A.W. van den Belt-Dusebout

Risk of endometrial cancer after tamoxifen treatment of breast cancer

Since large trials have been set up to assess whether tamoxifen decreases the risk of breast cancer in healthy women, it has become important to investigate the drugs potential adverse effects, including occurrence of endometrial cancer. We undertook a case-control study in the Netherlands to assess the effect of tamoxifen on the risk of endometrial cancer after breast cancer. Through the population-based Netherlands Cancer Registry and two older, hospital-based, registries, we identified 98 patients who had endometrial cancer diagnosed at least 3 months after a diagnosis of primary breast cancer. Detailed information about treatment was obtained for all these patients, and for 285 controls, who were matched to the cases for age, year of breast cancer diagnosis, and survival time with intact uterus. Tamoxifen had been used by 24% of patients with subsequent endometrial cancer and 20% of controls (relative risk 1.3 [95% CI 0.7-2.4]). Women who had used tamoxifen for more than 2 years had a 2.3 (0.9-5.9) times greater risk of endometrial cancer than never users. There was a significant trend of increasing risk of endometrial cancer with duration of tamoxifen use (p = 0.049), and also with cumulative dose (p = 0.046). The duration-response trends were similar with daily doses of 40 mg or 30 mg and less. These findings support the hypothesis that tamoxifen use increases the risk of endometrial cancer. This oestrogenic effect on the endometrium was not related to the dose intensity. Physicians should be aware of the higher risk of endometrial cancer in tamoxifen users.

Second cancer risk following Hodgkin's disease: a 20-year follow-up study.

PURPOSE To determine risk factors for the development of second primary cancers during long-term follow-up of patients with Hodgkins disease (HD). PATIENTS AND METHODS We assessed the risk of second cancers (SCs) in 1939 HD patients, who were admitted to the Netherlands Cancer Institute (NKI; Amsterdam) or the Dr Daniel den Hoed Cancer Center (DDHK; Rotterdam) between 1966 and 1986. For 97% of the cohort, we obtained a medical status up to at least January 1989. The median follow-up duration of the patients was 9.2 years; for 17% of the patients, follow-up was longer than 15 years. For more than 98% of all second tumors, the diagnosis was confirmed through a pathology report. RESULTS In all, 146 patients developed a SC, compared with 41.9 cases expected on the basis of incidence rates in the general population (relative risk [RR], 3.5; 95% confidence interval [CI], 2.9 to 4.1). The mean 20-year actuarial risk of all SCs was 20% (95% CI, 17% to 24%). Significantly increased RRs were observed for leukemia (RR, 34.7; 95% CI, 23.6 to 49.3), non-Hodgkins lymphoma (NHL) (RR, 20.6; 95% CI, 13.1 to 30.9), lung cancer (RR, 3.7; 95% CI, 2.5 to 5.3), all gastrointestinal cancers combined (RR, 2.0; 95% CI, 1.2 to 3.1), all urogenital cancers combined (RR, 2.4; 95% CI, 1.4 to 3.7), melanoma (RR, 4.9; 95% CI, 1.6 to 11.3), and soft tissue sarcoma (RR, 8.8; 95% CI, 1.8 to 25.8). As compared with the general population, the cohort experienced an excess of 63 cancer cases per 10,000 person-years. Cox-model analysis indicated the following as significant risk factors for developing leukemia: first-year treatment with chemotherapy (CT), follow-up treatment with CT, age at diagnosis of HD greater than 40 years, splenectomy, and advanced stage. Patients treated with CT in the 1980s had a substantially lower risk of leukemia than patients treated in the 1970s (10-year actuarial risks of 2.1% and 6.4%, respectively; P = .07). Significant risk factors for NHL were older age, male sex, and combined modality treatment as compared with either modality alone. Risk of lung cancer was strongly related to radiotherapy (RT), while an additional role of CT could not be demonstrated. After more than 15 years of follow-up, women treated with mantle-field irradiation before age 20 years had a greater than forty-fold increased risk of breast cancer (P < .001). CONCLUSION While the long-term consequences of HD treatment as administered in the 1960s and 1970s are still evolving, it is promising that patients who received the new treatment regimens introduced in the 1980s have a much lower leukemia risk than patients treated in earlier years. Beginning 10 years after initial RT, the follow-up program of women who received mantle-field irradiation before age 30 years should routinely include breast palpation and yearly mammography.

