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Remarkable improvements in outcomes for many haematological malignancies have been driven primarily by a proliferation of novel therapeutics over the past two decades. Targeted agents, immune and cellular therapies, and combination regimens have adverse event profiles distinct from conventional finite cytotoxic chemotherapies. In 2018, a Commission comprising patient advocates, clinicians, clinical investigators, regulators, biostatisticians, and pharmacists representing a broad range of academic and clinical cancer expertise examined issues of adverse event evaluation in the context of both newer and existing therapies for haematological cancers. The Commission proposed immediate actions and long-term solutions in the current processes in adverse event assessment, patient-reported outcomes in haematological malignancies, toxicities in cellular therapies, long-term toxicity and survivorship in haematological malignancies, issues in regulatory approval from an international perspective, and toxicity reporting in haematological malignancies and the real-world setting. In this follow-up report, the Commission describes progress that has been made in these areas since the initial report.

Background: Childhood cancer survivors (CCS) are at increased risk of developing subsequent malignant neoplasms, including gastrointestinal (GI) cancer. We performed a systematic review to summarize all available literature on the risk of, risk factors for, and outcome after subsequent GI cancer among CCS. Methods: A systematic search of the literature databases Medline/PubMed (1945-2014) and Embase (1947-2014) was performed to identify studies that consisted of >= 1000 CCS and assessed incidence of or mortality from subsequent GI cancer as an outcome. Results: A total of 45 studies were included. Studies that reported risk measures for subsequent GI cancer compared to the general population showed a 3.2 to 9.7-fold elevated risk in cohort studies including all childhood cancer types. Abdominal radiotherapy was associated with an increased risk of subsequent GI cancer in all four studies that assessed this risk. Survivors who had received procarbazine and platinum agents were also suggested to be at increased risk. Conclusion: Abdominal radiotherapy is a risk factor for developing a subsequent GI cancer. Few studies examined detailed treatment-related risk factors and most studies had small number of GI cancer cases. Therefore, no conclusions could be drawn on the effect of time since childhood cancer on GI cancer risk and on outcome after a subsequent GI cancer. Additional research is necessary to further explore risk factors for and outcome after a subsequent GI cancer, and to systematically evaluate the harms and benefits of GI screening among high-risk survivors in order to give sound screening recommendations. (C) 2015 Elsevier Ltd. All rights reserved.

Summary Female survivors of childhood, adolescent, and young adult (CAYA) cancer who were given radiation to fields that include breast tissue (ie, chest radiation) have an increased risk of breast cancer. Clinical practice guidelines are essential to ensure that these individuals receive optimum care and to reduce the detrimental consequences of cancer treatment; however, surveillance recommendations vary among the existing long-term follow-up guidelines. We applied evidence-based methods to develop international, harmonised recommendations for breast cancer surveillance among female survivors of CAYA cancer who were given chest radiation before age 30 years. The recommendations were formulated by an international, multidisciplinary panel and are graded according to the strength of the underlying evidence.

Purpose To evaluate the prevalence and severity of clinical adverse events (AEs) and treatment-related risk factors in childhood cancer survivors treated with cranial radiation therapy (CRT), with the aim of assessing dose-effect relationships. Methods and Materials The retrospective study cohort consisted of 1362 Dutch childhood cancer survivors, of whom 285 were treated with CRT delivered as brain irradiation (BI), as part of craniospinal irradiation (CSI), and as total body irradiation (TBI). Individual CRT doses were converted into the equivalent dose in 2-Gy fractions (EQD 2 ). Survivors had received their diagnoses between 1966 and 1996 and survived at least 5 years after diagnosis. A complete inventory of Common Terminology Criteria for Adverse Events grade 3.0 AEs was available from our hospital-based late-effect follow-up program. We used multivariable logistic and Cox regression analyses to examine the EQD 2 in relation to the prevalence and severity of AEs, correcting for sex, age at diagnosis, follow-up time, and the treatment-related risk factors surgery and chemotherapy. Results There was a high prevalence of AEs in the CRT group; over 80% of survivors had more than 1 AE, and almost half had at least 5 AEs, both representing significant increases in number of AEs compared with survivors not treated with CRT. Additionally, the proportion of severe, life-threatening, or disabling AEs was significantly higher in the CRT group. The most frequent AEs were alopecia and cognitive, endocrine, metabolic, and neurologic events. Using the EQD 2 , we found significant dose-effect relationships for these and other AEs. Conclusion Our results confirm that CRT increases the prevalence and severity of AEs in childhood cancer survivors. Furthermore, analyzing dose-effect relationships with the cumulative EQD 2 instead of total physical dose connects the knowledge from radiation therapy and radiobiology with the clinical experience.

