reduce mucositis have reported that patients and clinicians provide similar results. These include evaluations of oral cryotherapy,5,6 sucralfate,7 an allopurinol mouthwash,8 a chlorhexidine mouth wash,9 a chamomile tea mouthwash,10 oral antibiotic lozenges,11 and even palifermin in two other publications, including another article published in this issue of the Journal.2,12 In virtually all of these trials, results from patient provided data provided the same conclusions as did the results from clinician-determined data. Having said this, it is not uncommon to have some differences between patient-reported data and clinician-reported data. In their article, Stiff et al1 note that patients were able to report pain and soreness related to mucositis earlier than clinicians. In previous reports5,8 patient-reported data tended to reveal a bit more mucosal toxicity than was seen with clinician-reported data. These differences raise the question as to which is most accurate and particularly suitable for research outcomes: patient reports or clinician assessments. This has been a key question in outcomes research over the past 50 years as medical practice evolved from a paternalistic style to a more patient-centered approach.13 For example, as recently as 25 years ago it was thought that patients were unreliable assessors of their own pain.14 Today, it has been well-established that pain is what the patient says it is15 and that physician assessments of patients' pain are a poor proxy.16 It is important to note that this situation does not apply only to mucositis and pain, but rather to a number of other symptoms from which patients with cancer suffer. One of these symptoms is cancer anorexia. A substantial body of literature illustrates that anorexia can be accurately measured by patient-completed questionnaires. This illustration is substantiated by noting that the repetitive studies of a single agent, megestrol acetate, come to the same conclusion—megestrol acetate is an appetite stimulant.17 This result is despite the use of different questionnaires to evaluate anorexia. Further evidence is provided by noting that patients who report improvements in anorexia demonstrate a positive correlation with a more objective measure—the amount of nonfluid weight gain.18 Alternatively, it is noted that similarly negative results are seen across various trials19-21 when evaluating an agent that does not appear to work for cancer anorexia, such as eicosapentaenoic acid. Another well understood situation in which patient-completed data has accurately determined the efficacy of agents is related to postchemotherapy nausea and vomiting. Here, patient-determined data are accepted as providing the only relevant information, as it is virtually impossible for another individual to provide an accurate proxy assessment beyond simply counting the emetic episodes. Hot flashes represent yet another symptom for which patient questionnaires have been effectively utilized for outcome measurement. Evidence that self-reporting measures for hot flashes are valid includes the replication of study results with same drug. At least two different studies have shown that clonidine reduces hot flashes, although only to a small degree and with bothersome toxicity.22,23 Paroxetine24,25 and gabapentin26,27 also show similar results across different trials utilizing patient-completed data. With regard to hot flashes, attempts are in process to provide more objective measures to assess the frequency and severity of hot flashes. A recent National Institutes of Health (Bethesda, MD) request for applications28 has led to awarded grants to develop instruments to measure changes in skin temperature or sweating to provide such objective measures of hot flashes, for example. While newer measures of hot flashes may help to describe hot flash physiology in greater detail, such efforts should not, by themselves, invalidate self-reported prospective hot flash diaries. Supporting this contention, a recently published study evaluated the use of sternal skin conductance as a measure of hot flash intensity or distress. 29 The authors of this article concluded that sweat gland activity, as measured by sternal skin conductance, was not a valid measure of subjective hot flash severity or distress. Thus, even if machine-based assessments of hot flash activity prove to be valuable in some manner, it is vital to retain the subjectivity of the patient's opinion as to whether the hot flashes are bothersome or not. In total, it would not appear to be appropriate to base treatment on machine-generated estimates of hot flash activity if a woman does not subjectively experience the symptom. Quality of life literature also provides ample evidence that patient-reported assessments are optimal to obtain reliable and accurate estimates for any concept that has a subjective component.30 The only caveat to this finding is that the concept needs to be understandable to a lay person (such as any of the above symptoms). Physician-based assessments have been demonstrated repeatedly to be prone to underestimate the incidence and severity of quality of life-related outcomes.31,32 It should be noted that, as with any research endeavors, studies utilizing patient questionnaires are not perfect. Nonetheless, many