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Suicide death among cancer patients: new data from northern Italy, systematic review of the last 22 years and meta-analysis
European Journal of Cancer 125 (2020) 104e113
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Original Research
Suicide death among cancer patients: new data from northern Italy, systematic review of the last 22 years and meta-analysis Alessandra Ravaioli a, Emanuele Crocetti a, Silvia Mancini a, Flavia Baldacchini a, Orietta Giuliani a, Rosa Vattiato a, Lauro Bucchi a,*, Fabio Falcini a,b a Romagna Cancer Registry, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy b Azienda Usl della Romagna, Forlı`, Italy
Received 23 May 2019; received in revised form 13 August 2019; accepted 15 August 2019
KEYWORDS Suicide death; Cancer patients; Meta-analysis; Cohort study
Abstract Background: An increased risk of death by suicide in cancer patients has been documented since decades. We evaluated the risk of death by suicide in an Italian population-based cancer case series and added the results to a systematic review and metaanalysis of the literature. Methods: The Italian series, including 127,042 primary cancer patients diagnosed between 1996 and 2014, was obtained from the Romagna Cancer Registry (northern Italy). Standardised mortality ratios (SMRs) were calculated. Regarding the systematic review and metaanalysis, the PubMed database was searched for English language studies published up to 2017. Fifty-seven potentially eligible papers were reviewed in full, and 19 of them were selected for analysis. The SMR was the first outcome, replaced by rate ratio if the SMR was not available. Findings: In the Italian case series, an increased suicide risk was found for both sexes combined (SMR Z 1.5; 95% confidence interval [CI]: 1.3e1.8), for males (SMR Z 1.6; 95% CI: 1.4e1.9) but not females (SMR Z 1.1; 95% CI: 0.7e1.7), for patients aged 55 years, with poor prognosis and advanced-stage disease and during the first year after diagnosis. The absolute excess risk of suicide was 0.9 per 10,000 patient-years. Multivariate analysis confirmed the role of univariate factors except for poor prognosis. Meta-analysis showed a strong heterogeneity between studies. The risk was significantly elevated for both sexes combined (pooled
* Corresponding author: Romagna Cancer Registry, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Piero Maroncelli 40, Meldola, 47014, FC, Italy. E-mail address: [email protected] (L. Bucchi). https://doi.org/10.1016/j.ejca.2019.08.019 0959-8049/ª 2019 Elsevier Ltd. All rights reserved.
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SMR Z 1.7; 95% CI: 1.5e1.9), men (pooled SMR Z 1.8; 95% CI: 1.6e2.0) and women (pooled SMR Z 1.4; 95% CI: 1.3e1.6). There was no evidence for small-study effects. Interpretation: The Italian study confirmed the previous common finding that cancer patients are at increased risk for suicide. A clinical multidisciplinary approach to support them is needed. ª 2019 Elsevier Ltd. All rights reserved.
1. Introduction Worldwide deaths because of suicide are a serious public health concern. Suicide represents 1.4% of all deaths (the 18th leading cause of death in 2016) [1]. The diagnosis of any serious illness may increase the likelihood of committing suicide [2]. Cancer diagnosis is one of the most dramatic events in a person’s life, and for someone, diagnosis and treatment are experienced as challenging and even life threatening. Common fears among cancer patients include severe therapeutic side-effects, insufficient pain management and physical deterioration. An increased risk of death by suicide in cancer patients has been documented since decades [3,4]. The risk has been estimated to be up to the double than in the general population of United States, Europe, Australia, Taiwan and South Korea [4e12]. The majority of studies reported a higher relative risk of committing suicide by men [4,7,9,13e16] for cancers in advanced stage at diagnosis [3,7,16,17] and particularly for some cancers with poor prognosis, such as brain, lung, head and neck, pancreas, liver and stomach cancers [3,16,18,19]. Also, the risk is greatest in the first months or the first year after diagnosis [9,12,14,16,20]. In Italy [21] and elsewhere [22], cancer survival has improved over time. Therefore, survivorship of cancer patients is an increasing issue for the health systems [23]. Once the curability of cancer is reached, other aspects previously underrated have to be faced, including late effects of treatments, multiple primaries, fertility preservation, social discrimination, return to work and suicide risk. The aim of this study is to evaluate the risk of death due to suicide in an Italian population-based cancer series and to add this result to an up-to-date systematic review of the literature. A meta-analysis will summarise and quantify the current knowledge on this topic. 2. Materials and methods 2.1. Romagna Cancer Registry data 2.1.1. Data source Records of primary cancer patients diagnosed between 1996 and 2014 (n Z 130,436) were retrieved from the Romagna Cancer Registry, which covers one-third of
the Emilia-Romagna Region (northern Italy) [24]. Patients for whom the date of diagnosis was the same as the date of death (n Z 2274), patients lost to followup (n Z 155), patients with missing information on cause of death (n Z 477), patients with synchronous tumours (n Z 367) and autopsy cases (n Z 121) were not included. This left 127,042 cancer cases (66,919 among men and 60,123 among women) available for analysis. 2.1.2. Statistical analysis Data on death were taken from the official death certificate. Cause-of-death codes for suicide and selfinflicted injuries were E950-E959 according to International Classification for Disease 9 (ICD-9) [25] and X60X84, Y870 according to ICD-10 [26]. Person-years were computed from the date of diagnosis until the date of death or end of follow-up (31 December 2015), whichever occurred first. For individuals with more than one cancer diagnosis, the date of the first cancer was considered the start of the period at risk, and the date of the second cancer was considered the end of the period at risk. Sex-, age- and calendar periodestandardised mortality ratios (SMRs) [27] were calculated by dividing the observed number of suicides by the expected one. The expected number of suicides was calculated by applying the 5-year period incidence and 5-year age-specific rates of suicide in the Emilia-Romagna general population [28] between 1996 and 2015 to the person-years of observation in the cohort. The degree of urbanisation of the municipality of residence was classified according to the EUROSTAT [29]. The survival data from the Italian Association Cancer Registries were used to create two categories of tumour prognosis: good (30% relative survival at 5 years since diagnosis) and poor (<30%) [21]. To evaluate the calendar period effect, SMRs were calculated by diagnosis periods truncating the follow-up to the first 2 years to give the same length of follow-up to each period. Assuming that data followed a Poisson distribution, the 95% confidence intervals (CIs) for SMRs were calculated. Multivariate analyses were performed to identify factors associated with increased risk of suicide [27]. We used a multivariate Poisson regression model yielding the incidence rate ratio with 95% CIs. All tests were twotailed, and statistical significance was set at p-value
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<0.05. All statistical analyses were carried out using Stata software [30]. The absolute excess risk beyond the expected amount was calculated by subtracting the expected number of suicides from the observed number. The difference was then divided by the person-years, and the number of suicides in excess (or deficit) was expressed per 10,000 patient-years [31].
2.2.2. Inclusion criteria The abstracts were reviewed using the following inclusion criteria: (i) English language; (ii) death due to suicide; (iii) population-based or cancer-registry-based study; (iv) original data; (v) all tumour sites combined; (vi) data for the one or the other gender or both genders combined; and (vii) information on the number of deaths and the SMR or the hazard ratio. For multiple studies using the same cohort, the one including the most comprehensive case series was considered.
2.2. Systematic review and meta-analysis 2.2.1. Data source and search We performed a systematic search in PubMed for those papers published before 6 November 2017 identified by the following keys: ‘Neoplasms’[Mesh] OR Neoplas* [tw] OR Tumor* [tw] OR Malignanc* [tw] OR Cancer* [tw] AND ‘Registries’[Mesh] OR registry [tw] OR population Register* [tw] OR population based [tw] AND ‘Suicide’[Mesh] OR Suicid* [tw]. No time restriction was applied. The abstracts were independently reviewed for eligibility by two authors (A.R., E.C.), and a third one (L.B.) was involved in case of disagreement.
2.2.3. Systematic review The selection identified 57 eligible papers (Fig. 1). These were read in full and independently by three authors (A.R., L.B., E.C.). Twenty-one papers were excluded. The references of the remaining 36 papers were checked, and 11 publications previously not identified were added. Five were excluded because they were repetitive compared with other articles and five because concerning selected populations (childhood and patients 15e39 years old). Eighteen papers concerning only specific tumour sites were excluded. Therefore, 19 papers were included in the systematic review.
Fig. 1. Flow diagram for literature search and study selection.
