Affiliations of authors: P. Maisonneuve, Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy, and Department of Community and Preventive Medicine, New York Medical College, Valhalla; S. C. FitzSimmons, FitzSimmons and Associates, Epidemiology and Clinical Research, Bethesda, MD; J. P. Neglia, Departments of Pediatrics and Epidemiology, University of Minnesota Schools of Medicine and Public Health, Minneapolis; P. W. Campbell III, Cystic Fibrosis Foundation, Bethesda; A. B. Lowenfels, Departments of Surgery and Community and Preventive Medicine, New York Medical College.
Correspondence to: Albert B. Lowenfels, M.D., Departments of Surgery and Community and Preventive Medicine, New York Medical College, Valhalla, NY 10595 (e-mail: Lowenfel{at}nymc.edu).
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ABSTRACT |
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INTRODUCTION |
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Since the early 1990s, more than 1000 CF patients have undergone transplantation of the lung or other organs. These procedures are associated with an increased risk of lymphomas and various other types of cancer as is aging. Post-transplant lymphoproliferative disease has also been reported in pediatric CF patients (14).
In this study, which extended over a 10-year period, our aims were to 1) reassess the risk of cancer in nontransplanted CF patients; 2) assess the risk of cancer in transplanted CF patients; and 3) identify subgroups of patients at higher risk, on the basis of their demographic characteristics, genotype, characteristics at diagnosis, and eventual medical complications.
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PATIENTS AND METHODS |
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The cohort consisted of all 28 858 CF patients who were registered and followed from 1990 through 1999 at any of 115 centers in the United States accredited by the Cystic Fibrosis Foundation (CFF). The CFF registry currently includes about 22 000 living patients, representing 88% of the estimated 25 000 CF patients in the United States. On a yearly basis, all centers submitted information to the CFF patient registry by use of a standard questionnaire. The information included the patients demographics: date of birth, sex, race, date and patient characteristics at the time of diagnosis of CF, genotype, therapy, complications, transplantation, and vital status. In 1992, the standard questionnaire was redesigned to include a question about cancer. If cancer was listed as a complication, we verified the response and determined the type of cancer by directly contacting each center. Thus, since 1992, all cancer data were collected prospectively; for the years 1990 and 1991, we relied on previously collected data. The diagnosis of all cancers included in this study was confirmed by a pathologic report.
Genetic Testing
Of more than 900 identified mutations in the CF transmembrane conductance regulator (CFTR) gene, the American College of Medical Genetics recommends only those in the 24 major mutant alleles (F508, G551D, G542X, R553X, W1282X, R347P, NI303K, R560T,
I507, 17171G
A, A455E, S549N, 621+1G
T, R117H, 711+1G
T, R1162X, 3849+10kbC
T, 2789+5G
T, R334W, G85E, 1078
T, 1898+1G
T, 2184
A, 3659
C) for routine diagnostic and carrier testing (15). These are routinely recorded in the CFF registry, but rarer mutations can be recorded if they are identified by more comprehensive testing.
Statistical Analysis
To determine the number of cancers expected in the nontransplant group, the period during which patients were at risk was defined as the time from 1990 to death, transplant, or the end of the calendar year in which a patient was last reported to have been seen at a CF center. The time at risk for a patient registered after 1990 began at that persons date of diagnosis with CF. To determine the risk of cancer in the transplant group, the risk period began at the date of transplantation. Patients who developed tumors before transplantation were included in the nontransplant group. Data on all persons alive and actively followed were censored as of December 31, 1999.
The number of cancers expected during the at-risk period was determined by applying age- (within 5-year groups), sex-, race-, and calendar year-specific incidence rates obtained from the Surveillance, Epidemiology, and End Results (SEER)1 Program of the National Cancer Institute (16) to the total person-years accumulated in the corresponding categories. We used the standardized incidence ratio (SIR), defined as the ratio of the number of cancers observed to the number of cancers expected, to estimate the relative risk of cancer, and we calculated 95% confidence intervals (CIs) for the SIR by assuming that the observed cases of cancer followed a Poisson distribution (17). The absolute excess risk (AER) was defined as the greater than expected number of new cancer cases (i.e., the number of cancers observed minus the number of cancers expected) per 100 000 patients per year. Stratified analyses of the SIRs among subgroups of patients selected according to their genotype or symptoms at diagnosis were performed. Characteristics showing potential prognostic value for cancer development were evaluated with a Cox proportional hazards regression model adjusted for sex. The cumulative incidence of cancer diagnosed after 1990 determined by the complement of the KaplanMeier method was used to illustrate the difference in cancer incidence among selected subgroups of patients. All analyses were performed using SAS software (SAS Institute, Cary, NC), and all statistical tests were two-sided.
