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Acta Oncologica ISSN: 8-186X (Print) 1651-6X (Online) Journal homepage: http://www.tandfonline.com/loi/ionc Trends in the survival of patients diagnosed with cancers of the lip, oral cavity, and pharynx in the Nordic countries 196 3 followed up to the end of 6 Timo Hakulinen, Laufey Tryggvadóttir, Mette Gislum, Hans H. Storm, Freddie Bray, Åsa Klint & Gerda Engholm To cite this article: Timo Hakulinen, Laufey Tryggvadóttir, Mette Gislum, Hans H. Storm, Freddie Bray, Åsa Klint & Gerda Engholm (1) Trends in the survival of patients diagnosed with cancers of the lip, oral cavity, and pharynx in the Nordic countries 196 3 followed up to the end of 6, Acta Oncologica, 9:5, 561-577, DOI: 1.319/81869357537 To link to this article: https://doi.org/1.319/81869357537 Published online: 19 Feb 1. Submit your article to this journal Article views: 37 View related articles Citing articles: View citing articles Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalinformation?journalcode=ionc

Acta Oncologica, 1; 9: 561 577 ORIGINAL ARTICLE Trends in the survival of patients diagnosed with cancers of the lip, oral cavity, and pharynx in the Nordic countries 196 3 followed up to the end of 6 TIMO HAKULINEN 1, LAUFEY TRYGGVADÓTTIR,3, METTE GISLUM, HANS H. STORM, FREDDIE BRAY 5,6, ÅSA KLINT 7 & GERDA ENGHOLM 1 Finnish Cancer Registry, Pieni Roobertinkatu 9, FI-13 Helsinki, Finland, Icelandic Cancer Registry, Reykjavik, Iceland, 3 Department of Medicine, University of Iceland, Reykjavik, Iceland, Department of Cancer Prevention and Documentation, Danish Cancer Society, Copenhagen, Denmark, 5 Department of Clinical- and Registry-based Research, Cancer Registry of Norway, Oslo, Norway, 6 Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Norway and 7 Swedish Cancer Registry, National Board of Health and Welfare, Stockholm, Sweden Abstract Background. This is the first comprehensive population-based study on relative survival of lip, oral cavity and pharyngeal cancer in the Nordic countries. Material and methods. Relative survival of patients with cancers of the lip, oral cavity, and pharynx diagnosed in the Nordic countries in 196 3 and followed up to the end of 6 was studied and contrasted with trends in incidence and mortality. Results. There are marked differences in incidence between countries and over time. The stability of the relative survival ratios gives support to the hypothesis that the incidence differences are more likely to be real and not materially affected by differences in definitions and coding. Of particular note are the steep rises in pharyngeal cancer incidence in Denmark in both sexes. Survival has only moderately improved over time and has tended to be slightly higher in females than males. Conclusions. Co-morbidity caused by smoking and high alcohol consumption are likely to be partially responsible for differences between countries. Advances in therapy and standards of care are also likely to have played a role in the increasing survival trends. Key Words: Relative survival, excess mortality, cancer registry, population-based, pharyngeal cancer In the Nordic countries, cancers of the lip, oral cavity, and pharynx are relatively rare, accounting for about % of all new cancer cases observed in the Nordic countries in 6 [1]. The main known risk factors are smoking, oral tobacco consumption and alcohol, but the role of these factors varies greatly between the anatomic locations and sexes []. These risk factors, particularly smoking, result in patient co-morbidity which may impact on the relative survival differences between population groups. The role of HPV infection has been established as a risk factor, particularly for oropharyngeal cancer [3]. Rather little has been published thus far on the population-based survival experience of head and neck cancer patients in the Nordic countries. The EUROCARE studies [,5] have shown that the Nordic relative survival figures (with the occasional exception of Denmark) are among the highest observed in Europe. The aim of the present study is to describe and compare Nordic trends in relative survival and excess mortality of the patients from 196 3 to those of incidence and mortality, providing some basic interpretation of the findings. Material and methods The materials and methods are described in detail in an earlier article in this issue [6]. In brief, the Correspondence: Timo Hakulinen, Finnish Cancer Registry, Pieni Roobertinkatu 9, FI-13 Helsinki, Finland. E-mail: timo.hakulinen@cancer.fi (Received November 9; accepted 18 December 9) ISSN 8-186X print/issn 1651-6X online 1 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS) DOI: 1.319/81869357537

56 T. Hakulinen et al. 8 Incidence rates per 1 8 Incidence rates per 1 6 6 196 1969 197 1979 198 1989 199 1999 196 1969 197 1979 198 1989 199 1999 8 Mortality rates per 1 8 Mortality rates per 1 6 6 196 1969 197 1979 198 1989 199 1999 196 1969 197 1979 198 1989 199 1999 1 1 8 8 6 6 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 Figure 1. Trends in age-standardised (World) incidence and mortality rates per 1 and age-standardised (ICSS) 5-year relative survival for lip cancer by sex and country. Nordic cancer survival study 196 3. NORDCAN database contains comparable data on cancer incidence and mortality in the Nordic countries, as delivered by the national cancer registries, with follow-up information on death or emigration for each cancer patient available up to and including 6. Oral cavity and pharyngeal tumours were extracted according to ICD-1 for cancers of the lip (ICD-1 C), tongue (ICD-1 C1-), salivary glands (ICD-1 C7-8), mouth (ICD-1 C3-6), and pharynx (ICD-1 C9-1). Sex-specific 5-year relative survival was calculated for each of the diagnostic groups in each country for eight 5-year periods from 196 1968 to 1999 3. For the last 5-year period, so-called hybrid methods were used. Country-specific population mortality rates were used for calculating the