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2.2.4. Data extraction and statistical analysis The following information was retrieved from each paper: first author, year of publication, country, years of registration, number of cancer patients, effect estimate and CIs. We considered the SMR as the preferable outcome replaced by the rate ratio in the case the SMR was not available. In none of the studies selected was the hazard ratio used as an end-point. When the paper reported the results separately for men and women, we considered them independent populations. Natural logarithms of the SMRs were calculated. The use of logSMR is preferred when the reference population differs between studies and because it has more normal sampling distribution. The pooled log-SMRs were then back-transformed for interpretation. A meta-analysis was performed to estimate the pooled SMR and 95% CIs using the DerSimonian-Laird random-effects model [32]. When heterogeneity was substantial, we reported also a prediction interval (PI) rather than a CI to have a better appreciation of the uncertainty around the effect estimate. We assessed the presence and magnitude of statistical heterogeneity by the Q-test, the I2 metric and the estimate of between-study variance tau-squared. The risk of publication bias was evaluated by the visual inspection of the funnel plot and by assessing the Egger’s meta-regression model. We conducted a sensitivity analysis to investigate the influence of each study on the
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overall summary estimate of the meta-analysis, omitting one study in each turn. 3. Results 3.1. Romagna study The cohort accumulated a total of 618,054 person-years at risk. One hundred and fifty-eight patients (135 men and 23 women) died due to suicide. A 50% increased suicide risk was found for both sexes combined. The SMR, however, was significantly higher than the unity only for males (Table 1). The risk for suicide was as expected among patients aged 0e54 years, while significantly increasing for older age groups, with SMRs varying between 1.7 and 1.5. The greatest risk was observed during the first year after diagnosis, with a SMR of 3.4. Then, it decreased gradually and returned to the expected level 2 years after diagnosis. The risk varied depending on cancer prognosis, with a moderate 40% increase for patients with good prognosis and an almost 2.5-fold increase for patients with poor prognosis. The analysis provided evidence for an excess risk of suicide among people living in thinly populated areas and intermediate density areas. Also, the risk of suicide decreased during the study period from a SMR of 3.0 in 1996e2001 to 2.5 in 2008e2013. The right-hand column
Table 1 Romagna study: observed number of suicides, expected number of suicides (rounded to the nearest unity), person-years and mortality rate per 100,000, standardised mortality ratio (SMR) with 95% confidence intervals (95% CI), and absolute excess risk per 10,000 person-years overall, by gender, age, period of diagnosis, cancer prognosis and degree of urbanisation. Factor
Person-years
All patients 618,054 Gender Male 293,350 Female 324,703 Age at diagnosis 0e54 years 162,936 55e64 years 144,344 65e74 years 182,996 75 + years 127,777 Prognosis of cancer <30% RS 68,945 30% RS 549,109 Years since diagnosis <1 years 103,473 1e2 years 82,605 2e4 years 129,034 4e6 years 96,310 6 + years 206,632 Degree of urbanization High density area 502,885 Rural and intermediate density area 115,169 Period of diagnosis (restricted to 2 years of follow up) 1996e2001 50,030 2002e2007 60,851 2008e2013 66,784 1996e2013 177,665
Observed cases
Suicide rate
Expected cases
SMR
95% CI
Excess risk
158
25
104
1.5
1.3e1.8
0.9
135 23
46 7.1
83 21
1.6 1.1
1.4e1.9 0.7e1.7
1.8 0.1
13 29 58 58
8.0 20 32 45
13 17 36 39
1.0 1.7 1.6 1.5
0.5e1.7 1.1e2.5 1.2e2.1 1.1e1.9
0.01 0.8 1.2 1.5
34 124
49 23
14 9.6
2.5 1.4
1.7e3.4 1.1e1.6
2.9 0.6
63 26 24 15 30
61 31 19 16 15
19 14 22 16 34
3.4 1.8 1.1 0.9 0.9
2.6e4.4 1.2e2.7 0.7e1.6 0.5e1.5 0.6e1.3
4.3 1.4 0.2 0.1 0.2
115 43
23 37
85 20
1.4 2.2
1.1e1.6 1.6e2.9
0.6 2.0
32 29 25 86
64 48 37 48
11 11 10 32
3.0 2.7 2.5 2.7
2.0e4.2 1.8e3.9 1.6e3.7 2.2e3.4
4.2 3.0 2.2 3.0
Year
Country
Years of diagnosis
End year of follow- up
Cancer patients
Number of person-years
Deaths due to suicide
SMR (95% CI)
SMR (95% CI) Men
SMR (95% CI) Women Louhivuori Hem Innos Allebeck Camidge Yousaf Storm Kaceniene Robinson Vyssoki Oberaigner Levi Ravaioli Miccinesi Fox Misono Nasseri Ahn Lin Dormer
1979 2004 2003 1989 2007 2005 1992 2017 2009 2015 2014 1991 na 2004 1982 2008 2012 2010 2017 2008
Finland Norway Estonia Sweden Scotland Denmark Denmark Lithuania South-East England Austria Tyrol (Austria) Vaud (Switzerland) Romagna (Italy) Florence (Italy) Connecticut (USA) USA California (USA) Korea Taiwan Western Australia
1955,1960,1965 1960e1997 1983e1998 1962e1979 1981e1995 1971e1999 1971e1986 1993e2012 1996e2005 1983e2010 1991e2010 1976e1987 1996e2014 1985e1999 1940e1969 1973e2002 1976e2006 1993e2002 1985e2007 1981e2002
1970 1999 2000 1979 2000 1999 1986 2012 2005 2010 2011 1987 2015 2000 1975 2002 2008 2005 2009 2002
28,857 490,245 65,419 424,127 315,041 564,508 296,330 273,511 417,572 915,303 53,803 24,166 127,674 90,197 144,530 3,594,750 1,123,528 816,295 916,337 121,533
nr 2,536,152 192,078 nr nr 2,232,541 nr nr 1,100,000 14,532,682 285,038 57,164 618,054 nr nr 18,604,308 4,630,551 3,007,294 4,300,953 543,696
63 589 197 963 172 1241 568 654 166 2877 144 55 157 102 192 5838 1168 2065 2543 129
1.4 1.5 nr nr 1.5 nr nr 1.3 1.4 1.2 1.9 2.6 1.5 1.9 nr 1.9 nr 2.0 2.5 1.6
1.3 1.6 1.7 1.9 1.4 1.7 1.5 1.3 1.5 1.4 2.0 2.8 1.6 2.0 2.3 2.1 2.0 2.1 2.7 1.7
1.9 1.4 0.5 1.6 1.7 1.4 1.3 1.3 1.2 1.2 1.4 2.2 1.1 1.6 0.9 1.5 1.8 1.9 2.1 1.2
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Characteristics of the studies selected for the systematic review and included in the meta-analysis together with the present study on the Romagna data.
(1.1e3.1) (1.2e1.6) (0.4e0.7) (1.5e1.8) (1.4e2.2) (1.3e1.5) (1.1e1.5) (1.1e1.5) (0.9e1.6) (1.2e1.3) (0.9e2.1) (1.3e3.6) (0.7e1.7) (0.9e2.5) (0.6e1.3) (1.4e1.6) (1.6e2.1) (1.7e2.0) (1.9e2.2) (0.8e1.9) (1.3e1.8)
(1.2e1.4) (1.2e1.6) (1.2e1.3) (1.6e2.2) (2.0e3.4) (1.3e1.8) (1.6e2.3) (1.8e1.9)
(1.9e2.1) (2.4e2.6) (1.4e1.9)
(1.0e1.7) (1.4e1.7) (1.5e2.0) (1.8e2.1) (1.1e1.7) (1.6e1.9) (1.3e1.6) (1.2e1.4) (1.2e1.7) (1.4e1.5) (1.7e2.4) (2.0e3.8) (1.4e1.9) (1.6e2.5) (2.0e2.7) (2.0e2.2) (1.9e2.1) (2.0e2.2) (2.6e2.9) (1.4e2.1)
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1st Author
(1.1e1.8) (1.4e1.6)
of Table 1 shows the absolute excess risk. Overall, the number of exceeding suicides per 10,000 patient-years was 0.9. In multivariate analysis (Table 2), male sex, patient age, residence in rural and intermediate density areas and time since diagnosis were significantly associated with an increased risk of suicide. The role of prognosis (poor versus good prognosis) was not confirmed.
95% CI
SMR, standardised mortality ratio; 95% CI, 95% confidence intervals; na, not available; nr, not reported.
3.2. Meta-analysis Table 3 shows the characteristics and results of the 19 selected studies and of the present study, too. The study-specific estimates were substantially heterogeneous, and the CIs of many studies did not overlap. This was confirmed by the Q-test. The p-value for the Q-test rejected the null hypothesis for men, women and both genders (p-value Z 0.00). The I2 metric showed a strong heterogeneity, that is, 97% (95% CI: 96e98%), 92% (95% CI: 89e94%) and 98% (95% CI: 98e99%) for men, women and both sexes combined, respectively. The Q-test and I^2 metric showed a strong heterogeneity between the studies, so we calculated pooled SMRs with 95%CIs using the DerSimonian-Laird random-effects model. There was an increased risk of death due to suicide in men and women combined, with a pooled SMR of 1.7 (Fig. 2). When stratifying analysis by sex, we found for men (20 studies) a pooled SMR of 1.8, with a significant increased risk for all papers (Fig. 3). Regarding women (20 studies) the summary SMR showed a significant increased risk, with a SMR of 1.4, although one study showed a protective effect and five a non-significant increase (Fig. 4). As heterogeneity was substantial, we also reported the 95% PI (Figs. 2e4). Table 2 IRR
Romagna study: multivariate analysis. Factor
reference 1.5e4.8
reference 3.5e8.5 1.0 2.7
reference 0.97e2.1
1.0 5.5
1.0 1.4
reference 1.1e2.2
reference 2.0e3.9 1.0 1.6
1.0 2.8
Gender Female Male Age at diagnosis 0e54 years 55 + years Prognosis of cancer 30% RS <30% RS Years since diagnosis 1 + years <1 years Degree of urbanisation High density area Rural and intermediate density area
IRR, incidence rate ratio; 95% CI, 95% confidence intervals.
