Cancer Incidence after Childhood Nasopharyngeal Radium Irradiation: A Follow-up Study in Washington County, Maryland

Hsin-chieh Yeh1, Genevieve M. Matanoski1, Nae-yuh Wang2,3, Dale P. Sandler4 and George W. Comstock1

1 Department of Epidemiology, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD.
2 Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD.
3 Department of Biostatistics, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD.
4 Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A population from a hearing clinic in Washington County, Maryland, in 1943–1960 was followed to assess the risk of developing neoplasms from radium treatment of the nasopharynx for adenoid hypertrophy. Of the 2,925 subjects who attended the clinic, 904 received radium treatment. A nonconcurrent prospective study compared the cancer incidence among the irradiated persons with that among persons with other treatments. Seven brain tumor cases (three malignant and four benign) were identified in the irradiated group versus none in the nonirradiated group (relative risk = 14.8, 95% confidence interval: 0.76, 286.3). A nonsignificant excess risk of thyroid cancer was detected in the irradiated group based on two cases in the exposed group and one case in the nonexposed group (relative risk = 4.2, 95% confidence interval: 0.38, 46.6). Decreased risks of breast cancer, female genital cancers, and prostate cancer were observed among the irradiated individuals, although these deficits were not statistically significant individually. The decreased risk of sex hormone-related cancers in the irradiated group suggests possible radiation damage to the pituitary, with consequent reduction in pituitary hormone output and alterations in sexual and other hormonal development in early life. This hypothesis needs further evaluation.

nasopharynx; neoplasms; radiation; radium

Abbreviations: CI, confidence interval; RR, relative risk


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Acute upper respiratory infection often causes hypertrophy of nasopharyngeal lymphoid tissue. The hypertrophied tissue can result in obstruction of the eustachian tube and may induce hearing loss. Before the use of antibiotics, tonsillectomy and adenoidectomy were common treatments. However, incomplete surgical removal often allowed subsequent hypertrophy of the residual tissue. In 1924, Crowe (1Go) pioneered the use of radiation to treat hyperplasia of lymphoid elements of the nasopharynx. Radium treatment of the nasopharynx was widely used in Europe and the United States from the 1940s to the mid-1960s. The Centers for Disease Control and Prevention estimates that approximately 500,000 to two million individuals, mostly children, received radium treatment in the United States between 1946 and 1961 (2Go).

Based on short-term observations, several studies have reported that radiation treatment was effective in reducing adenoid size and possibly preventing deafness and other ear, nose, and throat symptoms (3GoGo–5Go). Three cohort studies assessed the long-term risk of developing cancer after radiation. Hazen et al. (6Go) conducted a questionnaire follow-up study of exposed subjects and their siblings as a comparison. A study in the Netherlands assessed the mortality of exposed patients compared with matched, nonexposed controls from the same clinic (7Go). These two studies did not observe any significantly increased cancer risk among the irradiated subjects. A third study conducted in 1978 in Washington County, Maryland, found a slight excess risk of tumors of the head and neck among irradiated individuals compared with nonirradiated children treated in the same clinic (8Go, 9Go). The radiation doses for populations treated in the study by Hazen et al. (6Go) and the study in the Netherlands (7Go) were approximately 14–28 percent of that in the Washington County population. All three studies were conducted when irradiated subjects had not reached the high-risk age for cancer. Our study continues the evaluation of the individuals treated in Washington County to provide an additional 17-year follow-up period with observations of study participants aged 39–92 years (median, 46 years).


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
Study subjects were identified from the records of the Clinic for Prevention of Deafness in Children in Washington County, Maryland, a semirural area in western Maryland where population mobility is low. The clinic was established in 1943 by the health department in collaboration with state, federal, and voluntary agencies to serve as both a primary health care resource and a referral service for the diagnosis and treatment of hearing defects (10Go). The clinic also operated in conjunction with a screening program in both public and private county schools to identify potential patients. Irradiation therapy was given at the clinic if elimination of nasopharyngeal lymphoid tissues was desirable and tonsillectomy and adenoidectomy were not indicated. If there was a large mass of adenoid tissue, surgical removal combined with irradiation was recommended (11Go).

