IJC International Journal of Cancer

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1 IJC International Journal of Cancer Survival in patients with acute myeloblastic leukemia in Germany and the United States: Major differences in survival in young adults Dianne Pulte 1, Lina Jansen 1, Felipe A. Castro 1, Agne Krilaviciute 1, Alexander Katalinic 2, Benjamin Barnes 3, Meike Ressing 4,5, Bernd Holleczek 6, Sabine Luttmann 7, Hermann Brenner 1,8,9 and for the GEKID Cancer Survival Working Group 1 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany 2 Cancer Registry of Schleswig-Holstein, L ubeck, Germany 3 National Center for Cancer Registry Data, Robert Koch Institute, Berlin, Germany 4 Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Centre, Mainz, Germany, Johannes Gutenberg University, Mainz 5 Cancer Registry Rhineland-Palatinate, Mainz, Germany 6 Saarland Cancer Registry, Saarbr ucken, Germany 7 Bremen Cancer Registry, Leibniz-Institute for Prevention Research and Epidemiology-BIPS, Bremen, Germany 8 Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany 9 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Previous epidemiologic studies on AML have been limited by the rarity of the disease. Here, we present population level data on survival of patients with AML in Germany and the United States (US). Data were extracted from 11 population-based cancer registries in Germany and the Surveillance, Epidemiology, and End Results (SEER13) database in the US. Patients diagnosed with AML in were included. Period analysis was used to estimate 5-year relative survival (RS) and trends in survival in the early 21st century. Overall 5-year age-adjusted RS for patients with AML in was greater in Germany than in the US at 22.8% and 18.8%, respectively. Five-year RS was higher in Germany than in the US at all ages, with particularly large differences at ages for whom 5-year RS was 64.3% in Germany and 55.0% in the US and 35 44, with 5- year RS estimates of 61.8% in Germany and 46.6% in the US. Most of the difference in 5-year RS was due to higher 1-year RS, with overall 1-year RS estimates of 47.0% in Germany and 38.5% in the US. A small increase in RS was observed between and in both countries, but no increase in survival was observed in either country for ages 751. To our knowledge, this is the first detailed description of AML survival in Germany. Comparison to the US suggests that further analysis into risk factors for poor outcomes in AML in the US may be useful in improving survival. Acute myeloblastic leukemia (AML) is an acutely life threatening, but often treatable, leukemia with a variable prognosis. Prognosis is related to a number of factors, key among them are age and specific mutations associated with AML. 1 3 In order for survival to be possible, patients must undergo an intense therapeutic regimen consisting of highly toxic induction chemotherapy followed by consolidation chemotherapy or hematopoietic stem cell transplant (HSCT). Potential barriers to therapy might include age or comorbid conditions making the patient unable to tolerate therapy or socioeconomic issues that make it difficult for the patient to access therapy. Key words: acute myeloblastic leukemia, survival, period analysis DOI: /ijc History: Received 16 Feb 2016; Accepted 29 Apr 2016; Online 13 May 2016 Correspondence to: Dianne Pulte, German Cancer Research Center Im Neuenheimer Feld , Heidelberg, pultedi@gmail. com In the past, examination of population level survival in Germany for rare cancers such as AML has been hampered by lack of high quality data from a unified national database. Recently, a collaborative project funded by the German Cancer Aid was set up between population based German cancer registries and the German Cancer Research Center to provide comprehensive data on cancer survival in Germany. 4 This collaboration allows for the study of survival in rare cancers, such as AML, and examination of survival by specific demographic characteristics such as age. Here, we examine survival of patients with AML in Germany and the US in detail. Methods Data sources A detailed description of the cancer registries from which data were obtained has been published previously. 4,5 Briefly, data extracted from 11 population-based cancer registries throughout Germany, representing a total base population of million people, were included. Patients age 15 or older with a primary diagnosis of AML (ICD-10-GM codes C92.0,