Table 3
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Fig. 2. Forest plot of standardised mortality ratios (SMR) with 95% CI from the random effects meta-analysis of 14 studies, men and women. Q-test with p-value, tau-squared and 95% predictive interval (PI) related to the overall estimate are shown. CI, confidence interval; na, not available.
Visual inspection of the funnel plots revealed a slight asymmetry in the result of pooled SMRs (Fig. 5aec) for men, women and both sexes combined. A standard
funnel plot does not explain the reasons for the asymmetry, which was more pronounced for women than men. The Egger’s meta-regression model showed
Fig. 3. Forest plot of standardised mortality ratios (SMR) and 95% CI from the random effects meta-analysis of 20 studies, men. Q-test with p-value, tau-squared and 95% predicted intervals related to the overall estimate are shown. CI, confidence interval; na, not available.
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Fig. 4. Forest plot of standardised mortality ratios (SMR) and 95% CI from the random effects meta-analysis of 20 studies, women. Q-test with p-value, tau-squared and 95% predicted intervals (PI) related to the overall estimate are shown. CI, confidence interval; na, not available.
the relationship between the observed effect size and the size of studies. The estimated bias coefficient was 2.0, with a standard error of 3.5, giving a p-value of 0.58 for males and females combined. Thus, the test provided no evidence for the presence of small-study effects. The publication bias was not significant both for males (Egger’s test Z 2.5, p-value Z 0.26) and females (Egger’s test Z e0.9, p-value Z 0.5). The results of the sensitivity analysis (not shown), which consisted in estimating the overall effect by removing one article at a time, highlighted a high reproducibility of the analysis for men and women and for the total of people. 4. Discussion In the present study, we evaluated the risk of death due to suicide in northern Italy and included the results in a systematic review of the literature. This covered virtually all cancer registryebased studies previously published. In the Italian data, there was a 50% excess risk of suicide. In absolute terms, however, the excess risk of suicide was as low as 0.9 events per 10,000 patient-years. This must be emphasised. Because they are rare, suicides of cancer patients are difficult to predict and prevent and are beyond the personal experience of many health professionals. Conversely, they may have disproportionately large impacts on families and hospital staff.
The risk increase was more pronounced for men, for patients aged >54 years, for patients with poor prognosis, during the first year after diagnosis and for people living in thinly populated areas. The excess risk was slightly less marked for the most recent incidence cohorts. Multivariate analysis confirmed the effect of sex, patient age, intermediate density areas and years since diagnosis. The meta-analysis confirmed a robust increase in the risk of death for both sexes combined. When it was repeated for studies providing gender-specific information, the estimated summary SMR was higher for men. In the data from the Romagna Cancer Registry, we found comparable results. Among the 20 studies included in the evaluation of the risk for female patients, one study showed a protective effect [14] and four [4,33e35] (excluding the present one) a non-significantly increased risk. Many factors may have influenced these results, including the different case-mix between sexes and the possible stage differences at diagnosis. In our case series, the risk of suicide was higher for older people. This confirms previously published observations [33,36,37] but is at variance with other studies, in which no association [4,9,12,13] or an inverse association [14] was demonstrated. The role of patient age is difficult to interpret, given its interrelationship with case-mix and stage at diagnosis.
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Fig. 5. (a) Funnel plot of 14 studies for men and women. Egger’s test and p-value are shown. (b) Funnel plot of 20 studies for men. Egger’s test and p-value are shown. (c) Funnel plot of 20 studies for women. Egger’s test and p-value are shown.
Poor prognosis was another risk factor, which confirms previous research [14,37,38]. This is also the case for the time since diagnosis. In this study and many previous ones, the risk was higher in the early period, although the estimates may be slightly different according to the cut-off adopted (1 month, 3 months and 12 months) [4,12,14,37,38]. In the first few months after cancer diagnosis, the distress caused by this and by primary treatment should be monitored, and patients’ supportive interventions should be implemented [39,40]. Among the strengths of this study is the use of clear and cogent criteria for inclusion in the systematic review. All eligible studies covered the whole patients’ population, except for three in which patients younger than 15 years were not eligible [13,33,35]. This may have overestimated the risk, considering that suicide is rather unusual among children. A second strength of this study is that the literature search was performed independently by pairs of screeners. In the case of disagreement, they have discussed each study until a common decision was reached.
The major limitations of the study include the following: First, the Romagna Cancer Registry, like most population-based cancer registries, does not collect information on personal characteristics, for example comorbidities, financial difficulty and marital status. Previous studies have associated being divorced/widowed with a higher risk in comparison with married patients [3,8]. Second, and more important, estimating the risk of death by suicide at the population level is prone to the problem of under-reporting. Suicides often present a challenge in the classification of the cause of death [41]. Despite this, few studiesdand none in Italydhave been done to assess the reliability of suicide statistics [42]. In addition, the registration of suicidedand of cancer as welldmay be constrained by national data privacy restrictions. For example, excessive confidentiality provides one possible explanation for the observed heterogeneity of certain cancer incidence data [43,44]. Regarding future research in Europe, these problems will be increasingly interrelated with the potential effects of the new General Data Protection Regulation by the
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European Union, which might jeopardise the use of cancer registry data and other epidemiologic activities [45]. Despite the ongoing increase in survival of cancer patients both in Italy [21] and worldwide [22], suicide is still a relevant cause of death. The need for providing effective psychological and pharmacological support is not met yet. Oncologic teams need to be trained to identify alarming signs and symptoms among their patients, especially around the date of diagnosis and to provide a multidisciplinary preventive support [46]. In addition, suicide is an experience not limited to the patient and has serious negative effects also for his/her family and the whole hospital staff. Early detection of sign and symptoms of psychological discomfort requires specific psychosocial skills. The Italian association of medical oncologists has recently included specific practice guidelines for the psychosocial care of patients [47]. In conclusion, cancer patients were confirmed to be a group at increased risk for suicide. A clinical multidisciplinary approach aimed at supporting them and at identifying symptoms and signs of anxiety and depression is needed. Oncologists’ awareness of the psychosocial needs of patients should be improved. Deaths due to suicide are avoidable. It is a commitment of the health systems to support cancer patients allowing them to fully benefit of the constant improvements in survival. Role of funding source This research did not receive any specific grant from funding agencies in the public, commercial or not-forprofit sectors. Conflict of interest statement There are no conflicts of interest.
References [1] World Health Organization. Mental death, Latest data on suicide. 2019. https://www.who.int/mental_health/prevention/suicide/ suicideprevent/en/. [Accessed 1 April 2019]. [2] Tauil CB, Grippe TC, Dias RM, Dias-Carneiro RPC, Carneiro NM, Aguilar ACR, et al. Suicidal ideation, anxiety, and depression in patients with multiple sclerosis. Arq Neuropsiquiatr 2018;76(5):296e301. https://doi.org/10.1590/0004-282X20180036. [3] Louhivuori KA, Hakama M. Risk of suicide among cancer patients. Am J Epidemiol 1979;109(1):59e65. [4] Fox BH, Stanek 3rd EJ, Boyd SC, Flannery JT. Suicide rates among cancer patients in Connecticut. J Chronic Dis 1982;35(2): 89e100. [5] Hem E, Loge JH, Haldorsen T, Ekeberg O. Suicide risk in cancer patients from 1960 to 1999. J Clin Oncol 2004;22:209e4216. [6] Nasseri K, Mills PK, Mirshahidi HR, Moulton LH. Suicide in cancer patients in California, 1997-2006. Arch Suicide Res 2012; 16:324e33.