Nordic lip, oral and pharyngeal cancer survival 563 Table I. Trends in survival for lip cancer by sex and country. Number of tumours (N) included and the 5-year age- standardised (ICSS) relative survival in percent with 95% confidence intervals (RS (CI)). Nordic cancer survival study 196 3. N RS (CI) N RS (CI) N RS (CI) N RS (CI) N RS (CI) 196 1968 735 95 (89 11) 716 8 (76 9) 91 (76 19) 6 88 (8 9) 88 95 (9 11) 1969 1973 6 95 (89 11) 659 83 (77 89) 9 91 (76 19) 576 96 (91 1) 868 93 (89 98) 197 1978 79 95 (9 1) 675 8 (79 9) 31 8 (65 97) 535 93 (87 98) 887 93 (89 97) 1979 1983 69 95 (91 1) 655 93 (88 99) 6 8 (65 97) 75 89 (8 95) 886 9 (9 98) 198 1988 536 9 (89 99) 639 9 (87 98) 3 91 (7 11) 6 91 (86 96) 756 91 (87 95) 1989 1993 55 9 (89 1) 557 9 (87 98) 16 91 (7 11) 39 95 (89 11) 663 93 (89 97) 199 1998 1 93 (88 98) 51 86 (81 9) 11 96 9 (88 11) 597 9 (88 96) 1999 3 8 89 (8 9) 381 91 (87 95) 1 9 91 (86 97) 88 91 (88 95) 196 1968 6 89 (76 1) 59 7 (6 91) 3 99 (87 113) 88 88 (78 99) 1969 1973 6 15 (96 116) 81 9 (8 1) 9 99 (87 113) 8 98 (87 19) 197 1978 88 9 (79 13) 96 8 (7 9) 35 1 (86 116) 13 8 (7 96) 1979 1983 89 76 (66 87) 13 95 (88 1) 3 55 95 (8 18) 11 85 (77 9) 198 1988 7 91 (79 1) 17 95 (89 11) 75 81 (71 93) 189 9 (88 1) 1989 1993 11 95 (86 15) 18 9 (8 98) 17 89 (8 98) 19 91 (85 98) 199 1998 115 91 (83 11) 95 (89 11) 3 1 91 (8 1) 91 (86 97) 1999 3 113 87 (81 95) 199 97 (9 11) 8 9 (87 11) 83 9 (9 98) Numbers in italics indicate that two or more cells had to be combined to get sufficient number of patients to calculate survival. Too few patients to calculate survival, see ref. [6]. Excess deaths per 1 person years, men 1 month after diagnosis Excess deaths per 1 person years, men Excess deaths per 1 person years, men 5 years after diagnosis 3 3 3 1 1 1 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 Excess deaths per 1 person years, women 1 month after diagnosis Excess deaths per 1 person years, women Excess deaths per 1 person years, women 5 years after diagnosis 3 3 3 1 1 1 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 Figure. Trends in age-standardised (ICSS) excess death rates per 1 person years for lip cancer by sex, country, and time since diagnosis in Nordic cancer survival study 196 3.

56 T. Hakulinen et al. Table II. Trends in 5-year age-specific relative survival in percent after lip cancer by sex and country. Nordic cancer survival study 196 3. Age 9 5 59 6 69 7 79 8 89 9 9 5 59 6 69 7 79 8 89 9 Denmark 196 1968 95 96 9 9 16 11 13 13 81 85 8 1969 1973 97 99 1 9 85 13 13 13 11 8 1 197 1978 1 1 9 91 95 9 9 9 76 115 1979 1983 95 1 91 11 86 39 93 93 91 6 39 198 1988 1 13 87 9 9 19 95 95 86 91 89 1989 1993 97 98 88 89 18 171 97 97 99 91 9 199 1998 9 96 1 9 8 87 87 95 1 73 1999 3 91 95 96 86 7 13 96 96 8 93 73 139 Finland 196 1968 93 86 87 79 77 78 78 88 68 51 1969 1973 91 91 8 77 78 96 96 8 17 75 197 1978 96 9 85 79 73 1 1 8 66 8 1979 1983 91 9 91 1 91 99 99 98 9 96 198 1988 91 88 99 93 85 51 13 13 13 89 7 131 1989 1993 86 9 91 86 11 9 88 88 15 9 57 5 199 1998 86 86 96 88 68 98 98 1 91 79 1999 3 95 91 9 88 86 3 97 97 1 9 88 1 Iceland 196 1968 93 93 93 1 67 1969 1973 93 93 93 1 67 197 1978 81 81 81 88 6 1979 1983 81 81 81 88 6 198 1988 87 87 87 1 9 1989 1993 87 87 87 1 9 199 1998 17 17 17 5 1999 3 17 17 17 5 Norway 196 1968 1 93 93 88 6 7 1 1 98 9 15 1969 1973 97 9 93 9 17 78 1 1 98 9 15 197 1978 1 9 95 97 77 1 1 9 15 16 1979 1983 98 95 89 93 69 63 1 1 97 1 7 198 1988 9 96 99 86 76 68 11 11 85 68 61 6 1989 1993 88 9 99 91 1 93 93 93 9 7 199 1998 97 9 9 83 11 8 93 93 8 1 77 79 1999 3 91 88 93 83 16 17 95 95 9 1 75 16 Sweden 196 1968 95 95 97 99 86 18 13 13 9 89 5 1969 1973 96 97 93 9 9 9 9 95 11 96 197 1978 98 11 93 9 85 17 96 96 69 89 79 1979 1983 9 97 91 98 91 6 96 96 9 83 61 87 198 1988 1 95 98 91 67 96 93 93 1 91 81 5 1989 1993 1 91 96 91 86 1 96 96 89 9 9 35 199 1998 98 95 95 91 79 11 98 98 9 91 78 13 1999 3 99 9 86 91 9 39 98 98 9 9 89 97 Numbers in italics indicate that two or more cells had to be combined to get sufficient number of patients to calculate survival. Too few patients to calculate survival, see ref. [6]. expected survival. Age-standardisation used the weights of the International Cancer Survival Standard (ICSS) cancer patient populations [7]. We present age-standardised (World) incidence and mortality rates, 5-year relative survival, and excess mortality rates for the follow-up periods of within one month, 1 3 months and 5 years following diagnosis, as well as age-specific 5-year relative survival by country, sex and 5-year period. Except for lip cancer, agespecific 5-year relative survival is not shown for the Icelandic patients because of the small number of patients involved.