2 1290 AML survival in Germany and the US What s new? The recent availability of comprehensive data in Germany has made it possible to study population-level survival for rare cancers such as acute myeloblastic leukemia (AML). Here, the authors offer the first detailed description of AML survival in the country, providing age-adjusted and age-specific 1- and 5-year survival estimates and analyzing survival trends. Comparison between Germany and the United States shows higher probability of 1- and 5-year survival in Germany, especially for younger patients. The results suggest incremental progress in the treatment of AML and a need to further investigate risk factors in the United States, especially regarding access to treatment. C92.3, C92.4, C92.5, supplemented with histology using ICD- O-3 codes) in and with mortality follow up through December, 2011, with or without preceding cancers, were included. Patients diagnosed by death certificate only (DCO) were excluded from the analysis as their survival is unknown. For some registries, data were available starting from later years only. To compare population level survival for AML in Germany with survival in the US, data from the Surveillance, Epidemiology and End Results (SEER13) database were analyzed. 6 The same inclusion criteria as for patients from the German cancer registries were applied for the same time period. The SEER13 database includes data from 13 regional cancer centers in the US, covering a population of about 41.5 million people. Centers are chosen for inclusion based on their high quality and epidemiologically interesting population groups. The SEER population is considered to be similar to the general US population with respect to most sociodemographic characteristics, although it may be more affluent than average and may have slightly higher than average survival for some cancers. 7 Statistical methods Five-year relative survival estimates for the time period were calculated using period analysis. 8 Period analysis, first introduced in 1996, 9 provides more up-to-date survival estimates than traditional cohort based analysis. In particular, it has been shown by extensive empirical evaluation, that period estimates of 5-year relative survival for a given period quite closely predict 5-year relative survival later observed for patients during the period of interest. 10,11 To make survival estimates comparable between both countries, age-adjusted survival estimates were derived by computing weighted sums of age-specific survival estimates using weights according to the International Cancer Survival Standard (ICSS) weight adapted for three age groups. Because survival in AML varies with age and sex, we examined survival by major age groups and by sex. Differences in survival between men and women, as well as between patients in Germany and the United States, were tested for statistical significance, overall and by single age groups, using model-based period analysis. 12 In model-based analysis, numbers of deaths were modeled as a function of the period of follow-up, age group, and country by Poisson regression with the logarithm of the person-months at risk as offset. Survival expectations vary significantly depending on the specific subtype of AML, with a number of specific mutations having been reported to lead to specific prognostic expectations. For example, acute promyelocytic leukemia (APL) and AML associated with Down syndrome (DS) have a better prognosis than other forms of AML. Conversely, patients with therapy related AML, AML with multilineage dysplasia and certain cytogenetic abnormalities such as translocation 6;9 and 11q23 (MLL) abnormalities have worse survival than average and frequently do not respond well to therapy. Because imbalances in these known prognostic characteristics may lead to differences in survival between the countries being compared, the frequency of each subtype was assessed to ensure that any differences observed were not due to major differences in known prognostic factors. The German data do not include cases of myelodysplastic syndrome and this group was therefore excluded from the US data as well. Trends in survival were examined, comparing 5-year survival for the periods , and to determine whether the prognosis of patients with AML was changing over time, either overall or for any specific age groups. Differences in survival were tested for statistical significance using model-based period analysis as described above. 12 Patients with AML are at highest risk of dying during the first year after diagnosis when initial induction chemotherapy is given and consolidation initiated. Therefore, one year survival may be used as a rough proxy marker for adequacy of initial treatment. Survival in years 2 5 is more dependent on ongoing consolidation and treatment of relapses. We calculated 1-year relative survival and 5-year conditional survival of patients who had survived one year after diagnosis. In this way, differences in survival after initial induction and consolidation treatment versus later survival could be compared. Relative survival was calculated as the ratio of actual (observed) survival to expected survival. Expected survival was estimated according to the Ederer II method 13 using national life tables stratified by age, sex and calendar year obtained from the German Federal Statistical Office. 14 Relative survival for the US patients was calculated using US sex, age, calendar year and race-specific life tables published by the Center for Disease Control (CDC). 15 All calculations were carried out using SAS software (version 9.4, SAS, Carey, NC), using macros developed for

