[Show abstract][Hide abstract] ABSTRACT: Organ transplantation increases risk of non-Hodgkin lymphoma (NHL), but long-term risk and time trends have seldom been evaluated. Immunosuppressive drug load is an important risk determinant, but the details are unclear. We studied NHL risk in a nationwide Swedish cohort of 11 081 graft recipients transplanted 1970-2008. Relative risks (RRs) were estimated within the cohort and versus the general population by age, sex, follow-up time and calendar period. NHL risk was also assessed by cumulative and average doses of immunosuppressive treatments in a nested case-control design throughout 1997 using conditional logistic regression. We observed 153 NHL cases during 97 853 years of follow-up. Compared with the general population, NHL risk was eightfold increased (RR 7.9; 95% confidence interval [CI] 6.6-9.4), and increased risks persisted after ≥15 years of follow-up among kidney (6.1; 95% CI 3.5-10) and nonkidney recipients (44; 14-103). Among nonkidney recipients, NHL risk was lower in the 2000s compared with the 1990s (0.5; 95% CI 0.3-1.0; p = 0.04). A high average dose of antithymocyte immunoglobulin (ATG) conferred an eightfold increased risk of NHL (OR 8.5; 95% CI 1.9-38). To conclude, posttransplant NHL risk decreased during the last decade among nonkidney recipients, possibly because of a more careful use of ATG, the introduction of new drugs, or both.
American Journal of Transplantation 08/2011; 11(11):2472-82. · 6.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Increased cancer risks are well documented in adult organ transplant recipients. However, the spectrum of malignancies and risk in the pediatric organ transplant population are less well described. We identified all solid organ transplanted patients aged <18 in Sweden between 1970-2007 (n = 536) in the National Patient Register and linked to the Cancer Register. Nationwide rates were used to calculate standardized incidence rate ratios and 95% CI estimating the association between transplant and cancer during maximum 36 years of follow-up. Nearly 7% of pediatric solid organ transplant recipients developed a premalignant or malignant tumor during follow-up. Transplantation was associated with an increased risk of any cancer (n = 24, SIR = 12.5, 95% CI: 8.0-18.6): non-Hodgkin lymphoma (NHL) (n = 13, SIR = 127, 95% CI: 68-217), renal cell (n = 3, SIR = 105, 95% CI: 22-307), vulva/vagina (n = 3, SIR = 665, 95% CI: 137-1934) and nonmelanoma skin cancers (n = 2, SIR = 64.7, 95% CI: 7.8-233.8). NHL typically appeared during childhood, while other tumors were diagnosed during adulthood. Apart from short-term attention toward the potential occurrence of NHL, our results suggest cancer surveillance into adulthood with special attention to skin, kidneys and the female genitalia.
American Journal of Transplantation 01/2011; 11(1):146-51. · 6.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BackgroundIf a patient agrees to take part in a randomised trial it is reasonable to presume that the patient would prefer to be allocated into the intervention. This study's aim was to investigate how patients react after they have been randomised into control group.MethodsNested study within two randomised trials. Telephone interviews with a structured questionnaire. The participants were invited after they had been randomised into the control group in two smoking cessation trials. The main outcome measures were reaction to control group allocation and drop-out rates.ResultsTwenty-seven out of 30 possible interviews were successfully completed. Fourteen persons expressed that they were disappointed of being allocated to the control group. Five persons said that they had not understood the consent information and three of these were very disappointed. Surprisingly these three persons said that they had not expected a randomization. A woman expressed that she “felt as if I was being swindled”. There were in total 9/117 (7.7%) lost to follow-up in the control group and there were 4/105 (3.8%) losses to follow-up in the intervention group (P = 0.26). Active withdrawal of consent was slightly higher among the control group, five in the control group (4.3%) and no active withdrawals in the intervention group (P = 0.06).ConclusionsDisappointment was common after allocation to the control group. This is a probable explanation of the higher drop-out rate in the control group. The consent information is of highest importance since those who were very disappointed claimed they did not receive understandable information.
[Show abstract][Hide abstract] ABSTRACT: It is known that smokers constitute an important risk group of patients undergoing surgery. It is unknown how smoking cessation intervention initiated 4 weeks prior to elective surgery affects the probability of permanent cessation. We randomly assigned 117 patients, scheduled to undergo elective orthopaedic and general surgery, to smoking cessation intervention and control group. The intervention group underwent a programme initiated, on average, 4 weeks prior to surgery with weekly meetings or telephone counselling and were provided with free nicotine replacement therapy (NRT). The control group received standard care. As a result, 20/55 (36%) patients the intervention group vs 1/62 (2%) in the control group became completely abstinent throughout the peri-operative period (p < 0.001). After 1 year, those in the intervention group was most likely to be abstinent (18/55 (33%) vs 9/62 (15%) of the controls (p = 0.03). Level of nicotine dependence and obesity seemed to be a predictor of long-term abstinence (p = 0.02).
