Nasopharyngeal Radium Irradiation

National Cancer Institute
Tuesday, 3 July 2001

Between the 1920s and 1960s, nasopharyngeal radium irradiation (NRI) was considered good medical practice and effective treatment for a number of medical problems of the head and neck. It consists of inserting two cylinders of radioactive radium sulfate into nasopharyngeal openings for short lengths of time. Its use was ended when concerns arose about possible side-effects, including cancer. At this time, worldwide studies have not yet confirmed a definitive link between NRI exposure and disease.

Background

NRI was introduced in the United States in 1926, as a treatment used to shrink swollen lymphoid tissue in the nasopharynx region near the back of the nose, especially in children. Typically, treatment in the United States consisted of inserting two cylinders, each containing 25 milligrams of radium sulfate, in nasopharyngeal openings for three sessions of 8.5 minutes each.

Many physicians during the 1940s and 1950s thought that conditions such as hearing loss, chronic ear infections, and middle ear problems could be treated more effectively with NRI than with surgery. It has been estimated that anywhere from 500,000 to 2 million people may have received NRI treatment, including a few thousand military submariners and aviators with aerotitis, a condition produced by air pressure changes in the middle ear.

Treatment with X-rays (external beam radiation) was also considered good medical practice and effective treatment for such conditions as ringworm of the scalp, enlargement of the thymus gland, deafness due to lymphoid tissue around the eustachian tubes, enlargement and inflammation of the tonsils and adenoids, and acne. Additionally, it was often the only method of treatment for some of these conditions before antibiotics became available. It was estimated that more than a million people might have been exposed, as children or young adults, to these treatments.

In the 1960s, a link was recognized between X-rays and thyroid cancer. As a result, in 1977, the National Cancer Institute (NCI) conducted a nationwide campaign to inform physicians and the public about the risks of irradiation-related thyroid cancer and to provide recommendations for monitoring of exposed patients. Since that time, other cancers of the head and neck area (including salivary gland and brain) have been linked to external X-ray treatment.

By the 1960s, reports by both the National Academy of Sciences Committee on the Biological Effects of Atomic Radiation and the British Medical Research Council had raised general concerns that use of radiation therapy might have adverse, long-term effects such as increased cancer risk. In addition, effective antibiotic regimens and better surgical methods reduced the demand for all types of radiation treatment for head and neck conditions. Use of NRI treatments stopped when concerns arose about possible side-effects including cancer.

Previous Studies

It is now well established from studies of various populations that exposure to high levels of ionizing radiation (such as X-rays or gamma rays) is a known cause of cancer in various tissues (UNSCEAR 2000, Boice et al, 1996).

In addition to two case reports (Katz & Preston-Martin, 1984; Soffermann & Heisse, 1985) of adenoid tissue cancers, three epidemiological studies systematically evaluated the cancer risk in patient populations treated by NRI. No significant increased cancer risk was observed in any of the latter studies.

In 1966, Hazen and others evaluated 417 people who, as children, received NRI treatment, an X-ray treated group of 971, and a control group of 2,746. In a follow-up period averaging 14.6 years, two malignant and five benign tumors were diagnosed in the radium-treated group; eight malignant and six benign tumors were observed in the group treated by X-ray; and 10 malignant and 23 benign tumors were found in the control group.

Sandler and others conducted a study with similar results in 1982. Out of 904 radium-treated children, Sandler reported four subsequent malignant and 19 benign incident tumors of the head and neck compared to no malignant tumors and 23 benign tumors in 2,021 non-irradiated subjects. Three of the four malignant tumors in the irradiated patients were in the brain and the other was an undifferentiated anaplastic cancer of the soft palate. Average follow-up time was 25 years.

Lastly, in 1989, Verduijn and others published results on cancer mortality among subjects who had been treated in five Dutch ear, nose, and throat (ENT) clinics. Two thousand five hundred ten treated individuals were compared with 2,199 individuals who did not receive radiation therapy. The average follow-up period was 25.3 years for the irradiated patients and 26.8 years in the control group. In the exposed group, 21 cancer deaths were observed while 15 deaths were observed among the control group. Specifically, one death from head and neck cancers was observed in the irradiated patients and while two deaths were observed in the control group (all three were brain tumors, one of which was benign). Additionally, there were three leukemia deaths among the exposed, vs. two among the non-exposed.