[7] Lin PH, Liao SC, Chen IM, Kuo PH, Shan JC, Lee MB, et al. Impact of universal health coverage on suicide risk in newly diagnosed cancer patients: population-based cohort study from 1985 to 2007 in Taiwan. Psycho Oncol 2017;26(11):1852e9. https: //doi.org/10.1002/pon.4396. [8] Ahn E, Shin DW, Cho SI, Park S, Won YJ, Yun YH. Suicide rates and risk factors among Korean cancer patients, 1993-2005. Cancer Epidemiol Biomark Prev 2010;19(8):2097e105. https: //doi.org/10.1158/1055-9965.EPI-10-0261. [9] Levi F, Bulliard JL, La Vecchia C. Suicide risk among incident cases of cancer in the Swiss Canton of Vaud. Oncology 1991; 48(1):44e7. https://doi.org/10.1159/000226893. [10] Fall K, Fang F, Mucci LA, Ye W, Andre´n O, Johansson JE, et al. Immediate risk for cardiovascular events and suicide following a prostate cancer diagnosis: prospective cohort study. PLoS Med 2009;6(12):e1000197. https://doi.org/10.1371/journal. pmed.1000197. [11] Camidge DR, Stockton DL, Frame S, Wood R, Bain M, Bateman DN. Hospital admissions and deaths relating to deliberate self-harm and accidents within 5 years of a cancer diagnosis: a national study in Scotland, UK. Br J Cancer 2007;96:752e7. https://doi.org/10.1038/sj.bjc.6603617. [12] Yousaf U, Christensen ML, Engholm G, Storm HH. Suicides among Danish cancer patients 1971-1999. Br J Cancer 2005;92(6): 995e1000. https://doi.org/10.1038/sj.bjc.6602424. [13] Allebeck P, Bolund C, Ringba¨ck G. Increased suicide rate in cancer patients. A cohort study based on the Swedish CancerEnvironment Register. J Clin Epidemiol 1989;42(7):611e6. [14] Innos K, Rahu K, Rahu M, Baburin A. Suicides among cancer patients in Estonia: a population-based study. Eur J Cancer 2003; 39(15):2223e8. [15] Misono S, Weiss NS, Fann JR, Redman M, Yueh B. Incidence of suicide in persons with cancer. J Clin Oncol 2008;26(29):4731e8. https://doi.org/10.1200/JCO.2007.13.8941. [16] Vyssoki B, Gleiss A, Rockett IR, Hackl M, Leitner B, Sonneck G, et al. Suicide among 915,303 Austrian cancer patients: who is at risk? J Affect Disord 2015;175:287e91. https://doi.org/10.1016/j.jad. 2015.01.028. [17] Storm HH, Christensen N, Jensen OM. Suicides among Danish patients with cancer: 1971 to 1986. Cancer 1992;69(6):1507e12. [18] Turaga KK, Malafa MP, Jacobsen PB, Schell MJ, Sarr MG. Suicide in patients with pancreatic cancer. Cancer 2011;117(3): 642e7. https://doi.org/10.1002/cncr.25428. [19] Sugawara A, Kunieda E. Suicide in patients with gastric cancer: a population-based study. Jpn J Clin Oncol 2016;46(9):850e5. https://doi.org/10.1093/jjco/hyw075. [20] Crocetti E, Arniani S, Acciai S, Barchielli A, Buiatti E. High suicide mortality soon after diagnosis among cancer patients in central Italy. Br J Cancer 1998;77(7):1194e6. [21] Coviello V, Buzzoni C, Fusco M, Barchielli A, Cuccaro F, De Angelis R, et al. Survival of cancer patients in Italy. Epidemiol Prev 2017;41(2 Suppl 1):1e244. https://doi.org/10.19191/EP17. 2S1.P001.017. [22] Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, et al. Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet 2015;385(9972):977e1010. https://doi.org/10.1016/S01406736(14)62038-9. [23] Ullman K. Cancer survivorship gains importance. JNCI 2014;106. https://doi.org/10.1093/jnci/djt450. [24] Falcini F, et al. Cancer incidence in Romagna, Italy (2008-2012). In: Bray F, Colombet M, Mery L, Pin˜eros M, Znaor A, Zanetti R, et al., editors. (2017) Cancer incidence in five continents, vol. XI. Lyon: International Agency for Research on Cancer; 2017 (electronic version) Available from: http://ci5.iarc.fr. [Accessed 24 July 2018].
A. Ravaioli et al. / European Journal of Cancer 125 (2020) 104e113 [25] International classification of diseases, 9th revision, clinical modification. Hospital Edition; 2007. [26] International statistical classification of diseases and related health problems. - 10th revision, edition 2010. Geneva: ª World Health Organization; 2011. [27] Breslow NE, Day NE. Statistical methods in cancer research. Volume II-the design and analysis of cohort studies. IARC Sci Publ 1987;(82):1e406. [28] Rilevazione Mortalita` e ReM - Sistema Informativo Politiche per la Salute e Politiche Sociali e Regione Emilia-Romagna; http:// salute.regione.emilia-romagna.it/siseps/sanita/rem. [29] https://ec.europa.eu/eurostat/statistics-explained/index.php/ Degree_of_urbanisation_classification_-_2011_revision#Degree_ of_urbanisation_classification. [Accessed 30 November 2018]. [30] StataCorp. Stata statistical software: release 15. College Station, TX: StataCorp LLC; 2017. [31] AIRTUM Working Group. Italian cancer figures, report 2013: multiple tumours. Epidemiol Prev 2013;37(4e5 Suppl 1):1e152. [32] DerSimonian R, Laird N. Meta-analysis in clinical trials. Contr Clin Trials 1986;7(3):177e88. [33] Robinson D, Renshaw C, Okello C, Møller H, Davies EA. Suicide in cancer patients in South East England from 1996 to 2005: a population-based study. Br J Cancer 2009;101(1):198e201. https: //doi.org/10.1038/sj.bjc.6605110. [34] Dormer NR, McCaul KA, Kristjanson LJ. Risk of suicide in cancer patients in Western Australia, 1981-2002. Med J Aust 2008;188(3):140e3. [35] Oberaigner W, Sperner-Unterweger B, Fiegl M, Geiger-Gritsch S, Haring C. Increased suicide risk in cancer patients in Tyrol/Austria. Gen Hosp Psychiatry 2014;36(5):483e7. https: //doi.org/10.1016/j.genhosppsych.2014.05.017. [36] Chatton-Reith J, el May H, Raymond L. The risk of suicide in cancer patients derived from a cancer registry. Rev Epidemiol SantePublique 1990;38:125e31. [37] Miccinesi G, Crocetti E, Benvenuti A, PacI: E. Suicide mortality is decreasing among cancer patients in Central Italy. Eur J Cancer 2004;40:53e7. https://doi.org/10.1016/j.ejca.2003.12.022. [38] Kaceniene A, Krilaviciute A, Kazlauskiene J, Bulotiene G, Smailyte G. Increasing suicide risk among cancer patients in Lithuania from 1993 to 2012: a cancer registry-based study. Eur J Cancer Prev 2017;26:S197e203. https://doi.org/10.1097/CEJ. 0000000000000375.
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[39] Liao MN, Chen SC, Chen SC, Lin YC, Chen MF, Wang CH, et al. Change and predictors of symptom distress in breast cancer patients following the first 4 months after diagnosis. J Formos Med Assoc 2015;114(3):246e53. https: //doi.org/10.1016/j.jfma.2013.06.009. [40] Gibbons A, Groarke A, Sweeney K. Predicting general and cancer-related distress in women with newly diagnosed breast cancer. BMC Cancer 2016;16(1):935. [41] Tøllefsen IM, Helweg-Larsen K, Thiblin I, Hem E, Kastrup MC, Nyberg U, et al. Are suicide deaths under-reported? Nationwide re-evaluations of 1800 deaths in Scandinavia. BMJ Open 2015; 5(11):e009120. https://doi.org/10.1136/bmjopen-2015-009120. [42] Tøllefsen IM, Hem E, Ekeberg Ø. The reliability of suicide statistics: a systematic review. BMC Psychiatry 2012;12:9. https: //doi.org/10.1186/1471-244X-12-9. [43] Storm HH, Engholm G, Pritzkuleit R, Kejs AM, Katalinic A, Dunst J, et al. Less pitfalls and variation in population based cancer survival comparisons within the European Union: lessons from colorectal cancer patients in neighbouring regions in Denmark and Germany - the Fehmarn Belt project. Eur J Cancer 2015;51(9):1188e98. https://doi.org/10.1016/j.ejca.2014.11.006. [44] Ferlay J, Colombet M, Soerjomataram I, Dyba T, Randi G, Bettio M, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer 2018;103:356e87. https: //doi.org/10.1016/j.ejca.2018.07.005. [45] Andersen MR, Storm HH, Eurocourse Work Package 2 Group. Cancer registration, public health and the reform of the European data protection framework: abandoning or improving European public health research? Eur J Cancer 2015;51(9):1028e38. https: //doi.org/10.1016/j.ejca.2013.09.005. [46] Granek L, Nakash O, Ariad S, Shapira S, Ben-David M. Oncologists’ identification of mental health distress in cancer patients: strategies and barriers. Eur J Cancer Care 2018;27(3): e12835. https://doi.org/10.1111/ecc.12835. [47] Associazione Italiana di Oncologia Medica. AIOM. Linee guida. 2018. https://www.aiom.it/linee-guida/linee-guida-aiom-2018assistenza-psico-sociale-dei-malati-oncologici/. [Accessed 20 November 2018].
