Cancer prevalence and mortality in centenarians: A systematic review

Critical Reviews in Oncology/Hematology 83 (2012) 145–152

Cancer prevalence and mortality in centenarians: A systematic review Nicholas Pavlidis a,∗ , Giorgio Stanta b , Riccardo A. Audisio c a

Department of Medical Oncology, Medical School, University of Ioannina, 451 10 Ioannina, Greece b Department of Medicine, Surgery and Health Science, University of Trieste, Italy c University of Liverpool, St Helens Teaching Hospital, St Helens WA9 3DA, United Kingdom Accepted 29 September 2011

Contents 1. 2. 3.

4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Data sources and demographics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Does the prevalence/incidence of cancer decrease after age 90? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. How often cancer is the cause of death in centenarians? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Which are the most frequent primary tumours in centenarians? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Does the metastatic rate differ in centenarians? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Are incidental cancers commonly discovered in centenarians? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. What is the incidence of multiple primary cancers in centenarians? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

146 146 146 146 146 148 148 148 149 149 149 150 150 150 151 152

Abstract Life expectancy has dramatically expanded, the global population has aged unprecedentedly and the number of centenarians has significantly increased. The analysis of autopsy series, cancer registries data, vital statistics and surveys specific to this age group allows unique observations with respect to incidence and prevalence, cause of death by cancer, frequency of primary tumours, metastatic patterns, occurrence of incidental cancers and of multiple primary tumours. Data analysis demonstrates how cancer incidence and cause of death present a threefold decrease after age 90 and reach 0–4% above age 100. In addition, the number of metastatic sites are remarkably less and incidental malignant tumours or multiple primary cancers are more frequent, indicating that cancer in centenarians carries a more indolent behaviour. The unique features of malignant tumours in this population is hereby presented and discussed following a systematic review of the available literature. Cancer in the very elderly is relatively uncommon as a disease and as a cause of death. It is characterized by a slow growth and a modest life-threatening potential. © 2011 Elsevier Ireland Ltd. All rights reserved. Keywords: Centenarians; Cancer; Mortality; Incidence; Cause of death

∗

Corresponding author. Tel.: +30 26510 99394; fax: +30 26510 99394. E-mail address: [email protected] (N. Pavlidis).

1040-8428/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2011.09.007

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N. Pavlidis et al. / Critical Reviews in Oncology/Hematology 83 (2012) 145–152

1. Introduction Worldwide, life expectancy at birth has been expanding during the last two centuries, especially in the second part of the 20th century, resulting into a major increase in the older age group. Since centenarians and supercentenarians surpass the current human life expectancy by 20–25 years, they represent the best model to study human longevity and to investigate the “healthy aging model”. Centenarians have been healthy throughout their lives and different geographical areas associate with a remarkable longevity such as the Japanese island of Okinawa, Sardinia in Italy or Loma Linda in California [1–6]. It has been clearly demonstrated that cancer is an age-related disease and that advanced age associated to the highest cancer risk. Although the incidence of cancer rises exponentially up to the 80s, there is adequate evidence to say that centenarians can be protected from various common chronic fatal conditions, including cancer. Decreased cancer prevalence, mortality and cancer related deaths, have been repeatedly reported in the very advanced age groups as compared to the earlier decades of life [7–10]. Clinically evident tumours decrease after the eighties and autopsy studies performed in unselected populations clearly show how cancer prevalence decrease and tumour spread is limited. Metastatic disease is less frequent in nonagenarians and centenarians and where the tumour takes the patient to death, this is often related to local complications like haemorrhage or infections [11]. In this article we systematically review the literature evidence related to cancer prevalence, cancer mortality, cancer as cause of death, the incidence of primary sites, of multiple cancers and of incidental cancers as well as the metastatic pattern of the oldest individuals.

