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Journal of Clinical Oncology, Vol 25, No 22 (August 1), 2007: pp. 3274-3280 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.3431 Recent Major Progress in Long-Term Cancer Patient Survival Disclosed by Modeled Period Analysis
From the German Cancer Research Center, Heidelberg, Germany Address reprint requests to Hermann Brenner, MD, MPH, Division of Clinical Epidemiology & Aging Research, German Cancer Research Center, Bergheimer Str 20, D-69115 Heidelberg, Germany; e-mail: h.brenner{at}dkfz-heidelberg.de
Purpose: To disclose most recent trends in long-term cancer patient survival. Methods: We estimated trends in 5- and 10-year relative survival of cancer patients in the United States in 1998 to 2003 from the 1973 to 2003 database of the Surveillance, Epidemiology, and End Results Program using recently introduced period-analysis modeling techniques that provide the most up-to-date and precise survival estimates. Results: Statistically significant and partly very substantial improvement in 5- and 10-year relative survival in the 1998 to 2003 period was seen for 14 of 24 of the assessed common forms of cancer, including breast and colorectal cancer. For example, by 2003, 5-year relative survival exceeded 90% for patients with breast cancer and reached levels of about two thirds for patients with colorectal cancer and kidney cancer and patients with non-Hodgkin's lymphoma. Unfortunately, 5-year relative survival remained essentially unchanged at approximately 16% for lung cancer patients, and, despite statistically significant improvement, as low as 7% for pancreatic cancer patients. Overall, improvement was most pronounced for patients with regional tumor spread and somewhat less so for patients with localized tumors, whereas hardly any improvement was achieved for patients with distant tumor spread. Conclusion: Our analysis discloses further major improvement in prognosis for most, but not all forms of cancer in recent years. The largest contribution to this improvement comes from improved prognosis of patients with regional tumor spread.
Progress in long-term cancer survival resulting from major advances in cancer research and cancer care should be disclosed in as timely a manner as possible. The recently introduced technique of modeled period analysis allows for the most efficient, precise, and timely disclosure of recent trends in long-term cancer survival.1 In this article, this technique is applied, for the first time to our knowledge, to estimate and disclose recent trends in population-based long-term cancer survival in the United States.
All data presented in this article are derived from the 1973 to 2003 public-use database of the Surveillance, Epidemiology, and End Results (SEER) Program of the US National Cancer Institute issued in April 2006.2 Data included in the 1973 to 2003 SEER database are from population-based cancer registries in Connecticut, New Mexico, Utah, Iowa, and Hawaii; Atlanta, GA; Detroit, MI; Seattle-Puget Sound, WA; and San Francisco-Oakland, CA, which together cover a population of approximately 30 million people. Geographic areas were selected for inclusion in the SEER Program on the basis of their ability to operate and maintain a high-quality population-based cancer reporting system and for their epidemiologically significant population subgroups. The SEER population is comparable to the general US population with regard to measures of poverty and education, even though it tends to be somewhat more urban and has a higher proportion of foreign-born persons than does the latter. For this analysis, we selected 1,440,447 patients aged 15 years or older with a first diagnosis of one of 24 common forms of cancer between 1988 and 2003, who have been followed for vital status until the end of 2003. Only patients with invasive cancer coded as malignant according to both Internal Classification of Diseases (ICD) –O-2 and –O-3 were included. After exclusion of 3,707 patients (0.26%) who were reported by autopsy only, 15,653 patients (1.09%) who were reported by death certificate only, and 8,664 patients (0.60%) with unknown race, there remained 1,412,467 patients (98.06%) for the survival analysis. Only survival experience in the period from 1998 to 2003 was used for analysis; all observations were left truncated at the beginning of 1998 as previously described.3 This so-called period analysis provides more up-to-date long-term survival estimates than does traditional "cohort-based" survival analysis, and quite closely predicts long-term survival expectations of cancer patients diagnosed within the period of interest.4,5 Most recently, a modeling approach to period analysis has been introduced that enhances precision of period survival estimates and allows for efficient estimation of trends within a recent period of interest.1 We employed this technique to the period of 1998 to 2003 to derive estimates of 5- and 10-year survival for 2003, the most recent calendar year for which data were available, at enhanced precision and to estimate trends in long-term survival in 1998 to 2003. A graphical illustration of the data used for analysis is given in Figure 1. Overall, the same database was used as for a "conventional" period analysis for the whole 1998 to 2003 period. However, rather than simply pooling observations within that period, we modeled survival probabilities for each combination of calendar year and year of follow-up within that period. For that purpose, we first calculated numbers of patients at risk and of deaths by year of follow-up for each single calendar year from 1998 to 2003, just as one would do in conventional period analyses for each of these calendar years. Next, we employed a Poisson regression model for the total 1998 to 2003 period. A formal description of the model is given elsewhere.1 Briefly, the numbers of deaths for each combination of calendar year and year of follow-up were modeled as a function of calendar year (included as a numerical predictor variable) and year of follow-up (included as a categoric predictor variable), with the logarithm of the person-years at risk as offset. Conditional survival probabilities for each year of follow-up, 5-year cumulative period survival estimates, and their SEs were then derived for each calendar year from the model results as previously described.1