All persons first seen at the clinic from January 1, 1940 to January 1, 1960, were included as the initial study population (n = 2,925). The exposed group included patients who had nasopharyngeal radium treatment (n = 904); the nonexposed group included individuals who had been given other treatments (n = 2,021), mainly tonsillectomy and adenoidectomy, to relieve their symptoms.

Table 1 lists the number of subjects included in each step of the current and previous studies by exposure status. Analysis of cancer incidence in this study was restricted to persons who were successfully located in the initial 1978 study (n = 2,627). Among these individuals, 83 had died by the time of the earlier follow-up, and 2,135 responded to a questionnaire survey at that time. These previous respondents were traced and contacted again in 1994–1995 to obtain updated health information. Those who refused or did not respond in the earlier study (n = 409) were traced only by searching death certificates and the cancer registry files. No direct personal contact with this group of subjects was attempted. Persons who were not traced in the earlier follow-up (n = 298) were excluded because there was no new information to allow further contact (12Go).


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TABLE 1. Number of subjects included in each step of the study by exposure status, Washington County, Maryland, 1940–1995

 
Follow-up in 1994–1995
Incident cancer cases were identified from a questionnaire survey, the Washington County cancer registry, and death certificates. During 1994–1995, a questionnaire was mailed to subjects who were not known to have died and whose addresses could be located. Resources utilized for tracing subjects included telephone directories, city directories, and Washington County private censuses. Located subjects received up to two mailings followed by a telephone reminder, if needed. The questionnaire included queries about diseases such as malignant and benign tumors, reproductive history for women, and other factors that could be potential confounding variables for cancer. Each subject was asked to sign a permission form allowing the retrieval of hospital or doctor's records for verification of disease history.

The Washington County cancer registry was used for both case identification and verification. The registry includes resident and locally diagnosed nonresident cancer cases from 1948 to the present. It identifies cases through review of records at the only hospital in the county as well as review of death certificates for county residents.

Vital status was obtained by searching Washington County mortality files as well as matching with Social Security death records. If subjects were not found in either source, they were assumed to be alive as of December 31, 1994. Death certificates were obtained for decedents to determine the causes of death. Specific causes of death were coded according to the International Classification of Diseases, Ninth Revision. If the date of the cancer diagnosis was not available from other sources, the date of death from cancer was used as the incidence date.

All cancer cases reported on the questionnaires were checked without knowledge of exposure status. Diagnoses were verified by matching with the cancer registry or by requesting medical records through hospitals and physicians. More than 92 percent of the cancers reported on the questionnaire were verified.

Radium treatment
The treatment provided by the clinic used a radium applicator that consisted of an 8-inch (203.2-mm) flexible rod with 50 mg of radium in its tip and a 0.3-mm monel metal (a nickel alloy) filter (8Go). This allowed emissions consisting of approximately 30 percent beta particles and 70 percent gamma rays (13Go). Treatment consisted of two applicators, one in each nostril, which were inserted along the floor of the nasal cavity beneath the inferior turbinate bone to eventually lie just medial to the pharyngeal ostium of the eustachian tube. The applicators were kept in place for approximately 12 minutes; three such doses, administered at 14-day intervals, constituted the standard course of therapy. The total exposure time was 60 mg-hour. Additional radium treatments were occasionally given if symptoms persisted or reappeared. Among the irradiated patients, 11 percent received dosages of less than 60 mg-hours, 74 percent received the standard course of treatment, and the remaining 15 percent received dosages of more than 60 mg-hours.

Approximate distances from the tips of the radium applicators to different sites varied by age and individual. The distances from various tissue sites were estimated in the 1978 study by using skull films of children at different ages (8Go). Distances measured in this way were used to estimate the exposures for thyroid, pituitary, and salivary glands, the sites of major interest for the risk of cancer. The doses to these sites were then estimated by taking into account the varying energies and absorption fractions of the different products of radium decay and known properties of radium application (14Go). Table 2 shows the absorbed doses at different ages and distances. On the basis of these estimations, the pituitary gland and lower portion of the brain received approximately 0.78 Gy from the standard three treatment series. In most instances, the thyroid gland was 9 cm from the applicators and received exposures of approximately 0.09 Gy.