2. Materials and methods We searched the MEDLINE (last search, February 2011) online database with the keywords: (centenarians OR supercentenarians OR nonagenarians OR old age OR very elderly OR geriatric) AND (cancer incidence OR morbidity OR mortality OR cause of death) AND (cancer registries OR autopsies OR forensic pathology). We reviewed articles in English language. Cross-searches were performed on MEDLINE using the names of investigators who were lead authors in at least one article. Our intention was to perform a narrative systematic review of the existent literature regarding the incidence, prevalence, morbidity, mortality and cause of death by cancer in centenarians. In addition, we aimed to search whether centenarians differ from younger ages concerning the incidence of primary tumours, the metastatic potential as well as the rate of incidental tumours or of a second or more primary cancers.

We looked at two different sources: (a) all articles including autopsy data and (b) data derived from cancer registries, vital statistics, questionnaires or surveys.

3. Results 3.1. Data sources and demographics Sixteen articles referred to autopsy studies and 7 were deriving from Vital Statistics, cancer registries, death certificates or surveys using questionnaires. The time period of these studies was ranging from 1918 to 2002. Thirty-nine percent of the studies were originated from USA, 34% from Europe (Italy, Netherlands, Austria, Iceland, Switzerland and Czech Republic), 21% from Japan, 4% from New Zealand and 4% from Brazil. One of these studies was a collaboration between USA and the Czech Republic. Nine (39%) out of the 23 articles were published in the decade 2000–2010, 7 (30%) between 1993–1999, 5 (22%) between 1982 and 1987 and only 2 (9%) in the 1970s (Tables 1 and 2). In total, 61,670 autopsies were included in the 16 used studies, 5675 of which were performed on centenarians. The oldest groups were 360 individuals aged ≥85 years, 4248 ≥ 90, 846 ≥ 90–100 and 221 aged ≥100 years. Several studies utilized control groups of younger ages. 3.2. Does the prevalence/incidence of cancer decrease after age 90? Incidence data from the SEER (Surveillance, epidemiology, and end results) U.S. Cancer Registry covering almost 26% of the US population for the period 1973–2003, demonstrated that the incidence of almost all cancers increases with age to about age 80. Interestly, incidence decreases after age 80 and drops close to zero after age 100 [12]. Post-mortem studies show how cancer prevalence is the highest in the age groups 60–70 and 70–80 years (ranging between 25% and 42%, respectively) but it gradually diminishes in the age group 80–90 and even more above age 90 (median: 16%) (Tables 1 and 2). Prevalence of breast cancer was carefully studied in 517 unselected consecutive necropsies: the presence of undetected carcinomas, of diagnosed but undertreated breast cancers and of previously treated carcinomas, was shown to have a similar prevalence in the age groups <80years, 80–90 years and >90 [13]. Noticeably, two Japanese autopsy studies during the period 1982–1996 showed no difference in cancer prevalence between centenarians and younger age groups [14,15]. However, two earlier Japanese reports (1955–1977) observed a striking decline in cancer incidence for centenarians [16,17].

Table 1 Cancer in centenarians. Data from autopsy studies. Country

Oldest ages (yrs)

Period

No autopsiesb Total/old ages (yrs)

Groups age (%)

1974 [31]

USA

≥86

1960–1970

3535/160 (>86)

I: >86: 36.2% II: 76–85: 29.4% III: 66–75: 20.7% I: 90–>95: 37.5% II: 80–89: 58.7% III: 65–79: 69.1% I: ≥90–100+: 1% II: 80–89: 20.4%

1979 [17]

Japan

≥90

1955–1977

940/8 (>90)

1980 [16]

Japan

≥90–100+

1971–1975

5106/395 (>90)

1982 [18] 1983 [19]

USA Iceland

>85 >90

1967–1980 1966–1979

–/200 (>85) 200/100 (>90)

1987 [29] 1993 [30] 1997 [11]

USA Switzerland Italy

>100 100–102 95–106

1918–1985 1972–1992 1977–1997

–/32 3000/9 (>100) 507/267 (>95)

