Late and very late mortality in 5-year survivors of childhood cancer: changing pattern over four decades--experience from the Nordic countries.

Long-term survivors of childhood cancer suffer from a higher mortality than the general population. Here we evaluate late and very late mortality, and patterns of causes of death, in 5-year survivors after childhood and adolescent cancer in cases diagnosed during four decades in the five Nordic countries. The study is population-based and uses data of the nationwide cancer registries and the cause of death registers. There were in all 37,515 incident cases, diagnosed with cancer before the age of 20 years, between 1960 and 1999. The 5-year survivor cohort used in the mortality analyses consisted of 21,984 patients who were followed up for vital status until December 31, 2005 (Norway, Sweden) or 2006 (Denmark, Finland, Iceland). At the latest follow-up, 2,324 patients were dead. The overall standardized mortality ratio was 8.3 and the absolute excess risk was 6.2 per 1,000 person-years. The pattern of causes of death varied markedly between different groups of primary cancer diagnosis, and was highly dependent on time passed since diagnosis. With shorter follow-up the mortality was mainly due to primary cancer, while with longer follow-up, mortality due to second cancer and noncancer causes became more prominent. Mortality between 5 and 10 years after diagnosis continued to decrease in patients treated during the most recent period of time, 1990-1999, compared to previous periods, while mortality after 10 years changed very little with time period. We conclude that improvement of definite survival demands not only reducing early but also late and very late mortality.

Radiotherapy and tamoxifen after mastectomy in postmenopausal women -- 20 year follow-up of the South Sweden Breast Cancer Group randomised trial SSBCG II:I.

AIMS: To evaluate long-term effects of radiotherapy and tamoxifen after mastectomy on recurrence and survival in stage II breast cancer. METHODS: A randomised phase III study with three treatment alternatives. (1) Radiotherapy 50 Gy/25 fractions to chest wall and regional lymph nodes (RT). (2) Radiotherapy and tamoxifen 30 mg/day for one year (RT+tam) and 3. Tamoxifen (tam). RESULTS: 724 postmenopausal women were included between 1978 and 1985 and the trial was close to population based. Follow-up for survival was 23 years. Locoregional recurrences were reduced from 18.5% in the tam arm to 5.3% in the RT+tam arm. Overall mortality at 20 years was 71% in the RT arm, 68% in the RT+tam arm and 62% in the tam arm. The difference between RT+tam and tam was not significant except in the receptor positive subgroup in favour of non-irradiated patients (p=0.047). The cumulative incidence of systemic disease at 20 years was lower in the RT+Tam arm than in the RT arm, 40% versus 50% (p=0.047). CONCLUSION: Postmastectomy radiotherapy significantly reduced loco-regional recurrences, but overall survival was not improved. At 20 years, a lower mortality was recorded for non-irradiated patients treated with tam.

[Strongly increasing incidence of adenocarcinoma of the esophagus and gastric cardia]. / Adenocancer i esofagus och ventrikelns kardiaregion ökar kraftigt.

The objective of this retrospective study was to see whether there was an increasing incidence of adenocarcinoma of the oesophagus and gastric cardia in the Swedish population 1970-1997. If there was, could it be explained as a period or cohort phenomenon? The data were compared with the incidence of squamous cell carcinoma and gastric adenocarcinoma with the gastric cardia excluded. Age standardised incidence for each sex was calculated using the age distribution of the world population as a reference. For the combined group of adenocarcinoma in the oesophagus and gastric cardia incidence gradually increased during the study period. The median increase between adjacent five-year intervals was 14% in men and 20% in women. Previously described risk factors are gastro-oesophageal reflux, obesity and smoking. This study suggests that the increasing incidence also can be explained as a shift in classification from squamous cell carcinoma to adenocarcinoma after 1985.

[Cancer in siblings of children with cancer]. / Cancer hos søskende til børn med cancer.

