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Geographical variability of cancer burden was almost exclusively estimated for common cancers. Since rare cancers (RC) have become an area of priority for basic and clinical research and public health organizations, this paper provides, using a common methodology, a detailed comparison of incidence and survival for RC in the US and Europe. We estimated incidence and net survival of 199 malignant RC from data of 2 580 000 patients collected by 18 US‐SEER and 94 European registries, diagnosed within the most recent common period 2000‐2007. RC were defined according to the criterion of crude annual incidence rates <6/100 000. In total, 196 RC were classified as rare in both populations. Of these, 43 had incidence rates significantly different by at least 0.2 per 100 000:34 higher in the US and 9 higher in Europe. Five‐year net survival for all RC combined significantly differed: 54% in the US and 48% in Europe. Survival for 62 RC was significantly higher in the US vs 6 higher in Europe. Differences were not concentrated in a particular cancer family, and were mostly relevant for cases diagnosed >65+ years of age. Use of standardized methods evidenced that incidence and survival rate of majority of RC were higher in the United States compared to Europe. Possible reasons for such differences, requiring further studies, include distribution of risk factors, ability to diagnose RC, different registration practices, and use of updated International Classification of Diseases for Oncology. Plot of crude incidence rates of rare and common cancers in Europe (y‐axis) vs the US (x‐axis) shows that most cancers were rare (crude incidence <6/100.000, low left square) in both population. Two cancers (thyroid carcinoma and Diffuse B lymphoma) classified as rare in the European population, however, were common in the US (low right square). In contrast, breast invasive lobular carcinoma was common in Europe and rare in the US (high left square).
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Cancer Medicine. 2020;9:5632–5642.
wileyonlinelibrary.com/journal/cam4
1
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INTRODUCTION
Patients diagnosed with rate cancers (RC) are disad-
vantaged with respect to those diagnosed with common
cancers. Due to their rarity, diagnosis of RC is often
delayed, clinical research is difficult, clinical manage-
ment is often complex and hard outside a few specialized
centers. Two recent papers described the burden of RC
in the US1 and Europe2 and estimated that a significant
proportion, 20%-24% of all patients diagnosed with can-
cer, are rare. Both papers defined rarity using an annual
incidence rate cut-off <6/100 000, and they used the
same list of clinically relevant and histologically defined
RC. The list was developed by the Surveillance of RC
Received: 16 January 2020
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Revised: 21 April 2020
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Accepted: 22 April 2020
DOI: 10.1002/cam4.3137
ORIGINAL RESEARCH
Incidence and survival of rare cancers in the US and Europe
LauraBotta1
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GemmaGatta1
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AnnalisaTrama1
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AliceBernasconi1
|
EladSharon2
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RiccardoCapocaccia3
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Angela B.Mariotto4
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the RARECAREnet working group
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original
work is properly cited.
© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
*Laura Botta and Gemma Gatta are co-first authors.
1Evaluative Epidemiology Unit, Fondazione
IRCCS Istituto Nazionale Tumori, Milan,
Italy
2Cancer Therapy Evaluation Program,
National Cancer Institute, Bethesda, MD,
USA
3Editorial Board, Epidemiologia &
Prevenzione, Castellanza, Varese, Italy
4Division of Cancer Control and Population
Sciences, National Cancer Institute,
Bethesda, MD, USA
Correspondence
Riccardo Capocaccia, Via Vespucci 41,
Rome, Italy.
Email: capocaccia.riccardo@gmail.com
Funding information
This work was supported by the NIH
Project title “Surveillance of Rare Cancers”
in the Surveillance, Epidemiology, and End
Results Program (SEER), Contract Award
n. HHSN261201700656P and the European
Union's Health Programme (2014-2020)
[grant no. 724161]. Project title “Joint
Action on rare Cancers” – JARC.
[Correction added on 23 June 2020, after
first online publication: The affiliation
of the corresponding author, Riccardo
Capocaccia, has been corrected in this
version.]
Abstract
Geographical variability of cancer burden was almost exclusively estimated for com-
mon cancers. Since rare cancers (RC) have become an area of priority for basic and
clinical research and public health organizations, this paper provides, using a com-
mon methodology, a detailed comparison of incidence and survival for RC in the US
and Europe. We estimated incidence and net survival of 199 malignant RC from data
of 2580000 patients collected by 18 US-SEER and 94 European registries, diag-
nosed within the most recent common period 2000-2007. RC were defined according
to the criterion of crude annual incidence rates <6/100000. In total, 196 RC were
classified as rare in both populations. Of these, 43 had incidence rates significantly
different by at least 0.2 per 100000:34 higher in the US and 9 higher in Europe.
Five-year net survival for all RC combined significantly differed: 54% in the US and
48% in Europe. Survival for 62 RC was significantly higher in the US vs 6 higher in
Europe. Differences were not concentrated in a particular cancer family, and were
mostly relevant for cases diagnosed >65+years of age. Use of standardized meth-
ods evidenced that incidence and survival rate of majority of RC were higher in the
United States compared to Europe. Possible reasons for such differences, requiring
further studies, include distribution of risk factors, ability to diagnose RC, different
registration practices, and use of updated International Classification of Diseases for
Oncology.
KEYWORDS
5years net survival, differences, Europe, incidence, rare cancers, USA
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BOTTA eT Al.
in Europe (RARECARE) group, which consists of pa-
thologists, hematologists, other clinicians, and epidemi-
ologists. Inferior clinical outcomes of rare vs common
cancers were reported in both papers, partially explained
by the differential distribution of stage at diagnosis be-
tween rare and common cancers as reported in the US.1
The European paper reported a low level of centralization
for RC patients treatment.2
Rare cancers have become an area of priority for basic and
clinical research, and public health organizations. The most
relevant initiatives in Europe are the European Community-
supported Joint Action on RC (JARC),3 whose major goal is
to include RC in national cancer plans, and the development
of the European Reference Network (ERN)4 on RC, aimed
at facilitating consultation for diagnosis and treatment of RC
and at promoting research. In the US, the National Clinical
Trials Network launched in 2014 provides, with focus on
RC and minorities, infrastructure for NCI-funded treatment,
screening, and diagnosis trials to improve the lives of patients
with cancer (https://www.cancer.gov/resea rch/areas /clini cal-
trial s/nctn).
Recently, the definition of cancer entities was revised5 ac-
cording to the 4th version of the WHO classification of tumors
publication, following the new WHO Blue Books (http://
whobl ueboo ks.iarc.fr/). This new definition was applied to
the European data and the Surveillance, Epidemiology, and
End Results (SEER) data.6
Although the two cited studies1,2 reported similar general
patterns of RC, they were not powered to identify specific
differences in US and Europe because they were conducted
independently using different definitions, diagnosis period,
and methods. The aim of this paper was to use the revised
list of RC and a common methodology to provide a more in-
depth comparison of incidence and survival for RC in the US
vs Europe. These comparisons have the potential to highlight
important differences and improve our understanding of RC
in both locations.
2
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MATERIAL AND METHODS
2.1
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Cases
We analyzed incidence and survival data collected in 18
SEER registries6 and in 94 European registries included in
the RARECAREnet website.5 Only population-based reg-
istries were considered. They are aimed at collecting all
the cases diagnosed in the reference population by merg-
ing all the available demographical, clinical, pathological,
and laboratory information, and are bound to code data
according to internationally agreed protocols. In addition,
CRs follow incident cases for vital status, mainly by link-
ing cancer registry database with the mortality database of
the National Statistical Office. Cause of death is collected
by SEER registries but not by all European registries. We
included all malignant cancers diagnosed during the pe-
riod 2000-2007. This period was chosen because it is the
most recent period for which European data are available.
