Nonmelanoma Skin Cancer in Survivors of Childhood and Adolescent Cancer: A Report From the Childhood Cancer Survivor Study
http://www.100md.com
《临床肿瘤学》
the Children's Hospitals and Clinics, Minneapolis
Department of Pediatrics, University of Minnesota Medical School and Cancer Center, Minneapolis, MN
Fred Hutchinson Cancer Research Center, Seattle, WA
Columbus Children's Hospital, Columbus, OH
University of Texas M.D. Anderson Cancer Center
Baylor College of Medicine, Houston, TX
Children's Hospital of Philadelphia, Philadelphia, PA
University of Michigan, Ann Arbor, MI
ABSTRACT
PURPOSE: Nonmelanoma skin cancer (NMSC) has become the most common type of cancer in many populations throughout the world. Ultraviolet and ionizing radiation are known risk factors. Because NMSCs are rarely lethal and most cancer registries do not routinely report data regarding these cancers, they have received little attention in studies evaluating long-term effects of cancer therapy. This article reports on the occurrence of secondary NMSC as a long-term effect of cancer therapy in survivors of childhood cancer.
PATIENTS AND METHODS: The Childhood Cancer Survivor Study (CCSS) is a cohort study of 5-year survivors of childhood and adolescent cancer from 25 participating institutions in North America. NMSC patients were defined by a history of basal cell or squamous cell carcinoma of the skin after primary malignancy treatment. Demographic and treatment data were collected and analyzed.
RESULTS: Among the 13,132 eligible CCSS participants, 213 have reported NMSC; 99 patients (46%) have had multiple occurrences. Median age of occurrence was 31 years (range, 7 to 46 years). Location of NMSC included head and neck (43%), back (24%), chest (22%), abdomen and pelvis (5%), extremity (3%), and unknown (4%). Ninety percent of patients had previously received radiation therapy (RT); 90% of tumors occurred within the RT field. RT was associated with a 6.3-fold increase in risk (95% CI, 3.5- to 11.3-fold).
CONCLUSION: Long-term survivors of childhood and adolescent cancer who were treated with RT are at highest risk for developing NMSC. Educational efforts need to be directed to this population to facilitate early diagnosis of NMSC and reduction in sun exposure.
INTRODUCTION
Nonmelanoma skin cancer (NMSC), primarily basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), represents a major health concern. NMSC is rapidly increasing in incidence and has become the most common type of cancer in many populations throughout the world.1,2 It has been estimated that approximately 1,000,000 cases of NMSC are diagnosed in the United States each year, and an estimated 95% of these patients will survive 5 years or more.3 The vast majority of NMSC occurs on sun-exposed skin of the face, head, and neck. BCC accounts for approximately 75% of all NMSCs. The incidence peaks at approximately 70 years of age, and the lifetime risk is estimated at 33%, with the risk for men greater than that of women. Despite the low mortality associated with these cancers, the lesions are often locally aggressive, causing disfigurement and significant health care costs.
Incidence rates of NMSC are noted to increase with increasing ambient solar UV exposure. Length of exposure, exposure at an early age, total accumulated exposure, and fairness of skin are important factors in NMSC development.4-7 Ionizing radiation is also a well-established carcinogen and a known cause of NMSC.8 Evidence of this association has been documented in workers using early radiation devices,9,10 individuals treated with low-dose ionizing radiation for tinea capitis or thymic enlargement in childhood,11-13 and survivors of the atomic bombings.14 A strong positive dose-response association was observed in the latter population.14 In several studies, the rate of NMSC occurrence continued to grow with increasing time since irradiation exposure.11-13
Less is known about the occurrence of NMSC secondary to previous cancer therapy. Given that radiation-induced NMSC is rarely lethal, these cancers have received little attention in studies evaluating long-term effects of cancer therapy and occurrence of second malignant neoplasms. NMSC has been found to be one of the most frequent second malignant neoplasms in several studies, but the data are typically excluded from analyses because of the lack of population incidence data.15-20 The Nordic Society of Pediatric Hematology and Oncology Association of the Nordic Cancer Registries has been able to report a standardized incidence ratio of 4.7 (95% CI, 2.7 to 7.8) for NMSC in survivors of childhood cancer compared with the general population.21
The present study was designed to investigate the occurrence of secondary NMSC as a long-term effect of cancer therapy in survivors of childhood cancer. The specific objectives were to describe the occurrence of secondary NMSC in a large cohort of childhood cancer survivors, evaluate the association between the occurrence of secondary NMSC and a history of radiation therapy (RT) exposure, and evaluate the role of several previously defined modulators of risk.
PATIENTS AND METHODS
The detailed methods of the Childhood Cancer Survivor Study (CCSS) cohort study have been published previously.22 In brief, the CCSS is a multi-institutional consortium (see Appendix), consisting of 25 participating clinical centers in the United States and Canada, established to observe a cohort of 5-year survivors of childhood and adolescent cancer. Each participating institution identified all patients who fulfilled the following eligibility criteria: (1) diagnosis and initial treatment of leukemia, CNS malignancy (excludes meningioma and craniopharyngioma), Hodgkin's disease, non-Hodgkin's lymphoma, neuroblastoma, soft tissue sarcoma, kidney cancer, or bone cancer; (2) diagnosis date between January 1, 1970, and December 31, 1986; (3) age less than 21 years at diagnosis; and (4) alive 5 years from the date of diagnosis.
The CCSS protocol and contact documents were reviewed and approved by the Human Subjects Committee at each participating institution. Data used in this analysis were collected for eligible subjects using a baseline and follow-up questionnaire administered beginning in 1994 and 2000, respectively. Next of kin, typically a parent or spouse, was contacted for those eligible subjects who were known to have died after achieving 5-year survivorship. The questionnaires addressed social and demographic information, medical conditions diagnosed by a doctor, health behaviors, cancer recurrence, development of subsequent neoplasms, and family history. Surveys used in data collection are available for review at the following Web site: www.cancer.umn.edu/ccss.
