Eric J. Holowaty

Mortality from myocardial infarction following postlumpectomy radiotherapy for breast cancer: a population-based study in Ontario, Canada.

PURPOSE To compare the risk of mortality from myocardial infarction (MI) after left-sided postlumpectomy radiotherapy (RT) to the risk after right-sided postlumpectomy RT. METHODS We conducted a population-based cohort study of cases of invasive female breast cancer in Ontario, diagnosed between January 1, 1982 and December 31, 1987 (n = 25,570). Records of the Ontario Cancer Registry (OCR) were linked to hospital procedure and discharge abstracts and to RT records from Ontario cancer centers. A case was labelled as lumpectomy if this was the maximum breast surgery within 4 months of diagnosis. Postlumpectomy RT occurred up to 1 year postdiagnosis. Laterality was assigned from the laterality descriptor of the RT records. A case was labelled as having had a fatal MI if ICD code 410 (myocardial infarction) was recorded as the cause of death in the OCR. We used logistic regression to compare the likelihood of utilization of: 1. Dose per fraction > 2.00 Gy; 2. cobalt vs. linac; and 3. boost RT. We used life table analysis and the log rank test comparing the time to fatal MI from diagnosis of breast cancer between women who received left-sided postlumpectomy RT and women who received right-sided. We used Cox proportional hazards models to study the relative risk for left-sided cases overall, and stratified by age, RT characteristics, and among conditional survival cohorts. RESULTS Postlumpectomy RT was received by 1,555 left-sided and 1,451 right-sided cases. With follow-up to December 31, 1995, 2% of women with left-sided RT had a fatal MI compared to 1% of women with right-sided RT. Comparison of the time to failure between women who had left-sided RT and women who had right-sided RT showed the left-sided RT group to be associated with a higher risk of fatal MI (p = 0.02). Adjusting for age at diagnosis, the relative risk for fatal MI with left-sided postlumpectomy RT was 2.10 (1.11, 3.95). CONCLUSION Among women who received postlumpectomy RT for breast cancer in Ontario between 1982-1987, left-sided postlumpectomy RT was associated with a higher risk of fatal MI compared to right-sided.

A POPULATION-BASED STUDY OF GLIOBLASTOMA MULTIFORME

PURPOSE To describe (1) the use of surgery and radiotherapy (RT) in the treatment of patients with glioblastoma (GBM) in Ontario, (2) survival, and (3) proportion of survival time spent in the hospital after diagnosis. METHODS AND MATERIALS We performed a population-based cohort study of all Ontario Cancer Registry (OCR) cases of GBM diagnosed between 1982 and 1994. We linked OCR records, hospital files containing surgical procedure codes from the Canadian Institute for Health Information, and province-wide RT records. We studied the odds of treatment using multivariate logistic regression. We expressed the time spent in the hospital as the mean number of days per case, and as a proportion of the interval between diagnosis and death, or 24 months following diagnosis, whichever came first. We used the life-table method and Cox proportional hazards regression to describe survival. RESULTS The proportion of patients with GBM undergoing any surgery directed at the tumor varied with age (p < 0.0001) and region of residence (p < 0.0001). The proportion undergoing RT varied with age (p < 0.0001), region of residence (p < 0.0001), and year of diagnosis (p = 0.01). RT dose > or = 53.5 Gy varied with age (p < 0.0001), region of residence (p < 0.0001), and year of diagnosis (p = 0.0002). Median survival was 11 months among patients receiving RT and 3 months among those not receiving RT. The percentage of survival time spent in the hospital was similar among those who received from 49.5 to < 53.5 Gy, compared to > or = 53.5 Gy. Overall survival and the adjusted relative risk of death varied with age and region of residence. CONCLUSION We observed practice variation in the treatment of patients with GBM according to age, region of residence, and year of diagnosis. Survival did not increase during the study period. The variation in RT dose between those receiving from 49.5 to < 53.5 Gy compared to > or =53.5 Gy was not paralleled by variation in survival between regions where one or the other of the dose ranges predominated, nor was variation in dose ranges among the regions paralleled by variation in the proportion of survival time spent in the hospital.

Cancer incidence in a cohort of Ontario and Quebec women having bilateral breast augmentation.

