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JACC CardioOncol
JACC CardioOncol
JACC: CardioOncology
2666-0873
Elsevier

S2666-0873(24)00208-4
10.1016/j.jaccao.2024.05.012
Letters
Research Letter
Mediterranean Diet Is Associated With Lower All-Cause and Cardiovascular Mortality Among Long-Term Cancer Survivors
Bonaccio Marialaura PhD marialaura.bonaccio@moli-sani.org
a∗
Di Castelnuovo Augusto PhD a
Costanzo Simona PhD a
Ruggiero Emilia PhD a
Esposito Simona MSc a
Panzera Teresa BSc a
Cerletti Chiara PhD a
Donati Maria Benedetta MD, PhD a
de Gaetano Giovanni MD, PhD a
Iacoviello Licia MD, PhD ab
a Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Italy
b Department of Medicine and Surgery, LUM University, Casamassima (Bari), Italy
∗ Address for correspondence: Dr Marialaura Bonaccio, Department of Epidemiology and Prevention, IRCCS Neuromed, Via dell’Elettronica, 86077 Pozzilli, Italy. marialaura.bonaccio@moli-sani.org
02 7 2024
8 2024
02 7 2024
6 4 602604
11 1 2024
15 5 2024
27 5 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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pmcResearch defining the associations between the Mediterranean diet (MD) and mortality among cancer survivors has not been conclusive. Most studies are conducted in the United States, with limited evidence from Europe.1 Many studies are also conducted among site-specific cancer survivors, limiting generalizability to the broader population of survivors.1 We therefore aimed to clarify the role of a traditional MD among Italian long-term cancer survivors in relation to mortality, using postdiagnosis dietary data.

We used data from the Moli-sani Study, a population-based cohort established from 2005 to 2010, including 24,325 men and women aged ≥35 years residing in the southern Italian region of Molise.2 We identified 849 participants who reported any type of cancer diagnosis at baseline visit and provided relevant medical records and information on cancer treatment (surgery, radiotherapy, and chemotherapy). After exclusions (ie, missing data on diet, extreme energy intake), we analyzed 802 cancer survivors. Participants’ dietary intake during the preceding 12 months was assessed using an interviewer-administered semiquantitative food frequency questionnaire. Adherence to a traditional MD was measured using an MD score (MDS).3

Mortality was ascertained from March 4, 2005, through December 31, 2020, through linkage with the regional Nominative Register of Causes of Death (Registro Nominativo delle Cause di Morte). Cause-specific mortality was validated by Italian death certificates (Istituto Nazionale di Statistica form) and coded according to the International Classification of Diseases-9th Revision (ICD-9). Cardiovascular disease mortality included deaths from diseases of the circulatory system, when the underlying cause of death included ICD-9 codes 390 to 459. Cancer death was identified when the underlying cause of death included ICD-9 codes 140 to 208. The Moli-sani Study was approved by the ethics committee of the Catholic University in Rome, Italy.

HRs with 95% CIs were derived from Cox proportional hazards models evaluating the associations between time from baseline to death or last follow-up with the MDS, adjusting for age, sex, and energy intake in each model. Other confounders were defined a priori on the basis of existing literature (Table 1). The MDS was evaluated as both categorical (poor, 0-3; average, 4 or 5; and high, 6-9) and continuous (per 2-point increment) on the basis of prior literature.3Table 1 Mortality HRs Associated With the Mediterranean Diet Score Among Cancer Survivors in the Moli-sani Study

	Mediterranean Diet Score	
Categories of Adherence	Continuous	
Poor (0-3)	Average (4 or 5)	High (6-9)	2-Point Increment	
All-cause mortality (n = 248)					
 Number of deaths/number of subjects	73/241	123/360	52/201	—	
 Person-years	2,719	4,121	2,439	—	
 Event rate per 10,000 person-years	268	298	213	—	
 Model 1, HR (95% CI)	Reference	0.97 (0.72-1.30)	0.60 (0.42-0.87)	0.82 (0.70-0.96)	
 Model 2, HR (95% CI)	Reference	1.10 (0.81-1.50)	0.68 (0.46-0.99)	0.84 (0.71-0.99)	
Cardiovascular mortality (n = 59)					
 Number of deaths/number of subjects	22/241	27/358	10/200	—	
 Person-years	2,719	4,100	2,426	—	
 Event rate per 10,000 person-years	81	66	41	—	
 Model 1, HR (95% CI)	Reference	0.83 (0.47-1.48)	0.43 (0.20-0.93)	0.71 (0.52-0.98)	
 Model 3, HR (95% CI)	Reference	0.79 (0.44-1.41)	0.42 (0.19-0.93)	0.69 (0.49-0.97)	
Cancer mortality (n = 140)					
 Number of deaths/number of subjects	39/241	69/358	32/200	—	
 Person-years	2,719	4,100	2,426	—	
 Event rates per 10,000 person-years	143	168	132	—	
 Model 1, HR (95% CI)	Reference	1.05 (0.70-1.56)	0.75 (0.46-1.21)	0.89 (0.73-1.10)	
 Model 3, HR (95% CI)	Reference	1.07 (0.72-1.60)	0.79 (0.48-1.26)	0.91 (0.73-1.12)	
HRs with 95% CIs from Cox proportional hazards regression models. Model 1 included sex, age, and energy intake. Model 2 included model 1 covariates and residence, educational level, housing tenure, marital status, smoking status, body mass index, physical activity, history of cardiovascular disease, hypertension, hyperlipidemia, aspirin use, menopausal status, hormone replacement therapy, oral contraceptive use, cancer type (ie, breast, genital, digestive cancers, etc), treatment (ie, radiotherapy, chemotherapy, surgery), and time since cancer diagnosis. Model 3 included variables associated with both the exposure and the outcomes with P values <0.15, as follows: age, sex, energy intake, and educational level for cardiovascular disease mortality and age, sex, energy intake, smoking status, physical activity, and hormone replacement therapy for analyses with cancer death.

