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Epidemiology:
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Is There a Common Etiology for the Rising Incidence of and Decreasing Survival with Adenocarcinoma of the Lung?

Janssen-Heijnen, Maryska L.G.1; Coebergh, Jan-Willem W.1,2; Klinkhamer, Paul J.J.M.3; Schipper, Rob M.4; Splinter, Ted A.W.5; Mooi, and Wolter J.6

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From 1Eindhoven Cancer Registry, Comprehensive Cancer Center South, Eindhoven, The Netherlands; 2Department of Public Health, Erasmus University Medical School, Rotterdam, The Netherlands; 3PAMM Regional Laboratory for Pathology and Microbiology, Eindhoven, The Netherlands; 4Department of Lung Diseases, Catharina Hospital, Eindhoven, The Netherlands; 5Department of Medical Oncology, University Hospital Dijkzigt, Rotterdam, The Netherlands; and 6Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Address correspondence to: M.L.G. Janssen-Heijnen, Comprehensive Cancer Center South, P.O. Box 231, 5600 AE Eindhoven, The Netherlands.

Submitted June 8, 1999; final version accepted September 8, 2000.

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Abstract

We studied possible explanations for the deteriorating survival for adenocarcinoma of the lung between 1975 and 1994 in relation with trends in incidence. The proportion of adenocarcinoma among men has been increasing since 1975 and for those born after 1920, while survival has decreased since 1975 and for those born since 1930. Among women, both the proportion of adenocarcinoma and survival have remained more or less constant. The rising incidence and the decreasing survival may both be related to changes in tobacco use, the increased use of low-tar filter cigarettes since the 1960s being the most likely candidate.

Among the histologic subtypes of non-small-cell lung cancer, a marked increase in the incidence of adenocarcinoma among men has been observed in many countries, including the southeastern Netherlands. 1–7 A recent analysis in this area, which has high incidence rates of lung cancer, indicated declining survival rates for patients with adenocarcinoma. 8 Since a decrease in survival is unusual in an area with good access to specialized care, we report here in more detail the changes in survival of adenocarcinoma against the background of trends in incidence, taking into account the period of diagnosis as well as birth year.

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Patients and Methods

The Eindhoven Cancer Registry collects data on patients with newly diagnosed cancer in the Dutch province of North Brabant and the northern part of the adjacent province of Limburg. During the period 1975–1994, the percentage of clinical diagnoses of lung cancer that lacked histological or cytological confirmation remained steady at 5% for patients younger than 70 and at 11% for those older than 70 years of age.

We computed age-standardized incidence rates using the European Standard (European Standardized Rates, ESR). We also calculated the proportional distribution of histological subtypes for each 10-year birth cohort, according to 10-year age groups.

Active follow-up of all patients diagnosed between 1975 and 1992 was performed on April 1, 1994. Only 0.4% were lost to follow-up. Relative survival is an approximation to risk of death due to lung cancer and is defined as the ratio of the crude to the expected rates (calculated from life tables for regional male and female populations). 9 We computed relative survival rates for each gender, according to period of diagnosis and birth cohort.

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Results

A total of 7,273 patients were diagnosed with non-small-cell lung cancer between 1975 and 1994; 1,287 had adenocarcinoma (1,030 men and 257 women). The peak in incidence rates for adenocarcinoma among men was reached in 1985, while that for squamous cell carcinoma was already reached in 1978 (Figure 1). Among women the incidence rates for all histological subtypes of non-small-cell lung cancer increased until 1994. The proportion of adenocarcinoma among non-small-cell lung cancer for men increased from 10% in 1975–1979 to 18% in 1990–1994, while this proportion for women remained about 40%; it has also been increasing among men born since 1920, while there was no such trend among women (Table 1).

Figure 1
Figure 1
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Table 1
Table 1
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There was a trend toward a more advanced stage among younger patients (the proportion of patients with advanced tumor stage increasing from 52% to 64%), while the trend among the elderly was opposite (decreasing from 54% to 44%). The proportion of tumors of unknown stage remained constant in both age groups. Between 1975 and 1992 the relative 1- and 3-year survival rates for younger patients with adenocarcinoma have decreased markedly from 59% to 43% and from 36% to 27%, respectively (Table 2); this decrease was most marked for men. After stratification according to stage, relative 1- and 3-year survival rates for adenocarcinoma remained more or less stable (Table 2). For males the 1-year survival rate increased from 35% for birth cohort 1900–1909 to 50% for cohort 1920–1929, but decreased thereafter to 44% for cohort 1940–1949. For women the 1-year survival rate increased from 42% for birth cohort 1910–1919 to 58% for cohort 1940–1949.