Objective To evaluate the self-reported psychosocial well-being of 11- to 18-year-old adolescents who were conceived by in vitro fertilization (IVF) and examine the role of IVF conception on behavior. Design Youth Self-Report (YSR) of 86 IVF and 97 control adolescents. Setting VU University Medical Center, Amsterdam. Patient(s) Adolescents of ages 11 to 18 years; mean age 15.71 (± 2.06) years in IVF and 15.07 (± 2.11) years in controls. Intervention(s) None. Main Outcome Measure(s) Behavior and socioemotional functioning reported by the children themselves. Result(s) The YSR scores were all within the normal range. No statistically significant differences were found between the IVF and control groups on the different scales. Conclusion(s) Behavior and socioemotional functioning as reported by 11- to 18-year-old adolescents conceived by IVF were found to be normal. Previously found reduced behavior of externalizing nature and more withdrawn/depressed behavior reported by parents and teachers could not be reproduced in this study. We found no significant influence of IVF conception on behavior in adolescence.

Purpose: To evaluate the prevalence and severity of adverse events (AEs) and treatment-related risk factors in long-term Wilms' tumor (WT) survivors, with special attention to radiotherapy. Methods and Materials: The single-center study cohort consisted of 185 WT survivors treated between 1966 and 1996, who survived at least 5 years after diagnosis. All survivors were invited to a late-effects clinic for medical assessment of AEs. AEs were graded for severity in a standardized manner. Detailed radiotherapy data enabled us to calculate the equivalent dose in 2 Gy fractions (EQD(2),) to compare radiation doses in a uniform way. Risk factors were evaluated with multivariate logistic regression analysis. Results: Medical follow-up was complete for 98% of survivors (median follow-up, 18.9 years; median attained age, 22.9 years); 123 survivors had 462 AEs, of which 392 had Grade 1 or 2 events. Radiotherapy to flank/abdomen increased the risk of any AE (OR, 1.08 Gy(-1) [CI, 1.04-1.13]). Furthermore, radiotherapy to flank/abdomen was associated with orthopedic events (OR, 1.09 Gy(-1) [CI, 1.05-1.13]) and second tumors (OR, 1.11 Gy(-1) [CI, 1.03-1.19]). Chest irradiation increased the risk of pulmonary events (OR, 1.14 Gy(-1) [CI, 1.06-1.21]). Both flank/abdominal and chest irradiation were associated with cardiovascular events (OR, 1.05 Gy(-1) [CI, 1.00-1.101, OR, 1.06 Gy(-1) [CI, 1.01-1.12]) and tissue hypoplasia (OR, 1.17 Gy(-1) [CI, 1.10-1.24], OR 1.10 Gy(-1) [CI, 1.03-1.18]). Conclusion: The majority of AEs, overall as well as in irradiated survivors, were mild to moderate. Nevertheless, the large amount of AEs emphasizes the importance of follow-up programs for WT survivors. (C) 2010 Elsevier Inc

In a large retrospective cohort of breast cancer patients, BRCA1 and BRCA2 germline mutations were analysed in DNA isolated from residual paraffin-embedded tissue samples. Because it was not feasible to ask individual for informed consent, a data and DNA coding protocol, based on the Dutch 'Code of Conduct', was developed. The corner stone of the protocol is that a trusted third party, in our case a notary, keeps the coding keys of clinical data and DNA. Because (re)linkage of the combined coded clinical and genotyping data (BRCA1/2) is only possible through the notary's keys, these can be considered to be comparable to anonymised data at the level of the researcher. Issues around retrospective genotyping of allegedly high-risk mutations and the coding procedure itself are discussed. Our protocol is an appropriate solution to safeguard the privacy of patients when using residual tissue or DNA of patients. Importantly, the coding procedure also allows re-linkage of new genotyping data or extended patient follow-up data to the valuable coded dataset.