For all CCSS participants who returned a signed medical release, a detailed summary of exposure to cancer treatment, including chemotherapy, RT, and surgery, was obtained. Information was abstracted regarding exposure to 49 specific chemotherapy agents and cumulative dose on 26 agents. Photocopies were made of all relevant RT records in each radiation oncology department. RT data were coordinated through M.D. Anderson Cancer Center's Department of Radiation Physics.22
NMSC cases were initially defined by self-report of a history of any skin cancer, including reports of both BCC and SCC after treatment for their primary malignancy. For all reported cases of NMSC in individuals who signed a medical release, an attempt was made to obtain pathologic confirmation, which was coordinated through the CCSS Pathology Review Center at Columbus Children's Hospital. Data collected included the specific type of NMSC, date of diagnosis, location of tumor(s), and whether or not there were multiple occurrences. Multiple occurrence was defined as having separate visits for NMSC removal at different points in time or having had more than one NMSC removed from completely different locations during the same visit. The NMSC had to have occurred at least 5 years after the original cancer diagnosis because this criterion was used to define overall cohort eligibility. All patients with NMSC reported before January 1, 2003, were included. Patients who reported NMSC before the 5-year survival date or reported a history of SCC located anywhere other than the skin were excluded.
To ensure validity of the analysis of the relation of NMSC to previous RT, the data were reviewed independently by two physicians (J.L.P., J.P.N.) to determine whether the NMSC occurred within or outside of the previous RT field(s). Discrepant reviews were discussed for consensus.
Data Analysis
The objective of this analysis was to estimate the relative rate of NMSC for the childhood cancer survivors and assess its modification by patient characteristics and cancer treatment factors on the development of NMSC. Incidence rates of NMSC were calculated as the number of NMSC incident cases before January 1, 2003, divided by the number of person-years at risk for NMSC. Person-years at risk were computed beginning on the date 5 years from the primary cancer diagnosis to the earliest date of the first NMSC diagnosis, death, or completion of the CCSS questionnaire.
With the use of the Poisson regression model, age-adjusted relative rates were estimated for each of the patient characteristics and therapeutic exposures listed in Table 1. Geographic location of the original treating facility and of patients at time of follow-up were defined using the US Bureau of the Census for the National Center for Health Statistics criteria.23 Eight factors were found statistically significant (P .10) and were entered into a multiple Poisson regression model to assess their simultaneous impact on the rate of developing NMSC (diagnosis, age at diagnosis, years since diagnosis, race, history of RT, family history of skin cancer, smoking history, and anthracycline exposure). We excluded age from the multiple regression analysis because it was functionally correlated with two other selected variables, age at diagnosis and years since diagnosis. Geographic locations at time of treatment and at follow-up were also highly correlated; therefore, only location at time of treatment was used for analysis purposes. All statistical tests were two sided.24
RESULTS
Of the 20,602 eligible 5-year survivors, 14,370 completed a baseline questionnaire, 3,035 were lost to follow-up, and 3,197 did not participate. Of the participants, 13,134 signed permission to abstract information from their medical record. Two survivors were excluded because of their development of NMSC before their 5-year survival date. Among the 13,132 CCSS participants, 213 have reported one or more BCC or SCC of the skin. The incidence rate of BCC was 168.4, 1,449.3, and 3,785.9 per 100,000 person-years for survivors who were less than 35 years, 35 to 44 years, and 45 to 54 years of age, respectively.
Of the 213 patients with NMSC, 615 occurrences of NMSC have been reported. Of these, 97% were BCC, and 1% were SCC. Multiple occurrences were seen in 99 patients (46%); 69 patients had two to four NMSCs, 17 had five to nine NMSCs, and 13 had 10 or more NMSCs. Eighty-two patients (38%) reported multiple visits for NMSC excisions, ranging from two to 12 office visits.
Characteristics of all CCSS patients who have developed a secondary NMSC compared with the total cohort are listed in Table 1. For the survivors who developed NMSC, the age at follow-up ranged from 8 to 49 years (median age, 23 years). Follow-up since diagnosis ranged from 6 to 30 years (median, 15 years). Median age of development of first NMSC was 31 years (range, 7 to 46 years). A significant number of NMSCs were seen in Hodgkin's disease survivors and in those who received RT.
The location of NMSC in CCSS patients were as follows: head and neck (43%), chest (22%), back (24%), extremity (3%), abdomen and pelvis (5%), and location not otherwise specified (4%). One hundred ninety-two patients (90%) were previously treated with RT. Details regarding NMSC location in relation to previous RT field are listed in Table 2. Primary RT sites included cranial and spinal (36%), neck and chest (46%), abdomen and pelvis (12%), extremities (2%), and total-body irradiation (5%). Among the patients with known RT field information and NMSC location, 90% of NMSCs occurred within the RT field. The overall incidence rate of BCC in irradiated patients was 350.1 compared with 22.9 per 100,000 person-years for nonirradiated patients.
Age-adjusted relative rates of NMSC by sex, race, original diagnosis, age at diagnosis and follow-up, years since diagnosis, smoking status, treatment history (RT, chemotherapy, and, specifically, exposure to epipodophyllotoxins, alkylating agents, anthracyclines, or platinum agents), occurrence of other second malignancies, patient family history (skin cancer or genetic conditions), original treating facility, and geographic location are listed in Table 3. Hodgkin's disease, leukemia, CNS tumor, and non-Hodgkin's lymphoma survivors, white patients, patients with a history of RT, patients who were oldest at follow-up and who had longest time since diagnosis, patients located in the West, and patients with a family history of skin cancer had increased age-adjusted relative rates of NMSC. No increased risk was observed by sex, age at diagnosis, overall history of chemotherapy, original treating facility, history of other second malignant neoplasms, or exposure to epipodophyllotoxin, alkylating, or platinum-based agents.
By multivariate analysis, original diagnosis of Hodgkin's disease, white race, oldest age at diagnosis and longest time since diagnosis, family history of skin cancer, and history of RT remained statistically significant. Patients with a positive history of smoking or exposure to anthracyclines had slightly decreased age-adjusted relative rates, although these differences did not remain statistically significant by multivariate analysis. Results of all univariate and multivariate analyses are listed in Table 3.