Different primary RC in a same patients were included in
the analysis but only the first primary of a given tumor
was considered.
2.2
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Methods
Rare cancers entities were defined according to the updated
RARECAREnet list (Table S1), slightly revised using to-
pography and morphology codes from the third edition of
the International Classification of Diseases for Oncology
(ICD-O-3) (https://apps.who.int/iris/handl e/) and the fourth
version of the WHO classification of tumors (http://whobl
ueboo ks.iarc.fr/). Cancers that satisfied the RC definition
criteria (ie crude incidence rates <6/100 000/y) in SEER
and European data were identified, and only those that were
rare in both datasets were selected to conduct more detailed
comparisons.
US and European data were collected using common
protocols worldwide agreed within the community of
population based cancer registries,7 but they might differ
according to the compliance to such protocols. As for
data quality indicators, the percentage over all cases of
those detected from death certificate only were 1.0% in
US vs 1.6% in EU, while the proportion of RC censored
alive with zero survival time was 0.2% in both datasets.
Finally, the proportion of all cases with not otherwise
specified (NOS) morphology codes was 3.2% and 9.6%
for solid tumors (M8000-8001, 8800-8801), and 7.1%
and 13.5% for hematological tumors (M 9590-9591,
9760, 9800-9801, 9820, 9860) in the US and Europe,
respectively.
Incidence was calculated as the ratio between the number
of all new cases diagnosed with a given tumor and the num-
ber of person-years lived in the reference population during
the considered period. Age-adjusted incidence rates (ASR,
USA 2000 standard population) were compared between
SEER and EU in terms of absolute differences and using the
z-test for statistical significance.
We estimated cancer-specific survival at 5-year from diag-
nosis by the net survival (NS) indicator, based on the excess
mortality from all causes of patients with respect to age and
sex comparable general population groups. We calculated
NS by the Pohar-Perme method,8 the standard method to
provide unbiased survival comparisons between populations
subjected to different non-cancer mortality risks. Survival
comparisons used the absolute difference between US and
EU NS.
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Incidence and survival comparisons by age at diagnosis
groups are provided using funnel plots,9 which are useful
to visualize the distribution of a large number of estimates
(here, large number of entities). For incidence, the dots rep-
resent the ratio (RR) between the ASR in the US divided by
that in Europe, and the cone-shaped area delimited RRs that
are not significant by the 3-standard deviations criterion, a
threshold normally used9,10 in funnel plot analysis of many
statistical units, corresponding to 99.8% confidence limits.
For survival, dots represent the difference of 5-year NS in
the US minus 5-year NS in Europe, and are again represented
together with the 3-standard deviation confidence limits. All
the analyses were carried out by SEER*Stat 4.0 software.
3
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RESULTS
3.1
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Incidence
The crude annual incidence rate for all RC together was
slightly but significantly lower in the US (114/100000) than
Europe (118/100000) (Table1). However, the European pop-
ulation was older (17% vs 22% aged 0-14 and 16% vs 11%
aged 65+), so the ranking reversed when comparing ASR
(118 vs 101), with the US significantly higher than Europe.
Age-specific incidence rates were lower in EU than in US for
the older age classes, so the age distribution of RC cases was
similar between the two population. Rare and common cancers
TABLE 1 Comparison between rare cancers (RC) in Europe and the US (2000-2007 diagnoses). US and European populations, RC
proportions, and rate ratio (a). Number of incidence cases (N), incidence rates standard errors (SE) and incidence rate ratios (b); 5-y net-survivals
(NS) and 5-y absolute survival differences (c)
(a) Age and sex
SEER EU
SEER/EU
rate ratio
Population
(%) Rate
RC cases
(%)
Population
(%) Rate
RC cases
(%)
00-14y 22 13.9 3 17 11.8 2 1.18
15-24y 14 18.8 2 13 19.5 2 0.96
25-44y 29 48.2 12 29 49.0 12 0.98
45-54y 14 128.6 16 14 120.3 14 1.07
55-64y 9 241.1 20 11 213.2 21 1.13
65-74y 6 408.5 21 9 323.5 24 1.26
75+ y 5 541.9 26 7 408.8 25 1.33
Male 49 110.4 48 49 120.1 50 0.92
Female 51 117.6 52 51 114.9 50 1.02
(b) Incidence comparisons Count Rate SE Count Rate SE
SEER/EU
rate ratio
All rare cancers (crude) 741658 114.1 0.13 1840137 117.5 0.09 0.97
All rare cancers (stand) 741658 118.3 0.14 1840137 100.7 0.07 1.17
Incidence discordances
Invasive lobular carcinoma of breasta 36623 5.63 0.03 121455 7.75 0.02 0.73
Carcinoma of thyroid glandb 59218 9.11 0.04 79420 5.07 0.02 1.80
Diffuse B lymphomab 43414 6.68 0.03 67645 4.32 0.02 1.55
(c) Survival comparisons Count 5-y surv (%) SE (%) Count 5-y surv (%) SE (%)
SEER-EU
5-y survival
difference (%)
Cancers rare in each dataset 722170 53.6 0.1 1787618 48.2 0.1 5.4
Invasive lobular carcinoma of breasta 36044 90.8 0.3 120973 85.8 0.1 5.0
Carcinoma of thyroid glandb 58573 96.1 0.2 78533 90.1 0.2 6.0
Diffuse B lymphomab 43199 56.3 0.3 67907 52.6 0.3 3.7
Cancers rare in both datasets 686274 51.6 0.1 1643618 46.0 0.1 5.6
Population and RC cases columns show age- and sex-specific percentages of the total population and overall cases. Rates are per 100000 and age-adjusted to the USA
2000 standard population.
aCommon in EU.
bCommon in SEER.
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BOTTA eT Al.
in the two populations are represented in Figure1, which plots
crude incidence rates estimated in Eutope (y-axis) vs the US
(x-axis). According to the RC definition (crude incidence
<6/100000), two cancers (thyroid carcinoma and diffuse B
lymphoma) classified as rare in the European population, how-
ever, were common in the US (Figure1, low right square). In
contrast, breast invasive lobular carcinoma was common in
Europe and rare in the US (Figure1, high left square). Table1
shows that incidence of thyroid carcinoma and diffuse B cell
lymphoma was, respectively, 80% and 55% higher in the US
compared with Europe. Breast invasive lobular carcinoma
had almost 40% lower incidence in the US than in Europe.
From this point forward, we only considered entities that were
rare in both datasets, and we excluded thyroid carcinoma, dif-
fuse B lymphoma and breast lobular carcinoma.
Among a total of 196 entities rare in both countries, we
reported in Table2 those with incidence rates significantly
different in the two populations by an (arbitrarily chosen) ab-
solute difference of at least 0.2 per 100000. Most of them
(34 out of 43 entities) had higher incidence in the US com-
pared to Europe. Lower incidence in the US compared to
Europe was observed for nine entities, including squamous
cell carcinoma of larynx, esophagus, and cervix uteri, and
esophageal adenocarcinoma (Table2). Also accounting for
the small number of cases through the precision level, differ-
ences in incidence appear to be minor for tumors occurring in
patients aged <25years (Figures S1-S5).
3.2
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Survival
Five-year NS for all RC combined significantly differed:
54% in the US and 48% in Europe (Table1). Figure2 shows
a funnel plot representing 5-year NS differences in the US vs
Europe and the 3-standard deviations control limits for 187
entities with at least 5 cases in each population. For most
entities, the dots representing NS lie between the 3-standard
errors confidence bounds. Survival was higher in the US for
62 and higher in Europe for 6 entities that fall respectively
above and below the limits. Entities with differences in sur-
vival were not concentrated in a particular cancer family.
