Trends in the survival of patients diagnosed with malignant melanoma of the skin in the Nordic countries 1964–2003 followed up to the end of 2006

Abstract

A previous Nordic study showed a marked and steady increase in the age-adjusted 5-year relative survival of skin melanoma patients diagnosed during the period 1958 through 1987. Males had considerably poorer survival than females. Material and methods. Using the NORDCAN database, we studied relative survival and excess mortality of patients diagnosed with melanoma of the skin in the Nordic countries 1964–2003 followed up to the end of 2006. These were contrasted with concomitant trends in incidence and mortality. Results. The overall incidence of melanoma almost quadrupled, but there was considerable variation in the trends in the five countries. Mortality was low but doubled during the study period. Survival ratios increased steadily to between 80% and 90% for patients diagnosed in 1999–2003. Swedish patients had consistently higher survival, whereas Danish patients had the highest excess death rates the first three months after diagnosis up until 1990, but thereafter, rates reached a similar low level to that observed in the other Nordic countries. The survival of Nordic women is still higher than that of men, but the difference has diminished, while the mortality rates among men are becoming increasingly higher relative to those for women among individuals 50 years and older. In younger individuals, mortality rates are similar in the two sexes, and declining. Conclusions. Nordic patient survival following melanoma diagnosis is generally high and has been steadily increasing in the last decades. Differences in incidence between the five countries are more pronounced than the differences in survival. The strong upward trends in incidence and survival may mainly be the result of extensive changes in sunbathing habits or other UV exposure and, more recently, of an increasing awareness by the medical community and the public concerning early detection of melanoma of the skin.

Malignant melanoma of the skin (melanoma) was a rare disease in the Nordic countries 50 years ago, but the incidence has risen dramatically over time, and currently comprises 4% of all cancers in the Nordic countries and almost 2% of all cancer deaths. In 1999–2003, an average of 4 500 incident cancers were diagnosed yearly and nearly 1 000 deaths occurred due to melanoma [1]. The main known environmental risk factor is intermittent exposure to ultraviolet (UV) radiation, but the effects of UV radiation are highly dependent on skin type, and to a certain extent on inherited mutations [2,3]. Higher socioeconomic groups have higher incidence and higher survival ratios than lower socioeconomic groups [4].

The most important prognostic factors for melanoma patients are lymph node involvement and/or metastatic spread as well as the thickness of the lesion. Other important factors are gender, presence or absence of ulceration, age at diagnosis, and the anatomical location of the tumour [5]. The most common location among women is at the extremities, a location that is associated with higher survival ratios than the more typical locations among males, i.e. on the trunk, head and neck. Women have generally higher survival than men, but this cannot be explained entirely by the higher incidence of extremity location, lower stage at diagnosis or other more favorable primary tumour characteristics as compared with men [6–8].

The survival of European melanoma patients is generally high and does not vary greatly. Nordic patients have slightly higher 5-year survival than the European mean, which was 83% in the EUROCARE-4 study [9]. A previous Nordic study showed a marked and steady improvement in the age-standardised 5-year relative survival of patients diagnosed during the period 1958 through 1987, with little variation between the Nordic countries, especially towards the end of the period [10]. The aim of the present study is to describe, compare and interpret the Nordic trends in melanoma with respect to incidence, mortality and relative survival in patients diagnosed between 1964 and 2003, as well as examine excess mortality due to this cancer according to time elapsed from diagnosis.

Material and methods

Melanoma of the skin is here defined as ICD-10 code C43. The data source and methods are described in detail in an earlier article in this issue [11]. In brief, the NORDCAN database contains comparable data on cancer incidence and mortality in the Nordic countries; data are delivered by the national cancer registries, with follow-up information on death or emigration for each cancer patient available up to and including 2006. We calculated sex-specific 5-year relative survival for each of the diagnostic groups in each country for eight 5-year periods from 1964–1968 to 1999–2003. For the last 5-year period, the hybrid method was used. Country-specific population mortality rates were used for calculating the expected survival. Age-standardisation of survival used the weights of the International Cancer Survival Standard (ICSS) cancer patient populations [12]. 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, one to three months and two to five years following diagnosis, as well as age-specific 5-year relative survival by country, sex and 5-year period.

Results

Incidence and mortality

There was great variation in incidence between the five Nordic countries, especially among females. All countries experienced in the 40-year period an almost fourfold increase, resulting in an age-standardised incidence in the period 1999–2003, ranging between 9.0 (per 100 000, Finland) and 14.5 (Norway) among men, and between 7.8 (Finland) and 19.8 (Iceland) among women. The relative increase was similar among men and women. Until the end of the 1980s, Iceland and Finland had the lowest incidence among both sexes, since then however, rapid increases in rates were observed in Iceland (Figure 1). Norwegian men had the highest incidence rates across the entire period, while Icelandic women surpassed their Norwegian counterparts circa 1997 to exhibit the highest ranked incidence. In Norway, incidence has not increased among either sex since 1990.

