Marieke W.J. Louwman

Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer

PURPOSE To compare radiotherapy and chemotherapy effects on long-term risks of second malignant neoplasms (SMNs) and cardiovascular diseases (CVDs) in testicular cancer (TC) survivors. PATIENTS AND METHODS In our nationwide cohort comprising 2,707 5-year TC survivors, incidences of SMNs and CVDs were compared with general-population rates by calculating standardized incidence ratios (SIRs) and absolute excess risks (AERs). Treatment effects on risks of SMN and CVD were quantified in multivariable Cox regression and competing risks analyses. RESULTS After a median follow-up time of 17.6 years, 270 TC survivors developed SMNs. The SIR of SMN overall was 1.7 (95% CI, 1.5 to 1.9), with an AER of 32.3 excess occurrences per 10,000 person-years. SMN risk was 2.6-fold (95% CI, 1.7- to 4.0-fold) increased after subdiaphragmatic radiotherapy and 2.1-fold (95% CI, 1.4- to 3.1-fold) increased after chemotherapy, compared with surgery only. Subdiaphragmatic radiotherapy increased the risk of a major late complication (SMN or CVD) 1.8-fold (95% CI, 1.3- to 2.4-fold), chemotherapy increased the risk of a major late complication 1.9-fold (95% CI, 1.4- to 2.5-fold), and smoking increased the risk of a major late complication 1.7-fold (95% CI, 1.4- to 2.1-fold), compared with surgery only. The median survival time was 1.4 years after SMN and 4.7 years after CVD. CONCLUSION Radiotherapy and chemotherapy increased the risk of developing SMN or CVD to a similar extent as smoking. Subdiaphragmatic radiotherapy strongly increases the risk of SMNs but not of CVD, whereas chemotherapy increases the risks of both SMNs and CVDs. Prolonged follow-up after chemotherapy is needed to reliably compare the late complications of radiotherapy and chemotherapy after 20 years.

Breast Cancer Risk in Female Survivors of Hodgkin's Lymphoma: Lower Risk After Smaller Radiation Volumes

PURPOSE We assessed the long-term risk of breast cancer (BC) after treatment for Hodgkins lymphoma (HL). We focused on the volume of breast tissue exposed to radiation and the influence of gonadotoxic chemotherapy (CT). PATIENTS AND METHODS We performed a cohort study among 1,122 female 5-year survivors treated for HL before the age of 51 years between 1965 and 1995. We compared the incidence of BC with that in the general population. To assess the risk according to radiation volume and hormone factors, we performed multivariate Cox regression analyses. RESULTS After a median follow-up of 17.8 years, 120 women developed BC (standardized incidence ratio [SIR], 5.6; 95% CI, 4.6 to 6.8), absolute excess risk 57 per 10,000 patients per year. The overall cumulative incidence 30 years after treatment was 19% (95% CI, 16% to 23%); for those treated before age 21 years, it was 26% (95% CI, 19% to 33%). The relative risk remained high after prolonged follow-up (> 30 years after treatment: SIR, 9.5; 95% CI, 4.9 to 16.6). Mantle field irradiation (involving the axillary, mediastinal, and neck nodes) was associated with a 2.7-fold increased risk (95% CI, 1.1 to 6.9) compared with similarly dosed (36 to 44 Gy) mediastinal irradiation alone. Women with >or= 20 years of intact ovarian function after radiotherapy at young ages (< 31 years) experienced significantly higher risks for BC than those with fewer than 10 years of intact ovarian function. CONCLUSION Reduction of radiation volume appears to decrease the risk for BC after HL. In addition, shorter duration of intact ovarian function after irradiation is associated with a significant reduction of the risk for BC.

