Background

Nasopharyngeal radium irradiation (NRI) was introduced in the United States in 1926 as a treatment to shrink swollen lymphoid tissue in the region of the head near the back of the nose, especially in children. Through the 1960s, NRI was considered good medical practice and effective treatment for a number of medical problems of the head and neck, such as hearing loss and chronic ear infections, and for reducing the size of tonsils and adenoids. Middle ear dysfunctions caused by changes in air pressure in aviators or submarine personnel were also treated with NRI.

NRI treatment consisted of inserting two cylinders of radioactive radium sulfate through the nostrils into the nasopharyngeal opening (the space behind the nose and mouth) for short lengths of time. Typically, each cylinder contained 25 milligrams of radium sulfate, and patients were exposed for three sessions of 8.5 minutes each.

The radium implant emitted three types of ionizing radiation—alpha particles, beta rays, and gamma rays. The alpha particles were blocked by the applicator and did not enter the tissue. The beta radiation, which travels short distances, targeted the nearby overgrown tissue in the nasopharynx. However, the gamma radiation, which penetrates further into the tissue than beta rays, was an unwanted by-product of the radium implant, and may be the source of adverse health effects, including cancer. Low doses of gamma radiation were delivered to the pituitary, thyroid, and salivary glands, and to the brain.

Because of its proximity to the treatment area, the pituitary gland received a higher radiation dose than either the thyroid or brain (about six to seven times greater), but a lower dose than that delivered to the nasopharnyx (25 times lower). Some scientists have speculated that damage to the pituitary gland from NRI treatment might affect circulating hormone levels, growth, and reproductive characteristics, such as fertility and early menopause. Such effects have been seen in children exposed to radiation doses much greater than that received from NRI.

By 1960, reports by both the National Academy of Sciences Committee on the Biological Effects of Atomic Radiation (1956 and 1960) and Britain's Medical Research Council (1960) raised general concerns that use of radiation therapy might have adverse, long-term effects, including increased cancer risk. In addition, effective antibiotic regimens and better surgical methods reduced the need for all types of radiation treatment for head and neck conditions. NRI treatments stopped in the early 1970s.

At least 8,000 military personnel and as many as 2.5 million civilians may have been treated with NRI in the United States. NRI therapy also was used in Canada and several European countries, including the Netherlands, where at least 24,500 patients were estimated to have been treated.

Evidence from an Early Observational Study

Several epidemiological studies have evaluated whether specific patient populations treated with NRI have an increased risk of cancer compared to untreated controls.

In one of the earliest studies, Hazen et al. (1966) compared the cancer risk of 417 children receiving NRI treatment, 971 children receiving X-ray treatment, and an untreated control group of 2,746. In follow-up periods averaging 14.6 years, no significantly increased cancer risk was observed among the treated groups compared to the controls.

Study of Military Personnel

World War II personnel such as pilots, divers, and submarine trainees (submariners) who were subject to differential air pressure between the middle ear and surrounding atmosphere commonly received NRI therapy for middle ear dysfunctions. In the first study of military personnel receiving NRI treatment, the Department of Veterans Affairs evaluated whether 1,214 NRI-exposed World War II submariners were at an increased risk of death compared to 3,176 untreated submariners (Kang et al, 2000).

The medical records revealed that the treated group had a higher probability of deaths due to all causes and all diseases of the circulatory system. Although researchers also found a small increased risk of death due to all cancers combined, as well as cancers of the head and neck, 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 the fact that the treated veterans were recruited during wartime, whereas the untreated control group of veterans was recruited during the post-war period. The researchers postulated that the fitness eligibility requirements may have been less stringent during the war or that the soldiers smoked more during the war than did the post-war group. However, based on comparisons of deaths related to tobacco use (e.g., respiratory diseases, lung cancer, and emphysema), it appeared unlikely that there was a difference in tobacco use between the two groups. The study was limited by the lack of data on risk factors other than radium exposure.

Study in Washington County, Md.

In another study involving NRI exposure in children, researchers at Johns Hopkins University in Baltimore, Md., assessed whether 904 NRI-exposed individuals had a greater risk of developing tumors of the head and neck than 2,021 non-irradiated patients (Yeh et al, 2001). The patients were treated at a hearing clinic in Washington County, Md., from 1943 to 1960. The median age of the study participants was 46 years at the time of the study.