The possibility that women, who receive breast implants for cosmetic purposes, have increased long‐term risks of developing cancer continues to be debated. The objective of our study was to prospectively examine cancer incidence among women who received breast implants. A cohort was assembled of 24,558 women, 18 years of age and older, who underwent bilateral cosmetic breast augmentation, and 15,893 women who underwent other cosmetic procedures in Ontario or Quebec between 1974 and 1989. These plastic surgery patients were selected from the same clinics as the implant population. Incident cancers were identified by linking to Canadian registry data up to December 31, 1997. In total, 676 cancers were identified among women who received breast implants compared to 899 expected based on general population rates (standardized incidence ratio (SIR) = 0.75; 95% confidence interval (CI) = 0.70–0.81). Overall cancer incidence rates among women who received breast implants were similar to that of the other plastic surgery patients (relative risk (RR) = 0.91, 95% CI = 0.81–1.02). However, women who received breast implants had lower breast cancer rates than the plastic surgery patients (RR = 0.64, 95% CI = 0.53–0.79). No increased risks were observed among the implant population for any of the other cancer sites examined. Comparisons involving only women who received breast implants found no association between long‐term breast cancer incidence and implant site (submuscular vs. subglandular), fill (saline vs. silicone) or envelope (polyurethane‐coated or not). In conclusion, women undergoing cosmetic breast augmentation do not appear to be at an increased long‐term risk of developing cancer.

Stomach Cancer Risk After Treatment for Hodgkin Lymphoma

PURPOSE Treatment-related stomach cancer is an important cause of morbidity and mortality among the growing number of Hodgkin lymphoma (HL) survivors, but risks associated with specific HL treatments are unclear. PATIENTS AND METHODS We conducted an international case-control study of stomach cancer nested in a cohort of 19,882 HL survivors diagnosed from 1953 to 2003, including 89 cases and 190 matched controls. For each patient, we quantified cumulative doses of specific alkylating agents (AAs) and reconstructed radiation dose to the stomach tumor location. RESULTS Stomach cancer risk increased with increasing radiation dose to the stomach (Ptrend < .001) and with increasing number of AA-containing chemotherapy cycles (Ptrend = .02). Patients who received both radiation to the stomach ≥ 25 Gy and high-dose procarbazine (≥ 5,600 mg/m(2)) had strikingly elevated stomach cancer risk (25 cases, two controls; odds ratio [OR], 77.5; 95% CI, 14.7 to 1452) compared with those who received radiation < 25 Gy and procarbazine < 5,600 mg/m(2) (Pinteraction < .001). Risk was also elevated (OR, 2.8; 95% CI, 1.3 to 6.4) among patients who received radiation to the stomach ≥ 25 Gy but procarbazine < 5,600 mg/m(2); however, no procarbazine-related risk was evident with radiation < 25 Gy. Treatment with dacarbazine also increased stomach cancer risk (12 cases, nine controls; OR, 8.8; 95% CI, 2.1 to 46.6), after adjustment for radiation and procarbazine doses. CONCLUSION Patients with HL who received subdiaphragmatic radiotherapy had dose-dependent increased risk of stomach cancer, with marked risks for patients who also received chemotherapy containing high-dose procarbazine. For current patients, risks and benefits of exposure to both procarbazine and subdiaphragmatic radiotherapy should be weighed carefully. For patients treated previously, GI symptoms should be evaluated promptly.

Population Based Survival Data on Urachal Tumors

PURPOSE Urachal carcinoma accounts for less than 1% of all bladder cancers. Limited data exist on disease related outcomes originating from case reports and select referral centers. We describe a population based outcomes analysis with long-term followup in patients in the province of Ontario. MATERIALS AND METHODS We reviewed the data source of the Ontario Cancer Registry for patients diagnosed with urachal cancer during 1976 to 2001. A cohort of 40 patients with urachal adenocarcinoma was found. Primary outcome measures were overall and disease specific survival. The effect of patient age, sex, grade, stage and university vs nonacademic treating hospital as predictors of outcome was determined. RESULTS Median patient age was 52 years. Median followup was 72.7 months. Mean overall survival +/- SD was 121.6 +/- 21 months. Mean disease specific survival in patients treated operatively was 165 +/- 27 months with 5 and 10-year disease specific survival of 61.3% and 49.2%, respectively. Disease specific mortality was not evident after 7 years from diagnosis. Well differentiated tumors in a third of the patients were associated with a 90% cure rate when treated operatively. Well differentiated tumors, and noninvolvement of adjacent organs and the peritoneum correlated with better prognosis (p = 0.004, p = 0.03 and 0.045, respectively). CONCLUSIONS Urachal adenocarcinoma occurs in all age groups. Long-term disease specific survival can be achieved with partial cystectomy. Covariates associated with better disease specific survival are well differentiated tumor grade and the absence of adjacent organ or peritoneal involvement. No relapses were observed after 7 years.