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RESULTS |
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In 1990, the mean age of prevalent patients was 14.2 years, and the mean age increased to 16.2 years in 1999. During the same period, the proportion of CF children younger than 15 years decreased from 57.8% to 51.8%, while the proportion of CF adults older than 35 years increased from 4.2% to 8.1%, reflecting the increased survival of the CF population.
By December 1999, 17 871 (62%) of the 28 858 CF patients had been genotyped for common mutations in the CFTR gene. Of these, 54% were homozygous for the F508 mutation, 38% were compound heterozygous for the
F508 mutation, 4% carried two other mutations, and 4% carried unidentified mutations.
During the same period, 1063 (3.7%) of the 28 858 patients were transplanted at a mean age of 25.5 years. Of these 1063 patients, 901 patients (85%) had transplantation of the lung, 41 (3.9%) of the heart and lung, 99 (9.3%) of the liver, 11 (1.0%) of the lung and liver, and six (0.6%) of the lung and another organ; for five patients (0.4%), the organ was not specified. The number of transplants performed increased over time from 356 (33.5% of 1063 transplants) during the first 5 years of the study to 707 (66.5%) during the last 5 years.
Cancer in Nontransplanted CF Patients
During 202 999 person-years of observation, 75 cancers were reported in nontransplanted CF patients or in CF patients before transplantation. During the same period, 69.7 cancers would have been expected, based on background age-, sex-, race-, and period-specific cancer incidence rates from the SEER registries, yielding an SIR of 1.1 (95% CI = 0.8 to 1.4; Table 1).
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We did not observe more nondigestive tract cancers than expected at any other site (52 observed versus 65.2 expected; SIR = 0.8, 95% CI = 0.6 to 1.0; P = .055). The number of melanomas and cancers of the respiratory tract, breast, female genitalia, and kidney was not statistically significantly reduced. For tumors common in childhood, such as cancer of the testis, brain, thyroid, or hematopoietic tumors, the numbers of observed and expected cancers were similar (Table 1).
Among nontransplanted patients, the mean age at diagnosis of digestive cancer was 39.3 years (range = 1962 years), and the mean age at CF diagnosis was 12.1 years (range = 060 years). For colon cancer, the mean interval between diagnosis of CF and development of cancer was 35 years. The SIRs for digestive tract cancer were similar for females (nine observed versus 1.67 expected; SIR = 5.4, 95% CI = 2.5 to 10.2) and for males (14 observed versus 2.88 expected; SIR = 4.9, 95% CI = 2.7 to 8.2) (Table 2). Only one patient developed digestive tract cancer before the age of 20 years; that cancer was a leiomyosarcoma of the duodenal wall diagnosed when the patient was 19 years old. The other 22 digestive tract cancers developed in patients aged 20 years or older, a group that constitutes 38% of the CF population. The age-specific SIRs in adult patients ranged from 4.8 in persons aged 2029 years to 6.6 in persons aged 4049 years, but these differences were not statistically significant, unlike the AER, which increased as CF patients reached an age at which digestive tract cancers are more common. The AER of digestive tract cancer became substantial for patients aged 4049 years (AER = 153.2 per 100 000 patients per year) and for patients aged 50 years or older (AER = 400.8 per 100 000 patients per year) (Table 2
). The detection rate of digestive tract cancer was constant over time: Thirteen digestive tract cancers were reported in 120 452 person-years (1.08 per 10 000 patients) until 1995, and 10 digestive tract cancers were reported in 82 547 person-years (1.21 per 10 000 patients) after 1995.
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Overall, the testicular cancer rate was not increased (five observed versus 4.7 expected; SIR = 1.1, 95% CI = 0.3 to 2.5) but the five CF patients who developed testicular cancer were homozygous for the F508 mutation, conferring on this subgroup a statistically significantly increased risk (five observed versus 1.46 expected; SIR = 3.4, 95% CI = 1.1 to 8.0).
Cancer in Transplanted CF Patients
During 2725 person-years of observation, 13 cancers were reported in 1063 transplanted CF patients, all after lung transplantation, but only 2.05 cancers were expected (SIR = 6.3, 95% CI = 3.4 to 10.8) (Table 3). As in nontransplanted CF patients, there was a statistically significantly increased number of digestive tract cancers (four observed versus 0.19 expected; SIR = 21.0, 95% CI = 5.8 to 54.2). These four cancers were one small bowel cancer (a carcinoid tumor of the ileum), two colon cancers (adenocarcinomas), and one liver cancer (a leiomyosarcoma). As expected in an immunosuppressed population, several patients developed malignant lymphoma (seven observed versus 0.16 expected; SIR = 43.8, 95% CI = 17.7 to 90.7) (Table 3
). Because the majority of transplanted CF patients were adults, the AER of digestive tract cancer was relatively large (AER = 140 per 100 000 patients per year). In addition, post-transplant lymphoproliferative disease was reported in 31 other patients. Cases of post-transplant lymphoproliferative disease were not included in the calculation of SIRs, and for the majority of these cases, pathology reports were not reviewed.