Table 3 lists 47 outlier entities with estimated differences
>5% in absolute value. Prostate transitional carcinoma,
sarcoma of Kaposi, and visceral sarcoma had significantly
better survival in Europe. However, most entities (44) had
better survival in the US, with the most important differences
(>15%) estimated for example for head and neck salivary
gland type tumor, lung salivary gland type tumor, chordoma,
eye and adnexa adenocarcinoma, CNS oligodendroglial tu-
mors, and histiocytic malignancies.
Five-year NS differences by age are represented, vs preci-
sion of estimates, in funnel plots, (Figures S6-S9). The num-
ber of significant differences increased by age group. CNS
oligodendroglial tumors were the only entity with significant
survival differences for childhood cancers (<15years), and
only four RC differed in the adolescent and young adult aged
15-24years. The highest number of survival differences sig-
nificantly higher in the US than European population, was
found for cases aged at diagnosis >65years.
Tables2 and 3 also report, for the entities with most rel-
evant differences in incidence and survival, their respective
estimates of survival and incidence. The same data are also
shown in Tables S2 and S3 with European incidence and sur-
vival indicators disentangled by European geographical re-
gion (North, UK & Ireland, Center, South and East). Overall,
no major relation was found between the two indicators for
the entities selected in the two tables. Only 14 cancers are
listed in both tables. Kaposi sarcoma had higher incidence
(0.6 vs 0.2) and lower survival (67 vs 79) in the US compared
to Europe. The other 13 entities had both quantities higher
in the US. Particularly striking incidence differences were
estimated for well differentiated not functioning endocrine
carcinoma of GEP (2.6 vs 0.9) and for other myelodysplastic
syndromes (3.8 vs 1.8), to which correspond a survival ad-
vantage of 13 and 9 percentage points, respectively.
4
|
DISCUSSION
This first comparative analysis shows that both incidence
and survival of RC, diagnosed during the period 2000-2007,
significantly differed between Europe and the US. We have
to remind that, while health care is under the competence of
single European countries, policy on rare disease (and rare
cancers) is coordinated by EU. Important programs have
been introduced in Europe, such as European Joint Actions
on rare cancers,3 the establishment of European Reference
Networks, and of cross-border care directive.4 Furthermore, a
FIGURE 1 Crude annual incidence rates for cancer entities in
Europe (y-axis) and the US (x-axis)
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TABLE 2 ASR of rare cancers with ASR statistically different between Europe and the US, and absolute difference >0.2. Number of cases
(N), standard error (SE), 5-year net survival (NS), incidence and survival absolute difference between the European and the US, also reported
Cancers
US-SEER EUROPE
Incidence
difference
Survival
difference
(%)N ASR (SE)
NS
(%) N ASR (SE)
NS
(%)
Head and neck Epithelial tumor of major
salivary glands
7550 1.21 (0.014) 69 15067 0.82 (0.007) 60 0.384 9
SCC of hypopharynx 4396 0.7 (0.011) 29 19828 1.06 (0.008) 25 −0.358 4
SCC of larynx 22337 3.57 (0.024) 60 72210 3.77 (0.014) 60 −0.209 −1
SCC of oropharynx 22816 3.55 (0.024) 56 49004 2.65 (0.012) 41 0.895 15
Rare digestive SCC of esophagus 10801 1.75 (0.017) 14 52597 2.74 (0.012) 11 −0.995 3
Adenocarcinoma of
esophagus
15049 2.43 (0.02) 18 51138 2.66 (0.012) 13 −0.238 5
SCC anal canal 7993 1.26 (0.014) 68 12691 0.69 (0.006) 62 0.569 6
Hepatocellular carcinoma
of liver and IBT
30828 4.88 (0.028) 15 50461 2.6 (0.012) 14 2.290 1
Adenocarcinoma of
extrahepatic biliary tract
9315 1.52 (0.016) 16 22507 1.16 (0.008) 19 0.359 −3
Rare thoracic Adenosquamous
carcinoma of lung
3738 0.61 (0.01) 28 4607 0.24 (0.004) 22 0.376 6
Large cell carcinoma of
lung
13178 2.15 (0.019) 14 31589 1.63 (0.009) 10 0.513 4
Mesothelioma of pleura
and pericardium
5534 0.92 (0.012) 5 28676 1.46 (0.009) 4 −0.544 0
Rare female
genital
Special types of
adenocarcinoma of breast
23213 3.72 (0.025) 98 48290 2.62 (0.012) 95 1.100 3
Serous (papillary)
carcinoma of corpus uteri
3427 0.56 (0.01) 45 1317 0.07 (0.002) 40 0.492 5
Mullerian mixed tumor of
corpus uteri
3509 0.57 (0.01) 38 6293 0.32 (0.004) 36 0.247 2
SCC of cervix uteri 19443 3.03 (0.022) 69 74103 4.37 (0.016) 66 −1.338 2
Mucinous adenocarcinoma
of ovary
2820 0.44 (0.008) 57 12066 0.67 (0.006) 60 −0.227 −3
Primary peritoneal serous/
papillary carcinoma of
ovary
2478 0.4 (0.008) 30 1280 0.07 (0.002) 21 0.337 8
Rare male genital
and urogenital
Infiltrating duct carcinoma
of prostate
535 0.09 (0.004) 84 8064 0.4 (0.005) 78 −0.315 6
Seminomatous testicular
cancer
9730 1.49 (0.015) 98 28516 1.81 (0.011) 97 −0.320 1
Transitional cell carcinoma
of pelvis and ureter
9186 1.52 (0.016) 48 21975 1.13 (0.008) 51 0.395 −3
Rare skin Adnexal carcinoma of skin 3969 0.64 (0.01) 91 5534 0.3 (0.004) 83 0.347 8
Sarcomas STS of limbs 8983 1.42 (0.015) 74 17186 0.96 (0.007) 67 0.459 7
STS of superficial trunk 4075 0.65 (0.01) 55 7807 0.43 (0.005) 48 0.217 7
STS of skin 4202 0.66 (0.01) 91 4734 0.28 (0.004) 90 0.389 1
Gastrointestinal stromal
sarcoma
4034 0.64 (0.01) 72 4706 0.25 (0.004) 72 0.394 0
Kaposi s sarcoma 4115 0.65 (0.01) 67 3893 0.23 (0.004) 79 0.423 −12
(Continues)
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universalist public health system is common to all European
countries. This paper was aimed at giving baseline compari-
son data between Europe as a whole and a big country as
US, differently organized with respect to health care system,
policy plans and with large health care disparities.
Age-adjusted incidence for all RC cancers combined was
significantly higher (+17%) in the US than in Europe and
almost half of the analyzed RC had higher incidence rates
in the US. Possible reasons for such differences include the
distribution of risk factors, “artificial” factors such as overdi-
agnosis, differences in the ability to diagnose RC, and differ-
ent registration practices and use of classification codes in
the two populations. In Figure S10, we show the major risk
factors associated with increased risks for those RC that had
significant differences in age-adjusted incidence between the
two populations and listed in Table2. Below, we highlight
the most important associations and provide insights on the
differences where possible.
Tobacco is associated with increased risk for most of the
epithelial RC and leukemias.11-14 Although smoking preva-
lence is now slightly higher in Europe than the US,15 the inci-
dence of many epithelial cancers and of leukemia, is higher in
the US compared to Europe. However, prevalence of smok-
ing has reduced more rapidly in the US than Europe, starting
from similar rates in 1980.
