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Risk of New Cancers After Radiotherapy in Long-Term Survivors of Retinoblastoma: An Extended Follow-Up

From the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services; International Epidemiology Institute, Rockville, MD; Ophthalmic Oncology Service, Memorial Sloan- Kettering Cancer Center, New York, NY; Massachusetts Eye and Ear Infirmary; Dana-Farber Cancer Institute, Boston, MA; and Department of Radiation Physics, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Ruth A. Kleinerman, MPH, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, EPS 7044, 6120 Executive Blvd, Rockville, MD 20852-7362; e-mail: Kleinerr{at}mail.nih.gov

	ABSTRACT

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PURPOSE: Many children diagnosed with retinoblastoma (Rb) survive into adulthood and are prone to subsequent cancers, particularly hereditary patients, who have germline Rb-1 mutations. We have extended the follow-up of a large cohort of Rb patients for 7 more years to provide new information on the risk of additional cancers after radiotherapy in long-term survivors.

PATIENTS AND METHODS: We analyzed the risk of new cancers through 2000 in 1,601 Rb survivors, diagnosed from 1914 to 1984, at two US medical centers. The standardized incidence ratio (SIR) was calculated as the ratio of the observed number of cancers after hereditary and nonhereditary Rb to the expected number from the Connecticut Tumor Registry. The cumulative incidence of a new cancer after hereditary and nonhereditary Rb and radiotherapy was calculated with adjustment for competing risk of death.

RESULTS: Subsequent cancer risk in 963 hereditary patients (SIR, 19; 95% CI, 16 to 21) exceeded the risk in 638 nonhereditary Rb patients (SIR, 1.2; 95% CI, 0.7 to 2.0). Radiation further increased the risk of another cancer in hereditary patients by 3.1-fold (95% CI, 2.0 to 5.3). Hereditary patients continued to be at significantly increased risk for sarcomas, melanoma, and cancers of the brain and nasal cavities. The cumulative incidence for developing a new cancer at 50 years after diagnosis of Rb was 36% (95% CI, 31% to 41%) for hereditary and 5.7% (95% CI, 2.4% to 11%) for nonhereditary patients.

CONCLUSION: Hereditary Rb predisposes to a variety of new cancers over time, with radiotherapy further enhancing the risk of tumors arising in the radiation field.

	INTRODUCTION

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Survivors of hereditary retinoblastoma (Rb), a rare childhood cancer of the eye caused by germline mutations of the Rb-1 tumor suppressor gene, have an elevated risk of developing sarcomas, brain cancer, or melanoma, whereas survivors with nonhereditary Rb do not seem prone to secondary cancer.^1-8 Past studies of cancer incidence and mortality in our large cohort of 1-year survivors of Rb have revealed increased risks for these cancers in hereditary patients, especially after radiotherapy,^2,4 in addition to an increase in lipomas, a benign tumor of adipose tissue.⁹ Recently, we reported an excess mortality of lung cancer in hereditary patients in our cohort, which suggested that carriers of the Rb-1 mutation may be highly susceptible to smoking-induced lung cancer.¹⁰ Because it is likely that the subsequent risk of cancer in hereditary Rb is sustained through adult life, we have continued to monitor this large cohort of Rb patients,^2,4 and in this report we provide new information on their cancer risk after 7 additional years of follow-up.

	PATIENTS AND METHODS

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We had identified a total of 1,729 Rb patients diagnosed from 1914 to 1984 at two medical centers in New York and Boston. We excluded 114 patients (6.4%) who died within 12 months of diagnosis of Rb, 11 patients (0.6%) who died outside of the United States, two patients (0.1%) with an unknown birth year, and one patient (0.1%) who was determined not to have Rb, which left 1,601 (92.7%) 1-year survivors of Rb eligible for study. Data on medical history, family history of Rb, treatment for Rb, reports of additional cancers, and causes of death were collected from medical records, radiotherapy records, and three subsequent telephone interviews in 1987, 1993, and 2000.

We classified 963 (60%) patients with both eyes affected or only one eye affected and Rb in a family member as hereditary, and 638 (40%) patients with one eye affected and no known family member with Rb as nonhereditary. The larger proportion of hereditary to nonhereditary patients in this cohort is not typical of the pattern in the general population, in which 10% of hereditary patients inherit a germline mutation from an affected parent, 30% have a de novo germline mutation, and 60% have the nonhereditary form of Rb.¹¹ Among 10% to 15% of patients with one eye affected, a family history of Rb has been noted.¹¹ The difference in distribution in our cohort likely reflects differential referral of patients for treatment at well-known tertiary care centers.

