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We are also concerned about the selection of six months as the cutoff point to differentiate a recurrence from a second primary tumor. It is important to know whether this time point was preselected, since a P value below 0.05 can easily be reached if multiple cutoff points are examined.2 Furthermore, sonography was scheduled every three months, but recurrence was noted at seven, eight, and nine months of follow-up. Systemic bias would easily emerge if the investigators were allowed to make a subjective decision about follow-up time. A much more reliable end point is the overall survival rate.
The authors failed to state clearly some statistical points that are pertinent to a phase 3 clinical trial. These include the time at which enrollment was closed, the point at which the results were disclosed after closure of the study, and the schedule for examining results during the trial. If the results were examined at multiple points, the study should be subject to the rule of multiple interim analyses, and a much lower P value would be required to establish statistical significance.3
Chih-Hsin J. Yang, M.D.
Ann-Lii Cheng, M.D., Ph.D.
National Taiwan University Hospital
Taipei, Taiwan 10016
References
Another important consequence of vitamin A deficiency is visual problems, particularly night blindness. The authors state that no disorders of visual acuity occurred. However, impaired adaptation to the dark occurs frequently below the threshold of 10 µg of plasma retinol per deciliter, even though it may be unrecognized in some patients.4 Moreover, no mention is made in the article of whether the retinoid modified plasma retinol levels. Other synthetic retinoids significantly decrease plasma retinol levels and induce diminished adaptation to darkness,5 a symptom that may affect the subjects' ability to drive.
Andrea Decensi, M.D.
Alberto Costa, M.D.
European Institute of Oncology
20141 Milan, Italy
References
To the Editor: In our study of the prevention of second primary hepatomas by an acyclic retinoid, we included all randomized subjects in the analyses rather than only those who were treated, were eligible, or could be evaluated. This intention-to-treat analysis is the strictest way to evaluate the efficacy of a treatment.1 For example, the first tick mark in the retinoid-treated group in Figure 2 of our article represents a patient who discontinued the drug on the first day because of headache, but who was followed up for another 61 months. The follow-up after randomization ranged from 28 to 64 months for all surviving patients. Withdrawal of patients due to death occurred in the polyprenoic acid group at 12, 13, 21, 25, 30, 32, and 33 months and in the placebo group at 10, 14, 19, 26, 28, 29 (two patients), 31, 32, 37, 39, and 45 months. We are following the remaining patients to determine overall survival rates, since they are the most reliable end points.
The decision to include a cutoff point of six months in the definition of second primary hepatoma was determined before the study. Another definition involving DNA analysis may be possible,2 but we believe our definition is advantageous for a multicenter trial. During the entire period before the study was closed to enrollment in August 1994, no interim analyses were either scheduled or performed. Thanks to the strict protocol and definitions of end points, we did not need to examine the data at multiple points after the study was closed. The data were updated in February 1996 solely to provide the latest follow-up data for a final revision of this article. It is very difficult to avoid a one-month deviation from scheduled examinations in the conduct of a clinical trial like ours.
Ingested retinoid is absorbed in the small intestine, stored in the liver, and delivered to target organs by retinol-binding protein, which is synthesized in the liver.3 The plasma retinol level is determined on the basis of either hepatic retinol stores or the synthesis of retinol-binding protein. In vitamin A deficiency, hepatic retinol stores disappear before the plasma retinol level declines, although retinol-binding protein is available. In contrast, impaired synthesis of retinol-binding protein reduces the plasma retinol level but does not affect hepatic retinol stores in liver cirrhosis. Plasma retinol levels of 8.7 or 8.9 µg per deciliter (not micrograms per milliliter, as was erroneously reported in Table 1 of our article) were consistent with those of patients with hepatoma in our previous study (18.4±14.6 µg per deciliter).4 In such patients, retinoid was not deficient in the noncancerous liver tissue (mean, 318 µg per gram).5 Therefore, the mechanism by which acyclic retinoid inhibited second primary hepatomas in the remnant liver is not related to supplementation of a deficient nutrient. In fact, administration of the retinoid for 12 months did not affect the plasma retinol level in the polyprenoic acid group (8.5±1.2 µg per deciliter). However, in organs other than the liver, symptomatic retinoid deficiency may appear as a result of decreased delivery of retinol by retinol-binding protein in such patients. Sensory disturbances such as impaired adaptation to the dark and diminished taste acuity are typical, as we reported previously.6 However, no sensory disorders were reported by the patients or observed by the investigators in the present study.
Yasutoshi Muto, M.D.
Hisataka Moriwaki, M.D.
Masataka Okuno, M.D.
Gifu University School of Medicine
Gifu 500, Japan
References
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