According to standard practice in population-based cancer survival analysis, relative rather than absolute survival was calculated. Relative survival reflects survival of cancer patients compared with survival of the general population. It is calculated as the ratio of absolute survival of cancer patients divided by the expected survival of a group of persons of the corresponding sex, age, and race in the general population.6,7 Estimates of expected survival were derived according to the so-called Ederer II method8 using the 2000 US sex-, age-, and race-specific life-tables.9 In addition to overall trends in 5- and 10-year relative survival rates, we also assessed changes in stage distribution from 1998 to 2003 as well as stage-specific trends in 5-year relative survival in 1998 to 2003 for solid tumors (19 cancer sites). For that purpose, the SEER "historic stage A" classification, which distinguishes localized, regional and distant tumor spread (for prostate cancer, a common category "localized/regional" is used), was used. Furthermore, sex-specific analyses were carried out for 18 cancers occurring among both sexes, and age-specific analyses for two major age groups (15 to 64 years, 65 years and older) were carried out for all cancers except testicular cancer, which is very rare above age 65. All analyses were performed with the SAS software package (SAS Institute, Cary, NC) using adapted versions of previously described macros for modeled period analysis.1
The results of modeled period analyses of trends in 5- and 10-year survival in the 1998 to 2003 period are shown in Table 1. For 14 of the 24 common forms of cancer, statistically significant improvement was achieved in 5-year relative survival. Improvement in 5-year relative survival was strongest for non-Hodgkin's lymphoma (+7.1% units), followed by kidney cancer and leukemias. Statistically significant improvement in 5-year relative survival by 3% to 4% units was achieved for some of the most common cancers, including prostate, breast, and colorectal cancer, and for some of the cancers with the poorest prognosis, including esophagus and liver cancer. As a result, 5-year relative survival came very close to 100% for patients with prostate cancer, exceeded 90% for patients with breast cancer, and reached levels of about two thirds for patients with colorectal and kidney cancer and patients with non-Hodgkin's lymphoma in 2003. For patients with cancers of the oral cavity and brain, 5-year relative survival of 61% and 30%, respectively, was achieved.
Still statistically significant but less pronounced improvements in 5-year relative survival were seen for patients with pancreatic cancer, skin melanoma, and testicular cancer. Nevertheless, 5-year relative survival remained as low as 7.1% for the former, whereas it reached 93% and 97%, respectively, in 2003 among the latter. By contrast, 5-year relative survival remained essentially unchanged (within ± 0.7% units) at high levels around 96% to 97%, 85%, and 80% for patients with thyroid cancer, Hodgkin's disease, and urinary bladder cancer, respectively, and at low levels of around 44%, one third, and 16% among patients with ovarian cancer, multiple myeloma, and lung cancer, respectively. Statistically nonsignificant decreases by more than 1% unit were seen for patients with laryngeal, cervical, and endometrial cancer. Estimates of 10-year relative survival were generally somewhat lower than those of 5-year relative survival (with differences being most pronounced for non-Hodgkin's lymphoma, multiple myeloma, and leukemia), but very similar trends were seen in 1998 to 2003 with both measures for most forms of cancer. Statistically significant improvements were seen for the same 14 forms of cancer. Improvement in 10-year relative survival was particularly strong for patients with prostate cancer (+9.4% units), whose 10-year relative survival estimate for 2003 (98.2%) indicates that these patients, meanwhile, have hardly any excess mortality compared with the male general population of the same age. Ten-year relative survival greater than 96% has also been achieved for patients with testicular cancer and thyroid cancer in 2003, and 10-year relative survival exceeded 90% and 85% for patients with skin melanoma and breast cancer, respectively. At the other end of the range of survival estimates, 10-year relative survival remained below 5% for patients with pancreatic cancer. Table 2 shows the numbers of patients and the stage distribution by cancer site for 1998 and 2003, the first and the last year within the period of investigation. Stage was known among more than 90% of cases for 15 of 19 solid cancers in 1998, and among more than 95% of cases for 15 of 19 cancers in 2003. The stage distribution varied strongly between cancer sites and was most unfavorable for pancreatic cancer (> 60% distant tumor spread), whereas approximately 95% of prostate cancers were localized or regional in both years. For approximately half of the cancers, there was no major shift in stage distribution between 1998 and 2003. However, substantial improvement in stage distribution was seen for liver, kidney, and thyroid cancer, and some more limited, but still statistically significant improvement was achieved for colon, rectum, and prostate cancer. On the other hand, a somewhat less favorable stage distribution was observed in 2003 for patients with skin melanoma, lung, breast, cervical, and endometrial cancer.