3 Pulte et al Table 1. Number of cases and characteristics by registry and specific prognostic group 1 and 5-year overall age-adjusted relative survival for Subgroup/characteristic Germany % (SE) US % (SE) % 5-year survival, % 5-year survival, All 13, (0.6) 21, (0.5) Median age 68 NA NA 68 NA NA Microscopically confirmed NA 98.5 NA NA 97.8 NA No histology NA Acute Promyelocytic Leukemia (4.6) (3.2) 11q (5.6) (7.0) Not otherwise specified (0.8) 10, (0.7) Rare (0.9) (0.8) Multilineage dysplasia (1.9) (1.5) Down Syndrome associated 0 0 NA 1 <0.1 NA Therapy related (4.3) (3.3) Acute Lymphoblastic Leukemia-like 0 0 NA NA Sarcoma (7.1) (4.6) t(6;9)(p23;q34) 0 0 NA 5 <0.1 NA t(8;21) (5.9) (4.3) Inversion NA 6 <0.1 NA 1 Cases were selected by histology using ICD-O-3 codes. When histology was listed as unknown, the ICD-10 codes for AML (C92.0, C92.3, C92.4, C92.5) were used to select cases. 2 May not sum to 100% due to rounding. 3 Includes ICD-O-3 codes 9840, 9867, 9870, , 9891, 9910, NA, not applicable, too few cases to calculate; SE, Standard error. standard and model-based period analysis. 12,16 A p values below 5% was considered as significant. Results Overall, 16,329 and 22,016 cases of AML were identified in the German registries and SEER13, respectively. Of these, 15.4% of cases in the German registries and 1.2% of cases in SEER13 were diagnosed by DCO, leaving 13,810 and 21,762 cases, respectively, for analysis. DCO rates for the period were slightly lower in each country at 12.9% and 0.9%, respectively, for Germany and the US. Median age at diagnosis was 68 in each country and rates of microscopically confirmed cases were similar. Microscopic confirmation of diagnosis was available for % of cases in the German registries and 97.8% of cases in the SEER database. Because subtype of AML can affect prognosis, the frequency of different subtypes was examined. A lower frequency of APL was observed in Germany at 2.9% versus 7.3% in the US (Table 1). A slightly higher incidence of multilineage AML was observed in Germany at 7.2% versus 6.0%. However, AML not otherwise specified (ICD-O-3 code 9861/3) was most common in each country and occurred at similar rates at 52.4% and 50.3% in each country. Overall, the differences were felt to be minor and a sensitivity analysis including only those patients with an average prognosis did not show results significantly different from those obtained from the overall analysis (data not shown). Five year relative survival for is noted for each subtype and varies from essentially zero for no histology to over 50% for APL. However, caution should be taken when interpreting the survival estimates as the standard error is very high for the rarer histologies. Overall 5-year relative survival in Germany was 22.8% (Table 2). Survival generally decreased with age, although 5- year relative survival estimates for ages 15 24, and were similar at 64.3%, 60.6% and 61.8%. Five-year relative survival was very low for patients age 751 at 5.3%. Five-year relative survival for patients in the US was 18.8% with estimates ranging from 55.0% for ages to 2.2% for ages 751. Point estimates of survival were higher in Germany for all ages, with differences ranging from 10.7 to 115.2% units, but the difference was not significant for ages or Because APL has a different prognosis compared to other forms of AML and the mild difference in rate of APL might affect the results, we performed a sensitivity analysis in which APL was excluded. When APL was excluded, 5-year agestandardized relative survival was 21.9% in Germany and 16.0% in the US (data not shown). Age-specific survival decreased slightly for each individual age group as well, with the greatest changes being observed for younger patients (<45) and with a greater differences being observed in the US. Survival by gender and age was examined. For men, overall 5-year relative survival was estimated at 21.6% in