[Show abstract][Hide abstract] ABSTRACT: Relatives of patients with aneurysmal subarachnoid haemorrhage (SAH) have an increased risk of this type of stroke. In a population-based study, we analysed individualized risks of SAH according to the number of affected first-degree relatives. We retrieved all patients diagnosed with SAH in 2001-05 from the Swedish Inpatient Register. For each of the 5,282 patients, we identified five controls (n = 26,402) through the nationwide Register of Total Population. Through the Multi-generation Register, we retrieved all first-degree relatives for patients and controls and checked whether these 130,373 relatives had been diagnosed with SAH. By means of conditional logistic regression, we calculated odds ratios with corresponding 95% confidence intervals (95% CI) for the risk of SAH according to the number of affected relatives, and to the gender, age and type of kinship of the patient and affected relative. The odds ratio of SAH for individuals with one affected first-degree relative was 2.15 (95% CI 1.77-2.59). For individuals with two affected first-degree relatives, the odds ratio was 51.0 (95% CI 8.56-1117). Gender, age and type of kinship did not influence the risk for individuals with one or more affected relatives. The risk of SAH is slightly increased in the cases with one, but strongly increased in cases with two or more affected first-degree relatives. The latter strongly increased risk corresponds to a considerable absolute life-time risk of SAH and underscores the need to consider screening for aneurysms in these individuals.
[Show abstract][Hide abstract] ABSTRACT: The effect of body mass index (BMI) and smoking on the risk of perforated appendix and postoperative complications in patients undergoing open appendicectomy for acute appendicitis was studied.
Record linkage was used to identify 6676 male construction workers who underwent open appendicectomy for acute appendicitis between 1971 and 2004. Multivariable binomial logistic regression analyses were performed.
After adjustment for age, calendar period and BMI, smoking was significantly associated with an increased risk of perforated appendicitis (PA) (P = 0.004). The relative risk was 1.29 (95 per cent confidence interval 1.11 to 1.50) among current smokers with more than 10 pack-years of tobacco use. In patients with non-perforated appendicitis (NPA), the relative risk of overall postoperative complications was significantly associated with BMI (P < 0.001), and was 2.60 (1.71 to 3.95) in obese patients and 1.51 (1.03 to 2.22) in current smokers with more than 10 pack-years of tobacco use. In patients with PA, overweight, obesity and smoking status were not associated with an increased risk of overall postoperative complications.
Perforation due to acute appendicitis was associated with current tobacco smoking. A BMI of 27.5 kg/m(2) or more and current smoking were associated with overall postoperative complications in patients with NPA.
British Journal of Surgery 06/2008; 95(6):751-7. · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Incidence estimates of subarachnoid haemorrhage (SAH) in Sweden vary, which may be caused by regional variations. Reliable estimates of age-specific case fatality rates are lacking. We analysed regional incidence rates and case fatality rates of SAH in Sweden.
The Swedish Hospital Discharge and Cause of Death Registries from 1987 to 2002 yielded data on 18 443 patients with SAH. Incidence and case fatality rates by age, gender, region and time period were calculated by Poisson regression.
The incidence rate was 12.4 per 100,000 person-years (95% CI 12.2 to 12.6) and increased with age, from 6.4/100,000 person-years in patients who were 30-39 years old to 25.8/100,000 person-years in patients who were older than 80 years. Incidence was higher for women (14.4 (95% CI 14.2 to 14.7)) than for men (10.3 (95% CI 10.3 to 10.6)), and higher in the north than in the south (RR 1.31 (95% CI 1.25 to 1.37)). This geographical gradient was more evident in women (RR 1.41 (95% CI 1.33 to 1.49)) than in men (RR 1.23 (95% CI 1.15 to 1.33)). The 28-day case fatality rate was 31.7% (95% CI 31.0 to 32.3). It increased with age from 18.1% (95% CI 16.0 to 20.3) in patients who were 30-39 years old to 57.6% (95% CI 55.2 to 59.9) in patients over 80 years, then levelling off. Over time (1995-2002 compared with 1987-1994), the incidence rate decreased (RR 0.93 (95% CI 0.90 to 0.96)) and case fatality rate decreased (RR 0.89 (95% CI 0.85 to 0.93)).