1997 [20]

USA/Czech Republic

>90

1985–1990

761/486 (>80)

1997 [14]

1999 [33]

Japan

Italy

≥90–100+

97–106

1982–1994

1984–1989

350/88 (>90)

265/114 (>97)

Cancer prevalence

– – I: 7.1% II: 9.5% III: 25% >80: 10%

II: 70–79: 25%

70–79: 25%

I: ≥90–100: 43% II: 89–75: 40.3% III: 74–48: 37.5%

I: 28.6% II: 45.6% III: 46%

I: 97–106: 6% II: 74–65: 42%

– I: 16.6% II: 20.8% III: 24.6% 2%

≥100: 0% >85: 27% >90s: 3.1% 80s: 6.1% 70s: 26% 60s: 33% –

1991–1996

–/3320 (>90)

2001 [21]

New Zealand

≥90

1988–1998

319

I: 100+: 45.8% II: 99–95: 46.5% III: 94–90: 47.5% –

2005 [22]

Austria

100–108

1985–2002

42,398/40 (>100)

–

2009 [23]

Brazil

≥90

1971–2000

533/15 (≥90)

236/140 (100–109)

–

40.6% 11.1% I: ≥99–106: 16% II: 95–98: 20% III: 75–90: 35% I: >80: 10%

≥90

100–109

–

–

–

Japan

Italy

Primary sitesa

100+: 0% 90–99: 25–30% 80–89: 45–50% 11.5% I: >90: 25% II: ≤70: 32%

2000 [15]

2010 [32]

Cancer death

(I) 100–109: 16.3% (II) 95–75: 39%

Metastatic rate

Rate of multiple cancers

I: 46.9% II: 53.9% III: 59.5% I: 66.7% II: 74.2% III: 74.3%

I: 11.6% II: 8.4% III: 10% I: 0% II: 12.6% III: 9.1%

–

–

–

–

–

–

– – I: 23.5% II: 30.6% III: 63.2%

– – I: 0% II: 10% III: 7%

GU 20% Lung 8.5% Prostate 17.4%

–

–

I: 25.6%

I: 8.3%

Colon: 12% Gastric 9.5% GI: 28.5% Gyn/Breast: 28.5% Lung: 14.3% Gastric: 10.2% Colon; 6.8% Lung: 6% Prostate: 33% CUP: 33% Lung: 17% –

II: 39.3% III: 58%

II: 21.6% III: 10.5%

–

–

I: 37.5% II: 41.5% III: 50.5% –

I: 7.2% II: 8.3% III: 9.4% –

–

–

–

–

–

Colon: 24% Prostate: 4.6% Breast; 2.5%

I: 26% II: 55%

–

Gastric 22.5% Lung 12.2% Hepatobilliary 10.1% Gastric 33.5% Hepatobilliary 20.5% Lung 15.9% – Gastric 7% Colon 5% Oesophagus 3% Adenocarcinoma 80% Hodgkin (1 patient) Breast 17% Colon 13.2% Gallbladder 11.3% GI 24.8%

N. Pavlidis et al. / Critical Reviews in Oncology/Hematology 83 (2012) 145–152

Year (ref)

yrs = years. a The 3 most common ones b 5675 centenarian autopsies out of 61.670 total autopsies. 147

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N. Pavlidis et al. / Critical Reviews in Oncology/Hematology 83 (2012) 145–152

Table 2 Cancer in centenarians. Data from other sources. Year

Country

Oldest ages (yrs)

Period

Source

1982 [18]

USA

80–100

1976

Vital statistics Death certificates

–

Vital statistics Census data

–

–

California Cancer Registry

–

90s: 2% >100s: 0.06%

Netherlands

95+: 0.3%

95+: 7–11%

Cancer Registry

≥85: 8.2%

55–64: 42–52%

1996 [26]