Second cancer risk following testicular cancer: a follow-up study of 1,909 patients.

PURPOSE Improved survival in testicular cancer has been accompanied by concern about long-term side effects of therapy. We assessed the evolution of second cancer (SC) risk over a prolonged follow-up period, which has been rarely studied in large patient series. PATIENTS AND METHODS We estimated the risk of SCs in 1,909 patients with testicular cancer diagnosed in the Netherlands from 1971 to 1985. Complete medical information was obtained up to at least January 1988 for 92% of patients. Median follow-up was 7.7 years. For 89% of second tumors the diagnosis was confirmed through review of histologic slides; for an additional 8%, the diagnosis was verified by pathology reports only. RESULTS Seventy-eight patients developed a SC 1 year or more after start of treatment, as compared with 47.6 expected on the basis of incidence rates in the general population (relative risk [RR], 1.6; 95% confidence interval [CI], 1.3 to 2.1). The mean 15-year actuarial risk of all SCs was 9.8% (95% CI, 7.5% to 12.8%). Significantly increased RRs were observed for all gastrointestinal cancers combined (RR, 2.6; 95% CI, 1.7 to 3.9), stomach cancer (RR, 3.7; 95% CI, 1.8 to 6.8), contralateral testicular cancer (CLTC) (RR, 35.7; 95% CI, 21.8 to 55.2), and leukemia (RR, 5.1; 95% CI, 1.4 to 13.0). Patients who had received irradiation to the paraaortic lymph nodes and who survived testicular cancer for more than 5 years were at particularly high risk of developing stomach cancer (RR, 6.9; 95% CI, 3.3 to 12.7). The median interval between the diagnosis of testicular cancer and stomach cancer was 12.4 years. Patients treated with chemotherapy (CT) did not experience an increase in SCs in general. Indeed, CT-treated patients, as compared with those who received radiotherapy (RT), or surgery alone, had significantly reduced risk of CLTC. This finding might be attributed to an eradicating effect of CT on carcinoma in situ or subclinical CLTC. The excess risk of leukemia was not found to be clearly related to CT. CONCLUSION Testicular cancer patients who receive RT experience elevated risk of gastrointestinal tumors. CT does not seem to increase SC risk and may even decrease the risk of a CLTC. Following testicular cancer, the 15-year actuarial risk of all SCs is only about half the risk experienced by patients with Hodgkins disease.

Leukemia risk following Hodgkin's disease: relation to cumulative dose of alkylating agents, treatment with teniposide combinations, number of episodes of chemotherapy, and bone marrow damage.

PURPOSE The development of leukemia is one of the most serious long-term complications of modern treatment for Hodgkins disease (HD). This study was undertaken to examine the relation between risk of leukemia and various treatment factors (including cumulative dose of cytostatic drugs and interaction with radiotherapy [RT]), while also assessing the effect of treatment-induced bone marrow damage. PATIENTS AND METHODS We conducted a case-control study in a cohort of 1,939 patients treated for HD between 1966 and 1986 in the Netherlands. Detailed information from the medical records was obtained for 44 cases of leukemia and 124 matched controls, in whom leukemia had not developed. RESULTS The cumulative dose of mechlorethamine was the most important factor in determining leukemia risk. As compared with patients who received RT alone, patients treated with six or fewer cycles of combinations including nitrogen mustard (mechlorethamine) and procarbazine had an eightfold increased risk of developing leukemia (P = .08), while patients who received more than six of such cycles had a greater than 40-fold excess risk (P < .001). Treatment with lomustine or a combination of teniposide and cyclophosphamide also significantly increased the risk of leukemia. Patients who had received chemotherapy (CT) during two or more time periods had a nearly 40-fold increased risk of leukemia as compared with patients treated only once. The extent of RT did not further increase leukemia risk among patients who also received CT. A significantly increased risk of leukemia was found among patients with low platelet counts, both in response to initial therapy and during follow-up. Patients who experienced 2 or more half-year periods with platelet counts less than 75 x 10(6)/mL had an approximately fivefold risk of developing leukemia, and a similar risk increase was found for patients who responded to initial treatment with a > or = 70% decrease of platelet counts (as compared with patients who had a < or = 50% decrease). CONCLUSION In addition to mechlorethamine, lomustine and teniposide combinations were also linked to an elevated risk of developing leukemia. Since the number of CT episodes was found to be a strong determinant of leukemia risk, it is important that new therapies for HD continue to yield high initial cure rates. Further studies are warranted to investigate whether patients at high risk for developing leukemia may be identified from the response of their platelets to initial therapy for HD.