Figure 1. Trends in age-standardised (World) incidence and mortality rates per 100 000 and age-standardised (ICSS) 5-year relative survival for malignant melanoma of the skin by sex and country. Nordic cancer survival study 1964–2003.

Mortality was low and more stable over time than incidence. However, there was a doubling of rates during the observation period, with the largest increase in Icelandic and Norwegian men. The mortality was highest among Norwegian men during the entire period, whereas Finnish and Icelandic men had the lowest rates. In 2003 mortality rates ranged from 2.0 (Iceland) to 3.9 (Norway) per 100 000 among men and from 1.0 (Finland) to 2.5 (Norway) per 100 000 among women. Even though incidence was similar in men and women throughout the period, all-ages mortality was higher among men and the sex-specific differences increased steadily with time.

Survival

The relative survival ratios of Nordic patients diagnosed with melanoma were high and have been steadily increasing. For the last period of diagnosis (1999–2003) the survival ratios ranged between 78% and 93% among men and between 88% and 92% in women (Figure 1 and Table I). Swedish patients have consistently had the highest survival ratios over calendar time, whereas Finnish and Danish patients have had the lowest survival. Due to the small numbers of Icelandic patients, it was not possible to estimate survival ratios until the most recent years, and these are difficult to interpret given the underlying random variation. Women had higher age-standardised 5-year relative survival ratios than men, but as the ratios among men increased relatively more, the sex-specific differences diminished with time.

Table I. Trends in survival for malignant melanoma of the skin 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 1964–2003.

	Denmark		Finland		Iceland		Norway		Sweden
	N	RS (CI)	N	RS (CI)	N	RS (CI)	N	RS (CI)	N	RS (CI)
Men
1964–1968	445	40 (35–46)	297	40 (34–47)	7	*	453	47 (42–53)	941	58 (54–62)
1969–1973	561	50 (45–56)	412	43 (37–50)	7	*	660	54 (49–59)	1254	60 (57–63)
1974–1978	852	59 (55–63)	556	58 (53–63)	13	*	920	65 (61–69)	1708	67 (65–70)
1979–1983	1050	65 (62–69)	756	68 (63–72)	25	*	1162	68 (65–72)	2161	73 (71–76)
1984–1988	1333	69 (65–72)	1086	74 (70–77)	20	*	1478	71 (69–74)	2903	76 (74–78)
1989–1993	1667	72 (69–75)	1199	79 (76–82)	29	*	2050	76 (74–78)	3393	84 (82–85)
1994–1998	2036	78 (76–81)	1434	77 (74–80)	63	72 (61–85)	2245	78 (76–80)	3804	84 (83–86)
1999–2003	2439	80 (78–82)	1701	82 (80–85)	90	93 (89–98)	2359	78 (77–80)	4256	86 (85–88)
Women
1964–1968	756	66 (62–71)	369	55 (50–61)	17	*	533	73 (68–78)	1066	76 (73–80)
1969–1973	866	69 (66–73)	499	63 (58–69)	17	*	715	73 (69–77)	1528	77 (74–79)
1974–1978	1204	75 (72–78)	682	73 (69–77)	30	82 (72–93)	1170	82 (79–85)	1951	81 (79–83)
1979–1983	1522	80 (78–83)	936	80 (77–83)	40	82 (72–93)	1466	82 (80–85)	2403	85 (83–86)
1984–1988	1810	82 (80–85)	1170	85 (82–87)	40	84 (76–92)	1932	86 (84–88)	3000	88 (86–89)
1989–1993	2224	85 (83–87)	1251	83 (81–86)	60	84 (76–92)	2340	89 (88–91)	3523	90 (89–91)
1994–1998	2577	88 (86–90)	1406	86 (84–88)	94	91 (85–97)	2471	89 (87–90)	3942	92 (91–93)
1999–2003	3013	90 (89–91)	1684	89 (87–90)	161	91 (85–97)	2633	88 (87–90)	4273	92 (91–93)

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 reference [11].

In the earlier periods, Denmark had a much higher excess death rate during the first three month after diagnosis, more notable for men than for women, but in the mid-1990s Denmark reached a level similar to the other Nordic countries (Figure 2). Sweden and Iceland had the lowest excess mortality during the first three months. The excess death rates became very similar across countries two to five years after diagnosis. Over the entire study period, a reduction in excess death rates during the first three months was observed in all countries, and a reduction was also apparent, albeit to a lesser extent, in the longer term in rates. The excess deaths per 100 person years were consistently higher among men than women,an observation noted soon after diagnosis, and one that was still seen 2-5 years after diagnosis. As shown in Table II the 5-year age-specific relative survival was highest in the youngest group and declined with advancing age in all countries throughout the period, but increase was seen in all age-groups over time.