Alcohol consumption is mainly related to the epithelial tu-
mors of head and neck, liver, and esophagus,11,16 however the
consumption was higher at the beginning of this century and
remains slightly higher in many of the major European coun-
tries (the UK, Germany, France Italy and the Netherlands).17
Cancers
US-SEER EUROPE
Incidence
difference
Survival
difference
(%)N ASR (SE)
NS
(%) N ASR (SE)
NS
(%)
Rare
neuroendocrine
Well diff. not funct.
endocrine carcinoma of
GEP
16683 2.62 (0.02) 84 15852 0.86 (0.007) 71 1.763 13
Poorly differentiated
endocrine carcinoma
4984 0.8 (0.011) 33 10421 0.55 (0.005) 35 0.244 −2
Typical and atypical
carcinoid of the lung
4321 0.69 (0.011) 87 6160 0.34 (0.004) 81 0.349 7
Neuroendocrine carcinoma
of skin
3312 0.55 (0.01) 54 3026 0.16 (0.003) 55 0.388 −1
Neuroendocrine carcinoma
of other sites
7265 1.17 (0.014) 24 14120 0.75 (0.006) 24 0.427 1
CNS Astrocytic tumors of CNS 29997 4.75 (0.028) 18 78005 4.31 (0.016) 15 0.444 3
Rare hemathologic Hodgkin lymphoma,
classical
17333 2.67 (0.02) 81 38588 2.37 (0.012) 81 0.305 0
Precursor B/T
lymphoblastic leuk/
lymphoma
13827 2.14 (0.018) 60 22795 1.57 (0.011) 58 0.568 2
T cutaneous lymphoma 5088 0.81 (0.011) 84 5526 0.3 (0.004) 81 0.506 3
Other T cell lymphomas
and NK cell neoplasms
5903 0.94 (0.012) 40 9656 0.53 (0.005) 39 0.406 1
Plasmacytoma/multiple
myeloma
36867 5.99 (0.031) 38 89440 4.65 (0.016) 34 1.340 4
Mantle cell lymphoma 4407 0.71 (0.011) 50 8748 0.45 (0.005) 42 0.262 7
Acute myeloid leukemia 26247 4.25 (0.026) 16 60891 3.33 (0.014) 17 0.919 0
Chronic myeloid leukemia 7694 1.22 (0.014) 65 17473 0.97 (0.007) 53 0.256 12
Other myeloproliferative
neoplasms
16073 2.59 (0.021) 80 33954 1.82 (0.01) 73 0.774 7
Other myelodysplastic
syndromes
22887 3.8 (0.025) 40 33542 1.79 (0.01) 31 2.011 9
Abbreviations: ASR, age-adjusted incidence rates; GEP, gastroenteropancreatic tract; IBT, intrahepatic biliary tract; NS, net survival; SCC, squamous cell carcinoma;
SE, standard error; STS, Soft tissue sarcoma.
TABLE 2 (Continued)
5638
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Actually, rates for esophageal and all the head and neck can-
cers, except the oropharyngeal cancer, are higher in Europe
than in the US.
The occurrence of RC of the cervix, stomach, liver, oro-
pharynx, nasopharynx, anogenital sites, lymphomas, and
Kaposi sarcoma is related to specific infectious agents.11,16 A
recent study showed that the attributable fractions of cancer
cases related to the infections were slightly higher in Europe
compared to the US.18
Obesity is more prevalent in the US. Obesity/overweight
is a risk factor for the epithelial tumors of the esophagus and
extrahepatic biliary tract (EBT). Also, a fraction of pancreas,
liver, kidney, corpus uteri, breast, ovary, and colorectal can-
cers are related to obesity, so rare entities of these cancer sites
are likely associated with obesity as well.16
According to the International Agency for Research on
Cancer (IARC) monographs and a review by Charbothel,19
many RC are consistently linked to occupational factors.
However, it is difficult to estimate the prevalence of individ-
uals exposed to occupational risk factors.
Access to effective screening, which is mostly organized
in Europe and opportunistic in the US, can affect the inci-
dence of cervix cancer and RC of the breast, colon and rec-
tum. Screening initially increases the number of cases that
are at an early stage at presentation and have high survival,
and it subsequently leads to a decrease in incidence, perhaps
followed by a stabilization. A different intensity of inves-
tigations for skin, kidney, prostate, and lung cancers could
also affect the incidence of rare lesions in these cancer sites.
Overdiagnosis leads to increased incidence and survival.
The incidence of gastrointestinal stromal tumor (GIST),
large cell carcinoma of lung, neuroendocrine tumors, and
many hematologic malignancies may be influenced by
sounder pathological diagnosis and/or prompter and more
correct adoption by registries of new entity codes in the ICD-
O-3 coding procedures. We also know that the availability of
tests for a correct diagnosis may be less in some European
countries, such as in eastern Europe.2 Furthermore, a cen-
ter of expertise with the option of a pathologic second opin-
ion may be less available in some small European countries.
Most tumors with higher incidence in the US than in Europe
have recently been subject to classification changes; there-
fore, we can infer that part of the difference is explained by
better tumor classification in the US by both pathologists and
registrars.
Five-year NS for all RC together was higher in the US
than Europe. Many of the factors described above for inci-
dence may also explain variations in survival,16 since differ-
ent risk factors can generate biologically different diseases
with different prognoses. This is the case for epithelial oro-
pharyngeal cancer and squamous cell carcinoma of anogen-
ital sites; a different proportion of tumors caused by HPV,
characterized by less aggressive lesions, may have influenced
the survival gap. A 2014 study showed that the proportion of
HPV-positive oropharynx cancers is higher in the US than
in the European populations.20 The high prevalence of HIV-
infected individuals in the US, related to high AIDS rates,
may explain the worse outcomes for the more aggressive
form of Kaposi sarcoma in the US.21
Early stage at presentation increases therapy effective-
ness and consequently improves survival. Timely access to
new drugs (eg for chronic myeloid leukemia and other he-
matological malignancies), updated treatment protocols, and
multimodality treatment influence survival. All these factors
may be differentially available, creating disparities between
countries. Although data are lacking on the patterns of care
for the two populations and among the European countries,
they may explain the higher survival for leukemia, especially
CML, in the US compared to Europe. Overall, the organiza-
tion of management of RC (centralization, hospital volume,
second opinion, multidisciplinary approach, clinical research,
network, etc) is crucial for improving the outcome, especially
for patients with RC. Also, new diagnostic approaches rele-
vant for improving problematic diagnoses, as those for many
RC, can be differently available in the two regions, as well
as the availability of more effective and expensive treatment
protocols.
Incidence and survival are higher in the US than Europe22,23
not only for rare but also for common cancers. The two re-
gions also differ in health system organization: universalistic
in Europe vs private in the US, and we cannot exclude the
possibility that more intensive investigations in the US popu-
lation produce higher cancer incidence and higher incidence
FIGURE 2 Difference between 5-y net survival (NS) for
rare cancers (RC) in US and Europe, period of follow-up 2000-
2007. Funnel plot in which each dot represents a single RC, the
y-axis displays the estimated difference in 5-y NS, and the x-axis
the corresponding precision in terms of the inverse of its SE. Three-
SE confidence bounds are represented by two symmetrical lines
progressively approaching the y=0 line with increasing x values. Dots
lying above or below the area between them correspond respectively to
tumors with 99.8% significantly higher or lower NS
|
5639
BOTTA eT Al.