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Original Research
Suicide death among cancer patients: new data from northern Italy, systematic review of the last 22 years and meta-analysis Alessandra Ravaioli a, Emanuele Crocetti a, Silvia Mancini a, Flavia Baldacchini a, Orietta Giuliani a, Rosa Vattiato a, Lauro Bucchi a,*, Fabio Falcini a,b a Romagna Cancer Registry, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy b Azienda Usl della Romagna, Forlı`, Italy
Received 23 May 2019; received in revised form 13 August 2019; accepted 15 August 2019
KEYWORDS Suicide death; Cancer patients; Meta-analysis; Cohort study
Abstract Background: An increased risk of death by suicide in cancer patients has been documented since decades. We evaluated the risk of death by suicide in an Italian population-based cancer case series and added the results to a systematic review and metaanalysis of the literature. Methods: The Italian series, including 127,042 primary cancer patients diagnosed between 1996 and 2014, was obtained from the Romagna Cancer Registry (northern Italy). Standardised mortality ratios (SMRs) were calculated. Regarding the systematic review and metaanalysis, the PubMed database was searched for English language studies published up to 2017. Fifty-seven potentially eligible papers were reviewed in full, and 19 of them were selected for analysis. The SMR was the first outcome, replaced by rate ratio if the SMR was not available. Findings: In the Italian case series, an increased suicide risk was found for both sexes combined (SMR Z 1.5; 95% confidence interval [CI]: 1.3e1.8), for males (SMR Z 1.6; 95% CI: 1.4e1.9) but not females (SMR Z 1.1; 95% CI: 0.7e1.7), for patients aged 55 years, with poor prognosis and advanced-stage disease and during the first year after diagnosis. The absolute excess risk of suicide was 0.9 per 10,000 patient-years. Multivariate analysis confirmed the role of univariate factors except for poor prognosis. Meta-analysis showed a strong heterogeneity between studies. The risk was significantly elevated for both sexes combined (pooled
* Corresponding author: Romagna Cancer Registry, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Piero Maroncelli 40, Meldola, 47014, FC, Italy. E-mail address: [email protected] (L. Bucchi). https://doi.org/10.1016/j.ejca.2019.08.019 0959-8049/ª 2019 Elsevier Ltd. All rights reserved.
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SMR Z 1.7; 95% CI: 1.5e1.9), men (pooled SMR Z 1.8; 95% CI: 1.6e2.0) and women (pooled SMR Z 1.4; 95% CI: 1.3e1.6). There was no evidence for small-study effects. Interpretation: The Italian study confirmed the previous common finding that cancer patients are at increased risk for suicide. A clinical multidisciplinary approach to support them is needed. ª 2019 Elsevier Ltd. All rights reserved.
1. Introduction Worldwide deaths because of suicide are a serious public health concern. Suicide represents 1.4% of all deaths (the 18th leading cause of death in 2016) [1]. The diagnosis of any serious illness may increase the likelihood of committing suicide [2]. Cancer diagnosis is one of the most dramatic events in a person’s life, and for someone, diagnosis and treatment are experienced as challenging and even life threatening. Common fears among cancer patients include severe therapeutic side-effects, insufficient pain management and physical deterioration. An increased risk of death by suicide in cancer patients has been documented since decades [3,4]. The risk has been estimated to be up to the double than in the general population of United States, Europe, Australia, Taiwan and South Korea [4e12]. The majority of studies reported a higher relative risk of committing suicide by men [4,7,9,13e16] for cancers in advanced stage at diagnosis [3,7,16,17] and particularly for some cancers with poor prognosis, such as brain, lung, head and neck, pancreas, liver and stomach cancers [3,16,18,19]. Also, the risk is greatest in the first months or the first year after diagnosis [9,12,14,16,20]. In Italy [21] and elsewhere [22], cancer survival has improved over time. Therefore, survivorship of cancer patients is an increasing issue for the health systems [23]. Once the curability of cancer is reached, other aspects previously underrated have to be faced, including late effects of treatments, multiple primaries, fertility preservation, social discrimination, return to work and suicide risk. The aim of this study is to evaluate the risk of death due to suicide in an Italian population-based cancer series and to add this result to an up-to-date systematic review of the literature. A meta-analysis will summarise and quantify the current knowledge on this topic. 2. Materials and methods 2.1. Romagna Cancer Registry data 2.1.1. Data source Records of primary cancer patients diagnosed between 1996 and 2014 (n Z 130,436) were retrieved from the Romagna Cancer Registry, which covers one-third of
the Emilia-Romagna Region (northern Italy) [24]. Patients for whom the date of diagnosis was the same as the date of death (n Z 2274), patients lost to followup (n Z 155), patients with missing information on cause of death (n Z 477), patients with synchronous tumours (n Z 367) and autopsy cases (n Z 121) were not included. This left 127,042 cancer cases (66,919 among men and 60,123 among women) available for analysis. 2.1.2. Statistical analysis Data on death were taken from the official death certificate. Cause-of-death codes for suicide and selfinflicted injuries were E950-E959 according to International Classification for Disease 9 (ICD-9) [25] and X60X84, Y870 according to ICD-10 [26]. Person-years were computed from the date of diagnosis until the date of death or end of follow-up (31 December 2015), whichever occurred first. For individuals with more than one cancer diagnosis, the date of the first cancer was considered the start of the period at risk, and the date of the second cancer was considered the end of the period at risk. Sex-, age- and calendar periodestandardised mortality ratios (SMRs) [27] were calculated by dividing the observed number of suicides by the expected one. The expected number of suicides was calculated by applying the 5-year period incidence and 5-year age-specific rates of suicide in the Emilia-Romagna general population [28] between 1996 and 2015 to the person-years of observation in the cohort. The degree of urbanisation of the municipality of residence was classified according to the EUROSTAT [29]. The survival data from the Italian Association Cancer Registries were used to create two categories of tumour prognosis: good (30% relative survival at 5 years since diagnosis) and poor (<30%) [21]. To evaluate the calendar period effect, SMRs were calculated by diagnosis periods truncating the follow-up to the first 2 years to give the same length of follow-up to each period. Assuming that data followed a Poisson distribution, the 95% confidence intervals (CIs) for SMRs were calculated. Multivariate analyses were performed to identify factors associated with increased risk of suicide [27]. We used a multivariate Poisson regression model yielding the incidence rate ratio with 95% CIs. All tests were twotailed, and statistical significance was set at p-value
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<0.05. All statistical analyses were carried out using Stata software [30]. The absolute excess risk beyond the expected amount was calculated by subtracting the expected number of suicides from the observed number. The difference was then divided by the person-years, and the number of suicides in excess (or deficit) was expressed per 10,000 patient-years [31].
2.2.2. Inclusion criteria The abstracts were reviewed using the following inclusion criteria: (i) English language; (ii) death due to suicide; (iii) population-based or cancer-registry-based study; (iv) original data; (v) all tumour sites combined; (vi) data for the one or the other gender or both genders combined; and (vii) information on the number of deaths and the SMR or the hazard ratio. For multiple studies using the same cohort, the one including the most comprehensive case series was considered.
2.2. Systematic review and meta-analysis 2.2.1. Data source and search We performed a systematic search in PubMed for those papers published before 6 November 2017 identified by the following keys: ‘Neoplasms’[Mesh] OR Neoplas* [tw] OR Tumor* [tw] OR Malignanc* [tw] OR Cancer* [tw] AND ‘Registries’[Mesh] OR registry [tw] OR population Register* [tw] OR population based [tw] AND ‘Suicide’[Mesh] OR Suicid* [tw]. No time restriction was applied. The abstracts were independently reviewed for eligibility by two authors (A.R., E.C.), and a third one (L.B.) was involved in case of disagreement.
2.2.3. Systematic review The selection identified 57 eligible papers (Fig. 1). These were read in full and independently by three authors (A.R., L.B., E.C.). Twenty-one papers were excluded. The references of the remaining 36 papers were checked, and 11 publications previously not identified were added. Five were excluded because they were repetitive compared with other articles and five because concerning selected populations (childhood and patients 15e39 years old). Eighteen papers concerning only specific tumour sites were excluded. Therefore, 19 papers were included in the systematic review.
Fig. 1. Flow diagram for literature search and study selection.