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DISCUSSION |
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In 1995, we reported more digestive tract cancer than expected in 28 511 CF patients from North America and 24 500 CF patients from Europe (11). The following are important differences between this study and our previous report. 1) Information in this study was collected solely from the large U.S. CFF registry instead of from North American registries and European CF institutions. 2) This study is a true prospective study, unlike our previous retrospective report, because information about cancer is now included in the annual questionnaire completed on all CF patients included in the registry. 3) The percentage of adult patients in this study is higher than in our previous study. 4) During the last decade, the proportion of genotyped patients has increased from 12% to 75%. 5) This study, unlike our previous study, was specifically designed to assess the risk of cancer after transplantation, a procedure that has become more common in recent years.
The increased risk of digestive tract cancer was primarily associated with the larger numbers of cancers detected in the small intestine, colon, and biliary tract. The two hepatic cancers reported in our cohort were cholangiocarcinomas (i.e., tumors of the intrahepatic bile duct) and the pancreatic tumor was a ductal adenocarcinoma of the head of the pancreas (i.e., a tumor originating from a peripheral pancreatic duct or ductule). Increased numbers of cancers were not observed in the stomach or rectum, and the increase in esophageal cancer was based on a single case. Thus, nearly all of the digestive tract organs in which more cancers were observed than expected are anatomically contiguous and would be exposed to biliary products. We examined the database for characteristics that might predict an increased risk of digestive tract cancer and found two that appeared important: failure to thrive as the initial manifestation leading to the diagnosis of CF and homozygosity for the F508 mutation. These characteristics are often predictors of disease severity and might lead to an increased risk of digestive tract cancer, but neither characteristic was associated with the risk of nondigestive tract cancer.
It is impossible to ascertain from the CFF registry data whether increased surveillance or screening was responsible for the detection of digestive tract cancer. However, the number of digestive tract cancers reported in the CFF registry after 1995 (the date of our previous report that CF patients were at higher risk of developing digestive tract tumors) did not increase substantially. In addition, digestive tract tumors have a poor prognosis, and even if these cancers were diagnosed at an early stage, patients would have developed symptoms the following year. As a consequence, we believe that the potential bias resulting from increased surveillance or screening is minimal.
Cancer of the small intestine is rare in the general population, despite the high rate of cancer in the neighboring stomach and colon, the large surface of the small intestine, and its continuous exposure to ingested food (18). Several medical conditions have been associated with cancer of the small intestine and colon, including familial adenomatous polyposis, Crohns disease, Peutz-Jeghers syndrome, celiac disease, and hereditary nonpolyposis colorectal cancer. Some of these diseases and CF share similar characteristics, such as malabsorption or intestinal stasis, and a common carcinogenic mechanism could be involved in all of these diseases. In particular, chronic inflammation has been found in the small bowel of CF patients that might lead to preinvasive changes (19).
Despite the increase in risk of digestive cancers, only a small number of digestive tract tumors developed during the 10-year study period in the North American CF population, suggesting that other modifying genes could promote or, alternatively, even decrease the risk of the development of cancer. Epithelial mucins are a family of secreted and cell surface glycoproteins expressed by epithelial tissues and implicated in epithelial cell protection, adhesion modulation, and signaling. Human MUC3, located at chromosomal position 7q22, is most highly expressed in the small intestine. Two novel mucin genes, whose expression is decreased in colorectal cancer, have been also localized to 7q22. In particular, Williams et al. (20) suggested that mucins may play a role in CF because patients with the same CFTR gene mutation can differ with respect to mucus obstruction. The existence of modifier genes has been postulated, and mucin genes are obvious candidates (21). The CFTR gene lies in the chromosome band (7q31) adjacent to the MUC3, MUC11, and MUC12 genes. MUC11 and MUC12 are expressed in many of the tissues affected by CF, and modifier genes might be involved in the etiology of this disease. Decreased expression of MUC3, MUC11, and MUC12 might explain the increased numbers of small bowel and colon cancers observed in CF patients, as well as cancers of the esophagus and oral mucosa.