We analyzed 476 women (59%) and 326 men (41%) with a mean age of 63 ± 12 years who reported diagnoses of any type of cancer at study entry. Diet was assessed an average of 8.8 ± 8.3 years after diagnosis, and the mean MDS was 4.4 ± 1.6. Participants with higher MD adherence tended to have higher socioeconomic status and were more likely to be physically active than those with poor conformity to this diet. During 12.7 years of follow-up (9,279 person-years), a total of 248 all-cause deaths were recorded, including 59 cardiovascular deaths and 140 from cancer. Among cardiovascular deaths, 25.4% were due to ischemic heart disease (ICD-9 codes 410-414) and 23.7% to cerebrovascular disease (ICD-9 codes 430-438).

In multivariable-adjusted Cox regression analyses, each 2-point increment in the MDS was associated with 16% (HR, 0.84; 95% CI, 0.71-0.99; P = 0.038) lower all-cause mortality rates (Table 1, model 2). HRs per 2-point increment in the MDS adjusted for variables associated with both the exposure and the outcomes at P < 0.15 (ie, age, sex, energy intake, and education for cardiovascular disease mortality; age, sex, energy intake, smoking status, physical activity, and hormone replacement therapy for analyses with cancer death) were 0.69 (95% CI: 0.49-0.97; P = 0.032) for cardiovascular disease mortality and 0.91 (95% CI: 0.73-1.12; P = 0.37) for cancer death (Table 1, model 3).

High adherence to a traditional MD was independently associated with a substantial reduction in all-cause mortality rates among cancer survivors, specifically in cardiovascular mortality. The latter observation is relevant because patients with cancer are considered a high cardiovascular disease risk population4 because of shared modifiable risk factors and, potentially, molecular mechanisms of disease, as postulated by the “common soil” hypothesis.5 The MD is abundant in foods that are natural sources of polyphenols, which are bioactive compounds with well-established anti-inflammatory, antioxidant, and antitumor activities that may be relevant not only to cancer onset and progression but also and possibly even more to cardiovascular mortality prevention.

Lack of a significant association with cancer mortality could be due to the different types of cancers included and the multifaceted nature of cancer progression and recurrence, which is strongly influenced by non-nutritional factors (eg, diagnostic and prevention strategies) varying substantially across socioeconomic strata of the population.

Strengths of this study include its prospective design, a long follow-up period, the use of a well-established food frequency questionnaire, and comprehensive information on relevant potential confounders. The use of a mixed cancer cohort allows generalizability to broad cancer secondary prevention, and although our patients had varying clinical histories and different mortality rates, adjustment for cancer type and treatment potentially accounts for these differences.

There are also limitations. This is an observational study, and therefore causality cannot be inferred, and the potential of residual confounding cannot be completely excluded. Self-reported dietary intakes are susceptible to misreporting, possibly attenuated by the exclusion of participants with extreme energy intakes; lack of repeated assessment of diet, and therefore longitudinal changes, might have modified the strength of the findings, although diet in adulthood tends to remain stable over time. There is a risk for survival bias, as study participants had already survived, on average, 9 years at baseline; thus people with the most active cancers may have died beforehand. The study lacks the statistical power to conduct analyses for specific cancer types, nor did we have data on tumor stage. Also, modeling the dietary exposure into categories may have resulted in less power, and our cutpoints might not be generalizable to all populations.

Our findings suggest maintaining or adopting a traditional MD even after a cancer diagnosis may be beneficial and, importantly, motivate additional science regarding the development of dietary recommendations specifically targeted for cancer survivors.

Funding Support and Author Disclosures

Data Availability Statement: The data underlying this article will be shared on reasonable request to the corresponding author. The data are stored in an institutional repository and access is restricted by the ethical approvals and the legislation of the European Union. The present analyses were funded under the National Recovery and Resilience Plan, Mission 4 Component 2 Investment 1.3—Call for Tender No. 341 of March 15, 2022, of the Italian Ministry of University and Research, funded by the European Union-NextGenerationEU. Project Code PE0000003, Concession Decree No. 1550 of October 11, 2022, adopted by the Italian Ministry of University and Research (CUP D93C22000890001), project title “Research and Innovation Network on Food and Nutrition Sustainability, Safety and Security—Working on Foods (ONFoods). The enrolment phase of the Moli-sani Study was supported by research grants from Pfizer Foundation, the Italian Ministry of University and Research—Programma Triennale di Ricerca, Decreto No. 1588, and Instrumentation Laboratory, Milan, Italy. The funders had no role in study design; collection, analysis, and interpretation of data; or in the writing of the manuscript or the decision to submit it for publication. All authors were and are independent from the funders. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. The present study was performed in the context of the Fondazione Umberto Veronesi ETS – IRCCS Neuromed framework agreement. The authors thank Moli-sani Study participants who enthusiastically joined the study and Associazione Cuore Sano ETS for its support of the communication research activities. Dr Ruggiero gratefully acknowledges support from Fondazione Umberto Veronesi ETS.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
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