Figure 2. Trends in age-standardised (ICSS) excess death rates per 100 person years for malignant melanoma of the skin by sex, country, and time since diagnosis in Nordic cancer survival study 1964–2003.

Table II. Trends in 5-year age-specific relative survival in percent after malignant melanoma of the skin by sex and country. Nordic cancer survival study 1964–2003.

	Men						Women
Age	0–49	50–59	60–69	70–79	80–89	90+	0–49	50–59	60–69	70–79	80–89	90+
Denmark
1964–1968	48	38	35	37	34	*	73	64	66	64	41	*
1969–1973	50	53	47	53	46	*	78	77	63	54	58	0
1974–1978	67	50	55	54	63	*	81	77	75	60	70	0
1979–1983	73	65	64	54	56	0	88	83	80	69	60	29
1984–1988	76	69	68	60	47	0	88	83	87	72	67	40
1989–1993	81	74	61	68	59	101	91	90	84	78	60	45
1994–1998	86	83	77	64	64	0	94	87	88	83	72	68
1999–2003	87	83	80	68	66	46	93	91	87	89	78	57
Finland
1964–1968	47	39	43	40	0	*	65	71	50	47	0	*
1969–1973	46	52	33	39	43	*	69	68	57	61	48	*
1974–1978	61	65	53	60	31	*	84	80	68	62	34	*
1979–1983	71	75	71	64	30	*	90	80	76	74	54	59
1984–1988	79	80	66	72	57	75	92	87	82	76	70	0
1989–1993	82	78	77	78	78	70	91	88	80	75	61	0
1994–1998	82	80	78	65	64	110	92	88	84	82	68	51
1999–2003	87	85	81	75	74	62	94	91	89	83	69	104
Iceland
1964–1968	75	75	75	26	*	*	81	69	66	40	*	*
1969–1973	75	75	75	26	*	*	81	69	66	40	*	*
1974–1978	56	56	56	*	79	*	101	95	64	57	63	*
1979–1983	56	56	56	*	79	*	101	95	64	57	63	*
1984–1988	74	74	74	45	*	*	95	71	81	106	20	*
1989–1993	74	74	74	45	*	*	95	71	81	106	20	*
1994–1998	81	81	81	48	29	*	97	86	92	92	70	*
1999–2003	97	97	97	88	69	*	97	86	92	92	70	*
Norway
1964–1968	61	40	42	25	59	*	79	74	72	66	58	0
1969–1973	62	55	49	44	44	0	83	74	71	65	42	*
1974–1978	76	72	68	41	29	0	89	85	80	74	62	43
1979–1983	73	72	64	56	74	0	91	85	79	72	63	128
1984–1988	81	75	70	61	41	158	92	89	85	77	69	76
1989–1993	84	81	77	63	47	31	94	90	91	83	75	52
1994–1998	86	77	80	72	51	74	95	92	86	82	76	87
1999–2003	85	79	78	69	67	81	93	92	86	79	80	95
Sweden
1964–1968	65	58	55	53	42	0	84	76	73	64	77	0
1969–1973	71	65	60	43	23	0	88	83	72	61	51	88
1974–1978	78	72	65	48	54	83	87	85	78	73	66	85
1979–1983	78	75	72	66	62	0	89	86	86	78	68	38
1984–1988	85	78	74	68	51	120	92	89	89	83	68	37
1989–1993	88	87	81	81	67	76	96	91	89	86	70	87
1994–1998	89	88	85	79	61	38	96	94	91	88	75	70
1999–2003	91	87	86	81	73	37	95	93	91	87	83	64

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 reference [11].

In Figure 3, the incidence and mortality trends (on a logarithmic scale) are shown separately for individuals below age 50 years, and 50 years and older. There have been considerably more pronounced changes in the older group with time, where the incidence in males and females has at least quadrupled and mortality doubled in both sexes. This contrasts with the trends in the younger group; the increase in incidence was threefold in both sexes while the mortality slightly decreased in men and women since circa 1989.

Figure 3. Trends in Nordic age-standardised (World) incidence and mortality rates per 100 000 by sex and by ages below and above 50 years. Nordic cancer survival study 1964–2003.

Discussion

In this large population-based study we found that the incidence of malignant melanoma in the Nordic countries almost quadrupled and the mortality doubled between 1964 and 2003, and was highest in Norwegian men. Relative survival improved markedly and is currently between 80% and 90%. It has remained consistently higher in women than men over time, although the differences have diminished.