Researchers found an elevated but statistically non-significant risk of developing brain cancer: three malignant tumors were identified in the treated group vs. none in the non-irradiated group. Four benign tumors were also reported in the exposed group vs. none in the controls. Additionally, a non-significant excess risk of thyroid cancer was detected: 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. None of these findings was statistically significant. 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.

Dutch Patients

Another well-studied population is a group of children who were treated with NRI at nine ear, nose and throat clinics in the Netherlands from 1945 through 1981.

Investigators assessed whether cancer mortality of the Netherlands cohort was higher among 5,358 NRI-exposed individuals compared to 5,265 non-exposed patients (Ronckers et al, 2001). At the time of the study, they had been followed for an average of 31.6 years. The investigators found no increased risk of death from cancers of the head and neck, nor from brain tumors. They did, however, find evidence of a marginally statistically significant increase in death from non-Hodgkin lymphoma. (Lymphomas are cancers of the lymphatic system, which is involved in fighting infections and other diseases.) The authors noted that this increased risk had not been observed in other studies of NRI-exposed patients and might have been a chance occurrence. They concluded that their study did not indicate that NRI-exposure in childhood was associated with an increased risk of cancer mortality.

In an analysis of the cancer incidence among 4,339 NRI-treated Dutch patients in the same Netherlands cohort (Ronckers et al, 2002b), the investigators found no elevated risk of cancer in general, nor of tumors of the head and neck in particular, compared to the 4,109 untreated participants. The study did not confirm the findings from the Washington County study (Yeh et al, 2001) that NRI leads to decreased risk of breast or other hormone-related cancers. The authors did report a three-fold increased risk of thyroid cancer (four cases in the exposed group vs. one in the non-exposed group). This compares to a four-fold increased risk in thyroid cancer in the Washington County study (two thyroid cancer cases in the exposed group vs. one in the control group), where the patients received about a six-fold higher dose of radiation to the thyroid. The thyroid findings in Washington County and the Netherlands are not statistically significant, but together may suggest a possible effect.

Recently, the same researchers (Ronckers et al, 2002a) evaluated the occurrence of nonmelanoma skin cancer, benign tumors, and hormonal disorders in the same Dutch cohort. They found that the exposed population (3,440 patients) was not at increased risk of thyroid disorders or benign head and neck tumors, including pituitary adenomas and salivary gland tumors. Although the exposed population did appear to have a marginally statistically significant increased risk of basal cell carcinoma (BCC) of the skin of the head and neck area, the authors believe that the results may reflect, instead, an unusually low rate of BCC among the untreated group. They also found a marginally statistically significant increased risk of infertility in exposed men compared to the unexposed men.

Comparison of the Groups Treated as Children

The majority of study participants who were treated in childhood (Hazen study, Washington County, and the Dutch cohort) have now been followed for cancer risk into young adulthood. The numbers of cancer cases and deaths in these study groups are still too small, in most cases, for the results to reach statistical significance. Those that are marginally statistically significant may not represent a true increased risk. However, in 10 to 15 years when most of the NRI-exposed subjects reach 40 to 60 years of age, when cancer rates tend to increase, analyses of the cancer patterns will allow the researchers to make more definite conclusions.

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, therefore, has not been established.