4 1292 AML survival in Germany and the US Table 2. Survival of patients with AML in Germany and the US by age for the period Overall Germany US Age N 5-year RS SE N 5-year RS SE Diff p values (Model) < < Overall a 11, , < N, Number of cases; RS, Relative Survival; SE, Standard Error; Diff, Difference between survival in Germany and the US; a, age adjusted using ICSS weights. Table 3. Survival by sex and age for patients with AML in Germany and the US, Men Germany US Age N 5-year RS SE N 5-year RS SE Diff p values (Model) < Overall a < Women Germany US Age N 5-year RS SE N 5-year RS SE Diff p values (Model) < Overall < age adjusted using ICSS weights; N, Number of cases; RS, Relative Survival; SE, Standard Error; Diff, Difference between survival in Germany and the US. Germany and 18.1% in the US (Table 3, p < for the country comparison). Survival again decreased with age, ranging from 61.9% and 48.2%, respectively, in Germany and the US for ages to 5.4% and 1.9%, respectively, for ages 751. Survival was higher in Germany at each age group and the differences were statistically significant at each age. For women, overall 5-year relative survival was 24.2% and 19.4%, respectively, for Germany and the US (p < for country comparison). As for men, survival estimates decreased with age, ranging from 62.6% and 59.0%, respectively, in Germany and the US for ages to 5.2% and 2.5%, respectively, for ages 751. Survival was generally greater for Germany versus the US, but the difference was not statistically significant for ages or ages Overall, 1-year relative survival (as an indicator of the adequacy of initial induction treatment) was higher in

5 Pulte et al Table 4. One-year relative survival and 5-year survival conditional on one-year survival for Germany and the US in the period Germany US Germany US Age N 1-year RS SE N 1-year RS SE Diff p values (Model) N Cond. 5-year RS SE N Cond. 5-year RS SE Diff p values (Model) < < < Overall < age adjusted using ICSS weights; N, Number of cases; RS, Relative Survival; SE, Standard Error; Diff, Difference between survival in Germany and the US; Cond, Conditional. Germany at 47.0% versus 38.5% in the US (p < ) (Table 4). Significant differences in survival were observed for each age except for Relative 1-year survival decreased with age, from 85.7% and 76.8%, respectively, for Germany and the US at years of age to 22.4% and 14.8%, respectively, at 751. Overall 5-year survival conditional on 1-year survival (as an indicator for successful maintenance and remission treatment) was slightly higher in Germany at 41.7% versus 39.1% in the US (p ), but the differences were much smaller and observed primarily for younger patients with differences in age based conditional survival being significant only for ages and A trend analysis comparing 5-year relative survival in the calendar periods , and was performed (Fig. 1). For Germany, overall age-adjusted 5-year relative survival increased from 20.1% to 24.6% between and (p ). Trends in survival were particularly pronounced for ages at 111.3% units (p ), for ages at 116.8% units (p ) and at 112.9% units (p ). For the US, age-adjusted overall 5-year relative survival increased from 16.7% in to 20.3% in (p ). A statistically significant change in survival was observed for ages 25 34, 45 54, and Only very small, statistically not significant changes were observed for either country for ages 65 and older. Discussion Five-year relative survival for AML was consistently higher in Germany than in the US. Most of the difference in 5-year relative survival could be accounted for by differences in 1- year survival, suggesting that initial presentation and treatment are important. However, there was also a significant gap in 5-year survival conditional on 1-year survival for Figure 1. Trend between , and in age-standardized and age-specific 5-year relative survival for Germany and the US. younger patients in the US compared to Germany. Overall, age-adjusted 5-year relative survival increased in both countries between and , although age-

6 1294 AML survival in Germany and the US specific survival demonstrated no change in survival for those age 65 and older. To our knowledge, this article presents the first detailed description of population level survival for patients with AML in Germany and provides an international comparison to put the results in context. Population level survival for patients with AML in the US has been previously reported Previous study has demonstrated increased survival for younger patients in the early 21st century, but an increasing gap in survival between non-hispanic whites and patients of minority ethnic background. 20 There are few publications examining survival in AML by detailed age group outside of the US. One study of survival in children and young adults with AML in Australia gave a five year survival estimate of 62.5% for adults age in and a study of 5-year survival for adults age with AML in Sweden showed an estimated survival of 60% in Both of these estimates are more similar to survival estimates seen in Germany than those seen in the US. Finally, the EUROCARE study showed an overall 1-year survival rate of 42.1% and a 5-year survival rate of 19.3% in Germany in Survival rates for other central and northern European countries were similar or slightly lower. 