A. Ravaioli et al. / European Journal of Cancer 125 (2020) 104e113
2.2.4. Data extraction and statistical analysis The following information was retrieved from each paper: first author, year of publication, country, years of registration, number of cancer patients, effect estimate and CIs. We considered the SMR as the preferable outcome replaced by the rate ratio in the case the SMR was not available. In none of the studies selected was the hazard ratio used as an end-point. When the paper reported the results separately for men and women, we considered them independent populations. Natural logarithms of the SMRs were calculated. The use of logSMR is preferred when the reference population differs between studies and because it has more normal sampling distribution. The pooled log-SMRs were then back-transformed for interpretation. A meta-analysis was performed to estimate the pooled SMR and 95% CIs using the DerSimonian-Laird random-effects model [32]. When heterogeneity was substantial, we reported also a prediction interval (PI) rather than a CI to have a better appreciation of the uncertainty around the effect estimate. We assessed the presence and magnitude of statistical heterogeneity by the Q-test, the I2 metric and the estimate of between-study variance tau-squared. The risk of publication bias was evaluated by the visual inspection of the funnel plot and by assessing the Egger’s meta-regression model. We conducted a sensitivity analysis to investigate the influence of each study on the
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overall summary estimate of the meta-analysis, omitting one study in each turn. 3. Results 3.1. Romagna study The cohort accumulated a total of 618,054 person-years at risk. One hundred and fifty-eight patients (135 men and 23 women) died due to suicide. A 50% increased suicide risk was found for both sexes combined. The SMR, however, was significantly higher than the unity only for males (Table 1). The risk for suicide was as expected among patients aged 0e54 years, while significantly increasing for older age groups, with SMRs varying between 1.7 and 1.5. The greatest risk was observed during the first year after diagnosis, with a SMR of 3.4. Then, it decreased gradually and returned to the expected level 2 years after diagnosis. The risk varied depending on cancer prognosis, with a moderate 40% increase for patients with good prognosis and an almost 2.5-fold increase for patients with poor prognosis. The analysis provided evidence for an excess risk of suicide among people living in thinly populated areas and intermediate density areas. Also, the risk of suicide decreased during the study period from a SMR of 3.0 in 1996e2001 to 2.5 in 2008e2013. The right-hand column
Table 1 Romagna study: observed number of suicides, expected number of suicides (rounded to the nearest unity), person-years and mortality rate per 100,000, standardised mortality ratio (SMR) with 95% confidence intervals (95% CI), and absolute excess risk per 10,000 person-years overall, by gender, age, period of diagnosis, cancer prognosis and degree of urbanisation. Factor
Person-years
All patients 618,054 Gender Male 293,350 Female 324,703 Age at diagnosis 0e54 years 162,936 55e64 years 144,344 65e74 years 182,996 75 + years 127,777 Prognosis of cancer <30% RS 68,945 30% RS 549,109 Years since diagnosis <1 years 103,473 1e2 years 82,605 2e4 years 129,034 4e6 years 96,310 6 + years 206,632 Degree of urbanization High density area 502,885 Rural and intermediate density area 115,169 Period of diagnosis (restricted to 2 years of follow up) 1996e2001 50,030 2002e2007 60,851 2008e2013 66,784 1996e2013 177,665
Observed cases
Suicide rate
Expected cases
SMR
95% CI
Excess risk
158
25
104
1.5
1.3e1.8
0.9
135 23
46 7.1
83 21
1.6 1.1
1.4e1.9 0.7e1.7
1.8 0.1
13 29 58 58
8.0 20 32 45
13 17 36 39
1.0 1.7 1.6 1.5
0.5e1.7 1.1e2.5 1.2e2.1 1.1e1.9
0.01 0.8 1.2 1.5
34 124
49 23
14 9.6
2.5 1.4
1.7e3.4 1.1e1.6
2.9 0.6
63 26 24 15 30
61 31 19 16 15
19 14 22 16 34
3.4 1.8 1.1 0.9 0.9
2.6e4.4 1.2e2.7 0.7e1.6 0.5e1.5 0.6e1.3
4.3 1.4 0.2 0.1 0.2
115 43
23 37
85 20
1.4 2.2
1.1e1.6 1.6e2.9
0.6 2.0
32 29 25 86
64 48 37 48
11 11 10 32
3.0 2.7 2.5 2.7
2.0e4.2 1.8e3.9 1.6e3.7 2.2e3.4
4.2 3.0 2.2 3.0
Year
Country
Years of diagnosis
End year of follow- up
Cancer patients
Number of person-years
Deaths due to suicide
SMR (95% CI)
SMR (95% CI) Men
SMR (95% CI) Women Louhivuori Hem Innos Allebeck Camidge Yousaf Storm Kaceniene Robinson Vyssoki Oberaigner Levi Ravaioli Miccinesi Fox Misono Nasseri Ahn Lin Dormer
1979 2004 2003 1989 2007 2005 1992 2017 2009 2015 2014 1991 na 2004 1982 2008 2012 2010 2017 2008
Finland Norway Estonia Sweden Scotland Denmark Denmark Lithuania South-East England Austria Tyrol (Austria) Vaud (Switzerland) Romagna (Italy) Florence (Italy) Connecticut (USA) USA California (USA) Korea Taiwan Western Australia
1955,1960,1965 1960e1997 1983e1998 1962e1979 1981e1995 1971e1999 1971e1986 1993e2012 1996e2005 1983e2010 1991e2010 1976e1987 1996e2014 1985e1999 1940e1969 1973e2002 1976e2006 1993e2002 1985e2007 1981e2002
1970 1999 2000 1979 2000 1999 1986 2012 2005 2010 2011 1987 2015 2000 1975 2002 2008 2005 2009 2002
28,857 490,245 65,419 424,127 315,041 564,508 296,330 273,511 417,572 915,303 53,803 24,166 127,674 90,197 144,530 3,594,750 1,123,528 816,295 916,337 121,533
nr 2,536,152 192,078 nr nr 2,232,541 nr nr 1,100,000 14,532,682 285,038 57,164 618,054 nr nr 18,604,308 4,630,551 3,007,294 4,300,953 543,696
63 589 197 963 172 1241 568 654 166 2877 144 55 157 102 192 5838 1168 2065 2543 129
1.4 1.5 nr nr 1.5 nr nr 1.3 1.4 1.2 1.9 2.6 1.5 1.9 nr 1.9 nr 2.0 2.5 1.6
1.3 1.6 1.7 1.9 1.4 1.7 1.5 1.3 1.5 1.4 2.0 2.8 1.6 2.0 2.3 2.1 2.0 2.1 2.7 1.7
1.9 1.4 0.5 1.6 1.7 1.4 1.3 1.3 1.2 1.2 1.4 2.2 1.1 1.6 0.9 1.5 1.8 1.9 2.1 1.2
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Characteristics of the studies selected for the systematic review and included in the meta-analysis together with the present study on the Romagna data.
(1.1e3.1) (1.2e1.6) (0.4e0.7) (1.5e1.8) (1.4e2.2) (1.3e1.5) (1.1e1.5) (1.1e1.5) (0.9e1.6) (1.2e1.3) (0.9e2.1) (1.3e3.6) (0.7e1.7) (0.9e2.5) (0.6e1.3) (1.4e1.6) (1.6e2.1) (1.7e2.0) (1.9e2.2) (0.8e1.9) (1.3e1.8)
(1.2e1.4) (1.2e1.6) (1.2e1.3) (1.6e2.2) (2.0e3.4) (1.3e1.8) (1.6e2.3) (1.8e1.9)
(1.9e2.1) (2.4e2.6) (1.4e1.9)
(1.0e1.7) (1.4e1.7) (1.5e2.0) (1.8e2.1) (1.1e1.7) (1.6e1.9) (1.3e1.6) (1.2e1.4) (1.2e1.7) (1.4e1.5) (1.7e2.4) (2.0e3.8) (1.4e1.9) (1.6e2.5) (2.0e2.7) (2.0e2.2) (1.9e2.1) (2.0e2.2) (2.6e2.9) (1.4e2.1)
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1st Author
(1.1e1.8) (1.4e1.6)
of Table 1 shows the absolute excess risk. Overall, the number of exceeding suicides per 10,000 patient-years was 0.9. In multivariate analysis (Table 2), male sex, patient age, residence in rural and intermediate density areas and time since diagnosis were significantly associated with an increased risk of suicide. The role of prognosis (poor versus good prognosis) was not confirmed.
95% CI
SMR, standardised mortality ratio; 95% CI, 95% confidence intervals; na, not available; nr, not reported.
3.2. Meta-analysis Table 3 shows the characteristics and results of the 19 selected studies and of the present study, too. The study-specific estimates were substantially heterogeneous, and the CIs of many studies did not overlap. This was confirmed by the Q-test. The p-value for the Q-test rejected the null hypothesis for men, women and both genders (p-value Z 0.00). The I2 metric showed a strong heterogeneity, that is, 97% (95% CI: 96e98%), 92% (95% CI: 89e94%) and 98% (95% CI: 98e99%) for men, women and both sexes combined, respectively. The Q-test and I^2 metric showed a strong heterogeneity between the studies, so we calculated pooled SMRs with 95%CIs using the DerSimonian-Laird random-effects model. There was an increased risk of death due to suicide in men and women combined, with a pooled SMR of 1.7 (Fig. 2). When stratifying analysis by sex, we found for men (20 studies) a pooled SMR of 1.8, with a significant increased risk for all papers (Fig. 3). Regarding women (20 studies) the summary SMR showed a significant increased risk, with a SMR of 1.4, although one study showed a protective effect and five a non-significant increase (Fig. 4). As heterogeneity was substantial, we also reported the 95% PI (Figs. 2e4). Table 2 IRR
Romagna study: multivariate analysis. Factor
reference 1.5e4.8
reference 3.5e8.5 1.0 2.7
reference 0.97e2.1
1.0 5.5
1.0 1.4
reference 1.1e2.2
reference 2.0e3.9 1.0 1.6
1.0 2.8
Gender Female Male Age at diagnosis 0e54 years 55 + years Prognosis of cancer 30% RS <30% RS Years since diagnosis 1 + years <1 years Degree of urbanisation High density area Rural and intermediate density area
IRR, incidence rate ratio; 95% CI, 95% confidence intervals.