Increased stomach cancer risk following radiotherapy for testicular cancer.

Background:Abdominal radiotherapy for testicular cancer (TC) increases risk for second stomach cancer, although data on the radiation dose–response relationship are sparse.Methods:In a cohort of 22 269 5-year TC survivors diagnosed during 1959–1987, doses to stomach subsites were estimated for 92 patients who developed stomach cancer and 180 matched controls. Chemotherapy details were recorded. Odds ratios (ORs) were estimated using logistic regression.Results:Cumulative incidence of second primary stomach cancer was 1.45% at 30 years after TC diagnosis. The TC survivors who received radiotherapy (87 (95%) cases, 151 (84%) controls) had a 5.9-fold (95% confidence interval (CI) 1.7–20.7) increased risk of stomach cancer. Risk increased with increasing stomach dose (P-trend<0.001), with an OR of 20.5 (3.7–114.3) for ⩾50.0 Gy compared with <10 Gy. Radiation-related risks remained elevated ⩾20 years after exposure (P<0.001). Risk after any chemotherapy was not elevated (OR=1.1; 95% CI 0.5–2.5; 14 cases and 23 controls).Conclusions:Radiotherapy for TC involving parts of the stomach increased gastric cancer risk for several decades, with the highest risks after stomach doses of ⩾30 Gy. Clinicians should be aware of these excesses when previously irradiated TC survivors present with gastrointestinal symptoms and when any radiotherapy is considered in newly diagnosed TC patients.

Do children make you happier? Sustained child-wish and mental health in women 11–17 years after fertility treatment

STUDY QUESTION Are fertility treatment-related factors, parenthood status and sustained child-wish associated with womens long-term mental health? SUMMARY ANSWER Sustaining a child-wish is more strongly associated with womens long-term mental health than fertility treatment-related factors and parenthood status. WHAT IS KNOWN ALREADY About one-third of the couples starting fertility treatment do not achieve parenthood and have to adjust to an unfulfilled child-wish. In women, remaining childless after treatment is associated with less favourable mental health. It is unclear if this is only related to their childlessness or if adjustment after unsuccessful treatment is affected by other variables. These include diagnostic and treatment-related factors (cause of fertility problems, age at first consultation, type and number of treatments) and the psychological ability to come to terms with the unfulfilled child-wish. Differentiating the relative contribution of these factors to womens long-term mental health will provide useful knowledge to support patients adjusting to negative treatment outcomes. STUDY DESIGN, SIZE, DURATION A cross-sectional study with a nationally representative sample of 7148 women who started fertility treatment at any of the 12 IVF hospitals in the Netherlands from 1995 through 2000. Of 16 482 women who were invited to participate, 7148 (43.4%) provided psychological data. PARTICIPANTS/MATERIALS, SETTING, METHODS The average age of women was 47 years and the average age at first fertility consultation was 30 years. Fifty-one per cent of women did IUI and 85% did IVF/ICSI. Ninety per cent of women were married/cohabiting, 20.9% remained childless and 5.9% had a child-wish. Women completed a questionnaire assessing diagnostic and treatment factors (retrospective data), parenthood status, sustained child-wish and mental health. MAIN RESULTS AND THE ROLE OF CHANCE A multiple regression analysis controlling for background variables showed that, first, male factor (P < 0.05) and/or idiopathic infertility (P < 0.001) were associated with better mental health. Secondly, starting fertility treatment at an older age was associated with better mental health (P < 0.01). Thirdly, the interaction between parenthood status and sustained child-wish was significant (P < 0.01). Having a child-wish was associated with worse mental health for women with (β = -0.058, P < 0.01) and without children (β =-0.136, P < 0.001), but associations were stronger for the latter. Predictive factors accounted for <5% of the variation in mental health status in the study population. LIMITATIONS, REASONS FOR CAUTION The sample was large and nationally representative. Response rate was in line with other studies but women without psychological data were less likely to have biological children and 15.9% of non-responders considered the questionnaire to be too confronting or to elicit too emotional memories. This could reflect an underestimation of the proportion of women with a sustained child-wish. WIDER IMPLICATIONS OF THE FINDINGS Sustaining a child-wish is a more important risk for long-term adjustment problems than parenthood status. Women adjust better when they start treatment at older ages and know they were not responsible for the cause of the fertility problem. Fertility staff can play an important role in preparing patients for the possibility of treatment failure and the associated grief process. They can also inform patients about the positive effect of refocusing their life goals. STUDY FUNDING/COMPETING INTERESTS This study was supported by a grant from the Dutch Cancer Society (2006-3631). No competing interests exist. TRIAL REGISTRATION NUMBER N/A.