1998 [27]

2000 [24]

2002 [28]

USA

USA

Netherlands

USA

≥90–100+

≥90 ≥95

≥90–100+

1990

1988–1993

1989–1995

1998

Prevalence/ Incidence

Death certificates –

2005 [12]

2007 [25]

USA

Japan

≥90

99–103

Health questionnaire (SEER data)

1992–2002

Mail survey

≥90: 20.3%

Cancer death 80s: 22% 90s: 12% 95s: 5% 100s: 0%

100+: 4.7% 90–99: 9.3% 80–89: 18.7% 70–79: 31.2% –

9.9% –

a

Primary tumours

Cancer mortality

–

–

Colorectal 13.5% Breast 13%

100+: 4% 50–69: 35–40%

Prostate 6% Colorectal: 20.8% Prostate: 13.1% Breast: 12.1% Colorectal 16%

Breast 11% Prostate 9.5% a Colorectal 2.6% Breast 1.5% Prostate 1.5% Breast: 28.7% Colorectal: 28.7% Prostate: 18.5% Breast: 30% Colon: 20% Gastric: 10%

– Increases continuously even at ages of 95+

–

–

–

Distribution of all causes of death (non-cancer and cancer).

3.3. How often cancer is the cause of death in centenarians? It appears that among the oldest-olds, cancer death is not related to tumour spread but most frequently to other causes such as bleeding due to stomach cancer, chest infection to due lung cancer, pulmonary embolism for pancreatic tumours, jaundice for gallbladder cancer, pneumonia “ab ingestis” for upper respiratory tract tumours or diffuse amyloidosis for multiple myelomas [11]. Although some autoptic studies seem to indicate how cancer frequency is still somehow high among centenarians, cancer mortality or cancer as cause of death decrease remarkably with age progression (median 21% for 90–99 years vs. 4% after age 100 years). This compares to a cancer mortality ranging between 25% and 46% for age groups younger than 80 (Tables 1 and 2) [11,14–16,18–24].

28.7%) and breast cancer (up to 28.7%) are the most frequent cancer sites, while pancreatic cancer (0.5%) is less frequent [12,20,26–30] (Tables 1 and 2). When gender is taken into account, Ishi et al. found stomach cancer to be the most common cancer in both males and females (21.3% and 12.2%, respectively), followed by prostate in men (12.7%) and lung cancer (6.4% in males and 9.5% in females) [16,17]. Stanta et al. showed prostate (28.5%), pancreatic (14.3%) and gall bladder cancers (14.3%) to be the most frequent neoplasms among males, and breast (23%), colon (12.8%) and stomach cancer (7.7%) among females [11]. Finally, a Californian Cancer Registry study noticed how prostate (32.8%), colon (16.2%) and lung cancer (10.9%) were the most frequently diagnosed malignancies in men, whereas were colon (23.9%), breast (20%) and haematological malignancies (8.8%) were the most common ones in women [27].

3.4. Which are the most frequent primary tumours in centenarians? 3.5. Does the metastatic rate differ in centenarians? The frequency of primary tumour sites among centenarians differs between studies and countries. For example, in Japan the most common primary site is gastric cancer (up to 33.5%) and the less common is ovarian cancer (up to 0.6%) [14–16,25]. On the contrary, in US colon cancer (up to

The incidence of metastatic sites in 6 autoptic studies was almost double in the younger group of patients as compared with centenarians (median 59% vs. 32%) [11,14,15,17,31,32].