Table 2
Table 2
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Discussion

Among men with non-small-cell lung cancer in the southeastern part of the Netherlands, the proportion of adenocarcinoma increased since 1975 and for those born since 1920, while among women this proportion remained roughly unchanged. For male patients with adenocarcinoma born since 1930 and for those diagnosed since 1975, the survival rate decreased.

The role of changes in detection or histological tumor typing in the increase in incidence for male patients born after 1920 is likely to be limited; despite better diagnostic techniques and the increase in the number of chest physicians, there was little indication of a shift in the stage of disease at the time of diagnosis. Furthermore, the rise in adenocarcinoma was not caused by an increase in bronchioloalveolar carcinoma, as was found in the United States. 10,11 Others have suggested that the increase in the incidence of adenocarcinoma in the United States was due to the increased use of low-tar filter cigarettes, especially since they only found an increase in adenocarcinoma among smokers. 6,12 The use of filters in longstanding smokers generally results in different inhalation behavior, for example, taking larger puffs and retaining smoke longer to compensate for the lower nicotine yield of filter cigarettes. The subsequent increased deposits of smoking particles in the bronchioles could enhance the risk for tumors in the peripheral lung zones, where the majority of pulmonary adenocarcinomas arise. 13 Furthermore, low-tar filter cigarettes may increase the risk for adenocarcinoma because of their higher nitrate content. 14 The percentage smoking low-tar filter cigarettes in the Netherlands has started to increase later than in the United States, but has steadily been increasing to 78% among male cigarette smokers and to 92% among female cigarette smokers in 1997 (derived from periodic surveys that were conducted for the Netherlands Foundation on Public Health and Smoking). Younger people in the Netherlands were more inclined to smoke low-tar filter cigarettes than the elderly. The change in exposure to filter cigarettes has been less marked for women, because smoking became popular among women only since the 1960s. They mainly smoked low-tar filter cigarettes and the proportion of adenocarcinoma remained considerably higher than for men during the whole study period.

While the prognosis for patients with the other histological subtypes of non-small-cell lung cancer remained unchanged, 8 we have searched for explanations for the decline in both the proportion with early disease and the survival rate for male patients with adenocarcinoma. Since peripheral lung tumors may give late signs, we wondered if the decrease in survival could be explained by the termination of the chest x-ray screening program for tuberculosis since the early 1980s. In a study among lung cancer patients diagnosed in Finland, mainly adenocarcinomas were detected during screening for tuberculosis, and screen-detected cancers had a favorable stage distribution and a better survival. 15 Termination of screening could explain the marked decrease in survival in the early study period. Our data, however, did not show the expected dip in incidence just after the termination of screening, and the survival of adenocarcinoma kept decreasing after 1980–1984, although less so. We hypothesize that, in addition to the effects of the termination of screening, the biological behavior of adenocarcinomas may have shifted toward a more rapidly metastasizing tumor. If so, this might be associated with the shift to smoking more low-tar filter cigarettes since the 1960s, especially by younger men. As indicated above, filter use could result in a deeper penetration of carcinogens in the peripheral lung zones. In this respect, cigarette smoke-induced K-ras mutations are of special interest; they are known to be associated especially with adenocarcinoma and are associated with a poor prognosis. 16–19

In the United States no decrease in survival of adenocarcinoma had occurred between 1978 and 1986, 20 but the increase in incidence of adenocarcinoma in the United States had mainly been caused by an increase in bronchioloalveolar carcinoma (with a fairly good prognosis), 10,11 which was not the case in the Netherlands. In short, the increased use of low-tar filter cigarettes may have been responsible for both the increased incidence and the decreased survival for adenocarcinoma of the lung.

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References

1. Janssen-Heijnen MLG, Nab HW, van Reek J, van der Heijden LH, Schipper R, Coebergh JWW. Striking changes in smoking behaviour and lung cancer incidence by histological type in the south-east Netherlands, 1960–1991. Eur J Cancer 1995; 31A: 949–952.