INTRODUCTION: In some rare inherited disorders, such as Li-Fraumeni syndrome, relatives of children with cancer are at increased risk of cancer. We aimed to assess relations between childhood cancer and sibling risk, and evaluate the influence of recessive conditions in cancer causation. MATERIAL AND METHODS: We did a population-based cohort study in the Nordic countries of 42,277 siblings of 25,605 children with cancer. Children with cancer were identified from records in the five Nordic cancer registries, and their siblings from nationwide population registries. Cancers in siblings were documented through record linkage with cancer registries and compared with national incidence rates. We also assessed cancer incidence in parents to identify familial cancer syndromes. RESULTS: 284.2 cancers were expected in siblings, whereas 353 were diagnosed (standardised incidence ratio 1.24 95% CI, 1.12-1.38). Risk ratios for siblings were highest in the first decade of life (2.59; 1.89-3.46). We excluded 56 families with genetic syndromes linked to cancer, which reduced this ratio from 1.7 to 1.0 (0.7-1.3) for siblings younger than 20 years and from 1.3 to 1.0 (0.8-1.3) for those aged 20-29 years. We found no new patterns of familial cancer that indicated inherited susceptibility, or evidence that recessive conditions might contribute to cancers not explained by syndromes. 40% of cancers in siblings that occurred before age 20 years could be attributed to known genetic factors, whereas 60% remained unexplained. DISCUSSION: Apart from rare cancer syndromes, paediatric cancer is not an indicator of increased risk in siblings.

Second malignant neoplasms in digestive organs after childhood cancer: a cohort-nested case-control study.

PURPOSE: Cancers of the digestive system constitute a major risk for childhood cancer survivors treated with radiotherapy once they reach adulthood. The aim of this study was to determine therapy-related risk factors for the development of a second malignancy in the digestive organs (SMDO) after a childhood cancer. METHODS AND MATERIALS: Among 4,568 2-year survivors of a childhood solid cancer diagnosed before 17 years of age at eight French and British centers, and among 25,120 patients diagnosed as having a malignant neoplasm before the age of 20 years, whose data were extracted from the Nordic Cancer Registries, we matched 58 case patients (41 men and 17 women) of SMDO and 167 controls, in their respective cohort, for sex, age at first cancer, calendar year of occurrence of the first cancer, and duration of follow-up. The radiation dose received at the site of each second malignancy and at the corresponding site of its matched control was estimated. RESULTS: The risk of developing a SMDO was 9.7-fold higher in relation to the general populations in France and the United Kingdom. In the case-control study, a strong dose-response relationship was estimated, compared with that in survivors who had not received radiotherapy; the odds ratio was 5.2 (95% CI, 1.7-16.0) for local radiation doses between 10 and 29 Gy and 9.6 (95% CI, 2.6-35.2) for doses equal to or greater than 30 Gy. Chemotherapy was also found to increase the risk of developing SMDO. CONCLUSIONS: This study confirms that childhood cancer treatments strongly increase the risk of SMDO, which occur only after a very long latency period.

Efficient reduction of loco-regional recurrences but no effect on mortality twenty years after postmastectomy radiation in premenopausal women with stage II breast cancer - a randomized trial from the South Sweden Breast Cancer Group.

PURPOSE: To study long term loco-regional and distant recurrence rate and survival after post-mastectomy radiotherapy in combination with oral cyclophosphamide in premenopausal women with stage II breast cancer. STUDY DESIGN: A three-armed randomized multicenter phase III trial comparing 1) Radiotherapy (RT) 2) RT+ oral cyclophosphamide for one year (RT+C) and 3) Oral cyclophosphamide only (C). Radiotherapy was administered, in 20 fractions, to 48Gy to the axilla and parasternal lymph nodes, 45Gy to infra- and supraclavicular fossae and 38Gy to the chest wall. Cyclophosphamide was prescribed as 12 courses of 130mg/m(2) od for 14 days every 4 weeks. PATIENTS AND METHODS: 367 patients from 15 surgical departments in Southern Sweden, representing 80% of all eligible patients, were included in the trial between 1978-1983. Median age was 47 years, median tumour size was 25mm, and 33% of the patients were lymph node negative. Median follow-up time was 24 years. RESULTS: RT reduced the risk at twenty years for loco-regional recurrence in C-treated patients at twenty years with 75% (13.9% vs. 3.5%). The risk reduction was highly significant in both N0 and N+ patients. No reduction in systemic disease or mortality was observed. CONCLUSION: Post-mastectomy radiotherapy reduced loco-regional recurrences in this premenopausal population, but no effect was seen on mortality with 20 years follow-up.

Lifelong cancer incidence in 47,697 patients treated for childhood cancer in the Nordic countries.

