August 6, 1994 To: Ron Neumann, M.D. ACHRE Staff From: E. W. Webster, Ph.D. Subject: S. Farber investigation of nasopharyngeal radium applicators for treatment of aerotitis media in military personnel In reviewing this July 1, 1994 submission (press release) by Farber and Garrity on behalf of the Submarine Survivors Group, two different groups of relevant comments arise. The first is whether the nasopharyngeal treatments given as early as 1945 for Eustachian tube dysfunction should be considered as "experiments." The second is whether there is convincing evidence in adults given this treatment that brain tumors were induced and if so whether the risks cited by Farber are reasonable for an exposed adult population. A. The experiment claim. Nasopharyngeal irradiation by application of sealed Radium-226 sources was introduced in the USA by Crowe and Baylor in 1924. It was designed to improve the function of the Eustachian tubes by shrinking lymphoid tissue in and around the tubal orifice. Crowe and Baylor published a paper on their early use of this technique in the Journal of the American Medical Association in 1939 (1). Use of the "beta ray nasopharyngeal applicator" became routine medical practice in the U.S. and Europe in the 1940s and 1950s (Glasser et al, 1961) (2). It was used for example to shrink the adenoids in order to reduce the frequency of ear, nose and throat infections and to prevent hearing loss associated with adenoid hypertrophy. This was discussed by S. J. Crowe, M.D. in his Wherry Lecture to the American Academy of Ophthalmology and Otolaryngology in 1946 (3). Logical application to the treatment of aerotitis was discussed in the Archives of Otolaryngology by Dr. E. P. Fowler in January 1946 (4). It is clear from the clinical experiences published by Crowe in 1939 based on his 10-year experience with radium irradiation of children with deafness problems that there was a medical benefit to this technique. Likewise there was benefit to Air Force personnel and submariners who suffered from aerotitis which interfered with their military fitness. It was not until some epidemiology was conducted by Hazen (5) in 1966 (a negative study that there was concern over the possible late effects of the irradiation. Ron Neumann, M.D. Page 2 August 6, 1994 B. Estimates of Risk. S. Farber in his submission to ACHRE gives the impression that the epidemiological study published by Sandler et al is the definitive study and that it can be extrapolated to much larger populations, including the adult population exposed during and after World War II. The EEIR V report which Farber quotes selectively, reviews 4 studies of children who received relatively low radiation doses to the brain (i.e., 0.15 Gy to 1.4 Gy) and reports absolute risks per 10,000 person-year-Gy as follows: 1.0, 0.71, 1.9 and 3.4 to 9.0, the latter range for the Sandler study. The EEIR V Report was prepared too early to include another study of children in Holland who had received treatment with a radium nasopharyngeal applicator (Verduijn, 1989). This study included 2510 persons of whom 38.5% were children ranging from 1 to 16 in age and 11.5% were in the age range 16-75. The average applicator does was 20mg-hrs compared with 70 mg-hrs in the Sandler study, but the number of persons followed was 2.77 times greater (2510 vs. 904). The control population has been treated in the same clinics for head and neck disease without radiation and was equal in size and matched by age and sex. The mean follow-up time was 28 years, slightly longer than the 25 years in the Sandler study. The results showed 1 death from brain cancer in the exposed group versus 3 deaths in the control group; that is, there was no evidence of a brain cancer excess. It should be noted that the Sandler excess of brain cancer (3 vs. 0 in the unexposed control) did not quite reach significance (lower 95% confidence limit for relative risk = 0.87. In this respect the Warlick (U.S. Navy statement that is contested by Farber on page 5 of his July 1, 1994 News Release, is technically correct. However there was a statistically significant excess of head and neck malignancies (including the 3 brain cancer cases) in the Sandler (4 vs. 0), but no such excess in the Verduijn study (1 vs. 2 due only to brain cancer). The relation between radiation exposure of the head and brain cancer is weaker in adults than it is for children. Ron Neumann, M.D. Page 3 August 6, 1994 It should be noted that excess brain cancer has not been noted in the mortality or incidence studies of the Japanese A-bomb survivors. There were 47 brain tumors noted in this population and the relative risk was not significantly elevated. As noted in the attached the excess risk was 0.01 per 10,000 persons per year per Gray which leads to 0.03 of a brain tumor death in 10,000 persons receiving 10 rads and followed for 30 years. The comparison by Farber of the number of brain cancers in the Navy/Air Force personnel with the total Japanese A-bomb cancer cases is laughable. His projection is ruled out by the A-bomb survivor study. Notwithstanding the above there was in a sense some "experimental" use of the radium treatment in its early application to the submarine personnel by using a "control" population at least in one center to compare the effect of radiation with the "aerotitis" subjects. However the basic effect of radiation on those subjects was well understood from the early work of Crowe in children. I support Farber for his interest in a much larger epidemiologic study of Navy and Air Force personnel in order to establish in adults whether there is a cancer excess and if so how large. I strongly suspect it is much smaller than Farber predicts in such a study, partly because adults are less sensitive than children. I will send you some extra published material by mail. References (1) Crow SJ and Baylor JW. The prevention of deafness. Jour. AMA 112, 585-590 (1939). (2) Glasser, Quimby et al. Physical foundations of Radiology. 3rd Edition, Paul B. Hoeber, Inc., Harper Brothers, New York (1961). (3) Crowe SJ. Irradiation of the nasopharynx. Trans. Amer. Acad. Ophthalmology 51, 20-35 (1946). (4) Fowler WP. Irradiation of the eustachian tube. Arch. Otolaryngology 43, pp. 1-11 (1946). (5) Hazen RW, Pfifer JW et al. Neoplasms following irradiation of the head. Cancer Res. 26, 305 (1966). (6) Verduijn PG, Hayes RB et al. Mortality after nasopharyngeal irradiation for eustachian tube dysfunction. Annals of Otol. Rhinol. Laryngol. 98, 839 (1989). FOR REFERENCE SEE (13bb01.gif) 1 FOR REFERENCE SEE (13bb02.gif) 2 FOR REFERENCE SEE (13bb03.gif) 3