TABLE 3 5-y net survival of rare cancers with net survival statistically different between Europe and the US. Number of cases (N), Net
survival and corresponding standarad errors (SE), age standardized incidence rates (ASR), and absolute survival and incidence differences between
Europe and the US, also reported
Cancers
US-SEER Europe Survival
difference
(%)
Incidence
differenceN
Net Surv
(SE) ASR N
Net Surv
(SE) ASR
Head and neck SCC of nasopharynx 3038 55.6 (1.12) 0.473 5589 48.1 (0.8) 0.316 8 0.157
Epithelial tumor of major
salivary glands
7493 69.3 (0.8) 1.206 14717 60.1 (0.58) 0.822 9 0.384
Salivary gland type tumor of
head and neck
2962 82.2 (1.1) 0.471 6684 66.6 (0.81) 0.367 16 0.105
SCC of oropharynx 22571 55.6 (0.43) 3.548 48584 41.1 (0.27) 2.653 15 0.895
SCC of oral cavity 17959 53.8 (0.52) 2.947 54229 48 (0.28) 2.957 6 −0.011
Rare digestive SCC of rectum 1209 59.6 (1.88) 0.192 1777 46.5 (1.54) 0.094 13 0.098
SCC of anal canal 7954 67.9 (0.73) 1.258 12847 62.2 (0.6) 0.688 6 0.569
Intraductal papillary mucinous
carcinoma of pancreas
119 57.6 (6.29) 0.019 171 31.4 (4.9) 0.009 26 0.011
Rare thoracix Adenosquamous carcinoma of
lung
3718 28.1 (0.97) 0.612 4566 21.8 (0.76) 0.236 6 0.376
Salivary gland type tumor of
lung
261 66.5 (3.84) 0.041 880 39.7 (1.94) 0.049 27 −0.007
Rare female
genital
Metaplastic carcinoma of breast 1708 70.6 (1.69) 0.272 1897 63.6 (1.62) 0.103 7 0.170
Adenocarcinoma of cervix uteri 5771 73.7 (0.72) 0.905 14221 66.6 (0.47) 0.837 7 0.067
Clear cell adenocarcinoma of
ovary
2022 66.2 (1.31) 0.311 4761 55.5 (0.88) 0.258 11 0.054
Primary peritoneal serous/
papillary carcinoma of ovary
2474 29.7 (1.23) 0.402 1280 21.4 (1.55) 0.066 8 0.337
Adenocarcinoma of falloppian
tube
1296 68.4 (1.82) 0.207 2690 58.8 (1.26) 0.140 10 0.066
Malignant/immature teratoma
of ovary
508 93.6 (1.21) 0.077 829 83.1 (1.47) 0.053 11 0.024
Germ cell tumor of ovary 620 92.6 (1.13) 0.094 1143 86.5 (1.12) 0.077 6 0.017
SCC of vulva and vagina 7852 68.5 (0.8) 1.283 26271 59.5 (0.48) 1.415 9 −0.133
Adenocarcinoma of vulva and
vagina
607 55.9 (2.65) 0.097 1115 45.9 (1.92) 0.060 10 0.037
Rare male genital
and urogenital
Transitional cell carcinoma of
prostate
125 33.8 (5.96) 0.021 941 56.6 (2.41) 0.049 −23 −0.028
Epithelial tumor of
eye and adnexa
Adenocarcinoma of eye and
adnexa
112 75.2 (5.76) 0.018 218 52.8 (4.33) 0.012 22 0.006
Mesothelioma Mesothelioma of peritoneum
and tunica vaginalis
618 21.1 (2.05) 0.100 1999 12.7 (0.93) 0.107 8 −0.007
Rare melanomas Malignant melanoma of uvea 3194 82.3 (1.16) 0.508 8024 70.7 (0.77) 0.311 12 0.075
Rare skin Adnexal carcinoma of skin 3864 91 (1.26) 0.643 5503 83.4 (1.25) 0.296 8 0.347
Embrional Neuroblastoma and
ganglioneuroblastoma
1441 73.8 (1.31) 0.220 2135 68 (1.09) 0.178 6 0.042
Sarcomas STS of limbs 8934 73.7 (0.69) 1.420 17101 67.1 (0.51) 0.961 7 0.459
STS of superficial trunk 4056 54.9 (1.03) 0.647 7717 47.7 (0.73) 0.430 7 0.217
STS of viscera 1845 32.1 (1.33) 0.299 5856 42.1 (0.8) 0.318 −10 −0.019
(Continues)
5640
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BOTTA eT Al.
of early-stage cases, leading to a more favorable outcome.
Furthermore, investments, management, and health care
plans are different between European countries, even with
universalistic provision of care. In all EUROCARE studies,
age-adjusted 5-year survival varied markedly between Nordic
and Central, and Eastern countries; this has also been shown
for RC combined, even after adjusting by case mix.24 Eastern
European countries had lower survival, and also lower inci-
dence, for many RC (Tables S2 and S3), but they only con-
tributed by 15% of the considered cases and 17% of the total
amount of person-years. Removal of Eastern European coun-
tries only slightly changed (not shown in tables) the incidence
and survival differences between EU and US.
The two datasets considered in this analysis have been
consistently used in previous comparative population based
international studies.22,23 Such studies were, however, mainly
addressing common cancers. A reliable epidemiological de-
scription of RC entities requires a low proportion of cases
detected by death certificates and of cases with NOS mor-
phology, as different and high proportions of unknown mor-
phology codes can affect the quality of comparison. In our
study, the proportions of DCO was negligible in both data-
sets, while those of NOS were higher in Europe than in US. A
SEER based study has shown that breast cancers with missing
information on biomarkers had poorer prognosis than those
with reported information.25 It may be plausible that tumors
coded as NOS are more likely to be rare or of more complex
diagnosis and poor prognosis. Thus, a higher proportion of
NOS morphologic groups is indicative of incidence underes-
timation for some RC.
The European database includes 94 registries, and even
with great standardization efforts, thanks to the European
Cancers
US-SEER Europe Survival
difference
(%)
Incidence
differenceN
Net Surv
(SE) ASR N
Net Surv
(SE) ASR
STS of retroperitoneum and
peritoneum
2127 45 (1.38) 0.342 4851 38.2 (0.86) 0.264 7 0.078
STS of pelvis 2000 55.3 (1.44) 0.318 3008 47.3 (1.13) 0.169 8 0.149
Ewing's sarcoma of soft tissue 690 54.1 (2.08) 0.106 1079 44.8 (1.69) 0.071 9 0.035
Osteogenic sarcoma 1933 58.2 (1.28) 0.298 3757 50.6 (0.93) 0.249 8 0.048
Chondrogenic sarcoma 1720 77.6 (1.35) 0.270 4521 69.4 (0.89) 0.263 8 0.007
Notochordal sarcoma,
chordoma
573 76.9 (2.59) 0.091 1127 59.3 (1.97) 0.064 18 0.027
Kaposi's sarcoma 4055 67.1 (1.04) 0.649 3830 78.8 (1.12) 0.226 −12 0.423
Rare
neuroendocrine
Well diff not functioning
endocrine carcinoma of GEP
16439 84 (0.47) 2.625 15656 71.4 (0.51) 0.862 13 1.763
Well diff functioning endocrine
carcinoma of GEP
150 83.6 (4.33) 0.024 407 60.3 (2.97) 0.023 23 0.001
Typical and atypical carcinoid
of the lung
4274 87.4 (0.88) 0.689 6058 80.6 (0.69) 0.340 7 0.349
CNS Oligodendroglial tumors of
CNS
2909 69.7 (0.99) 0.451 6124 51.5 (0.74) 0.365 18 0.086
Ependymal tumors of CNS 1591 82.1 (1.21) 0.246 3185 72.7 (0.91) 0.204 9 0.042
Neuronal and mixed neuronal-
glial tumors
55 78 (6.13) 0.008 74 49.4 (6.86) 0.005 29 0.004
Rare hemathologic Malignant meningiomas 889 64.7 (2.12) 0.146 3117 55.8 (1.14) 0.183 9 −0.036
Mantle cell lymphoma 4389 49.9 (1.08) 0.715 8797 42.4 (0.73) 0.453 7 0.262
Chronic myeloid leukemia 7560 65.3 (0.75) 1.223 16599 53.2 (0.5) 0.967 12 0.256
Other myeloproliferative
neoplasms
15861 80 (0.58) 2.591 33599 73.4 (0.4) 1.817 7 0.774
Other myelodysplastic
syndrome
22437 40.1 (0.54) 3.797 32576 30.7 (0.39) 1.786 9 2.011
Histiocytic malignancies 211 81.6 (3.06) 0.033 645 62.5 (2.28) 0.043 19 −0.011
Abbreviations: CNS, central nervous system; GEP, gastroenteropancreatic tract; SCC, squamous cell carcinoma; SE, standard errors; STS, soft tissue sarcoma.
