Long-term survival of cancer patients in Germany achieved by the beginning of the third millenium

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1 Original article Annals of Oncology 16: , 2005 doi: /annonc/mdi186 Published online 22 April 2005 Long-term survival of cancer patients in Germany achieved by the beginning of the third millenium H. Brenner 1 *, C. Stegmaier 2 & H. Ziegler 2 1 German Centre for Research on Ageing, Heidelberg; 2 Saarland Cancer Registry, Saarbrücken, Germany Received 11 November 2004; accepted 12 January 2005 Introduction Background: Over the last decades, long-term survival rates have substantially increased for many forms of cancer. However, these improvements have often been detected with substantial delay by traditional methods of survival analyses. Patients and methods: Using data of the population-based Saarland Cancer Registry, 5- and 10-year relative survival rates were derived for patients with 24 common forms of cancer in Saarland/ Germany for the years by period analysis and compared with conventional cohort estimates of 5- and 10-year relative survival rates pertaining to patients diagnosed in Results: For many forms of cancer, the period survival estimates were substantially higher than the corresponding estimates for the cohorts of patients diagnosed in For example, 10-year relative survival rates achieved in were close to 100% for patients with testis and thyroid cancer, >85% for patients with melanomas of the skin, 80% for patients with endometrial cancer and prostate cancer, close to 70% for patients with breast cancer and kidney cancer, and close to 60% for patients with colon cancer and lymphomas. Conclusions: Survival expectations of patients diagnosed with cancer at the beginning of the third millenium are substantially higher than previously available survival statistics have suggested. Key words: cancer registries, period analysis, prognosis, survival analysis For many forms of cancer, prognosis has gradually improved over time due to progress in early detection or therapy. However, progress in long-term survival, such as 5-, 10- or 15-year survival, has mostly been disclosed with substantial delay by application of traditional methods of survival analysis, by which long-term survival rates are derived for patients diagnosed many years ago [1 3]. A few years ago, a new method of survival analysis, denoted period analysis, was introduced to derive more up-to-date long-term survival estimates [4, 5]. Extensive empirical evaluation has shown that long-term survival rates derived by this method for some recent period, such as the most recent calendar years for which cancer registry data are available, quite closely predicts long-term survival observed many years later for patients diagnosed in that period [6 8]. Meanwhile, the method has been used to disclose recent progress in cancer patient survival in a number of countries, including the USA [9], the UK [10, 11], Finland [12], Sweden [13] and Estonia [14]. However, apart from *Correspondence to: Dr H. Brenner, Department of Epidemiology, German Centre for Research on Ageing, Bergheimer Strasse 20, D Heidelberg, Germany. Tel: ; Fax: ; Brenner@dzfa.uni-heidelberg.de some forms of childhood cancer [15 17] and some first applications for breast and ovarian cancer carried out in the 1990s [18, 19], up-to-date long-term period survival estimates are still lacking for most countries, including Germany. The aim of this paper is to provide estimates of 10-year survival for the most common forms of cancer achieved in Germany by the beginning of the third millenium. Methods Study population This analysis is based on data from the population-based Saarland Cancer Registry. Saarland is a state located in the South West of Germany, with borders to France and Luxembourg and a population of 1.1 million people. The Saarland Cancer Registry has been operating since 1967, and it is the only population-based cancer registry in Germany that has provided cancer incidence data meeting international standards in terms of completeness and quality throughout the last 35 years. Accordingly, it has been the only cancer registry in Germany (except from the Nationwide Childhood Cancer Registry) that has been regularly involved in the major international comparative analyses of cancer incidence and survival (e.g. [20 23]). Sources of registration include records from hospitals, medical practices, radiological and pathological institutions, and death certificates. Completeness of case ascertainment has been estimated to be 96% by capture recapture analyses [24]. Mortality follow-up is achieved by q 2005 European Society for Medical Oncology