N. Pavlidis et al. / Critical Reviews in Oncology/Hematology 83 (2012) 145–152

In the study by Suen et al. the distribution of metastases by site between patients older than 86 years and those younger than 75 years showed significant variation: lung cancer 45.5% vs. 75%, breast cancer 40% vs. 64% and rectal cancer 25% vs. 55.5%, respectively [31]. This indicates that the metastatic potential in the oldest olds is less prominent, suggesting a far less aggressive behaviour for cancer in centenarians (Table 1). On the other hand, one should keep in mind that older people die earlier due to other diseases, even without any anticancer treatment, leading to decrease chance to develop metastatic disease. 3.6. Are incidental cancers commonly discovered in centenarians? Cancers that were not diagnosed during life and did not contribute to the cause of death are regarded as incidental cancers. Suen et al. conducted post-mortem studies on 3535 patients >65 years and reported how incidental cancers were more frequent in patients >86 years (36.2%) as compared to patients >75 years of age (20.7%). The most common incidental cancers were prostate (62.5%), uterine (60%), rectal (50%), colonic (44%), gastric (37.5%) and lung cancers (36.5%) [31]. Imaida et al. discovered a 45.4% incidence of latent cancers among 350 autopsies where colon (10.6%) and lung (8.5%) cancer were found to be the most frequently detected at post-mortem examination [14]. Also, Ishii et al. observed two incidental cancers out of eight patients (one thyroid and one colorectal cancer) in a series of patients aged >90 years [17]. Bordin et al., out of 114 consecutive autopsies on patients aged 97–106 years, reported 16 cancers of which 7 were related to cancer death and 9 were incidental cancers [33]. It can therefore be concluded that the available literature shows a high rate of clinically undetected cancers in the oldest olds. 3.7. What is the incidence of multiple primary cancers in centenarians? Only 5 of the 16 available autoptic series present data on the incidence of multiple primary cancers. Double or triple cancers were found in almost 8% after age 90 [11,14,15,17,31]. Suen et al. showed that none of the cancer patients aged 66–75 years had more than two cancers, 1.1% patients aged 76–85 years had three cancers and 3.5% of the oldest group (≥86 years old) had three or more cancers [31]. The real incidence of multiple primary cancers in centenarians is not known, some authors suggest that the longer the cancer patients live, the more likely that they are to develop a second primary tumour, but most autoptic studies do not support this hypothesis.

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4. Discussion In the U.S.A. the number of people aged ≥85 years was 0.3% of the onational population (365,000) in 1940, and increased to 1.5% (4.2 million) in 2000 [34]. As life expectancy continues to increase we should expect to come across more age-related diseases. However, centenarians seem to be represent a potential exception: they markedly delay or escape age-associated morbidity from chronic degenerative illnesses such as cardiovascular disease, cancer, Alzheimer’s or diabetes. The literature suggests that centenarians have a relatively lower incidence of cancer. Data from autoptic studies or Cancer Registries, vital statistics or surveys, demonstrate how the very elderly people are somehow protected from developing malignant diseases. The present report is the first systematic review on cancer development in very old ages, to attempt collecting all existing data on incidence, prevalence, causes of death and frequency of primary tumours, incidental tumours, multiple cancers and metastases. The major cause of death among centenarians seems to be cardiovascular diseases or respiratory infections. Malignancies account as an infrequent cause of death. Berzlanovich et al. in an Austrian autopsy report on 40 centenarians (aged 100–108 years old) found that cardiovascular disease (predominantly chronic heart failure) was the main cause of death (68%) followed by respiratory disease (25%). Cerebrovascular disease and cancer were found in 2% and 0%, respectively [22]. Also, in a New Zealand forensic study with 319 centenarians (≥90 years old) the most frequent cause of death was ischemic heart disease (23%), bronchopneumonia (12%) and fractures (9%), while cancer accounted for only 2% [20]. In addition, in a large series of 1886 autopsied patients aged 85–108 years with unexpected out-of-hospital deaths, 77% causes of death were attributed to cardiovascular disease [35]. More recently, Motta et al. in an autopsy series of 140 centenarians (100–109 years old) showed that the most common pathologies were chest infections (40.4%), ischemic cardiopathies (37.8%) and cerebral ischemia (23.4%). Cancer was diagnosed in only 16.3% cases [32]. It must also be considered that in centenarians, deaths related to cancer are not often associated with tumour spreading but with other complications such as haemorrhage or infections [11]. It is important to point out that autopsy data should be taken with cautious since some of these sources are relatively old. According to autoptic data on centenarians the most frequent primary cancer sites for both genders affect the gastrointestinal track (predominantly gastric and colorectal cancers) with a prevalence of gastric cancer usually seen in Japanese studies [14–16,25]. Similarly, US reports from Vital Statistics, cancer registries, SEER data and surveys, showed that colorectal cancer is the most frequent cancer site and breast cancer the second most common primary tumour [12].