Second Cancer Risk Up to 40 Years after Treatment for Hodgkin’s Lymphoma

BACKGROUND Survivors of Hodgkins lymphoma are at increased risk for treatment-related subsequent malignant neoplasms. The effect of less toxic treatments, introduced in the late 1980s, on the long-term risk of a second cancer remains unknown. METHODS We enrolled 3905 persons in the Netherlands who had survived for at least 5 years after the initiation of treatment for Hodgkins lymphoma. Patients had received treatment between 1965 and 2000, when they were 15 to 50 years of age. We compared the risk of a second cancer among these patients with the risk that was expected on the basis of cancer incidence in the general population. Treatment-specific risks were compared within the cohort. RESULTS With a median follow-up of 19.1 years, 1055 second cancers were diagnosed in 908 patients, resulting in a standardized incidence ratio (SIR) of 4.6 (95% confidence interval [CI], 4.3 to 4.9) in the study cohort as compared with the general population. The risk was still elevated 35 years or more after treatment (SIR, 3.9; 95% CI, 2.8 to 5.4), and the cumulative incidence of a second cancer in the study cohort at 40 years was 48.5% (95% CI, 45.4 to 51.5). The cumulative incidence of second solid cancers did not differ according to study period (1965-1976, 1977-1988, or 1989-2000) (P=0.71 for heterogeneity). Although the risk of breast cancer was lower among patients who were treated with supradiaphragmatic-field radiotherapy not including the axilla than among those who were exposed to mantle-field irradiation (hazard ratio, 0.37; 95% CI, 0.19 to 0.72), the risk of breast cancer was not lower among patients treated in the 1989-2000 study period than among those treated in the two earlier periods. A cumulative procarbazine dose of 4.3 g or more per square meter of body-surface area (which has been associated with premature menopause) was associated with a significantly lower risk of breast cancer (hazard ratio for the comparison with no chemotherapy, 0.57; 95% CI, 0.39 to 0.84) but a higher risk of gastrointestinal cancer (hazard ratio, 2.70; 95% CI, 1.69 to 4.30). CONCLUSIONS The risk of second solid cancers did not appear to be lower among patients treated in the most recent calendar period studied (1989-2000) than among those treated in earlier periods. The awareness of an increased risk of second cancer remains crucial for survivors of Hodgkins lymphoma. (Funded by the Dutch Cancer Society.).

Risk of New Primary Nonbreast Cancers After Breast Cancer Treatment: A Dutch Population-Based Study

PURPOSE To assess the risk of secondary nonbreast cancers (SNBCs) in a recently treated population-based cohort of breast cancer patients focused on the association with treatment and prognostic implications. PATIENTS AND METHODS In 58,068 Dutch patients diagnosed with invasive breast cancer between 1989 and 2003, SNBC risk was quantified using standardized incidence ratios (SIRs), cumulative incidence, and Cox regression analysis, adjusted for competing risks. RESULTS After a median follow-up of 5.4 years, 2,578 SNBCs had occurred. Compared with the Dutch female population at large, in this cohort, the SIR of SNBCs was increased (SIR, 1.22; 95% CI, 1.17 to 1.27). The absolute excess risk was 13.6 (95% CI, 9.7 to 17.6) per 10,000 person-years. SIRs were elevated for cancers of the esophagus, stomach, colon, rectum, lung, uterus, ovary, kidney, and bladder cancers, and for soft tissue sarcomas (STS), melanoma, non-Hodgkins lymphoma, and acute myeloid leukemia (AML). The 10-year cumulative incidence of SNBCs was 5.4% (95% CI, 5.1% to 5.7%). Among patients younger than 50 years, radiotherapy was associated with an increased lung cancer risk (hazard ratio [HR] = 2.31; 95% CI, 1.15 to 4.60) and chemotherapy with decreased risk for all SNBCs (HR = 0.78; 95% CI, 0.63 to 0.98) and for colon and lung cancer. Among patients age 50 years and older, radiotherapy was associated with raised STS risk (HR = 3.43; 95% CI, 1.46 to 8.04); chemotherapy with increased risks of melanoma, uterine cancer, and AML; and hormonal therapy with all SNBCs combined (HR = 1.10; 95% CI, 1.01 to 1.21) and uterine cancer (HR = 1.78; 95% CI, 1.40 to 2.27). An SNBC worsened survival (HR = 3.98; 95%CI 3.77 to 4.20). CONCLUSION Breast cancer patients diagnosed in the 1990 s experienced a small but significant excess risk of developing an SNBC.