Trends in 5-year relative survival by cancer site and stage are shown in Table 3. Overall, the strongest improvements were seen among patients with regional tumor spread. For example, major significant improvements were observed for patients with regionally spread melanoma (+7.8% units), cervical (+7.8% units), esophageal (+7.0% units), rectal (+5.8% units), breast (+5.8% units), oral cavity (+5.5% units), and colon cancer (+4.7% units), respectively. For patients with localized cancer, the potential for improvement was somewhat more limited because 5-year relative survival was already quite close to 100% for a variety of cancers in 1998. Nevertheless, further significant improvements were seen for patients with colon cancer, skin melanoma, and breast cancer. In 2003, 5-year relative survival reached 100% for patients with localized prostate and testicular cancer, exceeded or came very close to 99% for patients with localized skin melanoma and breast and thyroid cancer, and reached levels between 93% and 97% for patients with localized colon, endometrial, ovarian, and bladder cancer. Strong improvements by 7.2% units and 6.9% units were observed for localized esophageal and pancreatic cancer (P for trend = .06 and .03, respectively). Nevertheless, 5-year relative survival remained as low as 20.9% in 2003 among patients with localized pancreatic cancer, and still rather poor for patients with localized esophageal cancer (36.8%). For most forms of cancer, prognosis among patients with distant tumor spread remained very poor.
Additional sex-specific analyses showed very similar trends in 5-year survival among women and men (Table 4). Improvement in 5-year relative survival was even stronger among women than among men for skin melanoma, so that the survival advantage for women with this cancer further increased in recent years.
For most cancer sites, trends were also similar among younger (< 65 years) and older (  65 years) patients (Table 5). The partly quite substantial survival advantage of younger patients compared with older patients thereby was essentially maintained for most cancers. An important exception is breast cancer. Five-year relative survival in older breast cancer patients had already been somewhat higher than in younger breast cancer patients in 1998, and this survival advantage even slightly increased in recent years (modeled 5-year relative survival in 2003 was 92.2% and 89.8% in the older and younger age group, respectively). By contrast, for all hematologic cancers, recent trends were somewhat less favorable among older compared with among younger patients. This way, the very large age gradient in survival between younger and older patients became even larger for these malignancies.
This first application of the recently introduced modeled period analysis to population-based analysis of cancer survival in the United States discloses further significant improvements in 5- and 10-year relative survival for 14 of 24 assessed common forms of cancer, including some of the most common forms, such as prostate, breast, and colorectal cancer. Improvements in long-term survival were strongest for prostate cancer, non-Hodgkin's lymphoma, and kidney cancer. Unfortunately, 10-year relative survival remained essentially unchanged at approximately 11% for lung cancer patients and below 5% for pancreatic cancer patients. In general, improvement was most pronounced for patients with regional tumor spread, and 5-year relative survival reached or approached 100% for an increasing number of cancer sites in case of localized disease. By contrast, hardly any improvement was seen among patients with distant tumor spread. This analysis updates and extends a previous, first analysis of long-term cancer patient survival in the United States using the period-analysis methodology, which had provided overall period estimates of long-term survival in 1998.10 Our current analysis not only provides more up-to-date and more detailed, stage-, sex- and age-specific estimates of long-term survival by relying on cancer registry data up to the year 2003, but it also allowed us to derive survival estimates for the most recent year at enhanced precision and to test for significance of trends within the most recent 5-year time window for which data were available. The combination of the period approach with a pertinent modeling strategy, both of which have been thoroughly empirically evaluated,1,4,5 allows for particularly efficient up-to-date monitoring of progress in cancer patient survival. Besides disclosing ongoing favorable trends in long-term survival in recent years for the majority of cancers, our analysis also provides some clues as to the major underlying mechanisms. Progress in early detection, treatment, or both are likely to have contributed to the improvements to a various extent for the various forms of cancer. For prostate and kidney cancer (and also, to some lesser degree, liver cancer), overall improvement in survival appeared to be mainly resulting from more favorable stage distribution, whereas no major changes in stage-specific survival were observed. Enhanced