DISCUSSION
The CCSS population is the largest and most extensively studied cohort of individuals established to date for the study of late effects of cancer and its treatment in children. It is unique in that the cohort under study has been extensively characterized according to previous cancer therapy and occurrence of outcomes of interest. The majority of individuals in this cohort have now reached adulthood; thus, it is possible to investigate the occurrence of medical conditions from the time of cancer diagnosis and treatment during childhood and adolescence through early adulthood and middle age. The current investigation was undertaken to evaluate the magnitude of NMSC in this group and to explore the underlying risk factors.
NMSC represents a major health concern worldwide. Although these cancers rarely metastasize, they are often locally invasive, and the surgical treatments may be disfiguring. Treatment of NMSC is also associated with a significant health care cost, particularly for those individuals who suffer from multiple occurrences.
An accurate estimate of the overall incidence of NMSC in the United States is difficult because the Surveillance Epidemiology and End Results25 program and most state-wide cancer registries do not collect data on the occurrence of NMSC. In a population-based study in New Hampshire, Karagas et al26 found that between 1979 to 1980 and 1993 to 1994, the incidence rates of BCC increased by 82% in both men and women, and incidence rates of SCC increased by 235% in men and by 350% in women. In the 1-year period between 1993 and 1994, 2,897 patients (79%) were diagnosed with BCC, and 779 patients (21%) were diagnosed with SCC. The incidence rates per 100,000 person-years for BCC in New Hampshire for this same time period were 8.7, 113.4, and 283.8 in the age groups of less than 35 years, 35 to 44 years, and 45 to 54 years, respectively. These incidence rates continued to increase with age, with a rate of 1,662.5 per 100,000 person-years for individuals who were 75 years of age or older.
In the first large-scale attempt to evaluate the burden of NMSC in the general population of the United States, Scotto et al27 surveyed approximately 10,000,000 people from four geographic areas: Dallas/Fort Worth, Minneapolis/St. Paul, Iowa, and San Francisco/Oakland in 1971 to 1972. There were 300,000 cases of newly diagnosed NMSC in a 6-month period, which comprised one half of the total of all other cancer types combined. Eighty percent of NMSCs occurred on the head and neck region, and BCC accounted for 77% to 86% of all NMSCs. Ten percent of patients presented with multiple NMSCs. The male to female ratio was approximately two to one, and the highest rates were found in the Dallas/Fort Worth area, where a relatively greater degree of UV exposure was implicated in this difference.
Less is known about the occurrence of secondary NMSC in survivors of cancer because data regarding incidence of BCC or SCC have previously been excluded from second malignancy analyses. In the CCSS, NMSC is the most commonly occurring type of second malignancy, accounting for 41% of all confirmed subsequent cancers. In contrast to the population in New Hampshire, the majority of NMSCs in the CCSS population were BCC (97%). The incidence rates in the CCSS population were also greater, with survivors less than 35 years of age having almost 19 times the incidence rate seen in the New Hampshire study. Survivors aged 35 to 44 years had incidence rates that were comparable with New Hampshire residents who were 75 years of age or older.
The patterns observed in CCSS are also quite different from those reported by Scotto et al27 and others. Most notably, NMSC in survivors showed more diversity in anatomic distribution, with only 42% occurring in the head and neck region and 46% with multiple occurrences. In the CCSS population, the risk was equal between males and females, and although patients living in the West had an increased relative rate of NMSC, this difference did not remain significant by multivariate analysis. Also, as Scotto et al27 described, NMSC is a disease primarily of older adults, with a median age of occurrence of 64 years. However, in the CCSS cohort, NMSC is occurring at a much younger age than expected in the general population, with NMSC seen in children as young as 7 years and nearly half of cases occurring in patients less than 30 years of age.
In the general population, the likelihood of developing skin cancer is related to environmental risk factors, of which ultraviolet exposure is the most prominent.27-32 Within the general population, UV exposure at early ages increases the risk of NMSC.4 Therefore, it was predicted that younger age at diagnosis (treatment) of primary malignancy would be associated with an increased risk of NMSC. This was confirmed, with patients youngest at time of treatment found to be at 1.6 times the risk of patients oldest at diagnosis. Development of NMSC in the general population is also suspected to be a long process that takes place with chronic UV radiation exposure. In CCSS, years since diagnosis, as expected, was associated with an increased risk of NMSC, with patients who were aged 25 to 29 years since diagnosis being at the highest risk.
Ionizing radiation is a well-established carcinogen and a known cause of NMSC. Treatment history was clearly a defining risk of NMSC for survivors in this cohort. In multivariate analysis, RT accounted for more than a six-fold increased risk relative to patients who had received no RT; this difference remained significant by multivariate analysis. Chemotherapy in and of itself did not account for a difference in risk of NMSC. However, patients with a history of anthracycline exposure were observed to have a slightly decreased risk of NMSC, although this difference did not remain significant by multivariate analysis. Other factors may be involved, such as a decrease in dosage or elimination of RT, in patients who received anthracyclines.
In the general population, the likelihood of developing skin cancer is also related to physical characteristics, with fair-skinned, sun-sensitive individuals being the most vulnerable. Additional information on skin type and previous sun exposure is currently being collected in CCSS to determine whether a multiplicative effect between skin sensitivity and exposure to radiation exists. These data may be useful in identifying survivors who are at highest risk for the development of NMSC and targeting these individuals for future risk-reducing interventions.
Patients with familial cancer syndromes, such as nevoid BCC syndrome (Gorlin syndrome), are also at increased risk for developing multiple BCCs at an early age,33-35 as are patients with genetic defects in DNA repair mechanisms such as xeroderma pigmentosum.36 It was expected that patients who developed NMSC would have a higher incidence of family members with skin cancer or genetic syndromes, and patients with a family history of skin cancer did show an increased risk that remained by multivariate analysis. None of the NMSC patients reported a positive family history for genetic diseases.