References

1. Block MA, Miller MJ, Horn RC. Carcinoma of the thyroid after external radiation to the neck in adults. Am J Surg 1969;118:764–9.
2. Boice JD Jr, Land CE, Preston DL. Ionizing radiation. In: Schottenfeld D, Fraumeni JF Jr, editors. Cancer Epidemiology and Prevention. 2nd ed. Philadelphia: J.F. Saunders; 1996. p. 319–54.
3. Clark DE. Association of irradiation with cancer of the thyroid in children and adolescents. JAMA 1955;159:1007–9.
4. Committee on the Biological Effects of Ionizing Radiation, National Research Council. Health Effects of Exposure to Low Levels of Ionizing Radiation: BEIR V., Washington, D.C.: National Academies Press; 1990.
5. Crowe SJ, Baylor JW. The prevention of deafness. JAMA 1939;112:585–90.
6. Ducatman AM, Farber SA. Radium exposure in U.S. military personnel. NEJM 1992;326:71.
7. Hazen RW, Pifer JW, Toyooka ET, Livingood J, Hempelmann LH. Neoplasms following irradiation of the head. Cancer Res 1966;26:305–11.
8. Kang HK, Bullman TA, Mahan CM. A mortality follow-up study of World War II submariners who received nasopharyngeal radium irradiation treatment. Am J Ind Med 2000;38:441–6.
9. Katz AD, Preston-Martin S. Salivary gland tumors and previous radiotherapy to the head or neck. Report on a clinical series. Am J Surg 1984;147:345–8.
10. Lindsay S, Chaikoff IL. The effects of irradiation in the thyroid gland with particular reference to the induction of thyroid neoplasms: a review. Cancer Res 1964;24:1099.
11. Medical Research Council. The hazards to man of nuclear and allied radiations. London: Her Majesty's Stationary Office; 1956.
12. Committees on Biological Effects of Atomic Radiation. Summary Reports. Washington, D.C.: National Academy of Sciences; 1956.
13. Committees on Biological Effects of Atomic Radiation. Summary Reports. Washington, D.C.: National Academy of Sciences; 1960.
14. Ronckers CM, Land CE, Hayes RB, Verduijm PG, Stovall M, van Leeuwen FE. Late health effects of childhood nasopharyngeal radium irradiation: nonmelanoma skin cancer, benign tumors, and hormonal disorders. Pediatr Res 2002a;52:850–8.
15. Ronckers CM, Land CE, Verduijn PG, Hayes RB, Stovall M, van Leeuwen FE. Cancer mortality after nasopharyngeal irradiation in the Netherlands: a cohort study. J Natl Cancer Inst 2001;93:1021–7.
16. Ronckers CM, van Leeuwen FE, Hayes RB, Verduijn PG, Stovall M, Land CE. Cancer incidence after nasopharyngeal radium irradiation. Epidemiology 2002b;13:552–60.
17. Sandler DP, Comstock GW, Matanoski GM. Neoplasms following childhood radium irradiation of the nasopharynx. J Natl Cancer Inst 1982;68:3–8.
18. Shy C, editor. Summary report of the panel. Panel of the Workshop on Public Health Response to Nasopharyngeal Radium Irradiation. Otolaryngol Head Neck Surgery 1996;115:442–6.
19. Skolnick AA. Government is in no rush to study thousands of veterans who received nasal radiation therapy. JAMA 1995;274:858–9.
20. Soffermann RA, Heisse JW. Adenoid cystic carcinoma of the nasopharynx after previous adenoid radiation. Laryngoscope 1985;95:458–61.
21. United Nations Scientific Committee on the Effects of Atomic Radiation. Sources and Effects of Ionizing Radiation. Volume II: Effects; Annex I. Epidemiological Evaluation of Radiation-Induced Cancer. E.00.IX.4; New York: United Nations; 2000.
22. Verduijn PG, Hayes RB, Habbema JDF, Looman C, van der Maas PJ. Mortality after nasopharyngeal radium irradiation for eustachian tube dysfunction. Ann Otol Rhinol Laryngol 1989;98:839–43.
23. Wilson EH, Asper SP. The role of X-ray therapy to the neck region in the production of thyroid cancer in young people. Arch Intern Med 1960;105:244–51.
24. Yeh H-C, Matanoski GM, Wang N-Y, Sandler DP, Comstock GW. Cancer incidence after childhood nasopharyngeal radium irradiation: A follow-up study in Washington County, Maryland. Am J Epidemiol 2001;153:749–56.

# # #

Related NCI materials and Web pages:

• National Cancer Institute Fact Sheet 6.37, Head and Neck Cancer: Questions and Answers ¹
  (http://www.cancer.gov/cancertopics/factsheet/Sites-Types/head-and-neck)
• Chemotherapy and You: Support for People With Cancer ²
  (http://www.cancer.gov/cancertopics/chemotherapy-and-you)
• Radiation Therapy and You: Support for People With Cancer ³
  (http://www.cancer.gov/cancertopics/radiation-therapy-and-you)
• Throat (Laryngeal and Pharyngeal) Cancer Home Page ⁴
  (http://www.cancer.gov/cancertopics/types/throat)
• What You Need To Know About™ Cancer of the Larynx ⁵
  (http://www.cancer.gov/cancertopics/wyntk/larynx)

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Glossary Terms

A tumor that is not cancer. It starts in gland-like cells of the epithelial tissue (thin layer of tissue that covers organs, glands, and other structures within the body).