2 982 annual record linkage of cancer registry records with records from official mortality statistics. This analysis includes patients with a first diagnosis of one of 24 common forms of cancer in Saarland in , who were followed with respect to vital status until the end of Patients recorded by death certificate only (6.1% of all patients) were excluded from the analysis, as were patients whose cancer was diagnosed by autopsy only (0.1%). The analysis was restricted to patients aged >_ 15 years at the time of diagnosis ( 99% of all cancer patients), owing to the very different nature of most childhood cancers. Statistical analysis We calculated 5- and 10-year survival for all cancer sites using two different approaches. In the first approach, 5- and 10-year survival were calculated for patients diagnosed in and followed with respect to survival until the end of This classical cohort approach is depicted by the horizontal solid frame in Figure 1. However, this approach would not reflect potential advancements in early detection or therapy achieved in the 1990s. We therefore took a second approach, in which 5- and 10-year survival was derived for the period as depicted by the vertical dashed frame in Figure 1. With this period analysis, the principle of which has been described in detail elsewhere [4, 5], only survival experience of patients in the period is considered in the analysis. Survival during the first year following diagnosis is estimated from patients diagnosed in , conditional survival in the second year following diagnosis is estimated from patients diagnosed in and so on, until survival during the 10th year following diagnosis, which is estimated from patients diagnosed in Throughout this paper, we report relative rather than absolute survival rates. Relative survival rates, which are commonly reported by population-based cancer registries, are obtained as the ratios of the observed (absolute) survival rates divided by the survival rates of a group of patients with similar age and sex distribution, and they thus exclusively reflect excess mortality due to the cancer of interest [3]. Expected survival rates were estimated from general sex- and calendar period-specific life tables for Germany according to Hakulinen s method [25]. Standard errors were calculated according to Greenwood s method [26]. All analyses were carried out using the SAS macro period [27]. Results The overall numbers of patients included in the analyses, as well as the numbers of patients diagnosed in and in , are shown by cancer site in Table 1. Together, the 24 forms of cancer listed in Table 1 accounted for 93.9% of all cancer diagnoses meeting the inclusion criteria in Saarland in Breast cancer was the most commonly diagnosed cancer in Saarland in , followed by lung cancer, colon cancer, prostate cancer and rectal cancer. For the majority of cancers, the numbers of diagnoses were larger in than in The increase was by far largest, both in absolute terms and in relative terms, for prostate cancer, but large increases were also seen for breast cancer and colorectal cancers. By contrast, major declines were seen for stomach cancer and bladder cancer. In addition to the numbers of cases by diagnostic period, Table 1 also provides estimates of 5- and 10-year relative survival with their standard errors for the cohorts of cancer patients and for the period. To provide Figure 1. Years of diagnosis and of follow-up included in traditional cohort analysis of survival for the cohort (solid frame) and in period analysis of survival for the period (dashed frame). The numbers within the cells indicate the years following diagnosis.

3 983 Table 1. Numbers of patients by cancer site and years of diagnosis included in the analysis, and 5- and 10-year relative survival rates for the cohort and the period Cancer site ICD-9 Total number of cases 5-year relative survival [% (SE)] 10-year relative survival [% (SE)] cohort a more comprehensive picture of the survival throughout the 10-year time span following diagnosis, the corresponding 10-year relative survival curves are given for 16 common forms of cancer in Figure 2. With the exception of cancers of the gall-bladder and the pancreas, prognosis seems to have improved for all major gastrointestinal cancers between and According to the period analysis, almost 60% and 55% of patients now appear to survive colon cancer and rectum cancer, respectively, for 10 years or longer. These estimates are almost 10% units higher than the corresponding estimates for the cohorts. One out of five patients with cancer of the oesophagus can now hope to still be alive 10 years after diagnosis, while this diagnosis was close to a definite sentence to death for patients diagnosed at the beginning of the 1990s. Unfortunately, this is still true for patients with pancreatic cancer, for whom no improvement can be seen at all, and, despite some improvement, for the majority of patients with liver cancer period cohort period Oral cavity (2.3) 51.0 (2.4) 30.6 (2.3) 39.7 (2.6) Oesophagus (2.5) 24.3 (3.5) 5.6 (2.2) 18.8 (4.4) Stomach (2.0) 35.1 (2.4) 26.8 (2.4) 31.4 (2.8) Colon (1.7) 61.2 (1.6) 50.3 (2.1) 58.6 (2.1) Rectum (2.1) 59.9 (2.0) 44.3 (2.5) 53.7 (2.5) Liver (2.0) 8.3 (2.7) 1.3 (1.3) 5.2 (2.5) Gallbladder (2.8) 17.6 (3.3) 16.3 (3.6) 15.8 (3.5) Pancreas (1.6) 5.4 (1.4) 5.0 (1.7) 4.6 (1.5) Larynx (3.9) 62.3 (4.4) 47.3 (4.4) 50.5 (5.0) Lung (0.9) 15.4 (1.0) 