The present analysis is the first formal study of NMSC in survivors of childhood cancer. The results are clearly limited by the self-report nature of the data. However, for all self-reported cases of NMSC, an attempt was made to obtain pathologic confirmation, and for nearly all cases, confirmation was obtained. Moreover, because of the lack of available US population incidence data, we were not able to directly compare our rates with population norms. The data on occurrence of NMSC were collected in a manner that allowed a radiation dose-response relationship to be defined. Future data collection efforts are planned to facilitate analyses involving site-specific dosimetry for NMSC site.
Although rarely fatal, NMSC is clearly an important late effect of childhood cancer therapy and an important public health issue. Survivors further from diagnosis and previously treated with RT seem to be at highest risk of developing NMSC, particularly on areas of skin previous exposed to RT. Survivors need to be counseled regarding surveillance for the development of these cancers, as well as avoidance of exposures that may further increase their risk of NMSC such as sun exposure. It will be important to continue to collect these data to evaluate whether the rates of NMSC continue to increase with time since exposure.
Appendix
The following Childhood Cancer Survivor Study (CCSS) institutions and investigators participated in this study: University of California, San Francisco, CA: Arthur Ablin, MD, institutional principal investigator; University of Alabama, Birmingham, AL: Roger Berkow, MD, institutional principal investigator; International Epidemiology Institute, Rockville, MD: John Boice, ScD, CCSS Steering Committee member; University of Washington, Seattle, WA: Norman Breslow, PhD, CCSS Steering Committee member; University of Texas Southwestern Medical Center at Dallas, TX: Kevin Oeffinger, MD, institutional principal investigator, CCSS Steering Committee member; George R. Buchanan, MD, former institutional principal investigator; Dana-Farber Cancer Institute, Boston, MA: Lisa Diller, MD, institutional principal investigator; Holcombe Grier, MD, former institutional principal investigator; Frederick Li, MD, CCSS Steering Committee member; Texas Children's Center, Houston, TX: Zoann Dreyer, MD, institutional principal investigator; Children's Hospital and Medical Center, Seattle, WA: Debra Friedman, MD, MPH, institutional principal investigator; Thomas Pendergrass, MD, former institutional principal investigator; Roswell Park Cancer Institute, Buffalo, NY: Daniel M. Green, MD, institutional principal investigator, CCSS Steering Committee member; Hospital for Sick Children, Toronto, ON, Canada: Mark Greenberg, MB, ChB, institutional principal investigator; St Louis Children's Hospital, St Louis, MO: Robert Hayashi, MD, institutional principal investigator; Teresa Vietti, MD, former institutional principal investigator; St Jude Children's Research Hospital, Memphis, TN: Melissa Hudson, MD, institutional principal investigator, CCSS Steering Committee member; University of Michigan, Ann Arbor, MI: Raymond Hutchinson, MD, institutional principal investigator; Stanford University School of Medicine, Stanford, CA: Neyssa Marina, MD, institutional principal investigator; Michael P. Link, MD, former institutional principal investigator; Sarah S. Donaldson, MD, CCSS Steering Committee member; Emory University, Atlanta, GA: Lillian Meacham, MD, institutional principal investigator; Children's Hospital of Philadelphia, Philadelphia, PA: Anna Meadows, MD, institutional principal investigator, CCSS Steering Committee member; Bobbie Bayton, CCSS Steering Committee member; Children's Hospital, Oklahoma City, OK: John Mulvihill, MD, CCSS Steering Committee member; Children's Hospital, Denver, CO: Brian Greffe, Lorrie Odom, MD, former institutional principal investigator; Children's Health Care, Minneapolis, MN: Maura O'Leary, MD, institutional principal investigator; Columbus Children's Hospital, Columbus, OH: Amanda Termuhlen, MD, institutional principal investigator; Frederick Ruymann, MD, former institutional principal investigator; Stephen Qualman, MD, CCSS Steering Committee member; Children's National Medical Center, Washington, DC: Gregory Reaman, MD, institutional principal investigator; Roger Packer, MD, CCSS Steering Committee member; Children's Hospital of Pittsburgh, Pittsburgh, PA: A. Kim Ritchey, MD, institutional principal investigator; Julie Blatt, MD, former institutional principal investigator; University of Minnesota, Minneapolis, MN: Leslie L. Robison, PhD, institutional principal investigator, CCSS Steering Committee member; Ann Mertens, PhD, CCSS Steering Committee member; Joseph Neglia, MD, MPH, CCSS Steering Committee member; Mark Nesbit, MD, CCSS Steering Committee member; Cincinnati Children's Hospital Medical Center, Cincinnati, OH: Stella Davies, MD, PhD, CCSS Steering Committee member; Children's Hospital Los Angeles, CA: Kathy Ruccione, RN, MPH, institutional principal investigator, CCSS Steering Committee member; institutional principal investigator; Memorial Sloan-Kettering Cancer Center, New York, NY: Charles Sklar, MD, institutional principal investigator, CCSS Steering Committee member; National Cancer Institute, Bethesda, MD: Barry Anderson, MD, CCSS Steering Committee member; Peter Inskip, ScD, CCSS Steering Committee member; Mayo Clinic, Rochester, MN: W. Anthony Smithson, MD, institutional principal investigator; Gerald Gilchrist, MD, former institutional principal investigator; University of Texas M.D. Anderson Cancer Center, Houston, TX: Louise Strong, MD, institutional principal investigator, CCSS Steering Committee member; Marilyn Stovall, PhD, CCSS Steering Committee member; Riley Hospital for Children, Indianapolis, IN: Terry A. Vik, MD, institutional principal investigator; Robert Weetman, MD, former institutional principal investigator; Fred Hutchinson Cancer Research Center, Seattle, WA: Yutaka Yasui, PhD, institutional principal investigator, CCSS Steering Committee member; John Potter, MD, PhD, former institutional principal investigator, CCSS Steering Committee member; University of California, Los Angeles, CA: Lonnie Zeltzer, MD, institutional principal investigator, CCSS Steering Committee member.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by grant No. CA 55727 from the National Cancer Institute, Bethesda, MD, and the Children's Cancer Research Fund, Minneapolis, MN.