SAH incidence rates in Sweden increase from south to north, more in women than in men. Octogenarians have a quadrupled incidence and a tripled case fatality compared with young adults. During 16 years, both incidence and case fatality have decreased.
Journal of neurology, neurosurgery, and psychiatry 04/2008; 79(3):294-9. · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The extent to which lifestyle factors such as tobacco consumption and obesity affect the outcome after inguinal hernia surgery has been poorly studied. This study was undertaken to assess the effect of smoking, smokeless tobacco consumption and obesity on postoperative complications after inguinal hernia surgery. The second aim was to evaluate the effect of tobacco consumption and obesity on the length of hospital stay.
A cohort of 12,697 Swedish construction workers with prospectively collected exposure data on tobacco consumption and body mass index (BMI) from 1968 onward were linked to the Swedish inpatient register. Information on inguinal hernia procedures was collected from the inpatient register. Any postoperative complication occurring within 30 days was registered. In addition to this, the length of hospitalization was calculated. The risk of postoperative complications due to tobacco exposure and BMI was estimated using a multiple logistic regression model and the length of hospital stay was estimated in a multiple linear regression model.
After adjusting for the other covariates in the multivariate analysis, current smokers had a 34% (OR 1.34, 95% CI 1.04, 1.72) increased risk of postoperative complications compared to never smokers. Use of "Swedish oral moist snuff" (snus) and pack-years of tobacco smoking were not found to be significantly associated with an increased risk of postoperative complications. BMI was found to be significantly associated with an increased risk of postoperative complications (P = 0.04). This effect was mediated by the underweighted group (OR 2.94; 95% CI 1.15, 7.51). In a multivariable model, increased BMI was also found to be significantly associated with an increased mean length of hospital stay (P < 0.001). There was no statistically significant association between smoking or using snus, and the mean length of hospitalization after adjusting for the other covariates in the model.
Smoking increases the risk of postoperative complications even in minor surgery such as inguinal hernia procedures. Obesity increases hospitalization after inguinal hernia surgery. The Swedish version of oral moist tobacco, snus, does not seem to affect the complication rate after hernia surgery at all.
[Show abstract][Hide abstract] ABSTRACT: The incidence of cutaneous malignant melanoma (CMM) and melanoma in situ (MIS) has been increasing during the last 50 years. Malignant melanoma (MM) is also the most common intraocular malignancy (IMM). Besides ultraviolet radiation, the cause of these tumours is largely unknown.
We designed a study to examine the effect of body mass index (BMI) and tobacco use on the risk for MM and MIS.
Analyses were performed on a nationwide cohort of 339 802 Swedish construction workers. Exposure information was collected prospectively by questionnaires combined with personal interviews.
Follow up yielded a total of 7 663 400 person-years during which 1639 workers developed MM/MIS. The risk for MM/MIS was reduced in current or previous smokers compared with those who had never smoked, both when analysing all smoking tobacco products combined and when analysing cigarette and pipe smokers separately. The risk was further diminished with longer duration of smoking and greater quantity of tobacco smoked. The effect was more evident in CMM/MIS than in IMM. Snuff taking conferred a decreased risk for CMM/MIS, and a BMI over normal weight range conferred an increased risk for CMM.
Tobacco smoking was found to be inversely associated with the risk for CMM and MIS. The mechanism of action is unknown but it has been suggested to be due to the immune suppressive effect that tobacco exerts which would be protective against deleterious immune reactions caused by, for example, the sun. Neither is the mechanism behind the higher risk for CMM due to being overweight known. One hypothesis is that it is an effect of a hormonal imbalance. Further studies are required to elucidate these mechanisms.
British Journal of Dermatology 02/2007; 156(1):99-105. · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Even with appropriate donor deferrals and advanced screening tests, the risk of disease transmission through blood transfusion cannot be completely disregarded. Efficient monitoring of possible disease transmission between blood donors and recipients should be an important component of a comprehensive haemovigilance system.
We assembled the Scandinavian Donations and Transfusions (SCANDAT) database, with data on virtually all blood donors and recipients who have been registered at least once in any of the computerized local blood bank databases in Sweden and Denmark since the start of computerized registration in 1966. The records of these individuals, with their entire computerized donation and/or transfusion histories and all donor-component-recipient connections, were linked to nationwide population and health registers to attain essentially complete follow-up for up to 36 years regarding reproduction, hospital morbidity, cancer, and death.