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TABLE 2. Estimated radiation doses to different anatomic sites from a standard course of therapy (three treatments) calculated by absorbed fraction method, Washington County, Maryland, 1940–1995

 
Data analysis
After examination of the distribution of all variables, the chi-square test for differences in proportions was used to compare the frequency distributions of selected variables in study subgroups. The beginning of follow-up was defined as the first date of radium treatment for the exposed group and the first date of a clinical visit for the nonexposed group. To calculate cancer incidence, we determined the end of follow-up date by the date of diagnosis, the date of death obtained from the death certificate (if there was no prior record of a cancer diagnosis), or the last date known to be free of cancer. In analyzing the incidence of endometrial and ovarian cancers, women with a known history of hysterectomy and/or oophorectomy were removed from person-year contributions at the time of surgery, based on the assumption that they were no longer at risk. Skin cancer was excluded from the analysis because of difficulty in confirming cases from the registry.

Internal comparisons were performed by Poisson regression to calculate the relative risks of tumor incidence, adjusting for possible confounding factors. Survival analysis was further carried out to gain insight on cancer incidence over the course of follow-up. Associations between exposure status and the cumulative incidence of tumors during the follow-up period were first evaluated by the Kaplan-Meier method. The significance levels of the difference between the two groups were assessed with the log-rank test. The Cox proportional hazards model was used for the multivariate analysis when the data met the proportionality assumption implicit in the model. All tests of significance were two-tailed, with an alpha level of 0.05.

Since breast cancer, ovarian cancer, and endometrial cancer may be considered as hormone-related cancers and share similar characteristics, these were also combined as the outcome in an additional set of regression analyses. Prostate cancer was added to this combined outcome category of genital cancers in both sexes.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In the current follow-up, 2,001 of the total 2,135 individuals included in active tracing were successfully located. Tracing was similarly successful for exposed and nonexposed study subjects, with 92.7 and 94.2 percent of each group, respectively, being traced (p = 0.16). There was no difference for demographic variables between the two groups.

Questionnaires were mailed to 1,882 persons who were found to be still alive, and 1,703 replied to the survey. This represents a 93.5 percent response among the exposed and 89.1 percent among the nonexposed persons. Seventy-six subjects did not return the questionnaires even after several contacts, and 103 individuals refused to participate in the study. A comparison of questionnaire respondents and nonrespondents indicated no differences in the percent exposed in the two groups (32 percent of respondents vs. 31 percent of nonrespondents received radium treatment). The respondents were, however, older than nonrespondents by an average of 2 years.

Baseline characteristics
Table 3 lists the frequency distribution of baseline characteristics in the exposed and nonexposed subjects who were eligible for cancer incidence analysis regardless of questionnaire response status. The two groups did not differ significantly by sex, race, or age at the beginning of follow-up, but they differed by year of birth and year at start of follow-up. The length of follow-up was longer in the exposed group by an average of 2 years (p < 0.01). Exposed and nonexposed individuals did not differ significantly by family history of deafness, yet more irradiated subjects had a history of adenoidectomy with or without tonsillectomy before the start of treatment at the clinic. Mild and severe hearing loss was also more common in the irradiated group at the first clinic visit.


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TABLE 3. Percent distribution of baseline characteristics of exposed and nonexposed subjects, Washington County, Maryland, 1940–1995

 
Cancer incidence
Relative risks of cancer incidence associated with exposure are presented in table 4 for the total period of observation. A total of 41 cancer cases were detected among the 808 exposed patients. In the nonexposed group, 83 cancer cases were identified in a population of 1,819 persons. Two cases of thyroid cancer were detected in the exposed group, and only one case of thyroid cancer was detected in the nonexposed group. No malignant salivary gland tumors developed in this population.

Three malignant and four benign brain tumors were identified in the exposed group versus none in the nonexposed group. The relative risk of malignant brain tumor is 14.8 (95 percent CI: 0.76, 286.3), and for the combined category of benign and malignant tumors, it is 30.9 (95 percent CI: 1.87, 541.7). Two of the malignant cases were astrocytomas, but sites in the brain were unknown. Among the benign cases, one was identified as a hemangioblastoma in the right cerebellar lobe, and one was a neurilemmoma in the posterior fossa of the cranial cavity. The medical records were not available to verify the other two tumors. The three malignant cases occurred within 12, 18, and 25 years after radiation. The four benign cases were diagnosed 35–44 years after radiation.