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Another important issue is to distinguish between “dying from cancer” and “dying with cancer”. This actually reflects two different findings: (a) cancer as the cause of death and (b) the incidence of incidental tumours among these individuals: the percentage of cancer deaths is decreasing remarkably in older ages. Among centenarians cancer mortality ranges 0–4% and it’s around 20–25% in nonagenarians [11,14–16,18–23]. Despite the fact that some malignancies are more frequent among the oldest olds (i.e. prostate cancer and latent tumours) these cancers are unlikely to be related to the cause of death. Latent or incidental cancers are much more frequent in very old people as compared to younger ones, as the result of a lower diagnostic accuracy in these patients. These findings are derived from autopsy series where the most common incidental cancers identified were of prostate, kidney, colon or thyroid. It has also been reported that the metastatic rate declines with advanced age [11,14,15,17]. Despite the discrepancy in cancer prevalence among several studies with oldest-olds, the median prevalence is still 16% ranging from 0.3% to 20%. Indeed, in two Japanese studies the prevalence was more than 40%, however deaths due to cancer as well as incidence of latent cancers differed significantly in these age groups indicating that individuals of advanced age have less malignancy potential. Interestingly, it has been reported that centenarians’ offspring have a lower all-cause mortality rates by 62%, cause-specific mortality rates for cancer by 71% and by 85% for coronary heart disease [36]. There is additional evidence that relative survival probabilities of siblings and mothers of supercentenarians showed substantial survival advantage more pronounced at the oldest ages [37]. Although the aetiology underling this phenomenon is not completely clear, various mechanisms have been implicated such as reduced tumour cell proliferation, increased apoptosis, decreased ploidy, immune response modifications, reduced angiogenesis, shortening of telomere length or capillary sclerosis induced in aging [11,38–41]. In advanced aging there is a progressive loss of stresscoping capacity taking to what is frequently called frailty, representing an exhaustion of any physiological reserve [42] and a defined pathology pattern [43]. This may be shown by the impairment of the haemopoietic reserve with a progressive reduction of the pluripotent haemopoietic stem cell and their proliferation inhibition by inflammatory cytokines such as IL-6 and TNF, detected in frail patients [44–46]. The assumption that frailty could be involved in the reduction of tumour prevalence in the extreme ages of life is supported by the fact that oldest people with cancer present higher functional levels and less comorbidity than those without cancer [47–49]. Aging cells present increasing alterations similar to cancer such as DNA mutations, hypermethylation, and formation of adducts [50,51], that can lead to activation of oncogenes and inactivation of tumour suppressor genes and to lose the ability