BACKGROUND: The pattern of cancer in long-term survivors from childhood cancer has not been investigated comprehensively. METHODS: We obtained a cohort of 47,697 children and adolescents aged 0-19 years with cancer as defined by the country-wide cancer registries of Denmark, Finland, Iceland, Norway, and Sweden during 1943-2005. Cohort members were followed through age 79 years for subsequent primary cancers notified to the registries, and the age-specific risk pattern of the survivors was compared with that of the national populations using country and sex standardized incidence ratios (SIRs). We used a multiplicative Poisson regression model to estimate relative risk of cancer for attained age, with adjustment for calendar period and age at diagnosis of primary cancer. We also calculated excess absolute risk (EAR) attributable to status as childhood cancer survivor and determined the cumulative incidence of second primary cancer as a function of attained age for three subcohorts defined by period of treatment for childhood cancer. RESULTS: A total of 1180 asynchronous second primary cancers were observed in 1088 persons, yielding an overall SIR of 3.3 (95% confidence interval = 3.1 to 3.5). The relative risk was statistically significantly increased in all age groups, even for cohort members approaching 70 years of age. The EAR for second primary cancer among survivors increased gradually from one additional case per 1000 person-years of observation in early life to six additional cases per 1000 person-years in the age group 60-69 years. For children treated in the prechemotherapy era (1943-1959), the cumulative risk for a second primary cancer reached 18%, 34%, and 48% at ages 60, 70, and 80 years, respectively. The age-specific incidence rates were highest for cohort members treated in the era of intensive, multiple-agent chemotherapy (1975-2005). CONCLUSION: Survivors of childhood cancer have a persistent excess risk for a second primary cancer throughout their lives, accompanied by continuous changes in the risk of cancers at specific sites.

What's new in target volume definition for radiologists in ICRU Report 71? How can the ICRU volume definitions be integrated in clinical practice?

The optimal definition of the size, shape and location of gross tumour volume is one of the most important steps in the planning of radiation therapy, and necessitates a proper understanding of the procedure from both the oncologic radiologist and the radiation oncologist. This overview reports on the different terms and concepts that have been recommended in the ICRU Reports for this purpose; the latest Report 71 focuses on both previously given recommendations, and especially on electron beam therapy. This paper also highlights some of the problems that are encountered in the use of the International Commission on Radiation Units and Measurements (ICRU) recommendations in clinical practice, and at the interface between the radiation oncologist and the diagnostic oncologist.

Survival from rare cancer in adults: a population-based study.

BACKGROUND: Rare cancers are a challenge to clinical practice, and treatment experience, even in major cancer centres to which rare cancers are usually referred, is often limited. We aimed to study the epidemiology of rare cancers in a large population of several countries. METHODS: We analysed survival by age, sex, subsite, and morphology in 57,144 adults with 14 selected rare cancers diagnosed 1983-94. Variations in survival over time and between European regions were also assessed for variations in quality of care. We also estimated the adjusted relative excess risk of death for every rare cancer. FINDINGS: Overall 5-year relative survival was good (ie, >65%) for placental choriocarcinoma (85.4% [95% CI 81.4-89.5]), thyroid medullary carcinoma (72.4% [69.2-75.5]), ovarian germ-cell cancer (73.0% [70.0-76.0]), lung carcinoid (70.1% [67.3-72.9]), and cervical adenocarcinoma (65.5% [64.3-66.6]); intermediate (ie, 35-65%) for testicular cancer at age 65 years or older (64.0% [59.3-68.7]), sarcoma of extremities (60.0% [58.9-61.2]), digestive-system endocrine cancers (55.6% [54.9-56.3]), anal squamous-cell carcinoma (53.1% [51.5-54.8]), and uterine sarcoma (43.5% [42.0-44.9]); low for carcinoma of adrenal-gland cortex (32.7% [28.3-37.2]) and bladder squamous-cell carcinoma (20.4% [18.8-22.0]); and poor for angiosarcoma of liver (6.4% [1.8-11.0]) and mesothelioma (4.7% [4.3-5.2]). Survival was usually better for women than men and poor in those aged 75 years or older. Survival significantly improved over time for ovarian germ-cell cancer, sarcomas of extremities, digestive-system endocrine tumours, anal squamous-cell carcinoma, and angiosarcoma of liver. Survival in northern Europe was higher than in the other geographic groupings for most cancers. INTERPRETATION: Because effective treatments are available for several of the rare cancers we assessed, further research is needed to ascertain why survival is lower in some European countries than in others, particularly in older patients. Audit of best practice for rare cancers with treatment protocols would be useful.