Epidemiologic studies indicate that diets high in omega-3 fatty acids are associated with a reduced risk of colon cancer (22). The omega-3 fatty acid docosahexaenoic acid appears to be associated with the largest reduction in risk, and several potential mechanisms of action have been reported (2225). Serum concentrations of docosahexaenoic acid are statistically significantly lower in CF patients than in healthy control subjects. In addition, serum docosahexaenoic acid concentrations in CF patients correlate with the severity of the CFTR mutation, suggesting an association between the basic defect and abnormal essential fatty acid metabolism (26). A membrane lipid imbalance is also found in the ileum, pancreas, and lung from CF mice (CFTR), which is characterized by an increase in phospholipid-bound arachidonic acid and a decrease in phospholipid-bound docosahexaenoic acid. This lipid imbalance is not caused by impaired intestinal absorption or hepatic biosynthesis of docosahexaenoic acid (27). Therefore, a nonfunctional CFTR in the intestines of CF patients that results in low membrane levels of docosahexaenoic acid may explain the increased frequency of digestive tract cancer in our cohort.
In view of persistent and often severe respiratory pathology in CF patients, it is somewhat surprising that only one case of lung cancer, a rare type known as sarcomatoid carcinoma, was diagnosed during the study period compared with three cases of lung cancer expected. Evidently, the pronounced inflammatory pulmonary changes that are such a prominent feature of CF do not predispose to the development of lung cancer.
In our previous study (11), we noticed fewer than expected nondigestive tract cancers, a result that we attributed to under-reporting. In this study, information on cancer was obtained prospectively, and we again noticed a deficit of nondigestive tract cancers (P = .055) that approached statistical significance; if real, this deficit might be attributed to reduced exposure to environmental carcinogens, such as smoking or sun exposure. Another explanation could be undernutrition, which is often observed in CF patients and has been associated with a decreased risk of cancer (28).
The first successful heartlung and lung transplant operations in CF patients were performed in 1983 and 1987, respectively (29). In 1999, emphysema and chronic obstructive pulmonary disease accounted for 42% of all primary lung transplants reported in the United Network for Organ Sharing database. CF alone was the basis of lung transplantation in 7.4% of the cases in 1990 and 15.8% in 1999 (30). Post-transplant lymphoproliferative diseases constitute an important complication for all organ transplant recipients, and the incidence in our series (38 in 2725 patient-years of follow-up; seven with lymphomas and 31 with post-transplant lymphoproliferative disease) is similar to that reported in other adult lung recipients (31). Although post-transplant lymphoproliferative disease is often viewed as a precursor of malignant lymphoma, many cases resolve with reduction of immunosuppression (32), and the progression to cancer should not be viewed as inevitable. Cases of post-transplant lymphoproliferative disease that were not histologically classified as lymphoma were not included in our SIR calculations, because there was no reference population for comparison.
Our first report on the incidence of cancer in CF patients used, in part, the same source of data used in this article. The analysis for North America was made on patients registered with the CFF registry from 1985 through 1992. Because cancer information was not yet routinely collected, we wrote to each CFF-accredited care center and inquired retrospectively about the incidence of cancer in their patients. Since 1992, data on the occurrence of cancer is systematically reported to the CFF registry, and information on recent prevalent cancer was obtained on the 1992 questionnaire. We restricted our analysis to 1990 through 1999 to avoid under-reporting of cancer cases before 1990. Still, both studies overlap for the years 1990, 1991, and 1992. When we restricted our analysis to patients registered between January 1, 1993, and December 31, 1999 (i.e., avoiding any overlap between this and the previous report), the results remained identical: 17 digestive tract cancers were reported among 26 704 nontransplanted CF patients versus 3.46 expected (SIR = 4.9, 95% CI = 2.9 to 7.9). All digestive tract cancers in transplanted patients were observed after 1992.
The absolute risk of cancer in the CF population is low, largely because of the relatively young age of the patients. Since our previous report, the proportion of adult patients has substantially increased, and the yearly number of new cancers reported has more than doubled, allowing us to look more precisely at site-specific cancer risk within the digestive tract. The current study shows that the risk of cancer is particularly elevated for the small bowel, colon, and biliary tract. Our results also indicate that CF initially diagnosed because of failure to thrive is associated with a higher risk of digestive tract cancer, and the risk of digestive tract cancer appears more pronounced after transplantation. As survival of the CF population continues to improve, these findings could help identify subgroups of patients who are more likely to develop digestive tract cancer and for whom screening for digestive tract cancer could be beneficial.
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NOTES |
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We acknowledge Monica Brooks and Ase Sewall for help with data collection for this analysis.
1 Editors note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research.
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Manuscript received May 17, 2002; revised December 17, 2002; accepted December 30, 2002.
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