Abstract presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Department of Pediatrics, University of Minnesota Medical School and Cancer Center, Minneapolis, MN
Fred Hutchinson Cancer Research Center, Seattle, WA
Columbus Children's Hospital, Columbus, OH
University of Texas M.D. Anderson Cancer Center
Baylor College of Medicine, Houston, TX
Children's Hospital of Philadelphia, Philadelphia, PA
University of Michigan, Ann Arbor, MI
ABSTRACT
PURPOSE: Nonmelanoma skin cancer (NMSC) has become the most common type of cancer in many populations throughout the world. Ultraviolet and ionizing radiation are known risk factors. Because NMSCs are rarely lethal and most cancer registries do not routinely report data regarding these cancers, they have received little attention in studies evaluating long-term effects of cancer therapy. This article reports on the occurrence of secondary NMSC as a long-term effect of cancer therapy in survivors of childhood cancer.
PATIENTS AND METHODS: The Childhood Cancer Survivor Study (CCSS) is a cohort study of 5-year survivors of childhood and adolescent cancer from 25 participating institutions in North America. NMSC patients were defined by a history of basal cell or squamous cell carcinoma of the skin after primary malignancy treatment. Demographic and treatment data were collected and analyzed.
RESULTS: Among the 13,132 eligible CCSS participants, 213 have reported NMSC; 99 patients (46%) have had multiple occurrences. Median age of occurrence was 31 years (range, 7 to 46 years). Location of NMSC included head and neck (43%), back (24%), chest (22%), abdomen and pelvis (5%), extremity (3%), and unknown (4%). Ninety percent of patients had previously received radiation therapy (RT); 90% of tumors occurred within the RT field. RT was associated with a 6.3-fold increase in risk (95% CI, 3.5- to 11.3-fold).
CONCLUSION: Long-term survivors of childhood and adolescent cancer who were treated with RT are at highest risk for developing NMSC. Educational efforts need to be directed to this population to facilitate early diagnosis of NMSC and reduction in sun exposure.
INTRODUCTION
Nonmelanoma skin cancer (NMSC), primarily basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), represents a major health concern. NMSC is rapidly increasing in incidence and has become the most common type of cancer in many populations throughout the world.1,2 It has been estimated that approximately 1,000,000 cases of NMSC are diagnosed in the United States each year, and an estimated 95% of these patients will survive 5 years or more.3 The vast majority of NMSC occurs on sun-exposed skin of the face, head, and neck. BCC accounts for approximately 75% of all NMSCs. The incidence peaks at approximately 70 years of age, and the lifetime risk is estimated at 33%, with the risk for men greater than that of women. Despite the low mortality associated with these cancers, the lesions are often locally aggressive, causing disfigurement and significant health care costs.
Incidence rates of NMSC are noted to increase with increasing ambient solar UV exposure. Length of exposure, exposure at an early age, total accumulated exposure, and fairness of skin are important factors in NMSC development.4-7 Ionizing radiation is also a well-established carcinogen and a known cause of NMSC.8 Evidence of this association has been documented in workers using early radiation devices,9,10 individuals treated with low-dose ionizing radiation for tinea capitis or thymic enlargement in childhood,11-13 and survivors of the atomic bombings.14 A strong positive dose-response association was observed in the latter population.14 In several studies, the rate of NMSC occurrence continued to grow with increasing time since irradiation exposure.11-13
Less is known about the occurrence of NMSC secondary to previous cancer therapy. Given that radiation-induced NMSC is rarely lethal, these cancers have received little attention in studies evaluating long-term effects of cancer therapy and occurrence of second malignant neoplasms. NMSC has been found to be one of the most frequent second malignant neoplasms in several studies, but the data are typically excluded from analyses because of the lack of population incidence data.15-20 The Nordic Society of Pediatric Hematology and Oncology Association of the Nordic Cancer Registries has been able to report a standardized incidence ratio of 4.7 (95% CI, 2.7 to 7.8) for NMSC in survivors of childhood cancer compared with the general population.21
The present study was designed to investigate the occurrence of secondary NMSC as a long-term effect of cancer therapy in survivors of childhood cancer. The specific objectives were to describe the occurrence of secondary NMSC in a large cohort of childhood cancer survivors, evaluate the association between the occurrence of secondary NMSC and a history of radiation therapy (RT) exposure, and evaluate the role of several previously defined modulators of risk.
PATIENTS AND METHODS
The detailed methods of the Childhood Cancer Survivor Study (CCSS) cohort study have been published previously.22 In brief, the CCSS is a multi-institutional consortium (see Appendix), consisting of 25 participating clinical centers in the United States and Canada, established to observe a cohort of 5-year survivors of childhood and adolescent cancer. Each participating institution identified all patients who fulfilled the following eligibility criteria: (1) diagnosis and initial treatment of leukemia, CNS malignancy (excludes meningioma and craniopharyngioma), Hodgkin's disease, non-Hodgkin's lymphoma, neuroblastoma, soft tissue sarcoma, kidney cancer, or bone cancer; (2) diagnosis date between January 1, 1970, and December 31, 1986; (3) age less than 21 years at diagnosis; and (4) alive 5 years from the date of diagnosis.
The CCSS protocol and contact documents were reviewed and approved by the Human Subjects Committee at each participating institution. Data used in this analysis were collected for eligible subjects using a baseline and follow-up questionnaire administered beginning in 1994 and 2000, respectively. Next of kin, typically a parent or spouse, was contacted for those eligible subjects who were known to have died after achieving 5-year survivorship. The questionnaires addressed social and demographic information, medical conditions diagnosed by a doctor, health behaviors, cancer recurrence, development of subsequent neoplasms, and family history. Surveys used in data collection are available for review at the following Web site: www.cancer.umn.edu/ccss.