Melanoma risk after ovarian stimulation for in vitro fertilization

STUDY QUESTION Do women treated with ovarian stimulation for IVF have an increased risk of melanoma? SUMMARY ANSWER Ovarian stimulation for IVF does not increase risk of melanoma, even after a prolonged follow-up. WHAT IS KNOWN ALREADY Although exposure to ultraviolet radiation is the major risk factor for melanoma, associations between female sex steroids and melanoma risk have also been suggested. The results of available studies on fertility drugs and melanoma risk are inconclusive since most studies had several methodological limitations such as short follow-up, a small number of cases and no subfertile comparison group. STUDY DESIGN, SIZE, DURATION In 1996, a nationwide historic cohort study (the OMEGA-cohort) was established to examine the risk of cancer after ovarian stimulation for IVF. After a median follow-up of 17 years, cancer incidence was ascertained through linkage with the Netherlands Cancer Registry. Melanoma risk in the cohort was compared with that in the general population and between the IVF group and non-IVF group using multivariable Cox regression analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS The cohort comprises 19 158 women who received IVF between 1983 and 1995 and a comparison group of 5950 women who underwent subfertility treatments other than IVF. Detailed IVF-treatment data were obtained from the medical records and complete information on parity and age at first birth was obtained through linkage with the Dutch Municipal Personal Records Database. MAIN RESULTS AND THE ROLE OF CHANCE In total, 93 melanoma cases were observed. The risk of melanoma was not elevated among IVF-treated women, neither when compared with the general population (standardized incidence ratio = 0.89; 95% confidence interval (CI): 0.69-1.12), nor when compared with the non-IVF group (adjusted hazard ratio (HR) = 1.27; 95% CI: 0.75-2.15). A higher number of IVF cycles was associated with apparent but statistically non-significant risk increases (5-6 cycles HR = 1.92; ≥7 cycles HR = 1.79). However, no significant trend emerged. In women with more follicle stimulating hormone/human menopausal gonadotrophin ampoules comparable non-significant risk increases were found. A longer follow-up did not increase melanoma risk. Nulliparous women did not have a significantly higher melanoma risk than parous women (HR = 1.22; 95% CI: 0.81-1.84). However, women who were 30 years of age or older at first birth had a significantly higher melanoma risk than women who were younger than 30 years at first birth (age: 30-34 years HR = 4.57; 95% CI: 2.07-10.08, >34 years HR = 2.98; 95% CI: 1.23-7.21). LIMITATIONS, REASONS FOR CAUTION Despite our large cohort, the number of melanoma cases was rather small, especially in our comparison group, which hampered subgroup analyses. WIDER IMPLICATIONS OF THE FINDINGS Our results are reassuring for women who underwent IVF or are contemplating to start IVF. Since our cohort study is one of the largest published so far, with long-term follow-up, a subfertile comparison group, and detailed IVF-treatment data, our results add important information to the available evidence. STUDY FUNDING/COMPETING INTEREST This study was supported by grants from the Dutch Cancer Society (NKI 2006-3631), the Health Research and Development Counsel (28-2540) and the Dutch Ministry of Health.