Response Audit of an Internet Survey of Health Care Providers and Administrators: Implications for Determination of Response Rates

Background Internet survey modalities often compare unfavorably with traditional survey modalities, particularly with respect to response rates. Response to Internet surveys can be affected by the distribution options and response/collection features employed as well as the existence of automated (out-of-office) replies, automated forwarding, server rejection, and organizational or personal spam filters. However, Internet surveys also provide unparalleled opportunities to track study subjects and examine many of the factors influencing the determination of response rates. Tracking data available for Internet surveys provide detailed information and immediate feedback on a significant component of response that other survey modalities cannot match. This paper presents a response audit of a large Internet survey of more than 5000 cancer care providers and administrators in Ontario, Canada. Objective Building upon the CHEcklist for Reporting Results of Internet E-Surveys (CHERRIES), the main objectives of the paper are to (a) assess the impact of a range of factors on the determination of response rates for Internet surveys and (b) recommend steps for improving published descriptions of Internet survey methods. Methods We audited the survey response data, analyzing the factors that affected the numerator and denominator in the ultimate determination of response. We also conducted a sensitivity analysis to account for the inherent uncertainty associated with the impact of some of the factors on the response rates. Results The survey was initially sent out to 5636 health care providers and administrators. The determination of the numerator was influenced by duplicate/unattached responses and response completeness. The numerator varied from a maximum of 2031 crude (unadjusted) responses to 1849 unique views, 1769 participants, and 1616 complete responses. The determination of the denominator was influenced by forwarding of the invitation email to unknown individuals, server rejections, automated replies, spam filters, and ‘opt out’ options. Based on these factors, the denominator varied from a minimum of 5106 to a maximum of 5922. Considering the different assumptions for the numerator and the denominator, the sensitivity analysis resulted in a 12.5% variation in the response rate (from minimum of 27.3% to maximum of 39.8%) with a best estimate of 32.8%. Conclusions Depending on how the numerator and denominator are chosen, the resulting response rates can vary widely. The CHERRIES statement was an important advance in identifying key characteristics of Internet surveys that can influence response rates. This response audit suggests the need to further clarify some of these factors when reporting on Internet surveys for health care providers and administrators, particularly when using commercially available Internet survey packages for specified, rather than convenience, samples.

Risk of treatment-related esophageal cancer among breast cancer survivors

BACKGROUND Radiotherapy for breast cancer may expose the esophagus to ionizing radiation, but no study has evaluated esophageal cancer risk after breast cancer associated with radiation dose or systemic therapy use. DESIGN Nested case-control study of esophageal cancer among 289 748 ≥5-year survivors of female breast cancer from five population-based cancer registries (252 cases, 488 individually matched controls), with individualized radiation dosimetry and information abstracted from medical records. RESULTS The largest contributors to esophageal radiation exposure were supraclavicular and internal mammary chain treatments. Esophageal cancer risk increased with increasing radiation dose to the esophageal tumor location (P(trend )< 0.001), with doses of ≥35 Gy associated with an odds ratio (OR) of 8.3 [95% confidence interval (CI) 2.7-28]. Patients with hormonal therapy ≤5 years preceding esophageal cancer diagnosis had lower risk (OR = 0.4, 95% CI 0.2-0.8). Based on few cases, alkylating agent chemotherapy did not appear to affect risk. Our data were consistent with a multiplicative effect of radiation and other esophageal cancer risk factors (e.g. smoking). CONCLUSIONS Esophageal cancer is a radiation dose-related complication of radiotherapy for breast cancer, but absolute risk is low. At higher esophageal doses, the risk warrants consideration in radiotherapy risk assessment and long-term follow-up.