Nordic lip, oral and pharyngeal cancer survival 565. Incidence rates per 1. Incidence rates per 1 1.5 1.5 1. 1..5.5. 196 1969 197 1979 198 1989 199 1999. 196 1969 197 1979 198 1989 199 1999. Mortality rates per 1. Mortality rates per 1 1.5 1.5 1. 1..5.5. 196 1969 197 1979 198 1989 199 1999. 196 1969 197 1979 198 1989 199 1999 1 1 8 8 6 6 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 Figure 3. Trends in age-standardised (World) incidence and mortality rates per 1 and age-standardised (ICSS) 5-year relative survival for cancer of the tongue by sex and country. Nordic cancer survival study 196 3. Results Cancer of the lip Incidence and mortality. The age-standardised incidence of lip cancer in males has been in a marked and steady decline in all the Nordic countries for decades (Figure 1). In 1999 3, the observed decrease in Iceland appeared to cease, but this may also be due to the inherent random variation. In 3, the incidence rates were all between 1. and 1.6 per 1, the lowest in Sweden and the highest in Finland. At the beginning of the observation period, the incidence rates in females were considerably lower than those in males but, with declining rates in males and slightly increasing rates in females, the rates are approaching each other.

566 T. Hakulinen et al. Table III. Trends in survival for cancer of the tongue by sex and country. Number of tumours (N) included and the 5-year age-standardised (ICSS) relative survival in percent with 95% confidence intervals (RS (CI)). Nordic cancer survival study 196 3. N RS (CI) N RS (CI) N RS (CI) N RS (CI) N RS (CI) 196 1968 68 7 (18 ) 85 3 (8 66) 1 16 31 (3 3) 183 37 (9 6) 1969 1973 1 3 (3 9) 9 36 (3 56) 3 111 3 ( ) 1 1 (33 51) 197 1978 116 37 (6 5) 8 39 (3 5) 13 36 (6 8) 61 (3 5) 1979 1983 13 3 (1 3) 19 39 (3 5) 165 39 (3 5) 97 36 (9 5) 198 1988 188 5 (19 33) 13 3 ( ) 5 19 1 (33 5) 318 3 (35 51) 1989 1993 1 3 (16 3) 166 (3 53) 7 186 39 (3 51) 338 39 (33 6) 199 1998 313 3 (5 ) 18 (3 5) 9 36 (3 ) 39 7 (1 5) 1999 3 363 35 (3 ) 7 5 ( 59) 8 5 (39 51) 3 6 (1 51) 196 1968 68 9 ( 6) 96 55 (3 69) 6 75 (31 58) 15 9 ( 6) 1969 1973 71 9 ( 6) 8 53 ( 71) 5 88 (33 58) 155 55 (6 65) 197 1978 9 3 (5 6) 18 8 (39 6) 5 85 (33 59) 1 53 (6 6) 1979 1983 19 (3 5) 113 5 (36 56) 5 9 9 (38 6) 193 6 (38 55) 198 1988 1 3 (33 5) 1 53 ( 65) 135 8 (39 58) 31 9 (1 57) 1989 1993 17 5 ( 61) 157 61 (5 71) 6 17 6 (5 7) 7 5 ( 58) 199 1998 18 5 (37 55) 19 65 (57 7) 8 117 5 ( 63) 36 61 (5 68) 1999 3 187 6 ( 53) 1 67 (61 7) 8 1 59 (51 67) 37 58 (53 6) Numbers in italics indicate that two or more cells had to be combined to get sufficient number of patients to calculate survival. Too few patients to calculate survival, see ref. [6]. Excess deaths per 1 person years, men 1 month after diagnosis 1 Excess deaths per 1 person years, men 1 Excess deaths per 1 person years, men 5 years after diagnosis 1 1 1 1 1 1 1 8 8 8 6 6 6 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 Excess deaths per 1 person years, women 1 month after diagnosis 1 Excess deaths per 1 person years, women 1 Excess deaths per 1 person years, women 5 years after diagnosis 1 1 1 1 1 1 1 8 8 8 6 6 6 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 Figure. Trends in age-standardised (ICSS) excess death rates per 1 person years for cancer of the tongue by sex, country, and time since diagnosis in Nordic cancer survival study 196 3. No Icelandic curves. Too few patients to calculate rates for Iceland.