The survival of melanoma patients has also been increasing for several decades in Australia, the US and in a number of European populations, a finding which has been mainly attributed to the raised public awareness due to educational programmes focusing not only on primary prevention, but also on the importance of skin examination in order to detect potential changes in moles (melanocytic naevi) and bringing them to the attention of doctors or dermatologists. This has led to increased diagnostic activity and earlier diagnosis in those countries [13,14].

Advances in the treatment of malignant cutaneous melanoma are likely to explain a much smaller part of the worldwide increased survival, as no dramatic changes have occurred. The standard treatment consists of a wide local excision, with or without sentinel lymph node biopsy, based on thickness of the lesion [15]. However, a small fraction of the increase may be attributed to advances in treatment, such as sentinel node biopsy and adjuvant treatment [16] and some of the increase may be due to lead time bias occurring when an earlier diagnosis does not affect the timing of death, and length bias which occurs because of an increasing inclusion of indolent cancers that would never have been life threatening [17].

Swedish patients had consistently the highest survival ratios relative to the other Nordic countries during the entire study period. It is likely that an important role is played by the establishment of the Swedish Melanoma Study Group in 1976, which had the objective of creating national guidelines for melanoma diagnosis, treatment and follow-up [18] and also by the establishment of public educational programmes in Sweden [19]. However, the reasons behind the survival also being highest in Sweden before the onset of those programmes are not obvious. The Swedish Cancer Registry does not register death certificate-initiated cases, but it is likely that this could only explain a small amount of the survival differences observed between Sweden and the other Nordic countries, since skin melanoma is rarely seen to be death-certificate initiated in the other Nordic countries.

The excess mortality in Denmark during the first months after diagnosis was well above that of the other countries, most notably among males, until around year 1990; thereafter excess death rates had reached a level similar to the other countries. The excess mortality has declined considerably in all countries during the past 40 years, especially within the first three months following diagnosis.

The most dramatic changes in incidence were observed in Iceland, a geographical area that has a low background UV radiation due to the northern latitude and frequent cloud cover. The increase is most notable from the late-1980s, and among women. This may partly result from a very high prevalence of sun bed use in Iceland, as well as a large increase in travel abroad to southern areas during the past four decades and partly because of increased diagnostic activity due to a nationwide cancer prevention programme which came into action in 1990 [20].

There were only minor differences between the sexes in the overall incidence in the Nordic countries throughout the period, but the mortality was higher among men and the sex-specific differences increased steadily with time. However, this was only seen in diagnoses at ages 50 and older, and the increase in mortality was also confined to this group. In the younger age groups there has been a slight decrease in mortality among both sexes since circa 1989. This favorable development among the young is noteworthy, especially since a relatively high proportion of deaths among melanoma patients occurs under 50 years of age because of a relatively low age at diagnosis. Among Nordic persons who died from melanoma in 1999–2003, about 14% were younger than 50 years (compared to 5% under 50 years when considering deaths from all types of cancer taken together [1]).

Contrasting mortality trends in younger and older age groups have previously been reported from other populations [21,22] and have been attributed to stronger influence on the younger generations of the educational programmes aiming at increased awareness of the precursors of malignant melanoma [21,23, 24].

Not enough is known about similar educational programmes in the Nordic countries except for Sweden [19]. However, it is likely that the internationally raised knowledge has also led to increased awareness among health professionals and the public in all the Nordic countries, but probably with considerable variations between countries in extent and timing.

A limitation of this study is the lack of information on stage and thickness of the tumours, as well as the body location. However, we found that the relative proportion of superficial spreading melanomas has been increasing during the study period, although to a different extent within countries (data not shown), which could indicate that the incidence increase may be associated with a relative increase of thin melanomas. The median melanoma thickness decreased significantly in Sweden between 1976 and 1987 [19], and in 1990–1999 [18]. It has been shown that a public education campaign in Scotland in 1985 was followed by a reduction in the absolute number of thick tumours as well as melanoma-related mortality [25].

Increased awareness among both the public and health professionals is likely to be strongly associated with the survival improvements during the past 20–30 years in the Nordic countries, but information is lacking. It is of great importance to study in detail the current status, and if possible to what extent the awareness has changed with time, and compare with the detailed sex- and age-specific changes with time in relative survival, incidence and mortality, according to thickness and body location of the tumours.

It can be concluded that Nordic patient survival following melanoma diagnosis is generally high and has been steadily increasing in the last decades. Differences in incidence between the five countries are more pronounced than the differences in survival. Improved understanding is needed of the forces behind those changes and of the status of the public knowledge about naevi, skin cancer and melanoma in the Nordic countries, in order to be better able to prevent further deaths from malignant melanoma.

Acknowledgements

The Nordic Cancer Union (NCU) has financially supported the development of the NORDCAN database and programme, 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.