New Findings

Findings from three new studies have recently been published. The most recent report involves collaborators from the Reinaert Kliniek, Maastricht-The Netherlands, the Netherlands Cancer Institute, the NCI, and the University of Texas M. D. Anderson Cancer Center, with financial support from the NCI and the Centers for Disease Control and Prevention (CDC). The investigators assessed whether cancer mortality was higher among 5,358 NRI-exposed individuals treated at Dutch ear, nose, and throat (ENT) clinics, compared to 5,265 non-exposed patients. Most of the patients were treated as children (who are thought to be the most vulnerable group for radiation-related cancer) between 1945 and 1981, and were followed for an average of 31.6 years.*

Researchers found no excess of deaths from cancers of the head and neck, or from brain tumors. However, the study did find evidence of excess deaths from malignancies of lymphoproliferative and hematopoietic origin, mainly from non-Hodgkin's lymphoma. It is important to note that excess lymphoma mortality has not been observed in other studies of NRI- exposed patients and may be a chance occurrence.

Analyses of cancer incidence in this cohort are underway to evaluate the risk of all cancers, including those with a generally good prognosis (e.g. thyroid and salivary gland malignancies). The majority of subjects treated in childhood have now been followed for cancer risk into young adulthood. In 10 to 15 years, once the majority of the NRI-exposed subjects reach between 40 and 60 years of age, specific analyses of the cancer patterns will be more feasible.

In another study published this year (Yeh et al., 2001), researchers at Johns Hopkins University in Baltimore, Md., assessed whether NRI-exposed individuals, most of whom were treated as children, had a greater risk of developing tumors of the head and neck than non-irradiated patients. The patients were treated at a hearing clinic in Washington County, Maryland, from 1943 to 1960. Of the 2,925 individuals, 904 received radium treatment. The original study was conducted in 1978.

After prolonged follow-up of these patients through 1995, researchers found an elevated but statistically non-significant risk of developing tumors of the head and neck. Seven brain tumor cases (three malignant and four benign) were identified in the irradiated group vs. none in the non-irradiated group. Additionally, a non-significant excess risk of thyroid cancer was detected in the irradiated group based on two cases in the exposed group and one case in the non-exposed group.

The researchers also found that the rates for cancers of the breast, endometrium, ovary and prostate were lower in the exposed population than in the non-exposed population. These findings were not statistically significant individually. Nevertheless, these results, along with findings from other studies, led to speculation that irradiating the pituitary gland might induce hormone alterations leading to lower cancer rates of hormone-sensitive organs among exposed subjects. However, researchers with the NCI-Netherlands study found no evidence that cancers of such organs, e.g., the female breast, occurred less often than expected.

Lastly, researchers from the Department of Veterans Affairs conducted a study (Kang et al., 2000) to assess whether NRI-exposed, World War II submarine trainees (or submariners) were at an increased risk of death from head and neck cancers. Navy submariners that received NRI treatments from January 1945 to May 1946 were identified through medical research records. Out of 1,214 submariners, an estimated 70 percent had received treatment.

Compared with 3,176 submariners who did not receive NRI treatment, the exposed group had a higher probability of deaths due to all causes and all diseases of the circulatory system. Researchers also found a small increased risk of death due to all cancers combined, as well as an increased risk of death from cancers of the head and neck. However, these findings were not statistically significant.

The higher death rate from circulatory disease was not expected. The authors speculated that the increased risk of circulatory and cancer-related deaths among treated veterans could be related to less stringent health requirements and different smoking patterns between treated and control group veterans. However, based on comparisons of mortality outcomes related to tobacco use (e.g. respiratory diseases, lung cancer, and emphysema) it appeared unlikely that there was a difference in tobacco usage between the two groups.

Although each of these three studies identifies possible associations between NRI treatment and subsequent disease, the findings are not consistent across studies. A clear link between NRI exposure and cancer risk has, therefore, still not been confirmed.

*The study is titled, "Cancer Mortality After Nasopharyngeal Radium Irradiation in The Netherlands: a Cohort Study." The authors are Cecile M. Ronckers, Charles E. Land, Pieter G. Verduijn, Richard B. Hayes, Marilyn Stovall, and Flora E. van Leeuwen. J. Natl. Cancer. Inst. 2001; Vol. 93:1021-1027.

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