Radiation dose and relapse are predictors for development of second malignant solid tumors after cancer in childhood and adolescence: a population-based case-control study in the five Nordic countries.

The aim of the study was to assess the risk with radiation therapy and chemotherapy of the first cancer in childhood and adolescence for the development of a second malignant solid tumor (SMST). Also, the role of relapse of the primary tumor was studied. It is a nested case-control study within a Nordic cohort of patients less than 20 years of age at first diagnosis 1960-1987. SMSTs were diagnosed in 1960-1991. There were 196 cases and 567 controls. The risk was increased only for radiotherapy given more than five years before the development of the SMST. A significantly increased relative risk of 1.8 was found already at doses below 1 Gy. The risk increased rapidly up to a maximum of 18.3 for doses above 30 Gy. Chemotherapy alone did not increase the risk to develop an SMST. However, in combination with radiotherapy, chemotherapy showed a significant potentiating effect. Relapse was found to be an independent risk factor for development of an SMST, with a higher relative risk for females than for males.

Developments in radiotherapy.

A systematic assessment of radiotherapy for cancer was conducted by The Swedish Council on Technology Assessment in Health Care (SBU) in 2001. The assessment included a review of future developments in radiotherapy and an estimate of the potential benefits of improved radiotherapy in Sweden. The conclusions reached from this review can be summarized as: Successively better knowledge is available on dose-response relationships for tumours and normal tissues at different fractionation schedules and treated volumes. Optimization of dose levels and fractionation schedules should improve the treatment outcome. Improved treatment results may be expected with even more optimized fractionation schedules. The radiosensitivity of the tumour is dependent on the availability of free oxygen in the cells. The oxygen effect has been studied for a long time and new knowledge has emerged, but there is still no consensus on the best way to minimize its negative effect in the treatment of hypoxic tumours. Development in imaging techniques is rapid, improving accuracy in outlining targets and organs at risk. This is a prerequisite for advanced treatment planning. More accurate treatment can be obtained using all the computer techniques that are successively made available for calculating dose distributions, controlling the accelerator and multileaf collimator (MLC) and checking patient set-up. Optimized treatment plans can be achieved using inverse dose planning and intensity modulation radiation therapy (IMRT). Optimization algorithms based on biological data from clinical trials could be a part of future dose planning. New genetic markers might be developed that give a measure of the radiation responsiveness of tumours and normal tissue. This could lead to more individualized treatments. New types of radiation sources may be expected: protons, light ions, and improved beams (and compounds) for boron neutron capture therapy (BNCT). Proton accelerators with scanned-beam systems and energy modulation give good dose distribution. The results reported with carbon ions from Japan and Germany are promising. An interesting development is to verify the dose and position for the irradiated volume with PET on line. Safer margins are obtained and the treatment volume can thus be limited. Very large accelerators are needed to accelerate the carbon ions. Still, it should be possible to keep the costs per patient at the same level as those for other types of advanced radiotherapy, since far fewer treatments per patient are needed. It might also be possible to treat new groups of patients. Increased resources are needed to introduce all the currently available techniques. New types of particle accelerators require large investments and a new structure of radiotherapy in Sweden.

Do changes in surgical procedures for breast cancer have consequences for hospital mean length of stay? A study of women operated on for breast cancer in Sweden, 1980-95.

BACKGROUND: Between 1986 and 1996, the overall mean overnight length of stay for all diagnoses in Sweden decreased from 20.8 to 7.1 days. OBJECTIVES: The study describes changes in surgical technique, from mastectomy to breast-conserving surgery, in treatment of female breast cancer and the parallel change in average length of hospital stay, and discusses the possible link between the trends. RESEARCH DESIGN: The study was performed as a descriptive register study on hospital admission data from the Swedish Hospital Discharge Register over a 16-year period (1980-95). RESULTS: During the study period, the mean length of stay for surgical curative breast cancer treatment in Sweden decreased by 56%. In 1980, the proportion of women receiving conservative surgery was 7%. At the end of the period, this share had increased to 51%. Breast-conserving surgery had an approximately 30% shorter mean length of stay compared with mastectomy. The gap was remarkably stable during the study period. The shift from mastectomy to breast-conserving surgery had a limited effect on the share of patients that went through lymph node dissection. Neither age nor the number of operations per woman could, to any significant extent, explain the decrease in mean length of stay. Approximately 14% of the overall decline can be attributed to the changes in technique. CONCLUSIONS: Clinical practice style, in this case the surgical technique, has had an effect on length of stay, but the surgical technique can only to some extent explain the trend.