For all CCSS participants who returned a signed medical release, a detailed summary of exposure to cancer treatment, including chemotherapy, RT, and surgery, was obtained. Information was abstracted regarding exposure to 49 specific chemotherapy agents and cumulative dose on 26 agents. Photocopies were made of all relevant RT records in each radiation oncology department. RT data were coordinated through M.D. Anderson Cancer Center's Department of Radiation Physics.22
NMSC cases were initially defined by self-report of a history of any skin cancer, including reports of both BCC and SCC after treatment for their primary malignancy. For all reported cases of NMSC in individuals who signed a medical release, an attempt was made to obtain pathologic confirmation, which was coordinated through the CCSS Pathology Review Center at Columbus Children's Hospital. Data collected included the specific type of NMSC, date of diagnosis, location of tumor(s), and whether or not there were multiple occurrences. Multiple occurrence was defined as having separate visits for NMSC removal at different points in time or having had more than one NMSC removed from completely different locations during the same visit. The NMSC had to have occurred at least 5 years after the original cancer diagnosis because this criterion was used to define overall cohort eligibility. All patients with NMSC reported before January 1, 2003, were included. Patients who reported NMSC before the 5-year survival date or reported a history of SCC located anywhere other than the skin were excluded.
To ensure validity of the analysis of the relation of NMSC to previous RT, the data were reviewed independently by two physicians (J.L.P., J.P.N.) to determine whether the NMSC occurred within or outside of the previous RT field(s). Discrepant reviews were discussed for consensus.
Data Analysis
The objective of this analysis was to estimate the relative rate of NMSC for the childhood cancer survivors and assess its modification by patient characteristics and cancer treatment factors on the development of NMSC. Incidence rates of NMSC were calculated as the number of NMSC incident cases before January 1, 2003, divided by the number of person-years at risk for NMSC. Person-years at risk were computed beginning on the date 5 years from the primary cancer diagnosis to the earliest date of the first NMSC diagnosis, death, or completion of the CCSS questionnaire.
With the use of the Poisson regression model, age-adjusted relative rates were estimated for each of the patient characteristics and therapeutic exposures listed in Table 1. Geographic location of the original treating facility and of patients at time of follow-up were defined using the US Bureau of the Census for the National Center for Health Statistics criteria.23 Eight factors were found statistically significant (P .10) and were entered into a multiple Poisson regression model to assess their simultaneous impact on the rate of developing NMSC (diagnosis, age at diagnosis, years since diagnosis, race, history of RT, family history of skin cancer, smoking history, and anthracycline exposure). We excluded age from the multiple regression analysis because it was functionally correlated with two other selected variables, age at diagnosis and years since diagnosis. Geographic locations at time of treatment and at follow-up were also highly correlated; therefore, only location at time of treatment was used for analysis purposes. All statistical tests were two sided.24
RESULTS
Of the 20,602 eligible 5-year survivors, 14,370 completed a baseline questionnaire, 3,035 were lost to follow-up, and 3,197 did not participate. Of the participants, 13,134 signed permission to abstract information from their medical record. Two survivors were excluded because of their development of NMSC before their 5-year survival date. Among the 13,132 CCSS participants, 213 have reported one or more BCC or SCC of the skin. The incidence rate of BCC was 168.4, 1,449.3, and 3,785.9 per 100,000 person-years for survivors who were less than 35 years, 35 to 44 years, and 45 to 54 years of age, respectively.
Of the 213 patients with NMSC, 615 occurrences of NMSC have been reported. Of these, 97% were BCC, and 1% were SCC. Multiple occurrences were seen in 99 patients (46%); 69 patients had two to four NMSCs, 17 had five to nine NMSCs, and 13 had 10 or more NMSCs. Eighty-two patients (38%) reported multiple visits for NMSC excisions, ranging from two to 12 office visits.
Characteristics of all CCSS patients who have developed a secondary NMSC compared with the total cohort are listed in Table 1. For the survivors who developed NMSC, the age at follow-up ranged from 8 to 49 years (median age, 23 years). Follow-up since diagnosis ranged from 6 to 30 years (median, 15 years). Median age of development of first NMSC was 31 years (range, 7 to 46 years). A significant number of NMSCs were seen in Hodgkin's disease survivors and in those who received RT.
The location of NMSC in CCSS patients were as follows: head and neck (43%), chest (22%), back (24%), extremity (3%), abdomen and pelvis (5%), and location not otherwise specified (4%). One hundred ninety-two patients (90%) were previously treated with RT. Details regarding NMSC location in relation to previous RT field are listed in Table 2. Primary RT sites included cranial and spinal (36%), neck and chest (46%), abdomen and pelvis (12%), extremities (2%), and total-body irradiation (5%). Among the patients with known RT field information and NMSC location, 90% of NMSCs occurred within the RT field. The overall incidence rate of BCC in irradiated patients was 350.1 compared with 22.9 per 100,000 person-years for nonirradiated patients.
Age-adjusted relative rates of NMSC by sex, race, original diagnosis, age at diagnosis and follow-up, years since diagnosis, smoking status, treatment history (RT, chemotherapy, and, specifically, exposure to epipodophyllotoxins, alkylating agents, anthracyclines, or platinum agents), occurrence of other second malignancies, patient family history (skin cancer or genetic conditions), original treating facility, and geographic location are listed in Table 3. Hodgkin's disease, leukemia, CNS tumor, and non-Hodgkin's lymphoma survivors, white patients, patients with a history of RT, patients who were oldest at follow-up and who had longest time since diagnosis, patients located in the West, and patients with a family history of skin cancer had increased age-adjusted relative rates of NMSC. No increased risk was observed by sex, age at diagnosis, overall history of chemotherapy, original treating facility, history of other second malignant neoplasms, or exposure to epipodophyllotoxin, alkylating, or platinum-based agents.
By multivariate analysis, original diagnosis of Hodgkin's disease, white race, oldest age at diagnosis and longest time since diagnosis, family history of skin cancer, and history of RT remained statistically significant. Patients with a positive history of smoking or exposure to anthracyclines had slightly decreased age-adjusted relative rates, although these differences did not remain statistically significant by multivariate analysis. Results of all univariate and multivariate analyses are listed in Table 3.