23 Five-year survival estimates for ages in Europe as a whole were 49.6%, similar to that in the US in our study, but there was considerable regional variation with considerably lower survival in eastern Europe compared to central Europe. However, it should be noted that APL was excluded from the analysis in the EUROCARE study. As noted earlier, exclusion of APL from our analysis resulted in a decrease in overall survival of a few percent units. Another EUROCARE publication from 2014 showed a survival for APL of 61.9% in , though survival estimates for APL cases in central Europe were lower. 24 In addition, the use of data from may have resulted in lower estimates compared to our study that pertained to survival experience in The majority of the difference in 5-year survival between Germany and the US could be accounted for by differences in 1-year survival between the two countries, although there was a small difference in conditional 5-year survival among younger patients. Since survival in AML is only possible if patients receive prompt, aggressive treatment on diagnosis, this may suggest a greater risk of delayed or incomplete treatment among patients in the US compared with Germany. Recent work examining survival in the US by insurance type has demonstrated lower survival for patients who are uninsured or who have Medicaid only. 25 This disparity, which is likely to be at least partly related to differences in treatment, may contribute to the difference in survival between Germany and the US, especially among younger people who are less likely to be insured. However, biological differences in disease characteristics other than those accounted for by the databases may also explain some of the observed differences, although the available data do not suggest that there are major differences in AML between the two countries. In addition, the greater ethnic diversity in the US may result in a greater number of patients with no match for transplant and therefore a larger number not receiving transplant or receiving a suboptimal (i.e., mismatched) transplant as well as the possibility that some patients in the US are unable to obtain a transplant for financial reasons. Standard of care treatment for AML includes induction with an anthracycline chemotherapeutic agent and cytarabine, using the protocol. 26 This protocol, with minor variations in type and amount of anthracycline given, has been the standard induction therapy in both Germany and the US for many years. Consolidation therapy and, particularly, the use of HSCT have been refined over the past decade. In particular, the use of non-ablative transplants has allowed transplant in patients who would previously have not been candidates for HSCT due to age or poor performance status. As HSCT becomes safer and treatment of complications becomes more feasible, the use of HSCT has expanded to include older patients 27 with studies showing that HSCT is associated with better outcomes for middle aged patients (age 40 60) with intermediate or poor risk disease. 28 This expansion may explain why survival increased between and for patients age in the US and Germany and in the US. Strengths of our study include the use of large databases with survival information from a number of different regions of both countries, allowing for evaluation of survival and subgroup analysis of this relatively rare tumor and decreasing the risk that survival differences between individual parts of the country will unduly influence the impression of survival in the country overall. Use of population-level data provides a more accurate understanding of how probable a patient with a given disease in the general population is to survive in contrast to data provided by clinical trials which tend to present the best-case scenario with respect to survival and may not be realistic for the general population. 29 Finally, the use of period analysis and modelled period analysis provide the most up-to-date estimates of survival possible. In interpreting our results, several limitations should be considered. First, despite the expansion of the database, the rarity of AML limits our ability to detect small differences in survival. Second, in the absence of a national death index in Germany, cancer registries rely on record linkage with vital statistics from the region that they cover and may miss deaths among patients who leave the region. Nevertheless, previous validation studies have suggested potential overestimation of survival due to deaths missed by migration to be very small. 5 Third, data on use of chemotherapy and biologic agents is minimal in the SEER and the German database, and therefore, we cannot estimate the effects of specific medications on survival. It should be noted that, although adults in both countries are generally treated initially with chemotherapy, pediatric protocols can vary. However, analysis of patients age does not produce a result substantially different from analysis of (Tables 2 and 4).