Nordic lip, oral and pharyngeal cancer survival 567 Table IV. Trends in 5-year age-specific relative survival in percent after cancer of the tongue by sex and country. Nordic cancer survival study 196 3. Age 9 5 59 6 69 7 79 8 89 9 9 5 59 6 69 7 79 8 89 9 Denmark 196 1968 1 38 7 68 6 7 5 3 1969 1973 3 7 3 3 68 6 7 5 3 197 1978 8 3 5 3 3 3 9 5 17 1 1979 1983 7 35 8 1 5 3 5 9 198 1988 8 33 7 5 33 5 9 1989 1993 33 3 17 1 19 9 56 9 5 199 1998 5 1 6 7 5 76 8 38 33 1999 3 5 6 9 37 13 79 53 7 36 9 Finland 196 1968 58 38 7 1 85 7 5 71 5 35 1969 1973 5 37 1 5 1 76 9 36 9 197 1978 36 5 7 58 5 6 7 11 1979 1983 36 5 7 7 7 36 56 11 198 1988 59 35 1 1 8 51 61 36 1989 1993 61 7 51 7 83 65 6 7 6 199 1998 57 59 31 5 3 76 66 68 67 3 1999 3 56 5 56 1 8 7 7 79 6 Norway 196 1968 68 5 5 18 16 58 58 51 16 8 1969 1973 3 5 3 15 51 51 6 3 19 197 1978 6 8 37 3 3 7 7 5 5 8 1979 1983 55 36 35 6 6 5 6 198 1988 68 7 35 3 6 6 51 39 3 1989 1993 59 37 31 69 69 73 9 55 188 199 1998 7 9 8 3 67 67 53 6 3 1999 3 55 59 51 1 16 7 7 6 58 3 Sweden 196 1968 7 5 33 33 1 63 6 38 7 7 1969 1973 6 3 8 5 35 9 59 6 38 197 1978 1 35 5 3 53 6 65 63 7 7 1979 1983 61 33 38 5 7 7 36 5 198 1988 7 5 37 36 53 69 6 55 5 3 89 1989 1993 6 5 31 39 8 6 71 57 3 36 199 1998 67 9 8 3 57 73 69 73 53 3 9 1999 3 71 5 6 36 77 6 6 53 36 5 Numbers in italics indicate that two or more cells had to be combined to get sufficient number of patients to calculate survival. Too few patients to calculate survival, see ref. [6]. Iceland not shown for the same reason. Mortality from lip cancer is quite minimal (Figure 1); the average annual number of deaths in the Nordic countries in 1999 3 due to this cancer being 17 and six in males and females, respectively. The mortality rates in males have decreased in the Nordic countries and appear to be approaching zero. In females, mortality rates have been consistently close to zero, on account of the rarity of the disease and the good prognosis of patients. Survival. The age-standardised 5-year relative survival ratios have been between 9% and 1% (Figure 1, Table I). Due to limited numbers the Icelandic female ratio could not be evaluated, and the figures presented for males are affected by random variation. In males, the excess death rates were higher in the first follow-up month than in the subsequent periods of follow-up (Figure ). There were no systematic inter-country differences. There was a tendency to observe somewhat poorer relative survival in patients aged 7 years or more (Table II). Some of the rates are higher than 1% due to zero observed deaths in the patient groups. This can result by chance where excess mortality is small or nonexistent and the patient groups are small.

568 T. Hakulinen et al.. Incidence rates per 1. Incidence rates per 1 1.5 1.5 1. 1..5.5. 196 1969 197 1979 198 1989 199 1999. 196 1969 197 1979 198 1989 199 1999. Mortality rates per 1. Mortality rates per 1 1.5 1.5 1. 1..5.5. 196 1969 197 1979 198 1989 199 1999. 196 1969 197 1979 198 1989 199 1999 1 1 8 8 6 6 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 Figure 5. Trends in age-standardised (World) incidence and mortality rates per 1 and age-standardised (ICSS) 5-year relative survival for cancer of the salivary glands by sex and country. Nordic cancer survival study 196 3. Cancer of the tongue Incidence and mortality. The incidence has increased quite rapidly in males during the entire period (Figure 3). During the last decade, the Danish rates have accelerated to a level much higher than those in the other countries. The Icelandic rates have been consistently the lowest among men in the Nordic countries, where age-standardised incidence rates range from.8 (Iceland) to 1.9 per 1 (Denmark) during the period 1999 3. In females, there is very little variation between the countries during the most recent two decades, although the Finnish rates have had a tendency of being higher than those in the other countries.

Nordic lip, oral and pharyngeal cancer survival 569 Table V. Trends in survival for cancer of the salivary glands by sex and country. Number of tumours (N) included and the 5-year agestandardised (ICSS) relative survival in percent with 95% confidence intervals (RS (CI)). Nordic cancer survival study 196 3. N RS (CI) N RS (CI) N RS (CI) N RS (CI) N RS (CI) 196 1968 139 56 (6 68) 63 3 (33 58) 6 5 (1 6) 19 51 (3 6) 1969 1973 115 5 (36 56) 59 3 (33 58) 71 5 (1 6) 15 56 (8 66) 197 1978 19 (31 53) 8 (33 58) 8 55 ( 69) 6 6 (53 71) 1979 1983 13 9 (38 63) 15 71 (58 88) 6 5 (37 67) 35 58 (5 67) 198 1988 119 (35 56) 96 7 (37 6) 3 69 58 ( 77) 31 69 (61 78) 1989 1993 11 61 (9 75) 97 55 ( 71) 18 65 (53 8) 6 65 (56 75) 199 1998 19 58 (9 7) 15 5 ( 63) 5 9 53 ( 66) 3 66 (59 7) 1999 3 1 56 (8 66) 18 58 (9 68) 9 11 57 (9 66) 6 6 (58 7) 196 1968 163 79 (68 9) 8 55 (3 71) 79 6 (51 7) 178 7 (6 8) 1969 1973 15 76 (66 87) 8 66 (5 79) 5 71 81 (68 96) 1 7 (6 81) 197 1978 75 63 (5 89) 96 59 (6 7) 57 75 (61 9) 36 79 (7 87) 1979 1983 96 5 ( 63) 98 59 (5 7) 75 76 (65 9) 9 83 (75 91) 198 1988 111 68 (58 81) 111 66 (56 77) 1 6 7 (6 8) 35 7 (67 81) 1989 1993 8 71 (58 86) 11 69 (59 8) 7 7 (6 8) 13 6 (55 71) 199 1998 113 6 (51 7) 118 66 (56 78) 5 93 63 (53 75) 1 73 (66 8) 1999 3 16 66 (58 76) 133 65 (58 7) 6 17 66 (57 76) 38 73 (67 79) Numbers in italics indicate that two or more cells had to be combined to get sufficient number of patients to calculate survival. Too few patients to calculate survival, see ref. [6]. Excess deaths per 1 person years, men 1 month after diagnosis 1 1 1 8 6 Excess deaths per 1 person years, men 1 1 1 8 6 Excess deaths per 1 person years, men 5 years after diagnosis 1 1 1 8 6 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 Excess deaths per 1 person years, women 1 month after diagnosis 1 1 1 8 6 Excess deaths per 1 person years, women 1 1 1 8 6 Excess deaths per 1 person years, women 5 years after diagnosis 1 1 1 8 6 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 Figure 6. Trends in age-standardised (ICSS) excess death rates per 1 person years for cancer of the salivary glands by sex, country, and time since diagnosis in Nordic cancer survival study 196 3. No Icelandic curves. Too few patients to calculate rates for Iceland.