Radiotherapy techniques in current use in Sweden.

A systematic assessment of radiotherapy for cancer was conducted by The Swedish Council on Technology Assessment in Health Care (SBU) in 2001. The assessment included a review of radiotherapy techniques in current use in Sweden. The following conclusions were drawn: Radiotherapy demands adequate knowledge of diagnostic methods, anatomy, cancer biology and of the physical and biological properties of ionizing radiation. Well-functioning teamwork on the part of the oncologist, medical physicist and oncology nurse is important. Radiotherapy has a high degree of technical sophistication, including the use of computers, which necessitates expert technical support. Technical development is rapid, and since the previous report, multileaf collimators and electronic portal imaging have been introduced in the clinical routine. The use of brachytherapy for treatment of non-gynaecological malignancies is rapidly increasing. The need for quality assurance in all steps of the radiotherapy procedure is stressed. A critical review of the literature on intraoperative radiotherapy is also included as an Appendix.

Radiotherapy and cancer care in Sweden.

A systematic assessment of radiotherapy for cancer was conducted by The Swedish Council on Technology Assessment in Health Care (SBU) in 2001. It included an overview of the organisation of radiotherapy and cancer care in Sweden and education of staff. It further included an update of cancer statistics for Sweden and an estimate of the need for radiotherapy resources by the year 2010. The following conclusions were drawn: Compared with a similar assessment in 1992, the number of departments of oncology at the county hospital level has increased by one, and one more department was scheduled to start radiotherapy during 2002. The speciality of oncology in Sweden includes all types of non-surgical cancer treatment, in contrast to the situation in most countries, where radiation oncology and medical oncology are independent specialities. Gynaecologic oncology is a unique speciality for Sweden. The number of new cancer cases increased by 13% between 1990 and 2000, and continues to increase by more than 1.0% per year. The projections of cancer incidence stated in the previous report were checked against observed data for the year 2000 and found to be an underestimation. To maintain the current capacity for radiotherapy in relation to number of new cancer cases by the year 2010, a total of 65 accelerators would be needed.

Incidence and survival of squamous cell carcinoma of the tongue in Scandinavia, with special reference to young adults.

In several countries, increased incidence of squamous cell carcinoma (SCC) of the tongue in young adults has been suspected during the last decades. Some reports indicate a lower survival rate for young patients compared to older patients. In other reports, there has not been any considerable difference in survival when comparing young adults to older patients, whereas some authors have shown better survival for young adults. This disease is rare in young adults, and early reports were based on comparable small numbers and selected patients. Our aim was first to perform a population-based study to determine if an increased incidence in SCC of the tongue could be verified in a larger population comprising the Scandinavian countries Denmark, Finland, Sweden and Norway. A second aim was to determine survival rates for young adults compared to older patients. The material was based on the annual cancer incidence and survival reports from the Scandinavian cancer registries. The study period was 1960-1994. During that period, 5,024 SCCs of the tongue were reported. Of these, 276 (5.5%) were young adults (20-39 years). The incidence increased at all ages except for women 65-79 years old. The increase was most pronounced in young adults: 0.06-0.32 for men and 0.03-0.19 for women, counted by 100,000 person-years. Relative survival was significantly better for young adults compared to older patients.

A prospective survey of radiotherapy practice 2001 in Sweden.