Radiation Treatment for Rb
In our cohort, irradiated patients were treated with external-beam radiotherapy (90%), brachytherapy (1%), or a combination of both techniques (9%). The most common external-beam treatments in this cohort were a two-field technique with nasal and lateral fields, or a single-field technique, either lateral or anterior. Before 1960, external-beam energies were orthovoltage x-rays (35%). After 1960, energies were 22 to 23 MV betatron (34%), megavoltage photons (14%), and cobalt-60 (⁶⁰Co) gamma rays (8%). Tumor doses to the affected eye ranged from 15 to 115 Gy (average, 48 Gy), with the highest doses delivered from orthovoltage external-beam radiation machines. Brachytherapy before 1960 was delivered by plaques containing Rn-222 seeds (average, 200 mg hour radium [mgh Ra] equivalents; range, 160 to 400 mgh Ra equivalents), whereas in the later time period, ⁶⁰Co plaques were used (average, 400 mgh Ra equivalents; range, 150 to 800 mgh Ra equivalents).

Dosimetry data allowed us to place patients in three categories according to whether the second tumor site was heavily, moderated, or lightly irradiated. The dosimetry data were based on out-of-beam measurements in a water phantom combined with a three-dimensional mathematical anthropomorphic phantom.^12,13 Table 1 lists the distribution of scatter radiation doses from orthovoltage and betatron external beam for a typical Rb treatment for a 1-year-old patient.

Follow-Up Procedures
We used various tracing sources (post office address correction updates, credit bureau searches, and social security administration mortality data; individual tracing; National Death Index) to update the vital status of the cohort before the most recent telephone survey in 2000. The Institutional Review Board of the National Institutes of Health approved this study, in which we surveyed patients or their families (for patients younger than 18 years) by telephone to update medical history, ascertain diagnoses of new cancers, and collect basic cancer risk factor information. Invasive cancers were confirmed by pathology reports (60.7%), hospital records or physician's records (20.6%), death certificates (15.5%), or autopsy reports (3.2%). Only confirmed invasive cancers, excluding nonmelanoma skin cancers, were included in the analysis. A trained nosologist coded all confirmed cancers according to the International Classification of Diseases for Oncology.¹⁴

Statistical Analysis
Accrual of person-years of follow-up began 1 year after diagnosis of Rb and ended at the date the patient was last known to be alive, date of death, or December 31, 2000, whichever occurred earlier. The expected number of subsequent cancers among Rb patients was estimated based on age-specific, sex-specific, and calendar-year–specific cancer incidence rates from the Connecticut Tumor Registry. The state of Connecticut has the oldest continuous cancer registry in the United States, with incidence rates reported since 1935. For rates before 1935, the rates for 1935 to 1939 were used to estimate expected rates. The standardized incidence ratio (SIR) was calculated as the ratio of observed (O) cancers to the expected (E) number of cancers, and exact 95% CIs were calculated based on the Poisson distribution.¹⁵ The excess absolute risk was calculated as the observed number of cancers minus the expected number of cancers divided by person-years times 10,000. We also calculated the cumulative incidence of a second cancer by type of Rb and treatment, with adjustment for competing risks of death according to the method of Gooley et al.¹⁶

	RESULTS

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Descriptive characteristics of the Rb cohort are listed in Table 2. The median year of RB diagnosis was 1966 for all patients. At the end of follow-up in 2000, 622 (64.6%) hereditary patients and 541 (84.8%) nonhereditary Rb patients were alive, 28 (2.9%) hereditary and 25 (3.9%) nonhereditary patients were lost to follow-up, and 313 (32.5%) hereditary patients and 72 (11.3%) nonhereditary patients had died. Follow-up since Rb diagnosis averaged 25.2 years for hereditary and 29.5 years for nonhereditary patients. At the last follow-up, 35% of nonhereditary and 22% of hereditary patients were age 40 years. Hereditary patients were typically treated with radiation for Rb (88%), whereas only 18% of nonhereditary patients were treated with radiotherapy. Nonhereditary patients were more often treated with surgery. In addition, chemotherapy was used alone or in combination with radiation for 41% of the hereditary patients and 13% of the nonhereditary patients.