DISCUSSION
The CCSS population is the largest and most extensively studied cohort of individuals established to date for the study of late effects of cancer and its treatment in children. It is unique in that the cohort under study has been extensively characterized according to previous cancer therapy and occurrence of outcomes of interest. The majority of individuals in this cohort have now reached adulthood; thus, it is possible to investigate the occurrence of medical conditions from the time of cancer diagnosis and treatment during childhood and adolescence through early adulthood and middle age. The current investigation was undertaken to evaluate the magnitude of NMSC in this group and to explore the underlying risk factors.
NMSC represents a major health concern worldwide. Although these cancers rarely metastasize, they are often locally invasive, and the surgical treatments may be disfiguring. Treatment of NMSC is also associated with a significant health care cost, particularly for those individuals who suffer from multiple occurrences.
An accurate estimate of the overall incidence of NMSC in the United States is difficult because the Surveillance Epidemiology and End Results25 program and most state-wide cancer registries do not collect data on the occurrence of NMSC. In a population-based study in New Hampshire, Karagas et al26 found that between 1979 to 1980 and 1993 to 1994, the incidence rates of BCC increased by 82% in both men and women, and incidence rates of SCC increased by 235% in men and by 350% in women. In the 1-year period between 1993 and 1994, 2,897 patients (79%) were diagnosed with BCC, and 779 patients (21%) were diagnosed with SCC. The incidence rates per 100,000 person-years for BCC in New Hampshire for this same time period were 8.7, 113.4, and 283.8 in the age groups of less than 35 years, 35 to 44 years, and 45 to 54 years, respectively. These incidence rates continued to increase with age, with a rate of 1,662.5 per 100,000 person-years for individuals who were 75 years of age or older.
In the first large-scale attempt to evaluate the burden of NMSC in the general population of the United States, Scotto et al27 surveyed approximately 10,000,000 people from four geographic areas: Dallas/Fort Worth, Minneapolis/St. Paul, Iowa, and San Francisco/Oakland in 1971 to 1972. There were 300,000 cases of newly diagnosed NMSC in a 6-month period, which comprised one half of the total of all other cancer types combined. Eighty percent of NMSCs occurred on the head and neck region, and BCC accounted for 77% to 86% of all NMSCs. Ten percent of patients presented with multiple NMSCs. The male to female ratio was approximately two to one, and the highest rates were found in the Dallas/Fort Worth area, where a relatively greater degree of UV exposure was implicated in this difference.
Less is known about the occurrence of secondary NMSC in survivors of cancer because data regarding incidence of BCC or SCC have previously been excluded from second malignancy analyses. In the CCSS, NMSC is the most commonly occurring type of second malignancy, accounting for 41% of all confirmed subsequent cancers. In contrast to the population in New Hampshire, the majority of NMSCs in the CCSS population were BCC (97%). The incidence rates in the CCSS population were also greater, with survivors less than 35 years of age having almost 19 times the incidence rate seen in the New Hampshire study. Survivors aged 35 to 44 years had incidence rates that were comparable with New Hampshire residents who were 75 years of age or older.
The patterns observed in CCSS are also quite different from those reported by Scotto et al27 and others. Most notably, NMSC in survivors showed more diversity in anatomic distribution, with only 42% occurring in the head and neck region and 46% with multiple occurrences. In the CCSS population, the risk was equal between males and females, and although patients living in the West had an increased relative rate of NMSC, this difference did not remain significant by multivariate analysis. Also, as Scotto et al27 described, NMSC is a disease primarily of older adults, with a median age of occurrence of 64 years. However, in the CCSS cohort, NMSC is occurring at a much younger age than expected in the general population, with NMSC seen in children as young as 7 years and nearly half of cases occurring in patients less than 30 years of age.
In the general population, the likelihood of developing skin cancer is related to environmental risk factors, of which ultraviolet exposure is the most prominent.27-32 Within the general population, UV exposure at early ages increases the risk of NMSC.4 Therefore, it was predicted that younger age at diagnosis (treatment) of primary malignancy would be associated with an increased risk of NMSC. This was confirmed, with patients youngest at time of treatment found to be at 1.6 times the risk of patients oldest at diagnosis. Development of NMSC in the general population is also suspected to be a long process that takes place with chronic UV radiation exposure. In CCSS, years since diagnosis, as expected, was associated with an increased risk of NMSC, with patients who were aged 25 to 29 years since diagnosis being at the highest risk.
Ionizing radiation is a well-established carcinogen and a known cause of NMSC. Treatment history was clearly a defining risk of NMSC for survivors in this cohort. In multivariate analysis, RT accounted for more than a six-fold increased risk relative to patients who had received no RT; this difference remained significant by multivariate analysis. Chemotherapy in and of itself did not account for a difference in risk of NMSC. However, patients with a history of anthracycline exposure were observed to have a slightly decreased risk of NMSC, although this difference did not remain significant by multivariate analysis. Other factors may be involved, such as a decrease in dosage or elimination of RT, in patients who received anthracyclines.
In the general population, the likelihood of developing skin cancer is also related to physical characteristics, with fair-skinned, sun-sensitive individuals being the most vulnerable. Additional information on skin type and previous sun exposure is currently being collected in CCSS to determine whether a multiplicative effect between skin sensitivity and exposure to radiation exists. These data may be useful in identifying survivors who are at highest risk for the development of NMSC and targeting these individuals for future risk-reducing interventions.
Patients with familial cancer syndromes, such as nevoid BCC syndrome (Gorlin syndrome), are also at increased risk for developing multiple BCCs at an early age,33-35 as are patients with genetic defects in DNA repair mechanisms such as xeroderma pigmentosum.36 It was expected that patients who developed NMSC would have a higher incidence of family members with skin cancer or genetic syndromes, and patients with a family history of skin cancer did show an increased risk that remained by multivariate analysis. None of the NMSC patients reported a positive family history for genetic diseases.