Risk of Leukemia Among Survivors of Testicular Cancer: A Population-based Study of 42,722 Patients

PURPOSE The aim of this study is to quantify excess absolute risk (EAR) and excess relative risk (ERR) of secondary leukemia among a large population-based group of testicular cancer survivors. METHODS We identified 42,722 1-year survivors of testicular cancer within 14 population-based cancer registries in Europe and North America (1943-2002). Poisson regression analysis was used to model EAR (per 100,000 person-years [PY]) and ERR of secondary leukemia. Cumulative risks were calculated using a competing risk model. RESULTS Secondary leukemia developed in 89 patients (EAR = 10.8 per 100,000 PY, 95% confidence interval [CI] = 7.6-14.6; ERR = 1.6, 95%CI = 1.0-2.2). Statistically significantly elevated risks were observed for acute myeloid leukemia (AML) (EAR = 7.2, 95%CI = 4.7-10.2) and acute lymphoblastic leukemia (EAR = 1.3, 95%CI = 0.4-2.8). In multivariate analyses, AML risk was higher among patients whose initial management included chemotherapy compared to those receiving radiotherapy alone (p = 0.1). Excess cumulative leukemia risk was approximately 0.23% by 30 years after testicular cancer diagnosis. CONCLUSIONS Although ERR of leukemia following testicular cancer is large, EAR and cumulative risk, which are better gauges of the population burden, are small.

Feasibility and utility of mapping disease risk at the neighbourhood level within a Canadian public health unit: an ecological study

BackgroundWe conducted spatial analyses to determine the geographic variation of cancer at the neighbourhood level (dissemination areas or DAs) within the area of a single Ontario public health unit, Wellington-Dufferin-Guelph, covering a population of 238,326 inhabitants. Cancer incidence data between 1999 and 2003 were obtained from the Ontario Cancer Registry and were geocoded down to the level of DA using the enhanced Postal Code Conversion File. The 2001 Census of Canada provided information on the size and age-sex structure of the population at the DA level, in addition to information about selected census covariates, such as average neighbourhood income.ResultsAge standardized incidence ratios for cancer and the prevalence of census covariates were calculated for each of 331 dissemination areas in Wellington-Dufferin-Guelph. The standardized incidence ratios (SIR) for cancer varied dramatically across the dissemination areas. However, application of the Morans I statistic, a popular index of spatial autocorrelation, suggested significant spatial patterns for only two cancers, lung and prostate, both in males (p < 0.001 and p = 0.002, respectively). Employing Bayesian hierarchical models, areas in the urban core of the City of Guelph had significantly higher SIRs for male lung cancer than the remainder of Wellington-Dufferin-Guelph; and, neighbourhoods in the urban and surrounding rural areas of Orangeville exhibited significantly higher SIRs for prostate cancer. After adjustment for age and spatial dependence, average household income attenuated much of the spatial pattern of lung cancer, but not of prostate cancer.ConclusionThis paper demonstrates the feasibility and utility of a systematic approach to identifying neighbourhoods, within the area served by a public health unit, that have significantly higher risks of cancer. This exploratory, ecologic study suggests several hypotheses for these spatial patterns that warrant further investigations. To the best of our knowledge, this is the first Canadian study published in the peer-reviewed literature estimating the risk of relatively rare public health outcomes at a very small areal level, namely dissemination areas.

Polymorphic MLH1 and risk of cancer after methylating chemotherapy for Hodgkin lymphoma

Background and objective: Methylating agents are effective chemotherapy agents for Hodgkin lymphoma, but are associated with the development of second primary cancers. Cytotoxicity of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of MLH1, a major component of DNA MMR, results in tolerance to the cytotoxic effects of methylating agents and persistence of mutagenised cells at high risk of malignant transformation. We hypothesised that a common substitution in the basal promoter of MLH1 (position -93, rs1800734) modifies the risk of cancer after methylating chemotherapy. Methods: 133 patients who developed cancer following chemotherapy and/or radiotherapy (n = 133), 420 patients diagnosed with de novo myeloid leukaemia, 242 patients diagnosed with primary Hodgkin lymphoma, and 1177 healthy controls were genotyped for the MLH1 -93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for cancer risk by MLH1 -93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression. Results: Carrier frequency of the MLH1 -93 variant was higher in patients who developed therapy related acute myeloid leukaemia (t-AML) (75.0%, n = 12) or breast cancer (53.3%. n = 15) after methylating chemotherapy for Hodgkin lymphoma compared to patients without previous methylating exposure (t-AML, 30.4%, n = 69; breast cancer patients, 27.2%, n = 22). The MLH1 -93 variant allele was also over-represented in t-AML cases when compared to de novo AML cases (36.9%, n = 420) and healthy controls (36.3%, n = 952), and was associated with a significantly increased risk of developing t-AML (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in patients previously treated with a methylating agent. Conclusions: These data support the hypothesis that the common polymorphism at position -93 in the core promoter of MLH1 defines a risk allele for the development of cancer after methylating chemotherapy for Hodgkin lymphoma. However, replication of this finding in larger studies is suggested.