An unexpected medical problem that happens during treatment with a drug or other therapy. Adverse effects do not have to be caused by the drug or therapy, and they may be mild, moderate, or severe. Also called adverse event.

A process in which anything complex is separated into simple or less complex parts.

A drug used to treat infections caused by bacteria and other microorganisms.

A type of skin cancer that arises from the basal cells, small round cells found in the lower part (or base) of the epidermis, the outer layer of the skin.

Not cancerous. Benign tumors may grow larger but do not spread to other parts of the body. Also called nonmalignant.

A growth that is not cancer. It does not invade nearby tissue or spread to other parts of the body.

Pertaining to biology or to life and living things. In medicine, refers to a substance made from a living organism or its products. Biologicals may be used to prevent, diagnose, treat or relieve of symptoms of a disease. For example, antibodies, interleukins, and vaccines are biologicals. Biological also refers to parents and children who are related by blood.

The growth of abnormal cells in the tissues of the brain. Brain tumors can be benign (not cancer) or malignant (cancer).

Glandular organ located on the chest. The breast is made up of connective tissue, fat, and breast tissue that contains the glands that can make milk. Also called mammary gland.

A term for diseases in which abnormal cells divide without control and can invade nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymph systems. There are several main types of cancer. Carcinoma is a cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is a cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is a cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the blood. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system. Central nervous system cancers are cancers that begin in the tissues of the brain and spinal cord. Also called malignancy.

A disease or condition that persists or progresses over a long period of time.

The system that contains the heart and the blood vessels and moves blood throughout the body. This system helps tissues get enough oxygen and nutrients, and it helps them get rid of waste products. The lymph system, which connects with the blood system, is often considered part of the circulatory system.

In science, a substance that is made up of more than one ingredient.

In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works.

In medicine, a disturbance of normal functioning of the mind or body. Disorders may be caused by genetic factors, disease, or trauma.

The amount of medicine taken, or radiation given, at one time.

A condition in which the ovaries stop working and menstrual periods stop before age 40. Natural menopause usually occurs around age 50. A woman is said to be in menopause when she hasn’t had a period for 12 months in a row. Symptoms of menopause include hot flashes, mood swings, night sweats, vaginal dryness, trouble concentrating, and infertility. Early menopause can be caused by some cancer treatments, surgery to remove the ovaries, and certain diseases or genetic conditions. Also called premature menopause, premature ovarian failure, and primary ovarian insufficiency.

Pulmonary emphysema is a disorder affecting the alveoli (tiny air sacs) of the lungs. The transfer of oxygen and carbon dioxide in the lungs takes place in the walls of the alveoli. In emphysema, the alveoli become abnormally inflated, damaging their walls and making it harder to breathe. People who smoke or have chronic bronchitis have an increased risk of emphysema.

The layer of tissue that lines the uterus.

The ability to produce children.

A type of high-energy radiation that is different from an x-ray.

One of many chemicals made by glands in the body. Hormones circulate in the bloodstream and control the actions of certain cells or organs. Some hormones can also be made in the laboratory.

A substance or object that is put in the body as a prosthesis, or for treatment or diagnosis.

The number of new cases of a disease diagnosed each year.

Invasion and multiplication of germs in the body. Infections can occur in any part of the body and can spread throughout the body. The germs may be bacteria, viruses, yeast, or fungi. They can cause a fever and other problems, depending on where the infection occurs. When the body’s natural defense system is strong, it can often fight the germs and prevent infection. Some cancer treatments can weaken the natural defense system.

The inability to produce children.

A type of radiation made (or given off ) by x-ray procedures, radioactive substances, rays that enter the Earth's atmosphere from outer space, and other sources. At high doses, ionizing radiation increases chemical activity inside cells and can lead to health risks, including cancer.

Treated with radiation.

The use of high-energy radiation from x-rays, gamma rays, neutrons, protons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body near cancer cells (internal radiation therapy). Systemic irradiation uses a radioactive substance, such as a radiolabeled monoclonal antibody, that travels in the blood to tissues throughout the body. Also called radiation therapy and radiotherapy.

Cancer that forms in tissues of the lung, usually in the cells lining air passages. The two main types are small cell lung cancer and non-small cell lung cancer. These types are diagnosed based on how the cells look under a microscope.