2. Vincent RG, Pickren JW, Lane WW, Bros I, Takita H, Houten L, Gutierrez AC, Rzepka T. The changing histopathology of lung cancer: a review of 1682 cases. Cancer 1977; 39: 1647–1655.

3. Wu AH, Henderson BE, Thomas DC, Mack TM. Changing patterns of lung cancer incidence by histological type. J Natl Cancer Inst 1986; 77: 53–56.

4. Devesa SS, Shaw GL, Blot WJ. Changing patterns of lung cancer incidence by histological type. Cancer Epidemiol Biomarkers Prev 1991; 1: 29–34.

5. Travis WD, Travis LB, Devesa SS. Lung cancer. Cancer 1995; 75 (suppl): 191–202.

6. Thun MJ, Lally CA, Flannery JT, Calle EE, Flanders WD, Heath CW. Cigarette smoking and changes in the histopathology of lung cancer. J Natl Cancer Inst 1997; 89: 1580–1586.

7. Levi F, Franceschi S, La Vecchia C, Randimbison L, Van-Cong T. Lung carcinoma trends by histologic type in Vaud and Neuchatel, Switzerland, 1974–1994. Cancer 1997; 79: 906–914.

8. Janssen-Heijnen MLG, Schipper RM, Klinkhamer PJJM, Crommelin MA, Mooi WJ, Coebergh JWW. Divergent changes in survival for histological types of non-small-cell lung cancer in southeastern Netherlands since 1975. Br J Cancer 1998; 77: 2053–2057.

9. Hakulinen T, Abeywickrama KH. A computer package for relative survival analysis. Computer Progr Biomed 1985; 19: 197–207.

10. Barkley JE, Green MR. Bronchioloalveolar carcinoma. J Clin Oncol 1996; 14: 2377–2386.

11. Barsky SH, Cameron R, Osann KE, Tomita D, Holmes EC. Rising incidence of bronchioloalveolar lung carcinoma and its unique clinicopathologic features. Cancer 1994; 73: 1163–1170.

12. Stellman SD, Muscat JE, Thompson S, Hoffmann D, Wynder EL. Risk of squamous cell carcinoma and adenocarcinoma of the lung in relation to lifetime filter cigarette smoking. Cancer 1997; 80: 382–388.

13. Morabia A, Wynder EL. Cigarette smoking and lung cancer cell types. Cancer 1991; 68: 2074–2078.

14. Hecht SS, Hoffmann D. Tobacco-specific nitrosamines, an important group of carcinogens in tobacco and tobacco smoke. Carcinogenesis 1988; 17: 116–128.

15. Hakama M, Holli K, Visakorpi T, Pekola M, Kallioniemi O-P. Low biological aggressiveness of screen-detected lung cancers may indicate over-diagnosis. Int J Cancer 1996; 66: 6–10.

16. Westra WH, Slebos RJ, Offerhaus GJ, Goodman SN, Evers SG, Kensler TW, Askin FB, Rodenhuis S, Hruban RH. K-ras oncogene activation in lung adenocarcinomas from former smokers. Evidence that K-ras mutations are an early and irreversible event in the development of adenocarcinoma of the lung. Cancer Res 1993; 72: 432–438.

17. Kern JA, Slebos RJC, Top B, Rodenhuis S, Lager D, Robinson RA, Weiner D, Schwartz DA. C-erbB-2 expression and codon 12 K-ras mutations both predict shortened survival for patients with pulmonary adenocarcinomas. J Clin Invest 1994; 93: 516–520.

18. Rodenhuis S, Boerrigter L, Top B, Slebos RJC, Mooi WJ, van ‘t Veer L, van Zandwijk N. Mutational activation of the K-ras oncogene and the effect of chemotherapy in advanced adenocarcinoma of the lung: a prospective study. J Clin Oncol 1997; 15: 285–291.

19. Nelson HH, Christiani DC, Mark EJ, Wiencke JK, Wain JC, Kelsey KT. Implications and prognostic value of K-ras mutation for early-stage lung cancer in women. J Natl Cancer Inst 1999; 91: 2032–2038.

20. Travis WD, Travis LB, Devesa SS. Histology of cancer incidence and prognosis: SEER population-based data, 1973–1987. Cancer 1995: 75: 191–202.

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Keywords:

cancer registry,; histology,; incidence,; lung neoplasms,; survival,; cigarettes,; smoking,; gender.

© 2001 Lippincott Williams & Wilkins, Inc.

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