57 T. Hakulinen et al. Table VI. Trends in 5-year age-specific relative survival in percent after cancer of the salivary glands by sex and country. Nordic cancer survival study 196 3. Age 9 5 59 6 69 7 79 8 89 9 9 5 59 6 69 7 79 8 89 9 Denmark 196 1968 86 71 53 5 1 97 85 8 7 7 1969 1973 51 71 56 9 99 88 69 8 197 1978 77 35 8 3 15 63 85 61 77 1979 1983 66 1 57 6 3 9 67 51 15 198 1988 81 55 3 6 3 81 56 68 78 53 1989 1993 75 6 59 73 9 6 95 83 6 79 1 199 1998 9 71 51 53 96 8 55 5 1999 3 87 7 63 91 76 66 6 5 Finland 196 1968 7 68 9 35 7 55 77 56 1969 1973 7 68 9 35 9 76 53 95 197 1978 65 67 37 5 87 69 5 5 55 1979 1983 71 85 87 67 38 79 66 63 73 198 1988 7 59 6 1 97 68 76 61 7 1989 1993 73 7 6 5 1 88 86 78 6 3 199 1998 83 9 5 59 1 9 1 68 7 1999 3 83 6 57 5 51 85 8 8 5 37 Norway 196 1968 8 61 53 5 19 95 69 78 61 1969 1973 8 61 53 5 19 9 8 85 88 8 197 1978 85 69 7 8 51 79 77 88 1979 1983 8 93 1 19 5 96 73 91 73 198 1988 8 71 61 6 1 9 75 7 7 8 1989 1993 8 7 67 53 69 9 75 7 7 8 199 1998 79 7 39 6 17 9 9 6 59 1999 3 87 86 56 7 9 77 69 61 37 Sweden 196 1968 87 5 58 55 9 85 79 55 53 1969 1973 93 67 59 51 9 78 73 71 5 197 1978 8 69 59 69 6 97 87 9 7 53 1979 1983 86 63 69 3 38 9 89 81 78 8 198 1988 8 7 71 66 57 89 89 83 69 37 1989 1993 91 6 7 55 56 91 7 57 6 3 199 1998 8 76 65 73 3 9 9 8 75 59 73 56 1999 3 75 71 71 6 39 95 7 81 61 63 39 Numbers in italics indicate that two or more cells had to be combined to get sufficient number of patients to calculate survival. Too few patients to calculate survival, see ref. [6]. Iceland not shown for the same reason. In Iceland, the rates before 198 were systematically higher in females than in males but the underlying numbers are small. The mortality rates show a much more modest increase in Danish males than seen in the incidence rates, while in the Norwegian trends, the mortality decrease apparent in men during 199 3, was not observed for incidence (Figure 3). Survival. The age-standardised 5-year relative survival ratios in Denmark have during the three last decades been below those observed in the other Nordic countries (Figure 3, Table III). Female patients tend to have higher survival compared to men, while the increases in survival over time also appear more rapid in females than in males. Danish patients tend to have higher excess death rates during the first three months than the patients in the other countries (Figure ). The excess death rates have stayed fairly constant over time during the first year of follow-up (data not shown for 3 1 months of follow-up). In the subsequent years of follow-up, rates have been lower. There is a tendency towards decreasing survival with advancing age at diagnosis (Table IV). Cancer of the salivary glands Incidence and mortality. The incidence rates in both sexes have stayed fairly constant over time in the last two decades, and there has been very little

Nordic lip, oral and pharyngeal cancer survival 571 5 Incidence rates per 1 5 Incidence rates per 1 3 3 1 1 196 1969 197 1979 198 1989 199 1999 196 1969 197 1979 198 1989 199 1999 5 Mortality rates per 1 5 Mortality rates per 1 3 3 1 1 196 1969 197 1979 198 1989 199 1999 196 1969 197 1979 198 1989 199 1999 1 1 8 8 6 6 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 Figure 7. Trends in age-standardised (World) incidence and mortality rates per 1 and age-standardised (ICSS) 5-year relative survival for cancer of the mouth by sex and country. Nordic cancer survival study 196 3. variation between countries (Figure 5). The agestandardised incidence rates have been around.6 per 1 in males and.5 in females. Before 198, a steep decline occurred in the rates in Denmark. The mortality rates conveyed a slightly decreasing trend with little systematic variation between countries, particularly among females (Figure 5). Survival. In males, the Swedish age-standardised 5-year relative survival ratios are somewhat higher than those in the other Nordic countries over the last two decades (Figure 5, Table V). There seems to be a slight upward tendency in the ratios in males, but overall they still have remained lower than those of females. The small frequencies in Iceland do not permit calculation of relative survival.

