Randomized controlled trials in general surgery

Letters to the editors Is glutamine required for the trophic effect of epidermal growth factor? To the Editors: We read with interest the article by Ko et al. (SURGERY 1993;114:147-54) on the requirement for glutamine before epidermal growth factor can have a trophic effect. However, this conclusion was based on the results of in vitro studies. We have shown in vivo that systemic epidermal growth factor is trophic to both the small and large intestine of rats receiving total parenteral nutrition, 1' 2 even though the parenteral feed used contained no glutamine. Although we appreciate that these rats are likely to have a small amount of endogenous glutamine available, we believe that the title of the article by Ko et al. could be misinterpreted. On the basis of our animal model we conclude that in the clinical setting exogenous administration of epidermal growth factor (or modification of endogenous levels of epidermal growth factor 3) is likely to be of benefit in maintaining gut growth in parenterally fed subjects, even in the absence of exogenous glutamine. Raymond J. Playford, M R C P Robert A. Goodlad, PhD Histopathology Unit Imperial Cancer Research Fund Lincolns Inn Fields London WC2A 3PN, U. K. References 1. Goodlad RA, Wilson TG, Lenton W, Wright NA, Gregory H, McCullagh KG. Intravenous but not intragastric urogastroneEGF is trophic to the intestinal epithelium of parenterally fed rats. Gut 1987;28:573-82. 2. Goodlad RA, Lee CY, Wright NA. The effects of luminal nutrition and urogastrone-EGF on the proportion and distribution of mitotic and labelled cells, growth fraction and cell population of the small intestinal and colonic crypts. Cell Prolif 1992;25:393404. 3. Effect of luminal growth factor preservation on intestinal growth. Playford RJ, Watanaba P, Woodman AC, Deprez PH, Calam J. Lancet 1993;341:843-8. 11/59/61267

Randomized controlled trials in general surgery To the Editors: The interesting data on randomized controlled trials (RCT) presented by Solomon et al. (SURGERY1994;115:707-12), while of concern, are no surprise. They are to be congratulated for clearly demonstrating what most of us have surmised. In their interesting discussion they attempted to explain the relative paucity of R C T in which surgeons played a leading role or that studied a surgical treatment. Their study also showed a striking difference in the relative number of studies generated from North America, the United Kingdom, and Scandinavia, which was not addressed. This difference could perhaps provide some clues. Accurate information on the number of general surgeons in Scandinavia is March 1995

not readily available. Reasonably accurate data are available for the United States, Canada, and the United Kingdom. In the United States and Canada there are approximately 42,000 general surgeons, who in 1990 published one R C T for every 600 or so surgeons. By contrast the United Kingdom, which has approximately 1200 general surgeons, produced in the same year one R C T for approximately every 40 surgeons. This difference existed despite the fact that the ratio of general surgeons to population in North America is approximately 1:6000, whereas in the United Kingdom it is approximately 1:48,000. This suggests that despite an overall much heavier clinical burden, U.K. surgeons are more actively involved in R C T than their North American colleagues. Surgeons on both sides of the Atlantic have demonstrated that R C T of surgical treatments can be performed even though they are methodologically much more difficult than R C T of medical therapies. The issue is not whether R C T of surgical therapy are feasible but rather why they are done so infrequently by North American surgeons. Funding for clinical research is even less readily available in the United Kingdom than in the United States or Canada, so lack of funding is not a likely explanation for this transatlantic difference. Lack of expertise, however, could be an important factor. It is most unusual to obtain a consultant appointment in general surgery in the United Kingdom without having spent a considerable amount of time engaged in research during a very prolonged training period. This ensures that most U.K. general surgeons, not just those in academic centers, are familiar with the scientific method, have been exposed during their training to clinical research, have been taught to think critically, and are skeptical of conclusions based on studies other than R C T . Thus most U.K. general surgeons are willing to participate in R C T in contrast to most North American surgeons in private practice. North American surgeons working full time in university departments have also largely had research exposure and yet are not as likely to initiate R C T as their U.K. counterparts. Could it be that a more urgent need to publish drives North American academic surgeons into bench research rather than into more time-consuming clinical research programs? A good experimental model can be relied on to generate a rapid stream of papers and presentations. What better way to quickly ascend from assistant to full professor. Another and perhaps more plausible explanation for the findings of Solomon et al. is that North American academic surgeons find it much easier to secure promotion by engaging in laboratory research than by conducting arduous RCT. American community surgeons are thus largely deprived of surgical leadership for the conduct of R C T . U.K. consultant surgeons by contrast are offered such leadership by the academic departments and are probably willing to give of their more limited time to those very difficult trials because they will directly affect the management of their patients. Finally, it must be conceded that the U.K. National Health Service is a more conducive socioeconomic environment in which to conduct R C T than the still prevailing North AmerSURGERY