7 Pulte et al Conversely, treatment for older patients with lower intensity protocols may change the survival rates in each country in ways that cannot be determined with the available data. Fourth, survival estimates from the SEER database may be higher than survival in the US population in general, 7 so some caution is necessary when comparing survival in the two countries. Fifth, the racial and ethnic makeup of Germany and the US varies and there is some evidence that 5- year survival with AML may be lower in patients of non- European background. 20 However, it should be noted that the observed differences may be more related to socioeconomic differences than to differences in disease biology. 20 In a related issue, patients in the United States are much more likely to be uninsured than those in Germany and lack of insurance is associated with lower survival for AML. 25 Since insurance data are available in SEER only from 2007 on, we cannot directly assess the effect that this factor has on survival, but it likely contributes to the lower survival observed in the United States. Sixth, it is not clear whether the rules for registering AML transformed from MDS are identical in each country, possibly leading to a relative over- or underregistration of AML transformed from MDS in one of the registries. However, it should be noted that transformation from MDS is rare in younger patients where some of the largest differences were observed. Seventh, information on biological markers of prognosis and other information generally used to stratify prognosis is severely limited in the available databases so we cannot rule out differences in the biology of the disease between the two countries. Nonetheless, available data do not show major differences, that is, the rate of APL and reported specific chromosomal abnormalities are similar. Finally, the higher proportion of DCO notifications in Germany might affect survival estimates. We aimed to address this concern by calculating a plausibility range for data from the German database. The plausibility range (i.e., the range of actual survival after accounting for DCO cases under plausible assumptions) 30,31 for overall 5-year survival was %, a range of less than two percent units whose References lower end exceeded the survival estimates for the United States. Thus, it is unlikely that the major survival differences between both countries are due to differences in data quality and completeness of case ascertainment. Overall, our results demonstrate higher survival for patients with AML in Germany than in the US. Most of the difference in 5-year survival could be accounted for by differences in 1-year survival. Five year survival increased in both countries between and , but the increase was limited to patients under the age of 65. These results suggest incremental progress in the treatment of AML as well as a need to further investigate treatment in the United States, with a particular emphasis on access to treatment. Acknowledgements Members of the GEKID Cancer Survival Working Group: Karla Geiss, Martin Meyer (Cancer Registry of Bavaria), Andrea Eberle, Sabine Luttmann (Cancer Registry of Bremen), Roland Stabenow (Cancer Registry of Berlin and the New Federal States), Stefan Hentschel, Alice Nennecke (Cancer Registry of Hamburg); Joachim Kieschke, Eunice Sirri (Cancer Registry of Lower Saxony), Bernd Holleczek (Saarland Cancer Registry), Katharina Emrich (Cancer Registry of Rhineland-Palatinate), Hiltraud Kaj uter, Volkmar Mattauch (Cancer Registry of North Rhine-Westphalia), Alexander Katalinic (Cancer Registry of Schleswig-Holstein), Benjamin Barnes, Klaus Kraywinkel (Robert Koch Institute, Berlin), Hermann Brenner, Felipe Castro, Lina Jansen, Agne Krilaviciute (German Cancer research Center). D.P. performed the analyses, contributed to the analysis of the results and wrote the manuscript. L.J. performed the analyses, contributed to the interpretation of the results, and critically reviewed the manuscript. H.B. designed the survival study, contributed to the interpretation of the results, and critically reviewed the manuscript. FC, AKatalinic, BB: contributed to the interpretation of the results and critically reviewed the manuscript. AKrilaviciute, MR, BH, SL: contributed to the organization of the database and interpretation of the results and critically reviewed the manuscript. All authors approved the final format of the manuscript. This work was supported in part by a grant from the German Cancer Aid (Deutsche Krebshilfe, no ) and a visiting scientist grant from the German Cancer Research Center to DP. Competing interests: DP has received clinical trials funding for unrelated trials from Selexys Pharmaceuticals and ApoPharma. FC is currently employed by Roche. 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