Table 4 indicates that the risk of subsequent cancer was elevated almost seven-fold in nonirradiated hereditary Rb patients, whereas radiotherapy further increased this risk by 3.1-fold (95% CI, 2.0 to 5.3). Among the irradiated, hereditary patients, the SIR was 22 (95% CI, 19 to 24) for all cancer sites combined, and the highest SIRs were noted for cancer in organs near or in the treatment field that were heavily irradiated ( 1 Gy). Among the hereditary patients, radiation treatment conferred more than twice the absolute excess risk of cancer compared with no radiation.

Among the irradiated hereditary Rb patients, 76% of all cancers diagnosed at age younger than 25 years were sarcomas, compared with 48% of all cancers that developed at age older than 25. For the nonirradiated hereditary Rb patients, 33% of all cancers diagnosed at age younger than 25 years were sarcomas, whereas only 8% of all tumors diagnosed at older ages were sarcomas. The bone cancers were mainly osteosarcomas (75 cases) of the skull and face (61%), lower limbs (29%), trunk (7.6%), and unknown location (3.8%). The connective tissue cancers included a variety of soft tissue sarcomas (80 cases) distributed across the head and face (70%), trunk (20%), lower limbs (3.8%), and unknown location (2.5%).

Notably, five of the seven uterine cancers were leiomyosarcomas (O/E, 376; 95% CI, 121 to 878), which are rare smooth muscle tumors that usually occur when patients are older than 50 years. The five uterine leiomyosarcomas were diagnosed in adults, ranging from age 31 to 47 years.

The cumulative incidence of a second cancer at 50 years after diagnosis of Rb, adjusting for competing risk of death, was 36% (95% CI, 30.9% to 41.1%) for hereditary Rb compared with 5.69% (95% CI, 2.4% to 11%) for nonhereditary Rb (Fig 1). Among the hereditary patients, radiotherapy increased the cumulative probability of developing a second cancer to 38.2% (95% CI, 32.6% to 43.8%) at 50 years, whereas the cumulative probability was 21.0% (95% CI, 9.42 to 35.6%) for nonirradiated patients (Fig 2). After orthovoltage radiation, which was predominantly used before 1960, the cumulative incidence at 40 years for hereditary Rb patients was 32.9% (95% CI, 27% to 38.9%) compared with 26.3% (95% CI, 21.1% to 31.7%) for hereditary patients who were treated after 1960 with other types of external-beam radiation with less scatter radiation (Fig 3).

View larger version (11K): [in this window] [in a new window]   Fig 1. Cumulative incidence and 95% CIs of new cancers by time since diagnosis of retinoblastoma by hereditary status.

View larger version (14K): [in this window] [in a new window]   Fig 2. Cumulative incidence and 95% CIs of new cancers by time since diagnosis of hereditary retinoblastoma by radiotherapy.

View larger version (14K): [in this window] [in a new window]   Fig 3. Cumulative incidence and 95% CIs of new cancers by time since diagnosis of hereditary retinoblastoma by orthovoltage radiotherapy.

	DISCUSSION

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We detected an enhanced effect for the risk of osteosarcomas after radiation with chemotherapy compared to radiation alone, which is consistent with the previous findings of Tucker et al.¹⁷

Radiotherapy likely contributed to the significantly increased risks that we observed for cancers of the brain, nasal cavities, and eye and orbit. All of the brain and the majority of the eye cancers were diagnosed in patients older than 5 years, whereas four of five pineoblastomas were diagnosed in patients younger than 5 years. No additional pineoblastomas, or trilateral retinoblastomas as they are often classified, have been diagnosed since the last follow-up of this cohort. This was not unexpected because these tumors are typically diagnosed at very young ages after Rb and the most recent year of Rb diagnosis in this cohort was 1984. In addition, it has been suggested that the declining incidence of pineoblastomas in another series of Rb patients may be due to the declining use of external-beam radiation therapy,²⁰ which supports the notion that high-dose radiotherapy is probably related to the earlier excess that we observed. Alternatively, it has been hypothesized that chemoreduction with a three-drug protocol, which has been used since 1995, might explain the more recent decrease in pineoblastoma incidence after Rb at another institution.²¹

The increased risk for melanoma, which was noted in our previous studies,^2,4 continued, probably due to genetic factors independent of radiation, because risks were elevated in both irradiated and nonirradiated patients.