to undergo apoptosis [52]. All these lesions could be caused by a protracted exposure to carcinogens [53]. Senescent cells are also more susceptible to carcinogens than young ones [50]. That aging and cancer are strictly connected, is also supported by the progeroid syndromes in which an early aging and an increased cancer incidence are related to accumulation of DNA reparation errors. P53, IGF-1 and mTOR pathways have an impact upon longevity and protection from late onset diseases such as cancer and diabetes [54,55]. Recently, the discovery of particular polymorphisms in these pathways were associated with increase longevity in both experimental animals and human populations i.e. Arg72Pro polymorphism of p53 pathway or SNPs in the human Forkhead box O3 A gene (F0X03 A) of IGF-1 pathway [56,57]. Also, inflammatory cytokines gene polymorphisms of the pro-inflammatory cytokine IL-6 (IL-6-174GG) and of the anti-inflammatory cytokine IL-10 (IL-10-082CC) were detected in centenarians, indicating the protective effect towards chronic inflammation process in oldest people [58–61]. Adequate information is also derived from experimental animals, such as mice, rats or dogs. It has been shown that in elderly animals, tumour growth is slow and metastases occur less frequently. Data are coming from several transplantable murine tumours i.e. B-16 melanoma, TRAMP-C2 (a prostate cancer cell line) or Englebreth–Holm–Swarm carcinoma mainly in C57BL mice [62–64]. Similar data were elicited from pet dogs (Rottweiler dogs), where extreme aged dogs of ≥13.3 years compared with a usual longevity group of 9–10 years old. Nineteen percent of extreme aged dogs died of cancer vs. 82% of the younger group [65]. 5. Conclusions Despite any possible biases of selection due to the lack of large amount of recent data the epidemiology of cancer in individuals of very advanced age could be characterized by: (a) decrease prevalence, (b) increase incidence of latent or incidental tumours, (c) decrease metastatic rate, (d) probably higher incidence of multiple primary cancers and (e) decrease cancer mortality. In general, cancer in oldest-olds seem to be a more silent disease, of slower growth and of less-threatening potential. Conflict of interest None declared.

Reviewers Professor Lodovico Balducci, M.D., H. Lee Moffitt Cancer Center and Research Institute, Senior Adult Oncology Program, Tampa, FL 33612, United States.

N. Pavlidis et al. / Critical Reviews in Oncology/Hematology 83 (2012) 145–152

Catherine Terret, M.D., Ph.D., Centre Léon Bérard, Department of Medical Oncology, 28, rue Laënnec, F-69373 Lyon Cedex 08, France.

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Biographies Nicholas Pavlidis M.D., Ph.D. is professor of medical oncology in the University of Ioannina, Greece. He is a member of the Steering Committee of ESMO Educational Committee and Chairman of the Guidelines Working Group. He is the programme coordinator and Chairman of European School of Oncology for Euro-Arab (EASO), of Annual ESO Masterclasses and of the Annual ESO Course for Medical Students. He is Editor-in-Chief of Cancer Treatment Reviews and Associate Editor of European Journal of Clinical Investigation. Giorgio Stanta is Professor of Pathology at the University of Trieste. For many years his main interests have been tumour epidemiology especially in the elderly and molecular pathology in fixed and paraffin-embedded tissues, called “archive tissues”. He has developed several methods in particular for RNA analysis in archive tissues. Prof. Stanta is the coordinator of the European group IMPACTS (www.impactsnetwork.eu), which involves over 20 European Universities in 11 different countries and whose task is to validate molecular methods for translational research and diagnostics in archive tissues. He is interested in the development of biobanking networks, starting from archive tissue biorepositories. The IMPACTS research group has prepared the Guidelines for Molecular Analysis in Archive Tissues, recently published by Springer Verlag. Riccardo A. Audisio was trained at the National Cancer Institute of Milan (1980–1994) he was appointed deputy director at the Department of General Surgery of European Institute of Oncology, Milan (1994–1998). He moved to the United Kingdom in 1999 to become Consultant Surgical Oncologist and Honorary Professor at the University of Liverpool. He is Editor-in-Chief of Surgical Oncology, Elsevier Publisher. He is member of several international scientific societies including BASO, ESSO, SSO, ASGBI, ESMO, ASCRS, AAA, SIOG and EUSOMA. He is ESMO Committee Member, chairs the Education & Training Committee of ESSO and is Honorary Scientific & Meeting Secretary for BASO. His clinical research focuses on Breast Cancer and Geriatric Oncology; President of SIOG (International Society of Geriatric Oncology).