After data cleaning, the database contained 1,134,290 blood donors who contributed 15,091,280 records of donations and 1,311,079 recipients who received 11,693,844 transfusions. The data quality in the existing data sources was satisfactory. From the data obtained from local blood banks, 4.6%, 1.6%, and 6.4% of the person, donation, and transfusion records, respectively, had to be discarded after review of the legitimacy of recorded values, and comparisons with independent, external databases.
It is possible to use existing computerized data, collected in routine health care, in haemovigilance systems for monitoring long-term outcome and disease concordance in blood donors and transfusion recipients.
[Show abstract][Hide abstract] ABSTRACT: We carried out a retrospective cohort study of 3309 patients undergoing primary total hip replacement to examine the impact of tobacco use and body mass index on the length of stay in hospital and the risk of short term post-operative complications. Heavy tobacco use was associated with an increased risk of systemic post-operative complications (p = 0.004). Previous and current smokers had a 43% and 56% increased risk of systemic complications, respectively, when compared with non-smokers. In heavy smokers, the risk increased by 121%. A high body mass index was significantly associated with an increased mean length of stay in hospital of between 4.7% and 7%. The risk of systemic complications was increased by 58% in the obese. Smoking and body mass index were not significantly related to the development of local complications. Greater efforts should be taken to reduce the impact of preventable life style factors, such as smoking and high body mass index, on the post-operative course of total hip replacement.
Journal of Bone and Joint Surgery - British Volume 11/2006; 88(10):1316-20. · 2.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated whether tobacco use causes cutaneous squamous cell carcinoma (CSCC) in a large cohort study with complete and long-term follow-up. A total of 756 incident cases occurred in a cohort of 337,311 men during a 30-year follow-up period, but no association was found between any kind of smoking tobacco use and CSCC risk, nor any risk change with increasing dose, duration or time since smoking cessation. Snuff use was associated with a decreased risk of CSCC. Overall, our study provides no evidence that tobacco use increases the risk of CSCC.
British Journal of Cancer 05/2005; 92(7):1326-8. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A substantial excess risk of lymphomas and nonmelanoma skin cancer has been demonstrated following organ transplantation. Large sample size and long follow-up time may, however, allow more accurate risk estimates and detailed understanding of long-term cancer risk. The objective of the study was to assess the risk of cancer following organ transplantation. A nationwide cohort study comprising 5931 patients who underwent transplantation of kidney, liver or other organs during 1970-1997 in Sweden was conducted. Complete follow-up was accomplished through linkage to nationwide databases. We used comparisons with the entire Swedish population to calculate standardised incidence ratios (SIRs), and Poisson regression for multivariate internal analyses of relative risks (RRs) with 95% confidence intervals (CI). Overall, we observed 692 incident first cancers vs 171 expected (SIR 4.0; 95% CI 3.7-4.4). We confirmed marked excesses of nonmelanoma skin cancer (SIR 56.2; 95% CI 49.8-63.2), lip cancer (SIR 53.3; 95% CI 38.0-72.5) and of non-Hodgkin's lymphoma (NHL) (SIR 6.0; 95% CI 4.4-8.0). Compared with patients who underwent kidney transplantation, those who received other organs were at substantially higher risk of NHL (RR 8.4; 95% CI 4.3-16). Besides, we found, significantly, about 20-fold excess risk of cancer of the vulva and vagina, 10-fold of anal cancer, and five-fold of oral cavity and kidney cancer, as well as two- to four-fold excesses of cancer in the oesophagus, stomach, large bowel, urinary bladder, lung and thyroid gland. In conclusion, organ transplantation entails a persistent, about four-fold increased overall cancer risk. The complex pattern of excess risk at many sites challenges current understanding of oncogenic infections that might become activated by immunologic alterations.
British Journal of Cancer 11/2003; 89(7):1221-7. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The causes of Hodgkin's disease remain incompletely known, but a higher incidence in men than in women has prompted an interest in the role of female sex hormones and reproductive history. Available epidemiological data are, however, contradictory. We analyzed possible associations between parity, age at first birth, and the risk of developing Hodgkin's disease by a linkage between the Swedish Cancer Register and a nationwide Fertility Register. Among women born between 1925 and 1972, 917 cases with Hodgkin's disease and concomitant fertility information were identified. For each case patient, five age-matched controls were randomly selected among women in the Fertility Register. Conditional logistic regression was used to estimate odds ratios of Hodgkin's disease associated with a birth. We found a slightly and nonsignificantly reduced risk of Hodgkin's disease in ever-parous compared with nulliparous women. Among parous women, the number of children was unrelated to risk, whereas there was some evidence of an increased risk with late age at first birth in women under age 45 at diagnosis. No clear temporal relations between childbearing and subsequent risk were discernible in any parity or age group. Although uncontrolled confounding might have affected our results, they do not indicate that hormonal or immunological changes associated with childbearing play a role in the development of Hodgkin's disease.