TABLE 3 (Continued)
|
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BOTTA eT Al.
Network of Cancer Registries (ENCR), and to centralized
quality checks by the EUROCARE and RARECAREnet
groups, one cannot eliminate a certain level of heterogeneity
in registration among the European registries, which may be
greater than in the 18 US registries considered.
The study period considered in this paper is not recent,
because of challenges in obtaining more updated data from
the European registries. However, by using the same period
of diagnosis, we provide more accurate comparisons than
previous papers.1,2 Finally, clinical information on stage and
treatment is incompletely collected by many European regis-
tries, which precludes a more extensive comparison.
Centralization and networking, the most appropriate an-
swers to the issues pertaining to RC, were not optimal in
Europe during the period of our analisys,2 but we know about
ameliorative efforts in the national organization plans, in the
majority of the studied countries.2 An opportunity to improve
survival (and possibly reduce incidence) in Europe, however
too recent to have impacted on the results of this paper, comes
from the implementation of the ERNs. The Joint Action of
Rare Cancers, the major European initiative aimed at prior-
itizing RC in the agendas of the European Member States,
ended in 2019.
The role of population based cancer registries still re-
mains crucial to describe the real world impact of cancer
and to evaluate progresses made. Their results have to be as
much as possible uniformed at the European level in timeli-
ness and in quality. This study suggests an important role for
registration/classification practices, which should be enabled
to keep up with advances in cancer research, codifying with
more precision the cancer's topography, morphology, stage,
and possibly other prognostic factors. We benefited from the
RARECARE definition of RC. The corresponding list will be
made available soon, and a variable in the SEER*Stat soft-
ware will provide the means to conduct further studies on RC
entities in the US.
In conclusion, we have shown using standardized meth-
ods that differences exist on incidence and survival of RC
in the US and Europe. We provided some interpretation for
incidence and survival differences. Our findings suggest
opportunities for further research to understand the burden
of RC and to spur greater international collaboration on the
study of RC, with the goal of greater awareness, knowledge
and therefore providing inputs in their prevention, diag-
nosis and treatment. We, also, provided basic information
for the organization of clinical studies. In RC research, the
larger is the collaboration the greater the chance to make
progress.
ACKNOWLEDGMENTS
We thank Otto Visser, Maria Jose Bento, Francesca Bella
for their important comments and Lucia Buratti for technical
support.
CONFLICT OF INTEREST
None.
AUTHOR CONTRIBUTIONS
Laura Botta contributed to conceptualization, data cura-
tion, formal analysis, methodology, software, visuali-
zation, writing – original draft and writing – review and
editing. Riccardo Capocaccia contributed to conceptualiza-
tion, data curation, formal analysis, methodology, funding
acquisition, software, writing – original draft, and writing
– review and editing. Annalisa Trama contributed to data
curation, project administration, and writing – review and
editing. Alice Bernasconi contributed to data curation and
writing – review and editing. Elad Sharon contributed to
writing – review and editing. Gemma Gatta contributed to
conceptualization, data curation, methodology, funding ac-
quisition, project administration, writing – original draft,
and writing – review and editing. Angela Mariotto contrib-
uted to conceptualization, methodology, funding acquisi-
tion, project administration, writing – original draft, and
writing – review and editing.
DATA AVAILABILITY STATEMENT
The US data that support the findings of this study are openly
available in “SEER” database at www.seer.cancer.gov. The
European data that support the findings of this study are avail-
able on request from the corresponding author, conditional to
the agreement of the contributing cancer registries. The data
are not publicly available due to privacy restrictions.
ORCID
Riccardo Capocaccia https://orcid.
org/0000-0002-1455-1992
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SUPPORTING INFORMATION
Additional supporting information may be found online in
the Supporting Information section.
How to cite this article: Botta L, Gatta G, Trama A, et
al; RARECAREnet working group. Incidence and
survival of rare cancers in the US and Europe. Cancer
Med. 2020;9:5632–5642. https://doi.org/10.1002/
cam4.3137
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... 11 The project for surveillance of RCs in Europe, RARECAREnet published a list of 198 RCs belonging to 12 cancer families, thus demarcating cancers with an incidence of ≤6/100,000 persons across Europe. 9,12,13 However, the RC incidence cut-off is arbitrary, as acknowledged by the RARECARE group, due to variable incidences of cancers in different populations. 1,4,12 There is a paucity of data on RCs from Asia. ...
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... 1,[5][6][7] Diagnostic delays, difficulties conducting clinical trials with the resultant shortage of randomized evidence and prevalent non-uniform practices, inadequate expert centers and lack of awareness are a few pressing issues in RC treatment. 1,4,[8][9][10] Clinicians and researchers often focus on common cancers; conferences and continuing education programs are also usually conducted on common topics rather than rare cancers. Pharmaceutical companies are also inclined to sponsor research on molecules intended for more patients. ...
... 11 The project for surveillance of RCs in Europe, RARECAREnet published a list of 198 RCs belonging to 12 cancer families, thus demarcating cancers with an incidence of ≤6/100,000 persons across Europe. 9,12,13 However, the RC incidence cut-off is arbitrary, as acknowledged by the RARECARE group, due to variable incidences of cancers in different populations. 1,4,12 There is a paucity of data on RCs from Asia. ...
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Rare cancers epidemiology is better known compared to the other rare diseases. Thanks to the long history of the European population-based cancer registries and to the EUROCARE huge database, the burden of rare cancers has been estimated the European (EU28) population. A considerable fraction of all cancers is represented by rare cancers (24%). They are a heterogeneous group of diseases, but they share similar problems: uncertainty of diagnosis, lack of therapies, poor research opportunities, difficulties in clinical trials, lack of expertise and of centres of reference. This paper analyses the major epidemiological indicators of frequency (incidence and prevalence) and outcome (5-year survival) of all rare cancers combined and of selected rare cancers that will be in depth treated in this monographic issue. Source of the results is the RARECAREnet search tool, a database publicly available. Disparities both in incidence and survival, and consequently in prevalence of rare cancers were reported across European countries. Major differences were shown in outcome: 5-year relative survival for all rare cancers together, adjusted by age and case-mix, varied from 55% or more (Italy, Germany, Belgium and Iceland) and less than 40% (Bulgaria, Lithuania and Slovakia). Similarly, for all the analyzed rare cancers, a large survival gap was observed between the Eastern and the Nordic and Central European regions. Dramatic geographical variations were assessed for curable cancers like testicular and non epithelial ovarian cancers. Geographical difference in the annual age-adjusted incidence rates for all rare cancers together varied between >140 per 100,000 (Italy, Scotland, France, Germany, and Switzerland) and <100 (Finland, Portugal, Malta, and Poland). Prevalence, the major indicator of public health resources needs, was about 7-8 times larger than incidence. Most of rare cancers require complex surgical treatment, thus a multidisciplinary approach is essential and treatment should be provided in centres of expertise and/or in networks including expert centres. Networking is the most appropriate answer to the issues pertaining to rare cancers. Actually, in Europe, an opportunity to improve outcome and reduce disparities is provided by the creation of the European Reference Networks for rare diseases (ERNs). The Joint Action of rare cancers (JARC) is a major European initiative aimed to support the mission of the ERNs. The role of population based cancer registries still remains crucial to describe rare cancers management and outcome in the real word and to evaluate progresses made at the country and at the European level.