Table 3
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Fig. 2. Forest plot of standardised mortality ratios (SMR) with 95% CI from the random effects meta-analysis of 14 studies, men and women. Q-test with p-value, tau-squared and 95% predictive interval (PI) related to the overall estimate are shown. CI, confidence interval; na, not available.
Visual inspection of the funnel plots revealed a slight asymmetry in the result of pooled SMRs (Fig. 5aec) for men, women and both sexes combined. A standard
funnel plot does not explain the reasons for the asymmetry, which was more pronounced for women than men. The Egger’s meta-regression model showed
Fig. 3. Forest plot of standardised mortality ratios (SMR) and 95% CI from the random effects meta-analysis of 20 studies, men. Q-test with p-value, tau-squared and 95% predicted intervals related to the overall estimate are shown. CI, confidence interval; na, not available.
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Fig. 4. Forest plot of standardised mortality ratios (SMR) and 95% CI from the random effects meta-analysis of 20 studies, women. Q-test with p-value, tau-squared and 95% predicted intervals (PI) related to the overall estimate are shown. CI, confidence interval; na, not available.
the relationship between the observed effect size and the size of studies. The estimated bias coefficient was 2.0, with a standard error of 3.5, giving a p-value of 0.58 for males and females combined. Thus, the test provided no evidence for the presence of small-study effects. The publication bias was not significant both for males (Egger’s test Z 2.5, p-value Z 0.26) and females (Egger’s test Z e0.9, p-value Z 0.5). The results of the sensitivity analysis (not shown), which consisted in estimating the overall effect by removing one article at a time, highlighted a high reproducibility of the analysis for men and women and for the total of people. 4. Discussion In the present study, we evaluated the risk of death due to suicide in northern Italy and included the results in a systematic review of the literature. This covered virtually all cancer registryebased studies previously published. In the Italian data, there was a 50% excess risk of suicide. In absolute terms, however, the excess risk of suicide was as low as 0.9 events per 10,000 patient-years. This must be emphasised. Because they are rare, suicides of cancer patients are difficult to predict and prevent and are beyond the personal experience of many health professionals. Conversely, they may have disproportionately large impacts on families and hospital staff.
The risk increase was more pronounced for men, for patients aged >54 years, for patients with poor prognosis, during the first year after diagnosis and for people living in thinly populated areas. The excess risk was slightly less marked for the most recent incidence cohorts. Multivariate analysis confirmed the effect of sex, patient age, intermediate density areas and years since diagnosis. The meta-analysis confirmed a robust increase in the risk of death for both sexes combined. When it was repeated for studies providing gender-specific information, the estimated summary SMR was higher for men. In the data from the Romagna Cancer Registry, we found comparable results. Among the 20 studies included in the evaluation of the risk for female patients, one study showed a protective effect [14] and four [4,33e35] (excluding the present one) a non-significantly increased risk. Many factors may have influenced these results, including the different case-mix between sexes and the possible stage differences at diagnosis. In our case series, the risk of suicide was higher for older people. This confirms previously published observations [33,36,37] but is at variance with other studies, in which no association [4,9,12,13] or an inverse association [14] was demonstrated. The role of patient age is difficult to interpret, given its interrelationship with case-mix and stage at diagnosis.
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Fig. 5. (a) Funnel plot of 14 studies for men and women. Egger’s test and p-value are shown. (b) Funnel plot of 20 studies for men. Egger’s test and p-value are shown. (c) Funnel plot of 20 studies for women. Egger’s test and p-value are shown.
Poor prognosis was another risk factor, which confirms previous research [14,37,38]. This is also the case for the time since diagnosis. In this study and many previous ones, the risk was higher in the early period, although the estimates may be slightly different according to the cut-off adopted (1 month, 3 months and 12 months) [4,12,14,37,38]. In the first few months after cancer diagnosis, the distress caused by this and by primary treatment should be monitored, and patients’ supportive interventions should be implemented [39,40]. Among the strengths of this study is the use of clear and cogent criteria for inclusion in the systematic review. All eligible studies covered the whole patients’ population, except for three in which patients younger than 15 years were not eligible [13,33,35]. This may have overestimated the risk, considering that suicide is rather unusual among children. A second strength of this study is that the literature search was performed independently by pairs of screeners. In the case of disagreement, they have discussed each study until a common decision was reached.
The major limitations of the study include the following: First, the Romagna Cancer Registry, like most population-based cancer registries, does not collect information on personal characteristics, for example comorbidities, financial difficulty and marital status. Previous studies have associated being divorced/widowed with a higher risk in comparison with married patients [3,8]. Second, and more important, estimating the risk of death by suicide at the population level is prone to the problem of under-reporting. Suicides often present a challenge in the classification of the cause of death [41]. Despite this, few studiesdand none in Italydhave been done to assess the reliability of suicide statistics [42]. In addition, the registration of suicidedand of cancer as welldmay be constrained by national data privacy restrictions. For example, excessive confidentiality provides one possible explanation for the observed heterogeneity of certain cancer incidence data [43,44]. Regarding future research in Europe, these problems will be increasingly interrelated with the potential effects of the new General Data Protection Regulation by the
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European Union, which might jeopardise the use of cancer registry data and other epidemiologic activities [45]. Despite the ongoing increase in survival of cancer patients both in Italy [21] and worldwide [22], suicide is still a relevant cause of death. The need for providing effective psychological and pharmacological support is not met yet. Oncologic teams need to be trained to identify alarming signs and symptoms among their patients, especially around the date of diagnosis and to provide a multidisciplinary preventive support [46]. In addition, suicide is an experience not limited to the patient and has serious negative effects also for his/her family and the whole hospital staff. Early detection of sign and symptoms of psychological discomfort requires specific psychosocial skills. The Italian association of medical oncologists has recently included specific practice guidelines for the psychosocial care of patients [47]. In conclusion, cancer patients were confirmed to be a group at increased risk for suicide. A clinical multidisciplinary approach aimed at supporting them and at identifying symptoms and signs of anxiety and depression is needed. Oncologists’ awareness of the psychosocial needs of patients should be improved. Deaths due to suicide are avoidable. It is a commitment of the health systems to support cancer patients allowing them to fully benefit of the constant improvements in survival. Role of funding source This research did not receive any specific grant from funding agencies in the public, commercial or not-forprofit sectors. Conflict of interest statement There are no conflicts of interest.
References [1] World Health Organization. Mental death, Latest data on suicide. 2019. https://www.who.int/mental_health/prevention/suicide/ suicideprevent/en/. [Accessed 1 April 2019]. [2] Tauil CB, Grippe TC, Dias RM, Dias-Carneiro RPC, Carneiro NM, Aguilar ACR, et al. Suicidal ideation, anxiety, and depression in patients with multiple sclerosis. Arq Neuropsiquiatr 2018;76(5):296e301. https://doi.org/10.1590/0004-282X20180036. [3] Louhivuori KA, Hakama M. Risk of suicide among cancer patients. Am J Epidemiol 1979;109(1):59e65. [4] Fox BH, Stanek 3rd EJ, Boyd SC, Flannery JT. Suicide rates among cancer patients in Connecticut. J Chronic Dis 1982;35(2): 89e100. [5] Hem E, Loge JH, Haldorsen T, Ekeberg O. Suicide risk in cancer patients from 1960 to 1999. J Clin Oncol 2004;22:209e4216. [6] Nasseri K, Mills PK, Mirshahidi HR, Moulton LH. Suicide in cancer patients in California, 1997-2006. Arch Suicide Res 2012; 16:324e33.