57 T. Hakulinen et al. Table VII. Trends in survival for cancer of the mouth by sex and country. Number of tumours (N) included and the 5-year age-standardised (ICSS) relative survival in percent with 95% confidence intervals (RS (CI)). Nordic cancer survival study 196 3. N RS (CI) N RS (CI) N RS (CI) N RS (CI) N RS (CI) 196 1968 13 38 (9 5) 8 39 (8 53) 6 153 36 (8 6) 3 9 ( 57) 1969 1973 9 5 (1 6) 81 39 (8 53) 17 36 (8 7) 368 9 ( 55) 197 1978 9 (35 51) 79 (9 5) 1 185 5 ( 6) 1 (37 9) 1979 1983 98 (35 51) 116 33 (5 ) 5 5 (37 5) 75 39 (3 5) 198 1988 361 (35 51) 137 6 (35 59) 9 59 6 (39 5) 55 (37 8) 1989 1993 8 36 (3 ) 15 (35 56) 1 8 3 (36 5) 518 7 (1 5) 199 1998 567 38 (33 5) 33 7 (38 57) 1 9 (38 5) 5 5 (5 55) 1999 3 6 1 (36 6) 65 3 (38 9) 13 5 8 ( 55) 78 5 (6 5) 196 1968 1 5 ( 6) 7 3 (33 56) 1 36 (6 8) 37 56 (9 6) 1969 1973 13 5 (3 63) 67 (31 56) 1 97 5 ( 65) 19 5 (6 6) 197 1978 18 53 (5 63) 97 51 (1 63) 1 17 67 (57 8) 73 5 (8 6) 1979 1983 8 9 ( 56) 17 8 (39 59) 9 15 57 (9 67) 8 59 (53 66) 198 1988 83 53 (7 6) 131 5 (3 63) 15 185 58 (51 66) 3 55 (9 61) 1989 1993 38 55 (9 6) 177 58 (5 68) 1 177 6 (5 7) 38 5 (8 6) 199 1998 35 51 (5 57) 19 6 (57 7) 19 56 ( 79) 61 (5 7) 3 61 (56 67) 1999 3 377 9 ( 5) 1 69 (63 75) 1 56 ( 79) 181 61 (55 68) 1 6 (56 6) Numbers in italics indicate that two or more cells had to be combined to get sufficient number of patients to calculate survival. Too few patients to calculate survival, see ref. [6]. Excess deaths per 1 person years, men 1 month after diagnosis 7 Excess deaths per 1 person years, men 7 Excess deaths per 1 person years, men 5 years after diagnosis 7 6 6 6 5 5 5 3 3 3 1 1 1 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 Excess deaths per 1 person years, women 1 month after diagnosis 7 Excess deaths per 1 person years, women 7 Excess deaths per 1 person years, women 5 years after diagnosis 7 6 6 6 5 5 5 3 3 3 1 1 1 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 Figure 8. Trends in age-standardised (ICSS) excess death rates per 1 person years for cancer of the mouth by sex, country, and time since diagnosis in Nordic cancer survival study 196 3.

Nordic lip, oral and pharyngeal cancer survival 573 Table VIII. Trends in 5-year age-specific relative survival in percent after cancer of the mouth by sex and country. Nordic cancer survival study 196 3. Age 9 5 59 6 69 7 79 8 89 9+ 9 5 59 6 69 7 79 8 89 9+ Denmark 196 1968 3 7 36 9 13 8 61 53 38 31 1969 1973 71 55 3 51 36 7 69 71 5 18 197 1978 6 3 3 3 58 66 58 5 9 1979 1983 8 39 3 6 67 6 73 198 1988 53 36 39 37 58 73 68 8 8 36 1989 1993 1 38 9 33 85 57 59 5 3 199 1998 5 3 35 8 59 53 5 1999 3 5 39 36 5 37 77 8 56 31 Finland 196 1968 69 35 9 3 71 71 53 6 1969 1973 69 35 9 3 63 63 56 9 197 1978 8 55 5 3 63 63 51 66 1979 1983 1 56 9 19 71 71 3 7 13 198 1988 55 6 1 9 5 69 69 6 3 1 1989 1993 55 1 8 39 1 6 6 79 5 199 1998 6 57 9 6 77 77 7 5 5 1999 3 57 5 5 8 86 86 6 6 5 7 Norway 196 1968 73 55 8 13 71 7 8 1 37 1969 1973 6 35 38 33 3 81 69 61 1 19 197 1978 66 6 3 8 8 5 68 6 1979 1983 9 56 5 1 76 77 5 5 33 5 198 1988 73 8 9 19 9 8 6 3 7 1989 1993 71 5 1 3 6 6 7 6 6 199 1998 75 55 36 37 35 7 61 6 61 6 1999 3 6 53 37 5 6 6 7 58 59 53 16 Sweden 196 1968 6 51 5 35 53 8 7 6 39 5 1969 1973 73 67 7 5 9 11 76 51 33 6 197 1978 63 39 7 39 9 76 7 55 37 6 1979 1983 59 38 6 35 18 83 68 67 55 7 198 1988 5 8 36 3 8 6 63 7 9 1989 1993 5 57 3 6 171 7 65 57 7 36 6 199 1998 7 58 5 39 63 7 76 6 5 51 51 1999 3 79 55 56 37 33 9 7 75 61 51 7 Numbers in italics indicate that two or more cells had to be combined to get sufficient number of patients to calculate survival. Too few patients to calculate survival, see ref. [6]. Iceland not shown for the same reason. There is a lot of random variation in the excess death rates, and no systematic differences between countries can be seen (Figure 6). The relative survival ratios are high in the youngest group, although they decline with advancing age at diagnosis (Table VI). Cancer of the mouth Incidence and mortality. Denmark has over time become the country with the highest incidence, with rates in men twice as high as those observed in the other Nordic countries (Figure 7). The temporal development has been quite heterogeneous in males between the countries. The increase in Denmark seems to have attenuated recently. In Norway and Sweden, the rates have been decreasing over the period 199 3. In Finland, the development is similar to Denmark, although in absolute terms, rates are at a much lower level, while rates in Iceland have not been substantively altered over the last years. Trends are similar in women, although the high incidence in Iceland is comparable to that among Danish women, with incidence and mortality rates similar between the sexes. The mortality rates display comparable patterns to the incidence rates but at a considerably lower level (Figure 7). Survival. The Danish age-standardised 5-year relative survival ratios have during the most recent years not