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Background: Infections with certain viruses, bacteria, and parasites are strong risk factors for specific cancers. As new cancer statistics and epidemiological findings have accumulated in the past 5 years, we aimed to assess the causal involvement of the main carcinogenic agents in different cancer types for the year 2012. Methods: We considered ten infectious agents classified as carcinogenic to human beings by the International Agency for Research on Cancer. We calculated the number of new cancer cases in 2012 attributable to infections by country, by combining cancer incidence estimates (from GLOBOCAN 2012) with estimates of attributable fraction (AF) for the infectious agents. AF estimates were calculated from the prevalence of infection in cancer cases and the relative risk for the infection (for some sites). Estimates of infection prevalence, relative risk, and corresponding 95% CIs for AF were obtained from systematic reviews and pooled analyses. Findings: Of 14 million new cancer cases in 2012, 2·2 million (15·4%) were attributable to carcinogenic infections. The most important infectious agents worldwide were Helicobacter pylori (770 000 cases), human papillomavirus (640 000), hepatitis B virus (420 000), hepatitis C virus (170 000), and Epstein-Barr virus (120 000). Kaposi's sarcoma was the second largest contributor to the cancer burden in sub-Saharan Africa. The AFs for infection varied by country and development status—from less than 5% in the USA, Canada, Australia, New Zealand, and some countries in western and northern Europe to more than 50% in some countries in sub-Saharan Africa. Interpretation: A large potential exists for reducing the burden of cancer caused by infections. Socioeconomic development is associated with a decrease in infection-associated cancers; however, to reduce the incidence of these cancers without delay, population-based vaccination and screen-and-treat programmes should be made accessible and available. Funding: Fondation de France.
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Background: Neuroendocrine neoplasms (NEN) are rare cancers mainly of lung and digestive tract. Little is known on risk factors. Aim of this work is to define the risk factors for NEN development by extensive review and meta-analysis of published data. Methods: The search was conducted on Medline, Scopus, and Web of Science following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The Newcastle-Ottawa scale was used for study quality. Meta-analyses were conducted by primary site. OR, HR, RR, SIR and associated 95% CI were abstracted. Data were combined and analyses performed for risk factors considered by at least two studies. Random effects model was adopted for study variation. Results: Of 1535 extracted articles 24 were enrolled. Meta-analyses were possible for pancreas, small intestine, and rectum. Risk for NEN associated with: i) family history of cancer at all investigated sites (lung, stomach, pancreas, small intestine, appendix and colon; OR 2.12- [95% CI: 1.40-3.22, I(2)=0.0%, p=0.681] at meta-analysis in pancreas); ii) body mass index or diabetes (stomach, pancreas and small intestine; OR of 2.76 [95% CI: 1.65-4.64, I(2)=58.5%, p=0.090] for diabetes at meta analysis in pancreas); iii) cigarette smoking (lung, stomach, pancreas and small intestine; OR of 1.34 [95% CI: 1.10-1.63, I(2)=0.0%, p=0.780] and of 1.59 [95% CI: 1.07-2.37, I(2)=32.9%, p=0.225] for smokers vs never smokers at meta-analysis for pancreas and small intestine); iv) alcohol consumption (pancreas and rectum; OR of 2.44 [95% CI: 1.07-5.59, I(2)=65.8%, p=0.054] and of 1.53 [95% CI: 0.99-2.35, I(2)=0.0%, p=0.630] for heavy drinkers vs never drinkers at meta-analysis for pancreas and rectum). Conclusions: Family history of cancer is the most relevant risk factor for NEN development at all investigated sites, followed by body mass index and diabetes. Cigarette smoking and alcohol consumption are potential risk factors for selected anatomical sites.
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Background: While incidence rates of breast cancer molecular subtypes are well documented, effects of molecular subtypes on breast cancer-specific survival using largest population coverage to date are unknown in the U.S. Population: Methods: Using SEER (Surveillance, Epidemiology and End Results) cancer registry data, we assessed survival after breast cancer diagnosis among women diagnosed during 2010-2013 and followed through 12/31/2014. Breast cancer molecular subtypes defined by joint hormone receptor (HR, estrogen receptor [ER] and/or progesterone receptor [PR]) and HER2 status were assessed. Multiple imputation was used to fill in missing receptor status. Four-year breast cancer-specific survival per molecular subtypes and clinical/demographic factors were calculated. A cox proportional hazards model was used to evaluate survival while controlling for clinical and demographic factors. Results: The best survival pattern was observed among women with HR+/HER2- subtype (survival rate of 92.5% at four years), followed by HR+/HER2+ (90.3%), HR-/HER2+ (82.7%), and finally worst survival for triple-negative subtype (77.0%). Notably, failing to impute cases with missing receptor status leads to overestimation of survival because those with missing receptor status tend to have worse prognostic features. Survival differed substantially by stage at diagnosis. Among de novo stage IV disease, women with HR+/HER2+ subtype experienced better survival than those with HR+/HER2- subtype (45.5% vs 35.9%), even after controlling for other factors. Conclusions: Divergence of survival curves in stage IV HR+/HER2+ vs. HR+/HER2- subtype is likely attributable to major advances in HER2-targeted treatment. Impact: Contrary to conventional thought, HR+/HER2+ subtype experienced better survival than HR+/HER2- in advanced stage disease.
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Background: In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014. Methods: CONCORD-3 includes individual records for 37·5 million patients diagnosed with cancer during the 15-year period 2000-14. Data were provided by 322 population-based cancer registries in 71 countries and territories, 47 of which provided data with 100% population coverage. The study includes 18 cancers or groups of cancers: oesophagus, stomach, colon, rectum, liver, pancreas, lung, breast (women), cervix, ovary, prostate, and melanoma of the skin in adults, and brain tumours, leukaemias, and lymphomas in both adults and children. Standardised quality control procedures were applied; errors were rectified by the registry concerned. We estimated 5-year net survival. Estimates were age-standardised with the International Cancer Survival Standard weights. Findings: For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden. For many cancers, Denmark is closing the survival gap with the other Nordic countries. Survival trends are generally increasing, even for some of the more lethal cancers: in some countries, survival has increased by up to 5% for cancers of the liver, pancreas, and lung. For women diagnosed during 2010-14, 5-year survival for breast cancer is now 89·5% in Australia and 90·2% in the USA, but international differences remain very wide, with levels as low as 66·1% in India. For gastrointestinal cancers, the highest levels of 5-year survival are seen in southeast Asia: in South Korea for cancers of the stomach (68·9%), colon (71·8%), and rectum (71·1%); in Japan for oesophageal cancer (36·0%); and in Taiwan for liver cancer (27·9%). By contrast, in the same world region, survival is generally lower than elsewhere for melanoma of the skin (59·9% in South Korea, 52·1% in Taiwan, and 49·6% in China), and for both lymphoid malignancies (52·5%, 50·5%, and 38·3%) and myeloid malignancies (45·9%, 33·4%, and 24·8%). For children diagnosed during 2010-14, 5-year survival for acute lymphoblastic leukaemia ranged from 49·8% in Ecuador to 95·2% in Finland. 5-year survival from brain tumours in children is higher than for adults but the global range is very wide (from 28·9% in Brazil to nearly 80% in Sweden and Denmark). Interpretation: The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer. Funding: American Cancer Society; Centers for Disease Control and Prevention; Swiss Re; Swiss Cancer Research foundation; Swiss Cancer League; Institut National du Cancer; La Ligue Contre le Cancer; Rossy Family Foundation; US National Cancer Institute; and the Susan G Komen Foundation.