10.0 (0.9) 13.5 (1.1) Melanoma (3.1) 87.1 (2.5) 80.5 (3.7) 85.8 (3.2) of the skin Breast (1.3) 80.6 (1.1) 64.9 (1.5) 69.0 (1.5) Cervix uteri (3.2) 60.4 (3.3) 56.6 (3.5) 55.2 (3.6) Corpus uteri (2.5) 82.8 (2.5) 80.8 (3.3) 81.9 (3.3) Ovary (3.4) 45.7 (3.4) 31.9 (3.6) 40.9 (3.8) Prostate (2.3) 87.6 (1.6) 69.7 (3.2) 77.9 (2.7) Testis (2.6) 100 (1.1) 93.2 (2.8) 100 (1.4) Urinary bladder (2.5) 58.9 (3.3) 65.8 (3.3) 59.3 (4.0) Kidney (2.7) 68.5 (2.6) 57.7 (3.2) 66.1 (3.2) Brain, (3.2) 22.7 (3.1) 19.7 (3.4) 20.9 (3.2) nervous system Thyroid (4.4) 95.0 (2.9) 76.3 (5.0) 96.0 (3.8) Lymphomas (2.7) 67.2 (2.6) 53.6 (3.0) 59.8 (3.1) Multiple myeloma (5.0) 27.6 (4.3) 22.6 (5.1) 23.0 (4.4) Leukaemias (3.4) 45.2 (3.4) 33.7 (3.5) 34.1 (3.6) ICD, International Classification of Diseases; SE, standard error. For the most common gynaecological cancers, developments have been quite diverse. Whereas patients with endometrial cancer already had 5- and 10-year relative survival rates >80% at the beginning of the 1990s, with virtually no deaths due to this cancer after the fifth year following diagnosis, no further improvement appears to have been achieved since then. Likewise, the (considerably worse) prognosis of patients with cervical cancer showed no improvement. By contrast, relative survival moderately improved for patients with breast cancer and patients with ovarian cancer. Nevertheless, the relative survival curve for patients with breast cancer still does not level off during the 10 years following diagnosis, which indicates persistent occurrence of a relatively high number of late deaths among patients with this most common form of cancer, whose incidence continues to rise. Despite some improvement, 10-year relative survival still remained as low as 40% for patients with ovarian cancer. With the exception of cancer of the urinary bladder, a substantial improvement in prognosis was found for the major

4 984 Figure 2. Ten-year relative survival curves for the cohort (solid lines) and the period (dashed lines) for 16 common forms of cancer. urological cancers. Most notably, patients with cancer of the testis no longer appear to have any excess mortality compared with the general population, at least not within 10 years following diagnosis. By contrast, similar to breast cancer patients, patients with prostate cancer continue to have substantial excess mortality throughout the 10-year time span after diagnosis, but their 10-year relative survival rate nevertheless increased from 70% to close to 80%. A similar increase was seen for patients with kidney cancer. According to the period analysis, two out of three of these patients meanwhile appear to survive their cancer for at least 10 years. The apparent decrease in survival rates of patients with cancer of the urinary bladder needs to be interpreted with caution and most likely reflects an artefact due to more restrictive

5 criteria for the diagnosis of invasive bladder cancer in more recent years compared with earlier years, which may also explain the much lower number of cases with this cancer in compared with Although lung cancer remains a highly fatal disease, there now seem to be somewhat higher odds for newly diagnosed patients surviving than at the beginning of the 1990s. According to the period analysis, 10-year relative survival now exceeds 85% for patients with malignant melanoma and, as for lung cancer, excess mortality appears to essentially cease 5 years after diagnosis. Unfortunately, this does not apply for patients with lymphomas, multiple myeloma or leukaemias, and there appears to have been no or only moderate improvement in prognosis for these patients within the last decade. Similarly, the prognosis remained essentially unchanged for patients with brain cancer, whereas 5- and 10-year relative survival rates increased by 20% units between and for patients with thyroid cancer. This is the largest increase seen for any of the cancers, and the relative survival rates for the period, which come close to 100%, suggest that the vast majority of patients with this cancer can now be cured. Discussion 985 This first comprehensive period analysis of cancer patient survival from a population-based cancer registry in Germany reveals recent major progress in long-term survival rates for many forms of cancer. For some forms of cancer, such as cancer of the testis and cancer of the thyroid, the period survival estimates for the period suggest that patients have no or very little excess mortality at the beginning of the third millenium. For some of the most common forms of cancer, such as colon and rectum cancer, 5- and 10-year survival rates have increased by almost 10% within the last decade, and even for lung cancer there finally seems to be some, albeit less pronounced, improvement. Unfortunately, no indication of any improvement could be seen for pancreatic cancer, for which 10-year relative survival remained below 5%. As expected, our cohort estimates of relative survival for the cohort of patients are very close to the latest previously available