[Show abstract][Hide abstract] ABSTRACT: Non-Hodgkin lymphoma is the seventh most commonly diagnosed malignant condition worldwide, and its incidence has increased markedly in recent decades. Blood transfusions have been implicated as a possible risk factor for non-Hodgkin lymphoma.
To determine whether blood transfusions are associated with an elevated risk for non-Hodgkin lymphoma.
Population-based, nested case-control study.
Nationwide cohort in Sweden.
361 patients with non-Hodgkin lymphoma and 705 matched controls, nested within a population-based cohort of 96795 patients at risk for blood transfusion between 1970 and 1983. Prospectively collected information on exposure was retrieved from computerized transfusion registries.
Odds ratios obtained from conditional logistic regression models were used as measures of relative risks.
No association was found between blood transfusions and the risk for non-Hodgkin lymphoma when patients who had received transfusions were compared with patients who had not received transfusions (odds ratio, 0.93 [95% CI, 0.71 to 1.23]). A reduction in risk was seen among persons who received transfusion of blood without leukocyte depletion (odds ratio, 0.72 [CI, 0.53 to 0.97]). Risk was not related to number of transfusions, and no interaction was seen with latency after transfusion.
The findings in this study do not support previous observations of an association between blood transfusions and the risk for non-Hodgkin lymphoma.
Annals of internal medicine 10/1997; 127(5):365-71. · 13.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The etiology of non-Hodgkin's lymphomas (NHL), including chronic lymphocytic leukemia (CLL), is likely to be related to immune function. In the light of the established immunologic effects of a pregnancy, we decided to examine the risk of NHL and CLL in relationship to full-term pregnancies. Within a nationwide cohort we identified 1,546 women with NHL and 198 women with CLL, all 15 years or older, born 1925-1972. Five age-matched controls were selected for each case patient. Conditional logistic regression was used to estimate the odds ratios after mutual adjustment for number of births and age at first birth. We found a weak, negative association between parity and risk of NHL (p for trend 0.11) and a transient, 10-40% decrease in risk within 5-14 years after the last birth among women with various parity status. The risk of CLL decreased more markedly, and orderly with increasing parity, but the trend was not significant (p = 0.18). Small numbers of cases with CLL prevented more detailed analyses of temporal relationships. Age at first birth appeared unrelated to the risk of both NHL and CLL. We conclude that the immunologic alterations associated with a pregnancy have limited, if any, relevance to the etiology of NHL and CLL; changing reproductive pattern is an unlikely contributor to the marked increase in incidence of NHL seen in many populations.
International Journal of Cancer 02/1997; 70(2):155-8. · 6.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This nested case-control study based on 1.7 million live births in Sweden explores the associations between maternal and perinatal factors and the occurrence of childhood non-Hodgkin's lymphoma (NHL). The National Swedish Cancer Registry ascertained 168 cases in successive birth cohorts from 1973 through 1989 recorded in the Swedish Medical Birth Registry. From the nationwide Birth Registry, 5 controls without NHL and alive at the date the case was diagnosed were randomly selected from the pool of children, with each case matched by gender, birth year and birth month. Standardized information on selected maternal and perinatal factors up to one month after delivery were recorded in the Medical Birth Registry. Mothers of children with NHL were more likely than mothers of controls to have undergone Cesarean section [Odds ratio (OR) 1.6] and to have been exposed to paracervical anesthesia during delivery (OR 1.8). Children with NHL were more likely than controls to have endocrine-metabolic disorders (OR 3.3). This study is one of the largest focusing on the etiology of childhood NHL. Most of the maternal and perinatal characteristics studied did not markedly affect risk for childhood NHL, which may be due to maternal and perinatal factors not included in these data or to exposures later in life.
International Journal of Cancer 04/1996; 65(6):774-7. · 6.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate a possible link between exposure to ultraviolet light and the almost epidemic increase in non-Hodgkin's lymphoma worldwide. Because ultraviolet light is known to cause skin cancers, the association between non-Hodgkin's lymphoma and skin cancer was studied.