57 T. Hakulinen et al. 5 Incidence rates per 1 5 Incidence rates per 1 3 3 1 1 196 1969 197 1979 198 1989 199 1999 196 1969 197 1979 198 1989 199 1999 5 Mortality rates per 1 5 Mortality rates per 1 3 3 1 1 196 1969 197 1979 198 1989 199 1999 196 1969 197 1979 198 1989 199 1999 1 1 8 8 6 6 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 Figure 9. Trends in age-standardised (World) incidence and mortality rates per 1 and age-standardised (ICSS) 5-year relative survival for pharyngeal cancer by sex and country. Nordic cancer survival study 196 3. shown the increasing trends observed in the ratios for Finland, Norway and Sweden (Figure 7, Table VII). Overall, the ratios in females have tended to increase more rapidly with time than those for males. The excess death rates of the patients have by and large decreased in the first month (although there is a large degree of random variation) and in females 5 years after diagnosis in addition (Figure 8). There is no discernible decline in excess mortality during the second and third month after diagnosis. There is however a tendency for relative survival to decrease with advancing age at diagnosis (Table VIII). Cancer of the pharynx Incidence and mortality. The incidence has increased sharply in Denmark, and to a lesser extent in Norway and Sweden, while rates are reasonably stable in

Nordic lip, oral and pharyngeal cancer survival 575 Table IX. Trends in survival for pharyngeal cancer by sex and country. Number of tumours (N) included and the 5-year age-standardised (ICSS) relative survival in percent with 95% confidence intervals (RS (CI)). Nordic cancer survival study 196 3. N RS (CI) N RS (CI) N RS (CI) N RS (CI) N RS (CI) 196 1968 19 5 (19 33) 15 6 (1 5) 6 16 15 (1 1) 89 3 (19 8) 1969 1973 19 18 (13 5) 15 6 (15 6) 1 6 16 (1 ) 83 5 ( 31) 197 1978 31 7 (1 3) 196 3 (17 3) 1 13 19 (1 5) 55 1 (17 5) 1979 1983 373 3 (19 9) 176 3 (3 1) 9 3 17 (13 3) 6 5 (1 3) 198 1988 75 6 (1 33) 17 (15 8) 9 99 (17 31) 666 3 (6 3) 1989 1993 58 3 (19 8) 19 (15 7) 9 38 5 ( 33) 697 33 (9 37) 199 1998 693 31 (6 37) 38 3 ( ) 9 369 9 (5 35) 77 3 (3 38) 1999 3 97 3 (3 38) 39 38 (33 ) 16 39 33 (9 37) 831 36 (3 39) 196 1968 88 31 ( ) 8 1 (13 35) 76 17 (11 9) 83 5 (1 31) 1969 1973 8 31 ( 5) 96 3 (1 36) 8 3 ( 5) 5 9 (3 36) 197 1978 1 3 (1 ) 11 3 (16 3) 86 8 ( 39) 8 35 (3 1) 1979 1983 157 3 (7 ) 115 5 (18 36) 7 89 1 (1 3) 33 (7 39) 198 1988 175 6 (1 3) 9 3 (1 1) 1 1 36 (7 9) 58 36 (3 3) 1989 1993 (33 8) 9 39 (3 51) 79 38 (9 9) 38 1 (35 8) 199 1998 5 36 (3 ) 89 36 (7 9) 5 11 36 (7 7) 66 (38 5) 1999 3 38 3 (9 39) 18 51 (3 61) 1 136 3 (5 36) 99 5 (1 5) Too few patients to calculate survival, see ref. [6]. Excess deaths per 1 person years, men 1 month after diagnosis 15 Excess deaths per 1 person years, men 15 Excess deaths per 1 person years, men 5 years after diagnosis 15 1 1 1 5 5 5 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 Excess deaths per 1 person years, women 1 month after diagnosis 15 Excess deaths per 1 person years, women 15 Excess deaths per 1 person years, women 5 years after diagnosis 15 1 1 1 5 5 5 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 1968 1973 1978 1983 1988 1993 1998 3 Figure 1. Trends in age-standardised (ICSS) excess death rates per 1 person years for pharyngeal cancer by sex, country, and time since diagnosis in Nordic cancer survival study 196 3. No Icelandic curves. Too few patients to calculate rates for Iceland.

576 T. Hakulinen et al. Table X. Trends in 5-year age-specific relative survival in percent after pharyngeal cancer by sex and country. Nordic cancer survival study 196 3. Age 9 5 59 6 69 7 79 8 89 9 9 5 59 6 69 7 79 8 89 9 Denmark 196 1968 1 7 31 6 8 3 3 1 1969 1973 36 5 15 36 33 8 9 197 1978 51 9 35 11 37 6 3 19 6 1979 1983 6 31 15 8 55 3 6 198 1988 1 1 33 9 1 3 15 1989 1993 35 5 7 9 59 1 13 199 1998 8 3 5 9 31 5 36 6 1999 3 51 38 9 6 39 58 8 38 17 5 Finland 196 1968 33 16 3 1 67 9 1 15 3 1969 1973 6 18 5 1 7 37 17 6 9 38 197 1978 5 1 56 8 1 1979 1983 1 3 33 18 53 19 8 11 198 1988 51 18 6 13 65 1 6 1 1989 1993 6 8 16 17 6 6 3 199 1998 59 8 8 19 3 5 35 7 1999 3 63 51 38 37 7 75 63 59 3 Norway 196 1968 8 17 19 3 3 3 1 17 1969 1973 31 18 5 3 3 6 9 5 197 1978 36 35 19 1 5 5 3 1 1979 1983 3 6 15 13 37 37 31 7 198 1988 5 39 1 18 5 5 7 3 7 1989 1993 5 33 19 18 1 71 71 33 9 199 1998 6 5 31 16 9 7 7 3 3 35 1999 3 68 5 3 17 8 6 6 6 1 1 Sweden 196 1968 6 3 18 7 7 51 5 15 1969 1973 8 7 1 17 7 59 3 6 1 197 1978 3 19 16 1 83 8 9 3 16 1979 1983 5 9 16 7 7 38 36 7 198 1988 59 3 5 9 66 6 36 3 9 1989 1993 6 39 3 3 67 58 37 36 16 199 1998 59 9 1 19 11 76 58 5 36 1999 3 68 58 1 1 7 7 51 3 9 Numbers in italics indicate that two or more cells had to be combined to get sufficient number of patients to calculate survival. Too few patients to calculate survival, see ref. [6]. Iceland not shown for the same reason. Iceland and Finland (Figure 9). The age-standardised incidence rates in 1999 3 ranged in males from 1.7 in Finland and Iceland to.7 per 1 in Denmark. In females, rates range from.5 in Finland to 1.5 per 1 in Denmark. Mortality has been increasing only in Denmark, whereas rates have remained fairly stable during the last decades in the other countries (Figure 9). Survival. The age-standardised relative survival ratios have been steadily increasing over time in both sexes (Figure 9, Table IX). The survival of female patients has been higher than that of male patients. The differences between the countries were fairly unsystematic but the ratios in Sweden have had a tendency to be slightly higher than the others. No ratios from Iceland can be reported due to the small numbers of cases. The excess death rates of the patients have been the highest in the first month after diagnosis, where they have decreased markedly with time (Figure 1). No such decreases are observable in the other follow-up periods studied. The relative survival tends to be highest among the youngest patients (Table X). There have been increments in survival in all age groups and countries, although in some age groups this cannot be documented because of the small number of cases.