[7] Lin PH, Liao SC, Chen IM, Kuo PH, Shan JC, Lee MB, et al. Impact of universal health coverage on suicide risk in newly diagnosed cancer patients: population-based cohort study from 1985 to 2007 in Taiwan. Psycho Oncol 2017;26(11):1852e9. https: //doi.org/10.1002/pon.4396. [8] Ahn E, Shin DW, Cho SI, Park S, Won YJ, Yun YH. Suicide rates and risk factors among Korean cancer patients, 1993-2005. Cancer Epidemiol Biomark Prev 2010;19(8):2097e105. https: //doi.org/10.1158/1055-9965.EPI-10-0261. [9] Levi F, Bulliard JL, La Vecchia C. Suicide risk among incident cases of cancer in the Swiss Canton of Vaud. Oncology 1991; 48(1):44e7. https://doi.org/10.1159/000226893. [10] Fall K, Fang F, Mucci LA, Ye W, Andre´n O, Johansson JE, et al. Immediate risk for cardiovascular events and suicide following a prostate cancer diagnosis: prospective cohort study. PLoS Med 2009;6(12):e1000197. https://doi.org/10.1371/journal. pmed.1000197. [11] Camidge DR, Stockton DL, Frame S, Wood R, Bain M, Bateman DN. Hospital admissions and deaths relating to deliberate self-harm and accidents within 5 years of a cancer diagnosis: a national study in Scotland, UK. Br J Cancer 2007;96:752e7. https://doi.org/10.1038/sj.bjc.6603617. [12] Yousaf U, Christensen ML, Engholm G, Storm HH. Suicides among Danish cancer patients 1971-1999. Br J Cancer 2005;92(6): 995e1000. https://doi.org/10.1038/sj.bjc.6602424. [13] Allebeck P, Bolund C, Ringba¨ck G. Increased suicide rate in cancer patients. A cohort study based on the Swedish CancerEnvironment Register. J Clin Epidemiol 1989;42(7):611e6. [14] Innos K, Rahu K, Rahu M, Baburin A. Suicides among cancer patients in Estonia: a population-based study. Eur J Cancer 2003; 39(15):2223e8. [15] Misono S, Weiss NS, Fann JR, Redman M, Yueh B. Incidence of suicide in persons with cancer. J Clin Oncol 2008;26(29):4731e8. https://doi.org/10.1200/JCO.2007.13.8941. [16] Vyssoki B, Gleiss A, Rockett IR, Hackl M, Leitner B, Sonneck G, et al. Suicide among 915,303 Austrian cancer patients: who is at risk? J Affect Disord 2015;175:287e91. https://doi.org/10.1016/j.jad. 2015.01.028. [17] Storm HH, Christensen N, Jensen OM. Suicides among Danish patients with cancer: 1971 to 1986. Cancer 1992;69(6):1507e12. [18] Turaga KK, Malafa MP, Jacobsen PB, Schell MJ, Sarr MG. Suicide in patients with pancreatic cancer. Cancer 2011;117(3): 642e7. https://doi.org/10.1002/cncr.25428. [19] Sugawara A, Kunieda E. Suicide in patients with gastric cancer: a population-based study. Jpn J Clin Oncol 2016;46(9):850e5. https://doi.org/10.1093/jjco/hyw075. [20] Crocetti E, Arniani S, Acciai S, Barchielli A, Buiatti E. High suicide mortality soon after diagnosis among cancer patients in central Italy. Br J Cancer 1998;77(7):1194e6. [21] Coviello V, Buzzoni C, Fusco M, Barchielli A, Cuccaro F, De Angelis R, et al. Survival of cancer patients in Italy. Epidemiol Prev 2017;41(2 Suppl 1):1e244. https://doi.org/10.19191/EP17. 2S1.P001.017. [22] Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, et al. Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet 2015;385(9972):977e1010. https://doi.org/10.1016/S01406736(14)62038-9. [23] Ullman K. Cancer survivorship gains importance. JNCI 2014;106. https://doi.org/10.1093/jnci/djt450. [24] Falcini F, et al. Cancer incidence in Romagna, Italy (2008-2012). In: Bray F, Colombet M, Mery L, Pin˜eros M, Znaor A, Zanetti R, et al., editors. (2017) Cancer incidence in five continents, vol. XI. Lyon: International Agency for Research on Cancer; 2017 (electronic version) Available from: http://ci5.iarc.fr. [Accessed 24 July 2018].
A. Ravaioli et al. / European Journal of Cancer 125 (2020) 104e113 [25] International classification of diseases, 9th revision, clinical modification. Hospital Edition; 2007. [26] International statistical classification of diseases and related health problems. - 10th revision, edition 2010. Geneva: ª World Health Organization; 2011. [27] Breslow NE, Day NE. Statistical methods in cancer research. Volume II-the design and analysis of cohort studies. IARC Sci Publ 1987;(82):1e406. [28] Rilevazione Mortalita` e ReM - Sistema Informativo Politiche per la Salute e Politiche Sociali e Regione Emilia-Romagna; http:// salute.regione.emilia-romagna.it/siseps/sanita/rem. [29] https://ec.europa.eu/eurostat/statistics-explained/index.php/ Degree_of_urbanisation_classification_-_2011_revision#Degree_ of_urbanisation_classification. [Accessed 30 November 2018]. [30] StataCorp. Stata statistical software: release 15. College Station, TX: StataCorp LLC; 2017. [31] AIRTUM Working Group. Italian cancer figures, report 2013: multiple tumours. Epidemiol Prev 2013;37(4e5 Suppl 1):1e152. [32] DerSimonian R, Laird N. Meta-analysis in clinical trials. Contr Clin Trials 1986;7(3):177e88. [33] Robinson D, Renshaw C, Okello C, Møller H, Davies EA. Suicide in cancer patients in South East England from 1996 to 2005: a population-based study. Br J Cancer 2009;101(1):198e201. https: //doi.org/10.1038/sj.bjc.6605110. [34] Dormer NR, McCaul KA, Kristjanson LJ. Risk of suicide in cancer patients in Western Australia, 1981-2002. Med J Aust 2008;188(3):140e3. [35] Oberaigner W, Sperner-Unterweger B, Fiegl M, Geiger-Gritsch S, Haring C. Increased suicide risk in cancer patients in Tyrol/Austria. Gen Hosp Psychiatry 2014;36(5):483e7. https: //doi.org/10.1016/j.genhosppsych.2014.05.017. [36] Chatton-Reith J, el May H, Raymond L. The risk of suicide in cancer patients derived from a cancer registry. Rev Epidemiol SantePublique 1990;38:125e31. [37] Miccinesi G, Crocetti E, Benvenuti A, PacI: E. Suicide mortality is decreasing among cancer patients in Central Italy. Eur J Cancer 2004;40:53e7. https://doi.org/10.1016/j.ejca.2003.12.022. [38] Kaceniene A, Krilaviciute A, Kazlauskiene J, Bulotiene G, Smailyte G. Increasing suicide risk among cancer patients in Lithuania from 1993 to 2012: a cancer registry-based study. Eur J Cancer Prev 2017;26:S197e203. https://doi.org/10.1097/CEJ. 0000000000000375.
113
[39] Liao MN, Chen SC, Chen SC, Lin YC, Chen MF, Wang CH, et al. Change and predictors of symptom distress in breast cancer patients following the first 4 months after diagnosis. J Formos Med Assoc 2015;114(3):246e53. https: //doi.org/10.1016/j.jfma.2013.06.009. [40] Gibbons A, Groarke A, Sweeney K. Predicting general and cancer-related distress in women with newly diagnosed breast cancer. BMC Cancer 2016;16(1):935. [41] Tøllefsen IM, Helweg-Larsen K, Thiblin I, Hem E, Kastrup MC, Nyberg U, et al. Are suicide deaths under-reported? Nationwide re-evaluations of 1800 deaths in Scandinavia. BMJ Open 2015; 5(11):e009120. https://doi.org/10.1136/bmjopen-2015-009120. [42] Tøllefsen IM, Hem E, Ekeberg Ø. The reliability of suicide statistics: a systematic review. BMC Psychiatry 2012;12:9. https: //doi.org/10.1186/1471-244X-12-9. [43] Storm HH, Engholm G, Pritzkuleit R, Kejs AM, Katalinic A, Dunst J, et al. Less pitfalls and variation in population based cancer survival comparisons within the European Union: lessons from colorectal cancer patients in neighbouring regions in Denmark and Germany - the Fehmarn Belt project. Eur J Cancer 2015;51(9):1188e98. https://doi.org/10.1016/j.ejca.2014.11.006. [44] Ferlay J, Colombet M, Soerjomataram I, Dyba T, Randi G, Bettio M, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer 2018;103:356e87. https: //doi.org/10.1016/j.ejca.2018.07.005. [45] Andersen MR, Storm HH, Eurocourse Work Package 2 Group. Cancer registration, public health and the reform of the European data protection framework: abandoning or improving European public health research? Eur J Cancer 2015;51(9):1028e38. https: //doi.org/10.1016/j.ejca.2013.09.005. [46] Granek L, Nakash O, Ariad S, Shapira S, Ben-David M. Oncologists’ identification of mental health distress in cancer patients: strategies and barriers. Eur J Cancer Care 2018;27(3): e12835. https://doi.org/10.1111/ecc.12835. [47] Associazione Italiana di Oncologia Medica. AIOM. Linee guida. 2018. https://www.aiom.it/linee-guida/linee-guida-aiom-2018assistenza-psico-sociale-dei-malati-oncologici/. [Accessed 20 November 2018].