The influence of age and comorbidity on receiving radiotherapy as part of primary treatment for cancer in South Netherlands, 1995 to 2002

The objective of this study was to study the influence of age and comorbidity on receiving radiotherapy (RT) in primary treatment of cancer.

Malignant mesothelioma after radiation treatment for Hodgkin lymphoma

Malignant mesothelioma is a relatively uncommon malignancy. Although the pathogenesis is primarily related to asbestos, the disease may be associated with radiation exposure. Recently, increased risks for second primary mesothelioma after radiation for lymphoma have been reported. Because these findings are based on small numbers of patients, they need to be confirmed. We examined mesothelioma risk in 2567 5-year survivors of Hodgkin lymphoma. The risk was almost 30-fold increased in Hodgkin lymphoma patients treated with irradiation compared with the general population. Although histology and survival of the mesothelioma cases were comparable with cases from the general population, asbestos exposure and the proportion of males were lower than expected. The evidence for radiotherapy as cause for mesothelioma independent of exposure to asbestos is expanding, and the diagnosis of mesothelioma should be kept in mind whenever related symptoms arise in patients who had previous irradiation.

Trends in incidence and detection of advanced breast cancer at biennial screening mammography in The Netherlands: a population based study

IntroductionThe aims of this study were to determine trends in the incidence of advanced breast cancer at screening mammography and the potential of screening to reduce it.MethodsWe included a consecutive series of 351,009 screening mammograms of 85,274 women aged 50-75 years, who underwent biennial screening at a Dutch breast screening region in the period 1997-2008. Two screening radiologists reviewed the screening mammograms of all advanced screen detected and advanced interval cancers and determined whether the advanced cancer (tumor > 20 mm and/or lymph node positive tumor) had been visible at a previous screen. Interval cancers were breast cancers diagnosed in women after a negative screening examination (defined as no recommendation for referral) and before any subsequent screen. Patient and tumor characteristics were compared between women with advanced cancer and women with non-advanced cancer, including ductal carcinoma in situ.ResultsA total of 1,771 screen detected cancers and 669 interval cancers were diagnosed in 2,440 women. Rates of advanced cancer remained stable over the 12-year period; the incidence of advanced screen-detected cancers fluctuated between 1.5 - 1.9 per 1,000 screened women (mean 1.6 per 1,000) and of advanced interval cancers between 0.8 - 1.6 per 1,000 screened women (mean 1.2 per 1,000). Of the 570 advanced screen-detected cancers, 106 (18.6%) were detected at initial screening; 265 (46.5%) cancers detected at subsequent screening had been radiologically occult at the previous screening mammogram, 88 (15.4%) had shown a minimal sign, and 111 (19.5%) had been missed. Corresponding figures for advanced interval cancers were 50.9% (216/424), 24.3% (103/424) and 25.1% (105/424), respectively. At multivariate analysis, women with a ≥ 30 months interval between the latest two screens had an increased risk of screen-detected advanced breast cancer (OR 1.63, 95%CI: 1.07-2.48) and hormone replacement therapy increased the risk of advanced disease among interval cancers (OR 3.04, 95%CI: 1.22-7.53).ConclusionWe observed no decline in the risk of advanced breast cancer during 12 years of biennial screening mammography. The majority of these cancers could not have been prevented through earlier detection at screening.