Nordic lip, oral and pharyngeal cancer survival 577 Discussion The survival of patients following a diagnosis of lip cancer is very high with a rather limited potential for further improvement in prognosis. There are few survival differences by country, sex, age, or time period. As well as solar radiation, smoking is a known risk factor for lip cancer and may cause some co-morbidity resulting in an excess risk of death among patients. The Icelandic figures should be interpreted with caution due to the extremely small numbers involved. The improvement in tongue cancer survival has been rather modest. The recent incidence peak in Denmark is not apparent in the relative survival even though the latter has been obtained by the hybrid method yielding the most up-to-date results. Continued follow-up will reveal whether the increase in incidence is accompanied by an increase in relative survival in Denmark, given the less dramatic changes in mortality. There has been very little improvement in relative survival of patients with cancer of the salivary glands with time, and the differences between countries are small. The trends may also be affected by coding practices; the clinical and morphological evaluation of mixed tumours (pleomorphic adenomas), their reporting and coding at the Finnish Cancer Registry have, for example, changed over time [8]. The stability of the relative survival ratios suggests that the increases in mouth and pharyngeal cancer incidence in Denmark are real and not primarily the result of differences in definitions or coding. The oral tumours form a heterogeneous group that may complicate comparisons. Smoking and alcohol are risk factors for oral cancers that may also have an effect on co-morbidity in a synergistic way, thus lowering the relative survival of the patients. Thus far, the higher consumption of oral tobacco in Sweden than in the other Nordic countries [9,1] is neither reflected in the incidence rates nor the relative survival ratios of the patients. Many recent advances in therapy together with new standards of care [11] are likely to play an important role in the observed increases in relative survival also in the Nordic countries. Also of particular clinical importance is the prognostic significance of the role of the HPV infection in squamous cell carcinomas of the oropharynx [3]. The HPVinfected patients have a better prognosis than those not infected [1]. Overall, patient survival has improved moderately in the Nordic countries. A likely continuation of the improvement may be expected with better targeted therapies. A lowering of risk and co-morbidity via primary prevention strategies that reduce the prevalence of smoking and alcohol in the Nordic populations presents a further challenge. Acknowledgement The Nordic Cancer Union (NCU) had financially supported the development of the NORDCAN database and program, as well as the survival analyses in this project. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References [1] Engholm G, Ferlay J, Christensen N, Bray F, Klint Å, Ólafsdóttir E, et al. (8). NORDCAN: Cancer incidence, mortality and prevalence in the Nordic countries, version 3.3. Association of Nordic Cancer Registries. Danish Cancer Society (http://www.ancr.nu). Accessed April 9. [] Mayne ST, Morse DE, Winn DM. Cancers of the oral cavity and pharynx. In: Schottenfeld D, Fraumeni JF Jr, editors. Cancer epidemiology and prevention. 3rd ed. Oxford: Oxford University Press; 6. pp. 67 96. [3] Fakhry C, Gillison ML. Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol 6; :66 11. [] Berrino F, Capocaccia R, Coleman MP, Estève J, Gatta G, Hakulinen T, et al., editors. Survival of cancer patients in Europe: the EUROCARE-3 Study. Ann Oncol 3;1: Suppl 5. [5] Verdecchia A, Guzzinati S, Francisci S, De Angelis R, Bray F, Allemani C, et al. Survival trends in European cancer patients diagnosed in 1988 to 1999. Eur J Cancer 9; 5:1 66. [6] Engholm G, Gislum M, Bray F, Hakulinen T. Trends in the survival of patients diagnosed with cancer in the Nordic countries 196 3 and followed up to the end of 6. Material and methods. Acta Oncol 1;9:55 6 [7] Corazziari I, Quinn M, Capocaccia R. Standard cancer patient population for age standardising survival ratios. Eur J Cancer ;:37 16. [8] Dickman PW, Hakulinen T, Luostarinen T, Pukkala E, Sankila R, Söderman B, et al. Survival of cancer patients in Finland 1955 199. Acta Oncol 1999;38:Suppl. 1. [9] Dreyer L, Winther JF, Pukkala E, Andersen A. Tobacco smoking. In: Olsen JH, Andersen A, Dreyer L, Pukkala E, Tryggvadottir L, Gerhardsson de Verdier M, et al. Avoidable cancers in the Nordic countries. APMIS 1997;15:Suppl 76:9 7. [1] Brennan P, Mucci L, Adami HO. Oral and pharyngeal cancer. In: Adami HO, Hunter D, Trichopoulos D, editors. Textbook of cancer epidemiology. nd ed. Oxford: Oxford University Press; 8. pp. 155 7. [11] Forastiere AA, Trotti A, Pfister DG, Grandis JR. Head and neck cancer: Recent advances and new standards of care. J Clin Oncol 6;:63 5. [1] Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, et al. Improved survival of patients with human papillomavirus positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 8;1:61 9.