Letter to the editor on ‘Body mass index and 20-specific cancers—re-analyses of dose-response meta-analyses of observational studies’
Authors: G. Markozannes, I. Kalliala, M. Kyrgiou, K.K. Tsilidis
Journal: Annals of Oncology (2018)

In a recently published paper in the Annals of Oncology [1.Choi E.K. Park H.B. Lee K.H. et al.Body mass index and 20-specific cancers: re-analyses of dose-response meta-analyses of observational studies.Ann Oncol. 2018; 29: 749Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar], Choi et al. evaluated the strength of the evidence in the literature for the association between body mass index and 20 cancers in a manner that resembles our umbrella review on the same topic [2.Kyrgiou M. Kalliala I. Markozannes G. et al.Adiposity and cancer at major anatomical sites: umbrella review of the literature.BMJ. 2017; 356: j477Crossref PubMed Scopus (285) Google Scholar]. We were surprised to see that there were many discrepancies between the two assessments. The current paper used a grading scheme consisting of similar criteria used in our umbrella review, but structured the grading differently without providing a justification for this choice. Our umbrella review used a grading scheme that has been extensively applied and justified in previous studies [3.Li X. Meng X. Timofeeva M. et al.Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies.BMJ. 2017; 357: j2376Crossref PubMed Scopus (133) Google Scholar], and the results for adiposity and cancer in our study were consistent with previous assessments by the World Cancer Research Fund (WCRF) and the International Agency for Research on Cancer (IARC) (Table 1) [4.World Cancer Research Fund CUP. https://www.wcrf.org/int/research-we-fund/continuous-update-project-cup (17 April 2018, date last accessed).Google Scholar, 5.Lauby-Secretan B. Scoccianti C. Loomis D. et al.Body fatness and cancer–viewpoint of the IARC Working Group.N Engl J Med. 2016; 375: 794-798Crossref PubMed Scopus (1084) Google Scholar]. We feel that the authors’ choice of grading scheme fails to correctly classify the evidence. Associations between adiposity and risk of postmenopausal breast, colon, gallbladder, gastric, liver, ovarian and thyroid cancers received weak or not significant evidence grades in the current paper in contrast to convincing evidence grades received in the previous reports [2.Kyrgiou M. Kalliala I. Markozannes G. et al.Adiposity and cancer at major anatomical sites: umbrella review of the literature.BMJ. 2017; 356: j477Crossref PubMed Scopus (285) Google Scholar, 4.World Cancer Research Fund CUP. https://www.wcrf.org/int/research-we-fund/continuous-update-project-cup (17 April 2018, date last accessed).Google Scholar, 5.Lauby-Secretan B. Scoccianti C. Loomis D. et al.Body fatness and cancer–viewpoint of the IARC Working Group.N Engl J Med. 2016; 375: 794-798Crossref PubMed Scopus (1084) Google Scholar].Table 1Strength of the evidence for the association of adiposity and cancer as evaluated by different organizations/investigatorsTypeChoi et al.IARCWCRF 2017Kyrgiou et al.Breast cancer, premenopausalWeakNAProbable decreased riskSuggestiveBreast cancer, postmenopausalWeakSufficientConvincing increased riskStrong (never HRT use)Colon cancerWeakSufficientConvincing increased riskaEvaluated as colorectal.Strong (men)Rectal cancerConvincingSufficientConvincing increased riskaEvaluated as colorectal.Strong (men)Endometrial cancerConvincingSufficientConvincing increased riskStrongGallbladder cancerWeakSufficientProbable increased riskStrongGastric cancerNon-significantSufficientProbable increased risk (cardia only)Strong (cardia)LeukemiaConvincingNRNRHighly suggestiveLiver cancerWeakSufficientConvincing increased riskHighly suggestiveLung cancerWeakInadequateLimited-no conclusionSuggestive (smokers)MelanomaNRInadequateNRWeakMultiple myelomaConvincingSufficientNRStrongNon-Hodgkin's lymphomaSuggestiveLimitedNRSuggestiveEsophageal adenocarcinomaConvincing (men)SufficientConvincing increased riskStrongOvarian cancerWeakSufficientProbable increased riskStrongPancreatic cancerConvincingSufficientConvincing increased riskStrongProstate cancerNon-significantLimitedProbable increased risk (advanced)Highly suggestive (mortality)Renal cell carcinomaConvincingSufficientConvincing increased riskStrongThyroid cancerWeakSufficientNRSuggestiveNR, not reported; HRT, hormone replacement therapy; WCRF, World Cancer Research Fund; IARC, International Agency for Research on Cancer.a Evaluated as colorectal. Open table in a new tab NR, not reported; HRT, hormone replacement therapy; WCRF, World Cancer Research Fund; IARC, International Agency for Research on Cancer. There are also a number of other methodological concerns that may affect the validity of the evidence grading in the current paper. First, the authors pooled studies from several meta-analyses on the same topic (e.g. for prostate and pancreatic cancer) without acknowledging/correcting for study overlap across meta-analyses, which is substantial. Second, the authors updated existing meta-analyses by selectively adding only one newly published study without conducting a systematic literature search. Third, the authors do not report or differentiate their analysis by study design (e.g. cohort versus case–control), which may have important implications in the quality of the evidence. Fourth, several associations by cancer subsite or according to modifying factors have been omitted from the current paper (e.g. by menopausal status or hormone replacement therapy use for gynaecological malignancies). Fifth, the authors used a P-value threshold of 0.05 for Egger’s regression asymmetry test as evidence for small-study effects, but this test is known to be underpowered and 0.10 is the widely accepted threshold. In summary, IARC, WCRF and our umbrella review have rated the quality of evidence in the field of adiposity and cancer by using different methodologies, but reached similar conclusions. In contrast, we are afraid that the current paper fails to correctly classify this evidence. This work was supported by Genesis Research Trust (Garfeld Weston Foundation, P63522 to MK); Sigrid Jusélius Fellowship (P52483 to IK and MK); World Cancer Research Fund International Regular Grant Programme (2014/1180 to KKT); Ovarian Cancer Action (PS5827 and PSA601 to MK); the Imperial Experimental Cancer Medicine Centre, the Cancer Research UK Imperial Centre, Imperial Healthcare NHS Trust NIHR BRC (P45272: MK). None of the funders had any influence on the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.