Objective To obtain consent from breast cancer survivors to use residual tissue for a study on carriership of germ line mutations in the BRCA 1 and 2 genes. To investigate which consent regimen patients prefer for research with archived tissue. Participants One hundred and thirty-two patients surgically treated for breast cancer between 1995 and 1997 in the Netherlands Cancer Institute were mailed a consent form and a questionnaire. Results A consent form was obtained from 90%; 3% withheld consent for the use of archived tissue. A completed questionnaire was returned by 84%. ‘One-time general consent’ was considered to be the best procedure for consenting to research with stored tissue by 56%, 23% favoured the current ‘opt-out’ procedure; 21% did not know or had no preference. Conclusion Obtaining fresh consent for genetic research with stored tissue is possible at the cost of time and effort. Most patients give consent for research with residual tissue.

Now that a substantial group of cancer patients has such a favourable prognosis, it has become increasingly important to evaluate the long-term complications of treatment. Of all late effects of treatment, secondary leukaemia is one of the most serious. Increased risk of AML has been observed both after RT and after CT; however, several types of CT have much stronger leukaemogenic properties than RT. Limited field radiation in the therapeutic dose range is associated with very little or no increased risk of leukaemia, which has been attributed to cell killing at the higher radiation doses. With respect to CT, two different syndromes of treatment-related AML have been recognized. Risk of alkylating agent-related AML is highest in the 5-10 year follow-up period and seems to decrease afterwards. This type of leukaemia is often preceded by MDS, and is characterized by deletions of chromosomes 5 and 7. Leukaemias related to treatment with the topoisomerase II inhibitors are characterized by a short induction period, presentation as myelomonocytic or monocytic leukaemia (rather than MDS) and balanced chromosomal translocations involving bands 11q23 and 21q22. This review addresses the risk of secondary AML and MDS following treatment of HD, NHL, testicular cancer, ovarian cancer, breast cancer and paediatric malignancies. In patients with HD, the risk of AML is higher with an increasing number of mechlorethamine-procarbazine-containing cycles, a greater number of CT episodes, and after splenectomy. The majority of data shows that RT does not add to the leukaemia risk from CT, but this issue is still surrounded by some controversy. ABV(D)-treated patients have a very low risk of AML. Generally, patients with NHL, testicular cancer and breast cancer experience much lower risk of AML than patients with HD. NHL and breast cancer treatment regimens with cumulative cyclophosphamide doses of 20 g or less do not confer an appreciable increase of AML. Recently, strongly increased AML risk has been observed following autologous bone marrow transplantation and other dose intensification strategies. Risk factors for this excess remain to be defined. PVB treatment for testicular cancer is not followed by increased leukaemia risk, but modern etoposide-containing regimens do confer excess risk, of which the magnitude at conventional drug doses is not yet well known. High risk of leukaemia has been reported in children treated with epipodophyllotoxins. The leukaemogenic hazards of cancer treatment should be weighed against their therapeutic benefits.