Risk and prognostic significance of metachronous contralateral testicular germ cell tumours

Background:Testicular germ cell tumour (TGCT) patients are at increased risk of developing a contralateral testicular germ cell tumour (CTGCT). It is unclear whether TGCT treatment affects CTGCT risk.Methods:The risk of developing a metachronous CTGCT (a CTGCT diagnosed ⩾6 months after a primary TGCT) and its impact on patient’s prognosis was assessed in a nationwide cohort comprising 3749 TGCT patients treated in the Netherlands during 1965–1995. Standardised incidence ratios (SIRs), comparing CTGCT incidence with TGCT incidence in the general population, and cumulative CTGCT incidence were estimated and CTGCT risk factors assessed, accounting for competing risks.Results:Median follow-up was 18.5 years. Seventy-seven metachronous CTGCTs were diagnosed. The SIR for metachronous CTGCTs was 17.6 (95% confidence interval (95% CI) 13.9–22.0). Standardised incidence ratios remained elevated for up to 20 years, while the 20-year cumulative incidence was 2.2% (95% CI 1.8–2.8%). Platinum-based chemotherapy was associated with a lower CTGCT risk among non-seminoma patients (hazard ratio 0.37, 95% CI 0.18–0.72). The CTGCT patients had a 2.3-fold (95% CI 1.3–4.1) increased risk to develop a subsequent non-TGCT cancer and, consequently, a 1.8-fold (95% CI 1.1–2.9) higher risk of death than patients without a CTGCT.Conclusion:The TGCT patients remain at increased risk of a CTGCT for up to 20 years. Treatment with platinum-based chemotherapy reduces this risk.

Increased breast cancer risk in in vitro fertilisation treated women with a multiple pregnancy: A new hypothesis based on historical in vitro fertilisation treatment data

BACKGROUND Breast cancer risk is temporarily increased after a full-term pregnancy and declines thereafter, possibly due to increased levels of gonadal and placental hormones during pregnancy. Inconsistent results, however, have been reported after twin pregnancies with higher hormone levels. Among women treated with in vitro fertilisation (IVF), for whom the number of embryos available for implantation is known, we recently observed that a multiple birth after implantation of all transferred embryos is associated with higher levels of vascular endothelial growth factor (VEGF). As VEGF is involved in breast cancer progression, we studied the effects of embryo implantation and a multiple birth on breast cancer risk in a nationwide Dutch cohort of IVF-treated women. METHODS We performed a cohort analysis among 12,589 women who had been treated with IVF between 1983 and 1995 and completed a risk factor questionnaire between 1997 and 1999. Data on IVF treatment were obtained from medical records. Breast cancer cases were ascertained through linkage with the population-based Netherlands Cancer Registry. Breast cancer risks associated with singleton and multiple births were estimated with Cox regression. FINDINGS There were 1688 women (13.4%) with multiples, 6027 (47.9%) with singletons and 4874 (38.7%) nulliparous women. Breast cancer occurred in 317 women of whom 57 had multiples. Breast cancer risk was 1.44 times higher in mothers of multiples than in mothers of singletons (95% confidence interval (CI) 1.06-1.97). Risk was highest in women who gave birth to multiples from all embryos transferred (adjusted hazard ratio (HR) 1.86, 95% CI 1.01-3.43), and lower for those with multiples after incomplete embryo implantation (adjusted HR 1.31, 95% CI 0.76-2.25). INTERPRETATION A womans potential to implant all transferred embryos may be associated with breast cancer risk. Further research is needed to confirm our results and to identify the underlying biological mechanisms.

Low oocyte yield during IVF treatment and the risk of a trisomic pregnancy

A low number of antral follicles may result in the selection of suboptimal oocytes that are prone to meiotic errors. The aim of this case-control study was to evaluate women receiving IVF treatment with low oocyte yield (defined as three or fewer oocytes retrieved after ovarian stimulation) who are at an increased risk of a trisomic pregnancy. Data were obtained from Danish and Dutch medical registries between 1983 and 2011. Analyses were carried out in 105 cases and 442 controls matched by age and year of IVF treatment. Cases were women with a trisomic pregnancy (trisomies 13, 18 or 21) resulting from fresh IVF treatment and confirmed by karyotyping. Cases were included regardless of pregnancy outcome. Controls were women with a live born child without a trisomy, resulting from fresh IVF treatment. Low oocyte yield was observed in 6.6% (29/440) of the women, of which 8.4% (7/83) were cases and 6.2% (22/357) controls. Low oocyte yield in IVF treatment was not associated with a higher risk of trisomic pregnancy (OR 1.43, 95% CI 0.64 to 3.19). Stratification for female age, adjustment for history of ovarian surgery, and gonadotrophin-releasing hormone protocol used did not change the results.