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© 2003 American Society for Clinical Oncology
Keratinocyte Growth Factor: Not Yet Ready for Prime TimeMayo Clinic, Rochester, MN CYTOTOXIC THERAPY-INDUCED mucositis, a syndrome associated with multiple chemotherapeutic drug regimens and radiation therapy, is a major clinical problem. Much of the alimentary tract epithelium, from the mouth to the rectum, is at risk. Such mucosal toxicity can clearly cause major symptoms and may limit the amount of cytotoxic therapy that can be prescribed. Unquestionably, means of inhibiting this therapy-induced toxicity are desirable. Keratinocyte growth factor (KGF), as described in this issue of the journal,1 is an interesting and logical approach to alleviate mucositis. Data from animal models demonstrate that KGF decreases mucosal ulceration or improves survival in mice that have received a number of different therapies, including radiation therapy, fluorouracil (FU), and nonsteroidal anti-inflammatory drugs. This trial has multiple positive attributes. It was well conducted and its results are clearly reported. It used a relatively novel study design, a phase I clinical trial methodology with a double-blinded, placebo-controlled, randomized component. This trial design, as opposed to a more standard phase I trial design, required a few more patients to participate as a placebo group, but these additional patients provide markedly enhanced information. Unlike a standard phase I clinical trial, this design provides substantial information regarding the potential efficacy and toxicity of the experimental agent. In addition to aiding in the assessment of the well-described placebo effect, this trial design also allows a better estimation of the less well-understood but still well-described nocebo effect, this being the potential toxicities that are ascribed to an inert substance.2 This is a clinical trial design that should be used more often, particularly in supportive-care trials. Another strength of this article is that it reports a comparison of intermittent investigator observations of oral mucositis in patients, compared with patients’ own reports of their mucositis symptoms. After demonstrating a marked concordance of these two measurement methods, the authors propose "that patient diaries, such as the one used in this study, be included in further trials of mucosal protectants to complement oral examination." Although the spirit of this claim is quite appropriate, we believe that it is even more appropriate to consider the patient diary information to be the most important end point of such a clinical trial, and that clinician oral examination information might possibly "complement" patient diaries. After all, are not the patient-reported symptoms more important than the report of clinician examiners? The findings from these observers regarding the utility of patient reports are in concert with results frequently reported in multiple clinical trials conducted through the North Central Clinical Trials Group (NCCTG), a group with substantial experience in the conduct of trials for alleviating gastrointestinal tract mucosal toxicity.3–10 These NCCTG trials have repeatedly illustrated that patient-reported information correlates quite closely with toxicity information obtained from healthcare providers. The data from the NCCTG trials reproducibly illustrate that patient questionnaire-derived data tend to report slightly more toxicity than is observed by healthcare provider evaluations. Given these slight differences, which reports are to be considered most accurate? Available data support that the patient-provided information is actually more accurate than that provided by healthcare providers. For example, one study of patients treated with radiation therapy for prostate cancer reported that 44% of patients who were rated by their healthcare professionals as having no diarrhea stated that they had significant problems with this symptom.11 In another situation, long-term bowel toxicity in patients treated with adjuvant pelvic radiation therapy for rectal cancer was generally considered to be relatively uncommon12–14 until an investigator directly interviewed patients and found multiple significant functional abnormalities, including a 56% incidence of at least occasional fecal incontinence.15 Similar studies of patients treated on phase III clinical trials have corroborated these results.16,17 A third strength of this trial was the vigilance of the study team. The investigators stopped the trial before their predetermined end points after observing unexpected adverse effects, such as skin toxicity, from the KGF. They soundly judged that it was better not to substitute substantial new toxicities while they were trying to prevent toxicity from chemotherapy. There is one concern with regard to the conduct of this study: This trial prohibited the use of oral cryotherapy (although it was stated that patients were "informed" about oral cryotherapy). The reason for this concern is that two reported randomized controlled clinical trials have evaluated oral cryotherapy as a method to prevent oral mucositis from bolus dose, FU-based chemotherapy regimens.2,18 Both of these trials demonstrated that oral cryotherapy reduced mucositis by approximately 50%. On the basis of these reports, a recent review concluded that oral cryotherapy