Our report of an increased lung cancer risk in hereditary Rb patients¹⁰ was confirmed recently by a cohort of nonirradiated Rb patients in the United Kingdom.¹⁹ Somatic mutations in the Rb-1 gene are known to contribute to the development of lung cancer,²² and smoking information in our cohort suggested that Rb patients may have an increased susceptibility to the carcinogenic effects of tobacco smoke.¹⁰

At the time of last follow-up, the excess risk of breast cancer seemed limited to nonhereditary Rb.² With additional follow-up, risks were similarly increased for irradiated patients with hereditary and nonhereditary Rb. Breast dose from scatter radiation after treatment for Rb was approximately 0.4 Gy. The risk of radiation-related breast cancer is known to be heightened when the exposure occurs at very young ages, as observed after irradiation for enlarged thymus glands (mean dose, 0.7 Gy) or hemangioma (mean dose, 0.5 Gy), and exposure to the atomic blasts in Japan (mean dose, 0.3 Gy).²³ It is interesting that an epithelioid leiomyosarcoma of the breast was noted after radiotherapy for hereditary Rb in a 33-year-old male in our series.

In our updated follow-up of hereditary Rb patients, new excess risks emerged for cancers of the salivary gland, tongue, and nasopharynx after radiotherapy, based on small numbers. Cancer of the salivary gland has been linked previously to radiotherapy during childhood for tinea capitis (mean dose, 0.4 Gy) and enlarged tonsils (mean dose, 4.6 Gy),²⁴ which is consistent with dose received by Rb patients (1.6 to 4.2 Gy). Salivary gland cancer has been noted after radiation (10 to 13 Gy) associated with bone marrow transplantation in children, but the role of radiation is unclear in the increased risk of tongue cancer after bone marrow transplantation.²⁵ Cancer of the tongue was diagnosed at age 10 in a hereditary Rb patient, who was treated with brachytherapy.²⁶ In our cohort, cancer of the tongue was diagnosed at ages 19 and 42 years. Cigarette smoking has been associated with cancer of the tongue,²⁷ however, neither of the two patients in our cohort smoked. Doses to the nasal region were high (3.2 to 34 Gy) in our series, and the two nasopharyngeal cancers included an osteosarcoma of the hard palate and carcinoma of the nasopharynx, not otherwise specified.

Also noted for the first time were excess risks of cancers of the colon and corpus uteri among the hereditary patients. Five of the seven uterine cancers and two of the three colon cancers were leiomyosarcomas. Risks were similarly increased in patients with and without prior radiotherapy for RB, which is consistent with genetic susceptibility to a variety of sarcomas in Rb patients.^28,29

In another series of long-term hereditary Rb survivors not treated with radiation,¹⁹ bladder cancer was significantly elevated and presumably attributed to tobacco smoking, although smoking data were not available. The risk of this tumor was markedly but not significantly increased in Rb patients in our study. One of the two bladder cancer patients was a nonsmoker, and the smoking status of the second patient is unknown.

In our extended follow-up, the cumulative incidence for developing a new cancer at 50 years after hereditary Rb, adjusting for competing risk of death, was 36%. As the Rb patients have aged, the competing risk of death has increased to 33% at 50 years for hereditary Rb and 11% for nonhereditary Rb. We had previously reported the Kaplan-Meier probability of developing a new malignancy of 51% at 50 years after hereditary Rb in this cohort, whereas both the cumulative incidence as well as the Kaplan-Meier probability was 5.7% for nonhereditary Rb.² The lack of adjustment for competing risks with the Kaplan-Meier statistic may explain some of the differences in these risk estimates between 1993 and 2000. The lower cumulative risk of a new cancer through 2000 for hereditary Rb patients compared with the earlier follow-up in 1993 with Kaplan-Meier probabilities is encouraging because it probably reflects in part the lower doses of scatter radiation received by patients after 1960. This is supported by the somewhat lower cumulative incidence of new cancers among patients treated with non–orthovoltage radiation compared with those patients treated with orthovoltage radiation. However, the persistently elevated cancer risk in hereditary but not nonhereditary Rb points to the role of germline Rb-1 mutations in a variety of secondary tumors, and emphasizes the need for life-long surveillance for subsequent cancers in hereditary Rb patients, especially those treated with radiation.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank Kathy Chimes (Westat Inc) for field work support, and Henry Chen (IMS Inc) for computer support.

	NOTES

 
Supported by N02-CP-81121 (National Cancer Institute) to Westat Inc (for field work), Rockville, MD.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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21. Meadows AT, Shields CL: Regarding chemoreduction for retinoblastoma and intracranial neoplasms. Arch Ophthalmol 122:1570, 2004[Free Full Text]

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Submitted May 11, 2004; accepted December 23, 2004.

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