The tissues and organs that produce, store, and carry white blood cells that fight infections and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes, and lymphatic vessels (a network of thin tubes that carry lymph and white blood cells). Lymphatic vessels branch, like blood vessels, into all the tissues of the body.

Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop.

Cancer that begins in cells of the immune system. There are two basic categories of lymphomas. One kind is Hodgkin lymphoma, which is marked by the presence of a type of cell called the Reed-Sternberg cell. The other category is non-Hodgkin lymphomas, which includes a large, diverse group of cancers of immune system cells. Non-Hodgkin lymphomas can be further divided into cancers that have an indolent (slow-growing) course and those that have an aggressive (fast-growing) course. These subtypes behave and respond to treatment differently. Both Hodgkin and non-Hodgkin lymphomas can occur in children and adults, and prognosis and treatment depend on the stage and the type of cancer.

Cancerous. Malignant tumors can invade and destroy nearby tissue and spread to other parts of the body.

A statistics term. The middle value in a set of measurements.

A measure of weight. A milligram is approximately 450,000 times smaller than a pound and 28,000 times smaller than an ounce.

The upper part of the throat behind the nose. An opening on each side of the nasopharynx leads into the ear.

Any of a large group of cancers of lymphocytes (white blood cells). Non-Hodgkin lymphomas can occur at any age and are often marked by lymph nodes that are larger than normal, fever, and weight loss. There are many different types of non-Hodgkin lymphoma. These types can be divided into aggressive (fast-growing) and indolent (slow-growing) types, and they can be formed from either B-cells or T-cells. B-cell non-Hodgkin lymphomas include Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma. T-cell non-Hodgkin lymphomas include mycosis fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblastic lymphoma. Lymphomas that occur after bone marrow or stem cell transplantation are usually B-cell non-Hodgkin lymphomas. Prognosis and treatment depend on the stage and type of disease. Also called NHL.

Skin cancer that forms in basal cells or squamous cells but not in melanocytes (pigment-producing cells of the skin).

A type of study in which individuals are observed or certain outcomes are measured. No attempt is made to affect the outcome (for example, no treatment is given).

A part of the body that performs a specific function. For example, the heart is an organ.

One of a pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus.

The main endocrine gland. It produces hormones that control other glands and many body functions, especially growth.

A gland in the male reproductive system. The prostate surrounds the part of the urethra (the tube that empties the bladder) just below the bladder, and produces a fluid that forms part of the semen.

Energy released in the form of particle or electromagnetic waves. Common sources of radiation include radon gas, cosmic rays from outer space, medical x-rays, and energy given off by a radioisotope (unstable form of a chemical element that releases radiation as it breaks down and becomes more stable).

The use of high-energy radiation from x-rays, gamma rays, neutrons, protons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body near cancer cells (internal radiation therapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that travels in the blood to tissues throughout the body. Also called irradiation and radiotherapy.

Giving off radiation.

A treatment plan that specifies the dosage, the schedule, and the duration of treatment.

Something that increases the chance of developing a disease. Some examples of risk factors for cancer are age, a family history of certain cancers, use of tobacco products, being exposed to radiation or certain chemicals, infection with certain viruses or bacteria, and certain genetic changes.

A gland in the mouth that produces saliva.

Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. Also called significant.

A procedure to remove or repair a part of the body or to find out whether disease is present. An operation.

Treatment.

The hollow tube inside the neck that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). The throat is about 5 inches long, depending on body size. Also called pharynx.

A gland located beneath the larynx (voice box) that makes thyroid hormone and calcitonin. The thyroid helps regulate growth and metabolism. Also called thyroid gland.

A group or layer of cells that work together to perform a specific function.

A plant with leaves that have high levels of the addictive chemical nicotine. The leaves may be smoked (in cigarettes, cigars, and pipes), applied to the gums (as dipping and chewing tobacco), or inhaled (as snuff). Tobacco leaves also contain many cancer-causing chemicals, and tobacco use and exposure to secondhand tobacco smoke have been linked to many types of cancer and other diseases. The scientific name is Nicotiana tabacum.

One of two small masses of lymphoid tissue on either side of the throat.

An abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumors may be benign (not cancer), or malignant (cancer). Also called neoplasm.

A type of high-energy radiation. In low doses, x-rays are used to diagnose diseases by making pictures of the inside of the body. In high doses, x-rays are used to treat cancer.