The present analysis is the first formal study of NMSC in survivors of childhood cancer. The results are clearly limited by the self-report nature of the data. However, for all self-reported cases of NMSC, an attempt was made to obtain pathologic confirmation, and for nearly all cases, confirmation was obtained. Moreover, because of the lack of available US population incidence data, we were not able to directly compare our rates with population norms. The data on occurrence of NMSC were collected in a manner that allowed a radiation dose-response relationship to be defined. Future data collection efforts are planned to facilitate analyses involving site-specific dosimetry for NMSC site.
Although rarely fatal, NMSC is clearly an important late effect of childhood cancer therapy and an important public health issue. Survivors further from diagnosis and previously treated with RT seem to be at highest risk of developing NMSC, particularly on areas of skin previous exposed to RT. Survivors need to be counseled regarding surveillance for the development of these cancers, as well as avoidance of exposures that may further increase their risk of NMSC such as sun exposure. It will be important to continue to collect these data to evaluate whether the rates of NMSC continue to increase with time since exposure.
Appendix
The following Childhood Cancer Survivor Study (CCSS) institutions and investigators participated in this study: University of California, San Francisco, CA: Arthur Ablin, MD, institutional principal investigator; University of Alabama, Birmingham, AL: Roger Berkow, MD, institutional principal investigator; International Epidemiology Institute, Rockville, MD: John Boice, ScD, CCSS Steering Committee member; University of Washington, Seattle, WA: Norman Breslow, PhD, CCSS Steering Committee member; University of Texas Southwestern Medical Center at Dallas, TX: Kevin Oeffinger, MD, institutional principal investigator, CCSS Steering Committee member; George R. Buchanan, MD, former institutional principal investigator; Dana-Farber Cancer Institute, Boston, MA: Lisa Diller, MD, institutional principal investigator; Holcombe Grier, MD, former institutional principal investigator; Frederick Li, MD, CCSS Steering Committee member; Texas Children's Center, Houston, TX: Zoann Dreyer, MD, institutional principal investigator; Children's Hospital and Medical Center, Seattle, WA: Debra Friedman, MD, MPH, institutional principal investigator; Thomas Pendergrass, MD, former institutional principal investigator; Roswell Park Cancer Institute, Buffalo, NY: Daniel M. Green, MD, institutional principal investigator, CCSS Steering Committee member; Hospital for Sick Children, Toronto, ON, Canada: Mark Greenberg, MB, ChB, institutional principal investigator; St Louis Children's Hospital, St Louis, MO: Robert Hayashi, MD, institutional principal investigator; Teresa Vietti, MD, former institutional principal investigator; St Jude Children's Research Hospital, Memphis, TN: Melissa Hudson, MD, institutional principal investigator, CCSS Steering Committee member; University of Michigan, Ann Arbor, MI: Raymond Hutchinson, MD, institutional principal investigator; Stanford University School of Medicine, Stanford, CA: Neyssa Marina, MD, institutional principal investigator; Michael P. Link, MD, former institutional principal investigator; Sarah S. Donaldson, MD, CCSS Steering Committee member; Emory University, Atlanta, GA: Lillian Meacham, MD, institutional principal investigator; Children's Hospital of Philadelphia, Philadelphia, PA: Anna Meadows, MD, institutional principal investigator, CCSS Steering Committee member; Bobbie Bayton, CCSS Steering Committee member; Children's Hospital, Oklahoma City, OK: John Mulvihill, MD, CCSS Steering Committee member; Children's Hospital, Denver, CO: Brian Greffe, Lorrie Odom, MD, former institutional principal investigator; Children's Health Care, Minneapolis, MN: Maura O'Leary, MD, institutional principal investigator; Columbus Children's Hospital, Columbus, OH: Amanda Termuhlen, MD, institutional principal investigator; Frederick Ruymann, MD, former institutional principal investigator; Stephen Qualman, MD, CCSS Steering Committee member; Children's National Medical Center, Washington, DC: Gregory Reaman, MD, institutional principal investigator; Roger Packer, MD, CCSS Steering Committee member; Children's Hospital of Pittsburgh, Pittsburgh, PA: A. Kim Ritchey, MD, institutional principal investigator; Julie Blatt, MD, former institutional principal investigator; University of Minnesota, Minneapolis, MN: Leslie L. Robison, PhD, institutional principal investigator, CCSS Steering Committee member; Ann Mertens, PhD, CCSS Steering Committee member; Joseph Neglia, MD, MPH, CCSS Steering Committee member; Mark Nesbit, MD, CCSS Steering Committee member; Cincinnati Children's Hospital Medical Center, Cincinnati, OH: Stella Davies, MD, PhD, CCSS Steering Committee member; Children's Hospital Los Angeles, CA: Kathy Ruccione, RN, MPH, institutional principal investigator, CCSS Steering Committee member; institutional principal investigator; Memorial Sloan-Kettering Cancer Center, New York, NY: Charles Sklar, MD, institutional principal investigator, CCSS Steering Committee member; National Cancer Institute, Bethesda, MD: Barry Anderson, MD, CCSS Steering Committee member; Peter Inskip, ScD, CCSS Steering Committee member; Mayo Clinic, Rochester, MN: W. Anthony Smithson, MD, institutional principal investigator; Gerald Gilchrist, MD, former institutional principal investigator; University of Texas M.D. Anderson Cancer Center, Houston, TX: Louise Strong, MD, institutional principal investigator, CCSS Steering Committee member; Marilyn Stovall, PhD, CCSS Steering Committee member; Riley Hospital for Children, Indianapolis, IN: Terry A. Vik, MD, institutional principal investigator; Robert Weetman, MD, former institutional principal investigator; Fred Hutchinson Cancer Research Center, Seattle, WA: Yutaka Yasui, PhD, institutional principal investigator, CCSS Steering Committee member; John Potter, MD, PhD, former institutional principal investigator, CCSS Steering Committee member; University of California, Los Angeles, CA: Lonnie Zeltzer, MD, institutional principal investigator, CCSS Steering Committee member.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by grant No. CA 55727 from the National Cancer Institute, Bethesda, MD, and the Children's Cancer Research Fund, Minneapolis, MN.
Abstract presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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