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Background: Major salivary gland cancers (M-SGCs) are rare, and have distinct heterogeneous histopathological subtypes. To the authors' knowledge, no consistent evidence of an association between cigarette smoking and the risk of M-SGCs has appeared to date. Furthermore, evidence of potential heterogeneity in the impact of smoking on histopathological subtypes is scarce, despite the fact that the histopathological subtypes of M-SGC exhibit different genetic features. Methods: The authors conducted a case-control study to investigate the association between smoking and M-SGC by histopathological subtype. Cases were 81 patients with M-SGCs and the controls were 810 age-matched and sex-matched first-visit outpatients without cancer treated at Aichi Cancer Center Hospital from 1988 to 2005. Odds ratios (OR) and 95% confidence intervals (95% CI) were assessed by conditional logistic regression analysis with adjustment for potential confounders. Results: Smoking was found to be associated with a significantly increased risk of M-SGC overall, with an OR of 3.45 (95% CI, 1.58-7.51; P =.001) for heavy smokers compared with never-smokers. A significant dose-response relationship was observed (P for trend, .001). When stratified by histological subtype, no obvious impact of smoking was observed among patients with mucoepidermoid carcinoma (MEC). In contrast, smoking demonstrated a significantly increased risk of M-SGCs other than MEC, with an OR of 5.15 (95% CI, 2.06-12.87; P<.001) for heavy smokers compared with never-smokers. The authors observed possible heterogeneity with regard to the impact of smoking on risk between MEC and M-SGCs other than MEC (P for heterogeneity, .052). Conclusions: The results of the current study demonstrate a significant positive association between cigarette smoking and the risk of M-SGC overall. However, the impact of smoking appeared to be limited to M-SGCs other than MEC. Cancer 2017. © 2017 American Cancer Society.
Article
Background Rare cancers pose challenges for diagnosis, treatments, and clinical decision making. Information about rare cancers is scant. The RARECARE project defined rare cancers as those with an annual incidence of less than six per 100 000 people in European Union (EU). We updated the estimates of the burden of rare cancers in Europe, their time trends in incidence and survival, and provide information about centralisation of treatments in seven European countries. Methods We analysed data from 94 cancer registries for more than 2 million rare cancer diagnoses, to estimate European incidence and survival in 2000–07 and the corresponding time trends during 1995–2007. Incidence was calculated as the number of new cases divided by the corresponding total person-years in the population. 5-year relative survival was calculated by the Ederer-2 method. Seven registries (Belgium, Bulgaria, Finland, Ireland, the Netherlands, Slovenia, and the Navarra region in Spain) provided additional data for hospitals treating about 220 000 cases diagnosed in 2000–07. We also calculated hospital volume admission as the number of treatments provided by each hospital rare cancer group sharing the same referral pattern. Findings Rare cancers accounted for 24% of all cancers diagnosed in the EU during 2000–07. The overall incidence rose annually by 0.5% (99·8% CI 0·3–0·8). 5-year relative survival for all rare cancers was 48·5% (95% CI 48·4 to 48·6), compared with 63·4% (95% CI 63·3 to 63·4) for all common cancers. 5-year relative survival increased (overall 2·9%, 95% CI 2·7 to 3·2), from 1999–2001 to 2007–09, and for most rare cancers, with the largest increases for haematological tumours and sarcomas. The amount of centralisation of rare cancer treatment varied widely between cancers and between countries. The Netherlands and Slovenia had the highest treatment volumes. Interpretation Our study benefits from the largest pool of population-based registries to estimate incidence and survival of about 200 rare cancers. Incidence trends can be explained by changes in known risk factors, improved diagnosis, and registration problems. Survival could be improved by early diagnosis, new treatments, and improved case management. The centralisation of treatment could be improved in the seven European countries we studied. Funding The European Commission (Chafea).
Article
There are limited published data on the burden of rare cancers in the United States. By using data from the North American Association of Central Cancer Registries and the Surveillance, Epidemiology, and End Results program, the authors provide information on incidence rates, stage at diagnosis, and survival for more than 100 rare cancers (defined as an incidence of fewer than 6 cases per 100,000 individuals per year) in the United States. Overall, approximately 20% of patients with cancer in the United States are diagnosed with a rare cancer. Rare cancers make up a larger proportion of cancers diagnosed in Hispanic (24%) and Asian/Pacific Islander (22%) patients compared with non-Hispanic blacks (20%) and non-Hispanic whites (19%). More than two-thirds (71%) of cancers occurring in children and adolescents are rare cancers compared with less than 20% of cancers diagnosed in patients aged 65 years and older. Among solid tumors, 59% of rare cancers are diagnosed at regional or distant stages compared with 45% of common cancers. In part because of this stage distribution, 5-year relative survival is poorer for patients with a rare cancer compared with those diagnosed with a common cancer among both males (55% vs 75%) and females (60% vs 74%). However, 5-year relative survival is substantially higher for children and adolescents diagnosed with a rare cancer (82%) than for adults (46% for ages 65-79 years). Continued efforts are needed to develop interventions for prevention, early detection, and treatment to reduce the burden of rare cancers. Such discoveries can often advance knowledge for all cancers. CA Cancer J Clin 2017. © 2017 American Cancer Society.
Article
Cancer constitutes an enormous burden on society in more and less economically developed countries alike. The occurrence of cancer is increasing because of the growth and aging of the population, as well as an increasing prevalence of established risk factors such as smoking, overweight, physical inactivity, and changing reproductive patterns associated with urbanization and economic development. Based on GLOBOCAN estimates, about 14.1 million new cancer cases and 8.2 million deaths occurred in 2012 worldwide. Over the years, the burden has shifted to less developed countries, which currently account for about 57% of cases and 65% of cancer deaths worldwide. Lung cancer is the leading cause of cancer death among males in both more and less developed countries, and has surpassed breast cancer as the leading cause of cancer death among females in more developed countries; breast cancer remains the leading cause of cancer death among females in less developed countries. Other leading causes of cancer death in more developed countries include colorectal cancer among males and females and prostate cancer among males. In less developed countries, liver and stomach cancer among males and cervical cancer among females are also leading causes of cancer death. Although incidence rates for all cancers combined are nearly twice as high in more developed than in less developed countries in both males and females, mortality rates are only 8% to 15% higher in more developed countries. This disparity reflects regional differences in the mix of cancers, which is affected by risk factors and detection practices, and/or the availability of treatment. Risk factors associated with the leading causes of cancer death include tobacco use (lung, colorectal, stomach, and liver cancer), overweight/obesity and physical inactivity (breast and colorectal cancer), and infection (liver, stomach, and cervical cancer). A substantial portion of cancer cases and deaths could be prevented by broadly applying effective prevention measures, such as tobacco control, vaccination, and the use of early detection tests. CA Cancer J Clin 2015;65: 87-108. (c) 2015 American Cancer Society.