Trends in sinonasal cancer in The Netherlands: More squamous cell cancer, less adenocarcinoma A population-based study 1973-2009

BACKGROUND Cancer of the nasal cavity or the paranasal sinuses (sinonasal cancer) is rare. Sinonasal cancer has been associated with various occupational risk factors such as exposure to dust of hard wood and leather. Also, a relationship with smoking habits has been suggested. We studied the long term trends in incidence to evaluate a putative effect of past preventive measures or changes in risk factors. DESIGN A retrospective population-based descriptive study. OBJECTIVE To interpret the long term trends in incidence of sinonasal cancer in The Netherlands. METHODS Data of all 3329 patients >15 years registered during 1989-2009 by the Netherlands Cancer Registry (NCR) were analysed, by data of 447 patients registered by the Eindhoven Cancer Registry (ECR) during 1973-2009 were analysed separately. Information on patients and tumour characteristics was obtained from both registries. The incidence was calculated per 1,000,000 person years and standardised using the European Standard Population. RESULTS Squamous cell carcinoma (SCC) was the most prominent histological type (48%), followed by adenocarcinoma (15%) and melanoma (8%). SCC was more frequently located in the nasal cavity or sinus maxillaris, but adenocarcinoma was more located in the ethmoid sinus. The male incidence increased during 1973-1995 with a peak of 15/1,000,000/year, decreasing since then to 11/1,000,000/year due to a declining incidence of both SCC and adenocarcinoma. In females the incidence remained stable around 5/1,000,000/year up to 2006 and increased to 7.5/1,000,000 in 2009 as a result of more SCC. The male/female ratio for SCC decreased from 2.7 to 2.0, and for adenocarcinoma from 3.4 to 2.8 since 1989. CONCLUSIONS The higher incidence in males and the different trends in incidence in males and females may reflect differences in previous exposure to risk factors. Adenocarcinoma, related to occupational exposures, tend to decline. The trends in both male and female sinonasal SCC are comparable with the trends in lung cancer.

Risk of multiple primary malignancies following treatment of Hodgkin lymphoma

We assessed risk, localization, and timing of third malignancies in Hodgkin lymphoma (HL) survivors. In a cohort of 3122 5-year HL survivors diagnosed before the age of 51 years and treated between 1965 and 1995, we examined whether risk factors for second and third malignancies differ and whether the occurrence of a second malignancy affects the risk of subsequent malignancies, using recurrent event analyses. After a median follow-up of 22.6 years, 832 patients developed a second malignancy and 126 patients a third one. The risk of a second malignancy was 4.7-fold increased (95% confidence interval [CI], 4.4-5.1) compared with risk in the general population; the risk for a third malignancy after a second malignancy was 5.4-fold (95% CI, 4.4-6.5) increased. The 10-year cumulative incidence of any third malignancy was 13.3%. Compared with patients still free of a second malignancy, patients with a second malignancy had a higher risk of developing subsequent malignancies. This risk depended on age, with hazard ratios of 2.2, 1.6, and 1.1 for patients aged <25, 25 to 34, and 35 to 50 years at HL treatment, respectively. In HL survivors who had a second malignancy, treating physicians should be aware of the increased risk of subsequent malignancies.

Prevalence of multiple malignancies in the Netherlands in 2007.

As the number of cancer survivors increases in the Netherlands, there is a concomitant increase in patients with multiple malignancies (MMs), the prevalence of which needs to be assessed to estimate care needs. This study analyzed incidence data on all malignant cancers diagnosed between 1989 and 2006 retrieved from the population‐based Netherlands Cancer Registry. The point prevalence of MMs was determined on January 1, 2007. Of all cancer survivors in 2007, 30,064 (7% of the total) were patients with MMs. Their median age was 74 (interquartile range 71–76) years. Ninety two percent (i.e., 27,660) of these patients had two cancer diagnoses. The most common subsequent cancers being squamous cell skin cancer (5,468), colorectal cancer (4,634), and breast cancer (3,959). High frequency of combinations included: (i) female breast and genital cancers (any order), (ii) urinary tract and prostate cancers (any order), (iii) Hodgkins lymphoma and subsequent female breast cancer and (iv) non‐Hodgkins lymphoma and subsequent squamous cell skin cancer. As the number of cancer survivors continues to increase and their survival improves, MMs are becoming more important in the field of cancer surveillance.