of the issues relating to patient questionnaires (for example, reliability, validity, accuracy, sensitivity, specificity) also relate to other clinical outcomes data.33 Thus, there is ample evidence to support the stance that patient-completed questionnaires can provide accurate measures of subjective symptoms. Shifting the Blame In the discussion section of the Stiff et al article1 the authors state that: "One of the major difficulties in the assessments of potential effective agents against oral mucositis has been the lack of a reliable, reproducible, easy-to-use, and accurate instrument to measure the severity of this complication." The last sentence of this paragraph notes: "An instrument that accurately measures both patient response and clinical observations remains elusive." We would like to propose another viewpoint regarding this issue, that is—when trial results are negative it is not uncommon to criticize the study outcome measure as the scapegoat, when the real issue is that the proposed therapy does not work.34 With regard to measurement of mucositis, the reader will hopefully be convinced by the data cited herein that there are a number of patient assessment measurement tools that can be utilized effectively to determine whether a therapy is efficacious. The same situation applies to physician assessments of mucositis. A relatively old article,35 which was new earlier in some of our careers, compared and contrasted a number of described clinician determined mucositis instruments. A quick review of this article can lead to the conclusion that all four of the discussed tools painted a very similar story. We submit that utilization of any of these instruments or any of a number of patient-centered measurement tools would have resulted in similarly positive results in the reported trial in this issue of the Journal.1 This situation can be illustrated when looking again at the cancer anorexia/cachexia syndrome. Multiple trials have been conducted to evaluate total parenteral nutrition as a means of alleviating this problem in patients with far advanced incurable cancer. These trials, which span decades, have repeatedly been unable to demonstrate an average overall benefit for total parenteral nutrition in such patients. It has been stated that one of the reasons for this is that there are "methodologic problems with all of these trials."36 In exploring this concept further, why is it that virtually all of the trials evaluating megestrol acetate as an appetite stimulant are positive and have similar estimates of efficacy? Does this mean that investigators evaluating megestrol acetate are better clinical trial methodologists than are those investigators looking at total parenteral nutrition? Or, rather, is it more likely that neither total parenteral nutrition nor eicosapentaenoic acid works in the stated situation, while megestrol acetate does stimulate appetite? Although megestrol acetate clearly does stimulate appetite, it is worth noting that this drug is certainly not a panacea for this problem.37 In summary, we should be wary when an investigator cites "clinical trial methodology problems" as a reason for a negative study result. This is somewhat reminiscent of the old axiom that it is the poor craftsman that blames his tools. While occasionally clinical trial methodology might, in fact, be a culprit for the failure to find positive study results, the more likely scenario in many situations is that the agent being tested just does not work. Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Author Contributions
NOTES published online ahead of print at www.jco.org on October 30, 2006. REFERENCES 1. Stiff PJ, Emmanouilides C, Bensinger WI, et al: Palifermin reduces patient-reported mouth and throat soreness and improves patient functioning in the hematopoietic stem-cell transplantation setting. J Clin Oncol 24 : 5186 -5193, 2006 2. Rosen LS, Abdi E, Davis ID, et al: Palifermin reduces the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy. J Clin Oncol 24 : 5194 -5200, 2006[CrossRef][Medline] 3. Spielberger R, Stiff P, Bensinger W, et al: Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 351
: 2590
-2598, 2004 4. Loprinzi CL, Martenson JA: Keratinocyte growth factor: Not yet ready for prime time. J Clin Oncol 21
: 1429
-1430, 2003 5. Mahood DJ, Dose AM, Loprinzi CL, et al: Inhibition of 5-fluorouracil-induced mucositis by oral cryotherapy. J Clin Oncol 9 : 449 -452, 1991[Abstract] 6. Cascinu S, Fedli A, Fedli SL, et al: Oral cooling (cryotherapy), an effective treatment for the prevention of 5-fluorouracil-induced stomatitis. Eur J Cancer, Part B: Oral Oncol 30B : 234 -236, 1994[CrossRef] 7. Loprinzi CL, Ghosh C, Camoriano J, et al: Phase III controlled evaluation of sucralfate for alleviating stomatitis in patients receiving fluorouracil-based chemotherapy. J Clin Oncol 15
: 1235
-1238, 1997 8. Loprinzi CL, Cianflone SG, Dose AM, et al: A controlled evaluation of an allopurinol mouthwash as prophylaxis against 5-fluorouracil-induced stomatitis. Cancer 65 : 1879 -1882, 1990[CrossRef][Medline] 9. Foote RL, Loprinzi CL, Frank AR, et al: Randomized trial of chlorhexidine mouthwash for alleviation of radiation-induced mucositis. J Clin Oncol 12
: 2630