BACKGROUND. Recent genome-wide association studies have identified at least 20 germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer incidence. Common genetic variation is likely also related to survival after colorectal cancer diagnosis; however, the genome-wide analysis approach has not been widely applied to the study of colorectal cancer survival. METHODS. Full genome scans, and imputation to HapMap, were conducted for 2,822 men and women with invasive colorectal cancer who were enrolled in one of six studies: the Health Professionals Follow-up Study (N=173), the Nurses' Health Study (N=298), the Physicians' Health Study (N=325), the Vitamins and Lifestyle Study (N=285), the Postmenopausal Hormones Study (N=280), and the Women's Health Initiative (N=1,461). We used Cox proportional hazards regression to assess SNPspecific associations with disease-specific survival and overall survival in models adjusted for age, sex, and principal components. SNPs were modeled additively to reflect associations per copy of the minor allele. Results were combined across studies via fixed-effects metaanalysis. To account for multiple-testing, a p-value threshold of p,1x10-8 was required for genome-wide significance. RESULTS. No common SNPs (i.e., minor allele frequency ≥5%) were significantly associated with survival outcomes, including previously identified colorectal cancer susceptibility SNPs. Two SNPs of low minor allele frequency were associated with disease-specific survival at a level exceeding or approaching genome-wide significance: the minor allele in one SNP near APC2, with a frequency of 1%, was associated with significantly poorer survival (p=1.2x10-9), and the minor allele in another SNP near PRIM2, present in 3% of cases, attained borderline significance in relation to poorer survival (p= 2.0x10-8). Two other SNPs, one near MAML2 and one near ZNF804B, exhibited adverse associations of borderline significance with both overall survival (p=8.4x10-7 and 6.7x107, respectively) and disease-specific survival (p=1.1x10-7 and 5.0x10-7); both of these SNPs also had low minor allele frequencies (1% and 2%, respectively). CONCLUSIONS. Common genetic variation, particularly with respect to polymorphisms present in ≥5% of the population, does not appear to be significantly associated with colorectal cancer survival. There is still, however, some indication that germline genetic variation is related to colorectal cancer survival outcomes. Our findings for SNPs with lowminor allele frequencies provide suggestive evidence of adverse survival outcomes in those with specific, less common polymorphisms. In light of the low frequency of the minor alleles in these SNPs, false-positive results are possible; thus, further follow-up is needed.

As members of the Dutch Expert Committee on DES-related Health Eff ects, we respond to the Comment by Ellen ‘t Hoen and Graham Dukes on compensation for diethylstilbestrol injury (Jan 20, p 173). Contrary to the opinion expressed by ‘t Hoen and Dukes, we, as well as the Dutch DES Centre, strongly believe that the recently agreed collective settlement of diethylstilbestrol claims in the Netherlands is unique and highly benefi cial for Dutch diethylstilbestrol victims. Our opinion is based on the large number of diethylstilbestrolrelated disorders covered and the fact that individual women do not have to start an expensive and emotionally diffi cult legal procedure with uncertain outcome, which could last several years. Individual women can now be compensated on the basis of medical evidence of diethylstilbestrol exposure and the presence of a diethylstilbestrol-related disorder covered by the settlement. In close collaboration with the DES Centre, a careful procedure was followed before a settlement was proposed. The Expert Committee fi rst reviewed published data on diethylstilbestrol-related health eff ects and decided for which disorders a causal association with diethylstilbestrol was established. We believe that no causal association has been established for breast cancer and early age at menopause in women whose mothers took diethylstilbestrol during pregnancy (“DES daughters”) because increased risks were reported 4 Costedoat-Chalumeau N, Amoura Z, Hulot JS, et al. Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum 2006; 54: 3284–90. 5 Petri M, Kim MY, Kalunian KC, et al. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med 2005; 353: 2550–58. in only one study. Subsequently, we determined the relative risk associated with diethylstilbestrol, on the basis of all available published data. A unique aspect of the Dutch collective settlement is that it also allows compensation for diseases with a weak but established association with diethylstilbestrol. DES mothers (those who took diethylstilbestrol during pregnancy) have a 1·35-fold increased risk of breast cancer. This implies that the attributable risk is 26%—ie, among DES mothers with breast cancer, one in four cases can be attributed to diethylstilbestrol. Since there is no way to identify the one woman whose breast cancer was indeed caused by diethylstilbestrol, it was agreed that all (living) DES mothers who developed (or will develop) breast cancer should be compensated, taking into account the attributable risk. The proposed collective settlement was widely publicised among those exposed to diethylstilbestrol, and, of more than 100 000 aff ected, the Amsterdam court received only four objections. The court validated the diethylstilbestrol agreement and ruled against the four defendants. We regret that this information was not included the Comment.