early detection including also some overdetection through prostate-specific antigen screening most likely is the main reason for the strong increase in survival expectations of patients with prostate cancer.11 For kidney cancer, improvement in stage distribution along with increased numbers of registered cases probably mainly reflects increased "incidental" detection of early stages by diagnostic procedures carried out for other purposes (such as ultrasound examinations),12,13 which, though, seems not to be accompanied by a reduction in mortality so far.13 For colon and rectal cancer, both earlier detection and improved stage-specific survival, especially improved survival of patients with regional cancer spread, contributed to quite substantial overall improvement in survival. These patterns may reflect enhanced utilization of effective screening procedures14 as well as advancements in chemotherapy and (neo)adjuvant therapy and their dissemination.15,16 At the same time, the remaining high proportions of patients with nonlocalized tumors indicates that there remains substantial room for enhanced prevention and early detection.17 For other cancers, including melanoma and cancers of the oral cavity, esophagus, and breast, substantial improvements in survival were seen without any improvement of or even less favorable stage distribution. Improved survival was mainly observed for patients with regional tumor spread. For breast cancer, progress in chemotherapy and (neo)adjuvant therapy and their dissemination on the population level might have made major contributions to this favorable development.18-20 Advancements in therapy most likely also account for most of the strong improvement seen for patients with non-Hodgkin's lymphoma.21 As a word of caution, however, the possibility of "stage migration" also has to be kept in mind in the interpretation of stage specific trends. Enhanced detection of tumor spread may have led to some shift in classification of tumors to more advanced stages in recent years. For example, stage migration resulting from introduction of sentinel node biopsy may have contributed to the apparent deterioration of stage distribution among patients with breast cancer,22 which seems to reverse previously observed opposite trends resulting from mammography screening23 and may explain part of the strong increase in survival of breast cancer patients with regional tumor spread.24 However, neither stage migration nor screening mammography could explain the improvement in overall survival that was achieved along with stable (and, beginning with 2003) even slightly falling breast cancer incidence during the period of analysis. These findings support a major role of advancement in development and dissemination of effective therapy. Our analysis also discloses where progress in prognosis has not been achieved in recent years. Unfortunately this seems to be the case for almost all cancers with distant spread. Overall, hardly any improvement was seen for lung cancer, still the third most common cancer and a cancer with a particularly poor prognosis. This finding underlines once more the continued, overwhelming importance of primary prevention to limit the toll of deaths from this mostly tobacco-attributable cancer. Also, with 10-year relative survival below 5%, prognosis of patients with pancreatic cancer remains dismal overall. However, there finally seems to be a first glimmer of hope even for this highly lethal cancer, in that a major recent increase in 5-year survival was disclosed for patients with localized cancer. So far, less than 10% of pancreatic cancer patients are diagnosed with local-stage disease. Any progress in early detection that does not merely prolong lead time, along with further progress in early-stage therapy, may thus have a substantial impact on reducing deaths from this cancer. Although, overall, recent trends in relative survival were similar among younger and older cancer patients, the previously described large age gradient with worse prognosis in older patients25 persisted for many, and even increased for some cancers, especially the hematologic malignancies. Given the expected substantial increase of older patients in the years to come,26 these patterns underline the need of efforts to enhance cancer control and care among older patients in particular. In conclusion, our survival analysis using the recently introduced period modeling technique discloses further major improvement in long-term cancer patient survival for the majority of common cancers in recent years. In particular, for many forms of cancer, stage-specific survival considerably increased among patients with regional tumor spread, and 5-year relative survival now comes close to 100% among patients with localized tumors for an increasing number of cancer sites. By contrast, progress continues to be very limited for prognosis of patients with distant tumor spread, which underlines the high and increasing importance of effective early detection for the reduction of the toll of cancer deaths.
The author(s) indicated no potential conflicts of interest.