-2633, 1994 10. Fidler P, Loprinzi CL, O'Fallon JR, et al: Prospective trial of a chamomile mouthwash for prevention of 5-FU-induced oral mucositis. Cancer 77 : 522 -525, 1996[CrossRef][Medline] 11. Okuno SH, Foote RL, Loprinzi CL, et al: A randomized trial of a nonabsorbable antibiotic lozenge given to alleviate radiation-induced mucositis. Cancer 79 : 2193 -2199, 1997[CrossRef][Medline] 12. Meropol NJ, Somer RA, Gutheil J, et al: Randomized phase I trial of recombinant human keratinocyte growth factor plus chemotherapy: Potential role as mucosal protectant. J Clin Oncol 21
: 1452
-1458, 2003 13. Frost MH, Sloan JA: Quality of life measurements: A soft outcome-or is it? Am J Managed Care 8 : S574 -S579, 2002[Medline] 14. Huschka M, Burger K: Does QOL provide the same information as toxicity data? Current Problems in Cancer, November 2005 (in press) 15. Pasero C, McCaffery M: The patient's report of pain. Am J Nursing 101 : 73 -74, 2001[Medline] 16. Marquie L, Raufaste E, Dominique L, et al: Pain rating by patients and physicians: Evidence of systematic pain miscalibration. Pain 102 : 289 -296, 2002[CrossRef] 17. Jatoi A, Kumar S, Sloan JA, et al: On appetite and its loss. J Clin Oncol 18
: 2930
-2932, 2000 18. Loprinzi CL, Michalak JC, Schaid DJ, et al: Phase III evaluation of four doses of megestrol acetate as therapy for patients with cancer anorexia and/or cachexia. J Clin Oncol 11 : 762 -767, 1993[Abstract] 19. Jatoi A, Rowland K, Loprinzi CL, et al: An eicosapentaenoic acid supplement versus megestrol acetate versus both for patients with cancer-associated wasting: A North Central Cancer Treatment Group and National Cancer Institute of Canada collaborative effort. J Clin Oncol 22
: 2469
-2476, 2004 20. Bruera E, Strasser F, Palmer JL, et al: Effect of fish oil on appetite and other symptoms in patients with advanced cancer and anorexia/cachexia: A double-blind, placebo-controlled study. J Clin Oncol 21
: 129
-134, 2003 21. Fearon KC, Von Meyenfeldt MF, Moses AG, et al: Effect of a protein and energy dense N-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: A randomized, double-blind trial. Gut 52
: 1479
-1486, 2003 22. Pandya KJ, Raubertas RF, Flynn PJ, et al: Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: A University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med 132
: 788
-793, 2000 23. Goldberg RM, Loprinzi CL, O'Fallon JR, et al: Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol 12 : 155 -158, 1994[Abstract] 24. Stearns V, Beebe KL, Iyengar M, et al: Paroxetine controlled release in the treatment of menopausal hot flashes: A randomized controlled trial. JAMA 289
: 2827
-2834, 2003 25. Stearns V, Slack R, Greep N, et al: Paroxetine is an effective treatement for hot flashes: Results from a prospective randomized clinical trial. J Clin Oncol 23
: 6919
-6930, 2005 26. Guttuso T Jr, Kurlan R, McDermott MP, et al: Gabapentin's effects on hot flashes in postmenopausal women: A randomized controlled trial. Obstet Gynecol 101
: 337
-345, 2003 27. Pandya K, Morrow GR, Roscoe JA, et al: Gabapentin for hot flashes in 420 women with breast cancer: A randomized double-blind placebo-controlled trial. Lancet 366 : 818 -824, 2005[CrossRef][Medline] 28. National Center for Complementary and Alternative Medicine: Improving Measurement Tools for Sternal Skin Conductance and hot flashes: Phase I. Bethesda, MD, National Center for Complementary and Alternative Medicine, National Institutes of Health, 2005 (SBIR RFA AT 05 005). http://nccam.nih.gov/research/announcements/past.htm 29. Carpenter JS, Azzouz F, Monahan PO, et al: Is sternal skin conductance monitoring a valid measure of hot flash intensity or distress? Menopause 12 : 512 -519, 2005[CrossRef][Medline] 30. Frost MF, Huschka, MM: Quality of life from a patient's perspective: Can we believe the patient? Current Problems in Cancer 29 : 326 -331, 2005[CrossRef][Medline] 31. Sneeuw KCA, Aaronson NK, Sprangers MAG, et al: Evaluating the quality of life of cancer patients: Assessments by patients, significant others, physicians and nurses. Br J Cancer 81 : 87 -94, 1999[CrossRef][Medline] 32. Macquart-Moulin G, Viens P, Bouscary M-L, et al: Discordance between physicians' estimations and breast cancer patients' self-assessment of side-effects of chemotherapy: An issue for quality of care. Br J Cancer 76 : 1640 -1645, 1997[Medline] 33. Sloan JA, Cella D, Frost M, et al: Assessing clinical significance in measuring oncology patient quality of life: Introduction to the symposium, content overview, and definition of terms. Mayo Clin Proc 77 : 367 -370, 2002[Medline] 34. Osoba D: What has been learned from measuring health-related quality of life in clinical oncology. Eur J Cancer 35 : 1565 -1570, 1999[CrossRef][Medline] 35. Spijkervet FK, Van Saene HK, Panders AK, et al: Scoring irradiation mucositis in head and neck cancer patients. J Oral Pathol Med 18 : 167 -171, 1989[CrossRef][Medline] 36. Barber MD, Fearon KCH, Delmore G, et al: Should cancer patients with incurable disease receive parenteral or enteral nutritional support? Eur J Cancer 34 : 279 -285, 1998[CrossRef][Medline] 37. Moynihan T, Kelly DG, Fisch MJ: To feed or not to feed: Is that the right question? J Clin Oncol 23
: 6256
-6259, 2005
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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