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Surgery March 7995

ican fee for service system. It is likely that R C T are more readily performed in the United Kingdom than in North America by all medical specialties and not just surgeons. Max M. Cohen, MD Cha,rman, Department of Surgery Rose Medical Center ProJessor of Surgery University of Colorado Health Sciences Center 4567 E. 9th Ave. Denver, CO 80220

11/59/61916 Reply To the Editors: We thank Dr. Cohen for his insightful comments in response to our article. We agree with him that relatively few randomized controlled trials are being performed by surgeons. However, although it appears that more randomized controlled trials are published in the British literature, our study was not performed to make comparisons between the frequency of randomized controlled trials performed in the United Kingdom and in North America; therefore further conclusions cannot be made. We agree that relatively few randomized controlled trials are being performed in North America. The reasons for this are probably muhifactorial. We agree with Dr. Cohen that generally surgeons are not well trained in clinical research methodology. In addition, there appears to be more prestige for academic surgeons engaging in laboratory based research. Clinical research is still thought of by most surgeons as retrospective chart reviews and something that can be done by those who cannot or are not trained to do basic research. We would make a plea, however, thai clinical research is fast becoming a major area of concern as health care resources dwindle. Thus the opportunity is great for surgeons to play a major role in the evaluation of treatment, outcome research, and other aspects that are in the realm of clinical research and health services research. However, to do so requires a commitment to train and support surgeons in these disciplines. Robin S. McLeod, MD Michael J. Solomon, MD Department of General and Coloreetal Surgery Mount Sinai Hospital 600 University Ave., Suite 449 Toronto, Ontario, Canada MSG IX5

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Cystic medullary thyroid cancer To the Editors: In a recent review of fine-needle aspiration biopsy (FNAB) of the thyroid, Gharib et al) state that "A (thyroid) cyst that recurs after repeated aspirations should be removed. Tetracycline hydrochloride or thyroxine suppression therapy in patients with recurrent cysts is not recommended." Our recent experience with two biopsy-negative cases of cystic medullary thyroid cancer (MTC) strongly supports this recommendation.

Patient 1 was a 29-year-old woman with normal thyroid function and a negative family history for thyroid cancer who was referred to our clinic in August 1990 for evaluation of a 2.5 X 4.5 em left thyroid nodule. Examination was otherwise unremarkable, and uhrasonogram revealed a complex cyst of roughly the same dimensions. At FNAB 12 ml of blood-tinged fluid was removed, and the lesion disappeared after aspiration. The biopsy specimen was sparsely cellular but negative for malignancy. When the patient was reevaluated in November 1990, the cyst had recurred and it was now larger at 4 X 6 cm. A subtotal thyroidectomy was performed and a cystic M T C was noted. Completion thyroidectomy with central node dissection was performed 7 days later. No other foci of M T C were noted, and all nodes were negative. Postoperative plasma calcitonin level was 6 pg/ml (Roche Biomedical Laboratories, Burlington, N.C.; normal, less than 26 pg/ml), but a plasma sample drawn before operation revealed a level of 4324 pg/ ml. Patient 2 was a 38-year-old man with normal thyroid function who was referred in September 1990 for evaluation of a 1.5 cm cold right thyroid nodule. Family history was negative for M T C . FNAB was performed, and 2 ml of strawcolored fluid was removed. The lesion was no longer palpable after aspiration, and cytologic analysis of the fluid was "nondiagnostic." The patient was reevaluated in J u n e 1991, and the 1.5 cm nodule was again present. Fluid was again removed and the nodule disappeared. FNAB specimen was reported as "benign". The small cyst recurred again in July 1991. Continued follow-up was recommended, but in January 1992 the patient requested surgery, and a solitary 1,5 cm cystic M T C was found at thyroidectomy. All lymph nodes were negative, and postoperative caleitonin level was 7.0 pg/ml. No preoperative plasma specimen was available. No clinical evidence of recurrence has been noted in either patient, and both have maintained stable plasma calcitonin levels in the low-normal range. The risk of malignancy in cystic thyroid lesions was once thought to be almost negligible.2 However, more recent literature has seriously questioned this belief. 3"5 On the basis of this information and of our own two cases of biopsy-negative cystic M T C presenting just 44 days apart, we support an aggresive surgical approach to recurrent thyroid cysts. Clearly, extreme caution is required when the technique of cyst sclerosis with tetracycline, ethanol, or other agents is used. This technique should be considered only for ultrasonographically "pure" cysts, and close follow-up should be performed to assure complete resolution--both clinical and ultrasonographic. Otherwise, cyst sclerosis may delay the diagnosis of thyroid malignancy. (The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.) LTC Kenneth ]. Simcic, MD, FACP Department of Medicine Endocrinology Service COL Warren F. Bowland, MD, FACS Department of Surgery William Beaumont Army Medical Center El Paso, Texas