A prospective survey of radiotherapy practice in Sweden was conducted during 12 weeks in the autumn of 2001. All hospitals that provided radiotherapy participated, and all patients who started radiotherapy during the study period were included. The final patient sample comprised 5,105 treatments given to 4,171 patients. The results were compared with those of a similar survey conducted in 1992, and the following conclusions were drawn: A substantial increase in the use of radiotherapy was noted; The estimated proportion of cancer cases receiving radiotherapy (compared to the incident number of cases) had increased from 32% in 1992 to 47%; The proportion of cancer patients receiving radiotherapy was estimated at between 37 and 46%; 54% of treatments were given with curative intent, a small increase since 1992; The difference between regional and county departments for proportion of treatments with curative intent had diminished; Treatments with curative intent used a higher proportion of resources measured in terms of fractions; The proportion of palliative treatment was slightly lower than in 1992, but the absolute number of treatments had increased by more than 20%; No improvement in participation in clinical trials was noted; Treatments given with curative intent were more complex with more fields; Hyperfractionation was used, mainly in treatments of cancers of the head and neck, lung, and bladder; The use of brachytherapy for non-gynaecological malignancies had increased dramatically; Treatment of bone metastases with a single or few fractions was used much more frequently; Dose planning and patient set-up showed a high standard but quality control of dosimetry of given treatment did not fully comply with Swedish and European recommendations; The treatment devices seem to be used more efficiently.

Radiotherapy practices in Sweden compared to the scientific evidence.

A systematic assessment of radiotherapy for cancer was conducted by The Swedish Council on Technology Assessment in Health Care (SBU) in 2001. The assessment included a critical review of the literature on radiotherapy for cancer published in 1994-2001 and a prospective survey of radiotherapy practice in Sweden during 12 weeks in the autumn of 2001. The results of the survey were compared with the evidence derived from the scientific literature, and the following conclusions could be drawn: Radiotherapy is currently given to approximately 47% of new cancer cases This figure is on a par with rates reported from other countries. For most tumour types, curative radiotherapy practices in Sweden are generally supported by the literature. Interstitial brachytherapy has been included in the treatment of non-gynaecological malignancies, and prostate cancer is now the most common indication. Palliative radiotherapy has increased and is today given in a more rational way using single or few fractions However, it still seems to be under-utilized in Sweden. The need for radiotherapy can be expected to increase until the year 2010.

Invasive cutaneous malignant melanoma in Sweden, 1990-1999. A prospective, population-based study of survival and prognostic factors.

BACKGROUND: The objective of the current study was to compile prospective, population-based data on cutaneous invasive melanomas in Sweden during the period from 1990 to 1999, to describe and analyze survival data and prognostic factors, and to make comparisons with previously published Swedish and international data. METHODS: Twelve thousand five hundred thirty-three patients, which included 97% of all registered melanomas in Sweden, were included and described. Among these, 9515 patients with clinical Stage I and II melanoma were included in an analysis of survival and in a univariate analysis, and 6191 patients were included in a multivariate analysis of prognostic factors. RESULTS: There was no significant change in melanoma incidence during 1990-1999. Favorable prognostic factors were found, especially in younger and female patients, resulting in a relative 5-year survival rate of 91.5%. In the multivariate analysis, significant factors that had a negative effect on survival were Clark level of invasion, Breslow thickness, ulceration, older patient age, trunk location, greatest tumor dimension, nodular histogenetic type, and male gender. CONCLUSIONS: During the period from 1990 to 1999, the 5-year survival of patients with malignant melanoma in Sweden was better compared with the previously reported rates in published, population-based studies from Sweden, probably as a result of better secondary prevention due to better knowledge and awareness by both patients and the medical profession. The more favorable prognostic factors and the change in melanoma location found in younger patients, compared with earlier reports, may reflect changes in clothing as well as tanning habits; however, a decrease also was found in Clark Level II and thin melanomas for the same patient group. The authors concluded that further improvements can be achieved with better access to health care and with the use of early melanoma detection campaigns.

Does stage at diagnosis explain the difference in survival after breast cancer in Denmark and Sweden?

Breast cancer survival differs 9 percentage points between the neighbouring countries of Denmark and Sweden. The authors' aim was to analyse whether this was caused by early detection in Sweden. The extent of disease and outcome was compared in two population-based breast cancer cohorts in 1983-1989. Breast cancer management was decentralized in Denmark without mammography screening whereas treatment in Sweden was centralized and the population partly screened. Ten- and 15-year relative survival was 15% and 6% higher in Sweden (p<0.001) with corresponding differences in crude and disease-specific survival. Stage distribution was significantly more favourable in the Swedish cohort. In multivariate analysis age, tumour size, extent of axillary surgery, and spread affected survival; however, the impact of region persisted (p<0.001). Reanalysis without screening-detected patients only slightly affected the impact of region. It was concluded that early detection had significant impact on survival but other regional differences might be of importance.