Conception and design: Hermann Brenner Data analysis and interpretation: Hermann Brenner, Adam Gondos, Volker Arndt Manuscript writing: Hermann Brenner Final approval of manuscript: Hermann Brenner, Adam Gondos, Volker Arndt
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Brenner H, Hakulinen T: Up-to-date and precise estimates of cancer patient survival: Model based period analysis. Am J Epidemiol 164:689-696, 2006 2. Surveillance, Epidemiology, and End Results (SEER) Program Public-Use Data (1973-2003). Bethesda (MD), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2006, based on the November 2005 submission. www.seer.cancer.gov 3. Brenner H, Gefeller O, Hakulinen T: Period analysis for up-to-date cancer survival data: Theory, empirical evaluation, computational realization and applications. Eur J Cancer 40:326-335, 2004[CrossRef][Medline] 4. Brenner H, Hakulinen T: Up-to-date survival curves of patients with cancer by period analysis. J Clin Oncol 20:826-832, 2002 5. Brenner H, Söderman B, Hakulinen T: Use of period analysis for providing more up-to-date estimates of long-term survival rates: Empirical evaluation among 370,000 cancer patients in Finland. Int J Epidemiol 31:456-462, 2002 6. Ederer F, Axtell LM, Cutler SJ: The relative survival rate: A statistical methodology. Natl Cancer Inst Monogr 6:101-121, 1961[Medline] 7. Henson DE, Ries LA: The relative survival rate. Cancer 76:1687-1688, 1995[CrossRef][Medline] 8. Ederer F, Heise H: Instructions to IBM 650 programmers in processing survival computations: Methodological note No 10. Bethesda, MD, National Cancer Institute, End Results Section, 1959 9. Arias E: United States life tables, 2000. Natl Vit Stat Rep 51:1-39, 2002 10. Brenner H: Long-term survival rates of cancer patients achieved by the end of the 20th century: A period analysis. Lancet 360:1131-1135, 2002[CrossRef][Medline] 11. Brenner H, Arndt V: Long-term survival rates of patients with prostate cancer in the prostate-specific antigen screening era: Population-based estimates for the year 2000 by period analysis. J Clin Oncol 23:441-447, 2005 12. Jayson M, Sanders H: Increased incidence of serendipitously discovered renal cell carcinoma. Urology 51:203-205, 1998[CrossRef][Medline] 13. Hollingsworth JM, Miller DC, Daignault S, et al: Rising incidence of small renal masses: A need to reassess treatment effects. J Natl Cancer Inst 98:1331-1334, 2006 14. Liang SY, Phillips KA, Nagamine M, et al: Rates and predictors of colorectal screening. Prev Chronic Dis 3:A117, 2006[Medline] 15. Macdonald JS: Adjuvant therapy for colon cancer. CA Cancer J Clin 47:243-256, 1997[Abstract] 16. Ragnhammar P, Hafstrom L, Nygren P, et al: Swedish Council of Technology Assessment in Health Care: A systematic overview of chemotherapy effects in colorectal cancer. Acta Oncol 40:282-308, 2001[Medline] 17. Vogelaar I, van Ballegooijen M, Schrag D, et al: How much can current interventions reduce colorectal cancer mortality in the US? Mortality projections for scenarios of risk factor modification, screening, and treatment. Cancer 107:1624-1633, 2006[CrossRef][Medline] 18. Bergh J, Jonsson PE, Glimelius B, et al: Swedish Council of Technology Assessment in Health Care: A systematic overview of chemotherapy effects in breast cancer. Acta Oncol 40:253-281, 2001[Medline] 19. Early Breast Cancer Trialists' Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomized trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 20. Berry DA, Cronin KA, Plevritis SK, et al: Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353:1784-1792, 2005 21. Armitage JO, Bierman PJ, Bociek RG, et al: Lymphoma 2006: Classification and treatment. Oncology 20:231-239, 242, 244, 249, 2006[CrossRef][Medline] 22. Van der Heiden-van der Loo M, Bezemer PD, Hennipman A, et al: Introduction of sentinel node biopsy and stage migration of breast cancer. Eur J Surg Oncol 32:710-714, 2006[CrossRef][Medline] 23. Anderson WF, Jatoi I, Devesa SS: Assessing the impact of screening mammography: Breast cancer incidence and mortality rates in Connecticut (1943-2002). Breast Cancer Res Treat 99:333-340, 2006[CrossRef][Medline] 24. Vanderveen KA, Schneider PD, Khatri VP, et al: Upstaging and improved survival of early breast cancer patients after implementation of sentinel node biopsy for axillary staging. Ann Surg Oncol 13:1450-1456, 2006 25. Brenner H, Arndt V: Recent increase in cancer survival according to age: Higher survival in all age groups, but widening age gradient. Cancer Causes Control 15:903-910, 2004[CrossRef][Medline] 26. Yancik R, Ries LA: Cancer in older persons: An international issue in an aging world. Semin Oncol 31:128-136, 2004[CrossRef][Medline] Submitted February 18, 2007; accepted May 3, 2007. This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