was the only effective treatment of eight tested prophylactic therapies for reducing chemotherapy-induced mucositis.19 Oral cryotherapy is associated with minimal toxicity, although in some patients it may cause operant conditioning that leads to an aversion to subsequent use of ice. Given this convincing evidence that oral cryotherapy does decrease bolus FU-based chemotherapy-induced mucositis, future trials should not deny patients this established therapy. Having discussed the conduct of this reported trial, what has it taught us about the potential use of KGF as a therapy to decrease FU-induced mucositis? First, this report provides data that support the finding that KGF decreases mucositis, to a moderate degree. Second, it suggests that KGF is relatively tolerable but causes some skin toxicity. There are several issues that need to be more fully addressed before the acceptance of recombinant human KGF as a therapy in general clinical practice. First, it will need to be established that KGF will substantially decrease therapy-induced mucositis to a degree that supersedes the toxicity it causes. It is reasonable to ask whether it is acceptable to use a second drug to reduce toxicity from a first drug, when the second drug may cause other toxicities. The answer may be affirmative if the benefit is greater than the adverse effects of the second drug. For example, benefits of 5-hydroxytryptamine-3 receptor antagonists for chemotherapy-induced emesis allow their widespread use even though they can cause their own separate toxicity (constipation) in a substantial number of patients. Second, the efficacy of KGF should be something that is provided in addition to other established mucositis protection methods. For bolus dose FU-based therapy, this would include the use of oral cryotherapy. Third, information should be obtained regarding the efficacy of KGF against other mucositis-inducing treatments, including other chemotherapy regimens and radiation therapy, and for other gastrointestinal mucosal regions such as the esophagus, stomach, colon, and rectum. Lastly, additional information is needed with regard to possible effects of KGF on tumor growth and on tumor responsiveness to chemotherapy. Although interesting and deserving of further study, the currently available information regarding KGF does not support its routine use in routine clinical practice. REFERENCES
1. 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
2. Barsky AJ, Saintfort R, Rogers MP, et al: Nonspecific medication side effects and the nocebo phenomenon. J Am Med Assoc 287:622–627, 2002 3. Mahood DJ, Dose AM, Loprinzi CL, et al: Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. J Clin Oncol 9:449–452, 1991[Abstract] 4. 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] 5. Rocke LK, Loprinzi CL, Lee JK, et al: A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer 72:2234–2238, 1993[CrossRef][Medline]
6. 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 7. 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]
8. Martenson JA, Bollinger JW, Sloan JA, et al: Sucralfate in the prevention of treatment-induced diarrhea in patients receiving pelvic radiation therapy: A North Central Cancer Treatment Group phase III double-blind placebo-controlled trial. J Clin Oncol 18:1239–1245, 2000
9. McGinnis WL, Loprinzi CL, Buskirk SJ, et al: Placebo-controlled trial of sucralfate for inhibiting radiation-induced esophagitis. J Clin Oncol 15:1239–1243, 1997 10. Kozelsky TF, Meyers GE, Sloan JA, et al: Ten phase III double-blind study of glutamine versus placebo for the prevention of acute diarrhea in patients receiving pelvic radiation therapy. J Clin Oncol (in press) 11. Watkins-Bruner D, Scott C, Lawton C, et al: RTOG’s first quality of life study: RTOG 90-20—A phase II trial of external beam radiation with etanidazole for locally advanced prostate cancer. Int J Radiat Oncol Biol Phys 33:901–906, 1995[CrossRef][Medline] 12. Krook JE, Moertel CG, Gunderson LL, et al: Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324:709–715, 1991[Abstract]
13. O’Connell MJ, Martenson JA, Wieand HS, et al: Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 331:502–507, 1994 14. Kollmorgen CF, Meagher AP, Wolff BG, et al: The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function. Ann Surg 220:676–682, 1994[Medline] 15. Tveit KM, Guldvog I, Hagen S, et al: Randomized controlled trial of postoperative radiotherapy and short-term time-scheduled 5-fluorouracil against surgery alone in the treatment of Dukes B and C rectal cancer: Norwegian Adjuvant Rectal Cancer Project Group. Br J Surg 84:1130–1135, 1997[CrossRef][Medline] 16. Dahlberg M, Glimelius B, Graf W, et al: Preoperative irradiation affects functional results after surgery for rectal cancer. Dis Colon Rectum 41:543–551, 1998[CrossRef][Medline] 17. Lundby L, Jensen VJ, Overgaard J, et al: Long-term colorectal function after postoperative radiotherapy for colorectal cancer. Lancet 350:564, 1997[CrossRef][Medline] 18. 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[Medline] 19. Clarkson JE, Worthington HV, Eden OB. Prevention of oral mucositis or oral candidiasis for patients with cancer receiving chemotherapy (excluding head and neck cancer). Cochrane Database Syst Rev 2:CD000978, 2000
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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