While the exposed group had a higher risk of cancers of the head and neck, the rates for cancers of breast, endometrium, ovary, and prostate in those who were exposed were lower than for the nonexposed (table 4). The risk of developing this combined group of sex hormone-related cancers was 56 percent lower in the irradiated group (relative risk = 0.44, 95 percent CI: 0.20, 0.96).


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TABLE 4. Relative risks of cancer incidence and 95 percent confidence intervals of selected cancers among exposed compared with nonexposed subjects using Poisson regression, Washington County, Maryland, 1940–1995

 
To examine further the difference in cancer incidence over the course of follow-up, we performed survival analysis for selected cancers with five or more cases in both groups. The results of this additional analysis were similar to those estimated by Poisson regression. For the combined category of breast, endometrium, ovary, and prostate cancers, the estimated Cox relative risk was 0.29 (95 percent CI: 0.13, 0.65). Figure 1 shows the cumulative incidence of this combined category for both exposed and nonexposed groups estimated with the Kaplan-Meier product limit method.



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FIGURE 1. Cumulative incidence of breast, endometrium, ovary, or prostate cancer among exposed and nonexposed patients, Washington County, Maryland, 1940–1995.

 
Reproductive characteristics
The exposed and nonexposed groups were compared with respect to other characteristics identified from the questionnaire to determine whether any of these factors might explain the observed differences in cancers of reproductive organs. As shown in table 5, the exposed women were older, had completed more years in school, and were less often current cigarette smokers than were nonexposed women. The differences in age at menopause and at first full-term pregnancy were suggestive but nonsignificant, with the exposed women being older. The two groups were not significantly different in family history of breast cancer, percentage of subjects who had ever been pregnant, age at menarche, history of taking oral contraceptives, history of receiving hormone replacement therapy, infertility, and number of children. In men, those who were exposed were older, but there was no difference in number of children, infertility, and family history of prostate cancer between the two groups (data not shown.) The similarity in the reproductive characteristics of the two groups makes it unlikely that those factors played a role in the difference in cancer risk.


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TABLE 5. Percent distribution of characteristics of female respondents by exposure status, Washington County, Maryland, 1940–1995

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Although there was an excess risk of brain tumors associated with radiation, a dose-response effect could not be demonstrated because of the small number of cases. However, previous studies have shown a possible etiologic role of low-dose radiation in the development of brain tumors. Children who received x-ray treatment for tinea capitis (15Go, 16Go) and atomic bomb survivors were found to have elevated risks of malignant and benign brain tumors from radiation doses as low as 0.27 Gy (17Go). The finding of this study regarding risk of brain tumors is consistent with evidence from previous studies. The average dose to pituitary fossa was 0.78 Gy in the study population. The brain doses, as estimated by Land (18Go) were between 0.15 to 0.4 Gy, a value in the same range as the lower end of exposures in other reports.

Radiogenic brain tumor types have often been identified as meningiomas but glioma, astrocytoma, hemangioblastoma, and acoustic neuroma have also been reported (15Go, 16Go, 19Go). The histologic types observed in this study were not different from those in other studies. One interesting observation was that all of the malignant cases occurred within the first 25 years after radiation (age range, 25–39 years), and all of the benign cases were diagnosed 35 years or more after the beginning of follow-up (age range, 44–75 years). In the general population, the mean age of presentation of astrocytoma is 45 years (20Go). Physiologically, sensitivity to radiation may vary among different brain tissues. The induction period after irradiation may be shorter for malignant tumors than for benign tumors. On the other hand, benign tumors might be diagnosed late in life instead of having a late onset. They may have existed for a very long period of time without clinical symptoms but were incidentally detected during other ear examinations.

Two thyroid cancer cases occurred in the exposed group, and one case developed in the nonexposed group. These cases represented a higher risk in the exposed population, but little weight can be placed on the finding because of the small number of cases. The thyroid cases received radiation doses similar to the group's median thyroid dose of 0.09 Gy. Significantly increased risks of thyroid cancer have been reported in many radiation studies, including A-bomb survivors (17Go), children exposed to x-rays for tinea capitis in Israel (21Go), and patients treated for thymus enlargement (22Go). Among these populations, the thyroid doses ranged from 0.09 Gy in the Israeli tinea capitis cohort (21Go) to 1.36 Gy in the Rochester Thymus Study (22Go). Another tinea capitis cohort in New York did not find any thyroid cancer cases (15Go) but did report six thyroid adenomas in irradiated patients versus none in controls.