cancer survival figures for Germany, which were cohort survival estimates of patients diagnosed in similar time windows. For example, the recently published EUROCARE-3 study, in which (apart from childhood cancer) the Saarland Cancer Registry contributed about half of the cases from Germany, reported 5-year relative survival rates for patients diagnosed in [23]. The last comprehensive survival analysis of cancer patients in Germany published in 1999, in which the Western part of Germany was exclusively represented by data from the Saarland Cancer Registry, reported 5-year relative survival rates of patients diagnosed up to 1988 only [28]. None of these reports therefore reflected the major improvements achieved during the 1990s and at the beginning of the 21st century. Two previous studies had used period analysis to address progress in longterm survival of cancer patients in the 1990s, but these were restricted to breast [18] and ovarian [19] cancer, and they referred to much earlier periods ( and , respectively). Period estimates of long-term survival for a large number of common forms of cancer have meanwhile been reported for a few countries, including Finland [12], Sweden [13], Estonia [14], the UK [10] and the USA [9]. With the exception of the Swedish data, these reports referred to periods in the 1990s. The 5- and 10-year relative survival rates found in our study for the period are mostly much higher than those reported for the period in Estonia and the period in the UK, somewhat higher than those reported for the period in Finland and, despite some major variation by cancer site, on average similar to those reported for the year 1998 in the USA. Apart from international variation, these differences again essentially reflect recent improvement that was disclosed in our study by application of period analysis to the most recent time period for which data are now available in Germany. The reasons for the improvements in long-term survival rates during the past decade are likely to vary by cancer site. For some forms of cancer, such as cancer of the testis and cancer of the thyroid, widespread delivery of effective therapy is likely to play the key role. For other forms of cancer, such as prostate cancer, early detection by more widespread prostate-specific antigen testing, which also accounts for the strong increase in numbers of detected cases, is likely to be the most important factor. Whether increased survival in this situation truly represents progress against this cancer, or merely reflects increased lead time or even over-diagnosis of cancers that would otherwise have remained undetected altogether, remains to be seen from additional data, such as long-term developments in prostate cancer mortality rates. For yet other forms of cancer, such as breast cancer and colorectal cancer, both progress in therapy as well as earlier detection (e.g. by increasing use of colonoscopy and mammography) might have contributed to the increased survival rates. When looking at our data, the following limitations should be kept in mind. Although generally used to estimate cancer survival in Germany in national and international studies due to lack of other cancer registry data of comparable quality, the survival rates for Saarland may not necessarily be fully representative of survival rates for cancer patients in Germany as a whole. However, as there is generally little regional variation in patterns of cancer care in Germany, and as Saarland includes proportions of urban and rural areas similar to the national average, it is unlikely that survival rates would be strongly different for Germany as a whole. However, owing to the small size of Saarland, the numbers of cancer patients included in some of the cancer specific analyses were small, and the standard errors for some of the survival estimates were as high as 5%. Therefore, a possible role of chance variation has to be taken into account. Although case ascertainment in the Saarland Cancer Registry is better than in other population-based German cancer

6 986 registries, we had to exclude 6% of cases, who were reported by death certificate only. As unregistered patients are typically somewhat older and tend to have shorter survival times than other patients, our survival estimates may be slightly too optimistic [29, 30]. However, the proportion of death certificate-only cases decreased from 8.1% to 3.5% between and , suggesting that the improvement in survival rates over time may have been underestimated rather than overestimated due to this limitation. Finally, although the period survival estimates have been shown to predict future survival rates of cancer patients diagnosed in the respective period quite closely, they still tend to be slightly too pessimistic rather than too optimistic [6 8]. Therefore, the 5- and 10-year relative survival rates of patients diagnosed in may well turn out to be even higher than estimated in this study once long-term follow-up has been completed. 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