Secondary occurrence of either malignant melanoma or squamous cell skin cancer in cohorts of patients with a first diagnosis of either non-Hodgkin's lymphoma or chronic lymphocytic leukaemia, and vice versa, were studied. Expected numbers of subsequent cancers were calculated by sex, age, and period specific national incidence rates multiplied by the person years under observation in the cohorts.
Denmark (1943-89) and Sweden (1958-89).
Four population based cohorts identified in the nationwide cancer registries (34,641 people with non-Hodgkin's lymphoma, 17,400 with chronic lymphocytic leukaemia, 34,989 with malignant melanoma, 25,980 with squamous cell skin cancer). A total of 562,085 person years were accrued for the analysis.
The ratios of observed to expected cancers (the standardised incidence ratio) served as a measure of the relative risk.
The relative risk for developing squamous cell skin cancer was 5.5 (95% confidence interval 4.6 to 6.6) among patients with non-Hodgkin's lymphoma and 8.6 (7.2 to 10.3) among patients with chronic lymphocytic leukaemia. The relative risks remained high over more than 15 years of follow up. Relative risks for malignant melanoma were 2.4 (1.8 to 3.2) for patients with non-Hodgkin's lymphoma and 3.1 (2.1 to 4.4) for patients with chronic lymphocytic leukaemia. After squamous cell skin cancer had been diagnosed there was a twofold excess risk for non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. By contrast, in each of the cohorts the general cancer risks excluding skin and lymphoproliferative malignancies were close to the expected.
The occurrence of non-Hodgkin's lymphoma and skin cancer are strongly associated; this supports the hypothesis that the secular increase in exposure to ultraviolet light may have contributed to the increasing incidence of non-Hodgkin's lymphoma in recent decades.
BMJ Clinical Research 07/1995; 310(6993):1491-5. · 14.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cyclophosphamide is an established bladder carcinogen, but few studies have examined the relationship between dose and effect. The largest analysis to date included only seven cases of bladder cancer. No investigation has estimated the risk of kidney cancer.
The purpose of this study was to quantify the risk of bladder and kidney cancer following cyclophosphamide therapy.
Within a cohort of 6171 two-year survivors of non-Hodgkin's lymphoma (NHL), 48 patients with secondary cancer of the urinary tract were identified and matched to 136 control subjects with NHL who did not develop a second malignancy. Detailed information on chemotherapeutic drugs and cumulative dose received was collected for all subjects. Radiation dose to the target organ was estimated from individual radiotherapy records. Evaluations of the risk of second cancer as a result of treatment with cyclophosphamide alone, radiation alone, or both therapies were made relative to those patients who were exposed to neither treatment modality.
A significant 4.5-fold risk of bladder cancer (95% confidence interval [CI] = 1.5-13.6) followed therapy with cyclophosphamide, and risk was dependent upon cumulative dose. Among patients who received a total amount of cyclophosphamide of less than 20 g, a nonsignificant 2.4-fold risk of bladder cancer was apparent. Significantly elevated sixfold (95% CI = 1.3-29) and 14.5-fold (95% CI = 2.3-94) risks of bladder malignancy followed cumulative doses of 20-49 g and 50 g or more, respectively (P value for trend = .004). Radiotherapy given without cyclophosphamide was associated with a nonsignificant increased risk of bladder malignancy. Excess bladder cancer risk following treatment with both radiotherapy and cyclophosphamide was as expected if individual risks were summed. Neither radiotherapy nor cyclophosphamide was associated with excesses of kidney cancer.
Cyclophosphamide-related bladder cancer is dose dependent. For patients given cumulative doses between 20 and 49 g, the absolute risk of bladder cancer is on the order of three excess cancers per 100 NHL patients after 15 years of follow-up. At cumulative doses of 50 g or more, the excess risk increases to approximately seven excess bladder cancers per 100 NHL patients.
The strong dose-response relationship and high absolute risk of bladder cancer underscore the importance of limiting the cumulative dose of cyclophosphamide to what is required to achieve therapeutic end points. The risk of secondary bladder malignancy and other late sequelae of therapy must be carefully weighted against the curative gains provided by cyclophosphamide. Moreover, long-term side effects of therapy that might be acceptable in cancer treatment may need to be re-evaluated for patients with non-neoplastic disorders.
JNCI Journal of the National Cancer Institute 05/1995; 87(7):524-30. · 14.34 Impact Factor