The current cohort received estimated thyroid doses similar to those of the children with tinea capitis. Ron et al. (23Go) proposed a linear dose-response model for risk of developing thyroid cancer. On the basis of the model derived from Israeli tinea capitis patients, 1.86 cases were expected for the group exposed to radium, which was identical to the number observed in the study (two cases).

The irradiated women had lower rates of breast cancer than did nonirradiated women despite the fact that the exposed group had a slightly higher frequency of risk factors commonly associated with the risk of breast cancer. The exposed group was older, better educated, older at the first pregnancy, younger at menarche, and older at menopause, and yet they had a lower risk of breast cancer (table 5). A decreased risk of breast cancer in irradiated individuals was also observed in the nasopharyngeal radium irradiation study in the Netherlands (7Go) as well as in the study by Hazen et al. (6Go). The Netherlands study found no breast cancer deaths in exposed women but two deaths in the nonexposed, for rates of zero and eight per 100,000, respectively. Hazen et al. reported no cases of breast cancer in the exposed and three cases in the sibling controls. Although these differences are not statistically significant in any of the studies, the consistency of findings across the studies is important. Furthermore, our study found that the risks of endometrial, ovarian, and prostate cancers were lower in the irradiated group. The findings lead to speculation that alterations of hormone level from pituitary irradiation might have been responsible for the decreased cancer rates among the exposed subjects.

Because of the proximity of the radium applicator to the pituitary, the radiation from the treatment might have resulted in cell damage in the pituitary and might have caused subsequent mild hypopituitarism and lower levels of luteinizing hormone and follicle-stimulating hormone. This might result in lower levels of estrogen secretion via the ovary in the irradiated women due to insufficient stimulation from the pituitary. Since high levels of estrogen have been indicated as a risk factor for female cancers, the lower levels in irradiated females might have resulted in a lower risk of those hormone-related cancers. Testosterone levels might have been similarly affected in men, resulting in changes in prostate cancer. These speculations need further support and additional testing through hormone studies of the population.

The relation between low-dose pituitary irradiation and hormone-related cancers has not been documented in other studies. However, an inverse relation between risk of breast cancer and pelvic radiotherapy (24GoGo–26Go) has been found in several populations. Serologic studies further revealed that estrogen concentrations were reduced among irradiated women (27Go), which might explain the reduced risk of breast cancer. Similar hormonal changes might occur after pituitary irradiation.

Although this cohort is small, one of the strengths of this Washington County study is the availability of childhood clinic records and a relatively stable population that can be followed for many years. The exposure status was clearly recorded for all subjects in the fixed cohort of hearing clinic patients, and it was, therefore, possible to construct an internal comparison group. It has been difficult to establish a large cohort of children exposed to nasopharyngeal radiation, since treatment records are available in only a very few places. However, consistency of findings in different study populations would be a strong argument for a causal association.

Most studies of radiation have focused on the increased cancer effects of such exposures. However, the results of follow-up of this population with nasopharyngeal exposure suggest the hypothesis that exposure of hormone-regulating organs to radiation in a period prior to puberty may result in a low risk of breast, uterus, ovary, and prostate cancers in later years. Further studies to evaluate the hormonal profiles in irradiated and nonirradiated persons would advance our understanding of the mechanism of hormone-induced cancers.


    ACKNOWLEDGMENTS
 
Supported in part by grants from the Texaco Fund, the Johns Hopkins University Summer Epidemiology Program Scholarship, and the Matanoski Gift Fund. Dr. Comstock is supported by Research Career Award HL 21670 from the National Heart, Lung, and Blood Institute.

The authors thank the staff of the Johns Hopkins Training Center for Public Health Research for their extensive help with data collection and the Washington County Department of Health for the long-term support of the research.


    NOTES
 
Reprint requests to Dr. Hsin-chieh Yeh, Department of Epidemiology, Johns Hopkins School of Hygiene and Public Health, 2024 E. Monument Street, Suite 2-600, Baltimore, MD 21205.


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication August 21, 1999. Accepted for publication August 10, 2000.