Long-term All-Cause Mortality in Cancer Patients With Preexisting Diabetes Mellitus: A Systematic Review and Meta-analysis

In the paper

“A random-effects model meta-analysis of 23 articles showed that diabetes was associated with an increased mortality HR of 1.41 (95% confidence interval [CI], 1.28-1.55) compared with normoglycemic individuals across all cancer types.”

• Also stated in: § Meta-analysis · plain

  “Preexisting diabetes was associated with an increase in all-cause mortality following cancer diagnosis (HR = 1.41; 95% CI, 1.28-1.55).”

• Also stated in: § Comment · plain

  “Preexisting diabetes in cancer patients at the time of diagnosis was associated with an HR of 1.41 for the risk of all-cause mortality compared with individuals without diabetes when pooled across 23 studies of various types of cancer.”

In the paper

“Of 9 estimates from 8 articles reporting the association of diabetes with cancer-specific mortality, 2 estimates found significantly higher risk,48,78 2 estimates found a nonsignificantly higher risk,36,77 2 estimates found a nonsignificantly lower risk,42,77 and 3 articles did not report a direction of effect.47,68,76”

In the paper

“The sign test rejected the null hypothesis of equal mortality in patients with and without preexisting diabetes whether we excluded studies that did not report a direction of effect (P = .001) or assumed studies that did not report a direction of effect fell evenly in either category (5 each side, P=.005).”

In the paper

“The omission of any one study did not appreciably change the pooled HR, and the estimates in each case were well within the confidence limits of the overall estimate.”

In the paper

“Heterogeneity was significant by the Q statistic (205 on 24 df, P < .001) and by I2 (88.3%, P < .001).”

In the paper

“Our subsidiary analysis of studies that distinguished between cancer and noncancer mortality was inconclusive, so this possibility cannot be excluded.”

In the paper

“Of the 3 studies evaluating noncancer mortality, 2 found a significant association with increased risk among patients with preexisting diabetes36,79 and 1 article reported a nonsignificant association with no direction of effect.67”

In the paper

“Overall, 32 study estimates found diabetes was associated with increased risk of mortality, 7 found diabetes was associated with decreased risk of mortality, 1 found a null effect, and 10 did not report a direction of effect.”

In the paper

“It is possible that high insulin or insulin-like growth factor levels may promote cancer cell and tumor growth.10”

What the sources say

• Not checked yetcites [10] Richardson LC Pollack LA Therapy insight: influence of type 2 diabetes on the development, treatment and outcomes of cancer Nat Clin Pract Oncol 2005 2 1 48 53 16264856

In the paper

“Because some cancers—including cancers of the breast,2 colorectum,3 endometrium,4 liver,5 and pancreas6—occur more commonly in individuals with diabetes”

What the sources say

• Not checked yetcites [2] Larsson SC Mantzoros CS Wolk A Diabetes mellitus and risk of breast cancer: a meta-analysis Int J Cancer 2007 121 4 856 862 17397032
• Not checked yetcites [3] Larsson SC Orsini N Wolk A Diabetes mellitus and risk of colorectal cancer: a meta-analysis J Natl Cancer Inst 2005 97 22 1679 1687 16288121
• Not checked yetcites [4] Friberg E Orsini N Mantzoros CS Wolk A Diabetes mellitus and risk of endometrial cancer: a meta-analysis Diabetologia 2007 50 7 1365 1374 17476474

In the paper

“Using the method described by Cohn and Becker,27 post hoc power calculations based on the overall and site-specific pooled HRs revealed excellent power (≥95%) for overall, endometrial, breast, and colorectal cancer estimates and low power (<50%) for prostate, gastric, hepatocellular, lung, and pancreatic cancer estimates.”

What the sources say

• Not checked yetcites Cohn and Becker,27

In the paper

“Diabetes is a well-established risk factor for cardiovascular mortality in adults without cancer,86”

What the sources say

• Not checked yetcites [86] Morrish NJ Wang SL Stevens LK Fuller JH Keen H Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes Diabetologia 2001 44 suppl 2 S14 S21 11587045

In the paper

“Third, patients with preexisting diabetes may have poorer response to cancer treatment, including increased infection risk and intraoperative mortality.39,81”

What the sources say

• Not checked yetcites [39] Meyerhardt JA Catalano PJ Haller DG Impact of diabetes mellitus on outcomes in patients with colon cancer J Clin Oncol 2003 21 3 433 440 12560431
• Not checked yetcites [81] Weiser MA Cabanillas ME Konopleva M Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexatecytarabine regimen Cancer 2004 100 6 1179 1185 15022284

In the paper

“Of the 12 authors contacted, 3 were able to provide additional information, 4 were unable to furnish the necessary information, and 5 did not respond to our request.”

In the paper

“Cancer patients with diabetes may receive less aggressive cancer treatment or less aggressive diabetes care, both of which could compromise survival.10”

What the sources say

• Not checked yetcites [10] Richardson LC Pollack LA Therapy insight: influence of type 2 diabetes on the development, treatment and outcomes of cancer Nat Clin Pract Oncol 2005 2 1 48 53 16264856

In the paper

“Fleming et al83 found that women older than 67 years with preexisting diabetes had a 17% greater risk of being diagnosed with late vs early stage breast cancer in the SEER database compared with normoglycemic women.”

What the sources say

• Not checked yetcites Fleming et al83

In the paper

“Fourth, patients with preexisting diabetes may present with later-stage disease because of suboptimal cancer screening practices.82”

What the sources say

• Not checked yetcites [82] Beckman TJ Cuddihy RM Scheitel SM Naessens JM Killian JM Pankratz VS Screening mammogram utilization in women with diabetes Diabetes Care 2001 24 12 2049 2053 11723081

In the paper

“Adults with diabetes experienced increased cancer mortality in the American Cancer Society Cancer Prevention Study II,8 but not in the Second National Health and Nutrition Examination Survey Mortality Follow-Up.9”

What the sources say

• Not checked yetcites [8] Coughlin SS Calle EE Teras LR Petrelli J Thun MJ Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults Am J Epidemiol 2004 159 12 1160 1167 15191933
• Not checked yetcites [9] Saydah SH Loria CM Eberhardt MS Brancati FL Abnormal glucose tolerance and the risk of cancer death in the United States Am J Epidemiol 2003 157 12 1092 1100 12796045

In the paper

“Quality was assessed using elements of the STROBE checklist for cohort studies considered important for quality in these studies.11”

What the sources say

• Not checked yetcites [11] von Elm E Altman DG Egger M Pocock SJ Gøtzsche PC Vandenbroucke JP STROBE initiative: the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies J Clin Epidemiol 2008 61 4 344 349 18313558

In the paper

“While the association of diabetes and site-specific mortality risk reached statistical significance only for cancers of the endometrium, breast, and colorectum, diabetes appeared to be associated with some additional mortality risk for all types of cancer.”

In the paper

“The majority of the studies included in the review evaluated multiple prognostic variables, which likely decreased the risk of publication bias with respect to the relationship between diabetes and mortality in this patient population”

In the paper

“Finally, differences in follow-up time, which was not always reported, may also limit interpretation of the results.”

In the paper

“One reviewer performed a full abstraction and other reviewers verified accuracy.”

In the paper

“However, experts in cancer epidemiology recognize that attribution of cause of death is often problematic and that undue reliance on attributed cause can bias estimates of risk related to cancer treatment.87-90”

What the sources say

• Not checked yetcites [87] Begg CB Schrag D Attribution of deaths following cancer treatment J Natl Cancer Inst 2002 94 14 1044 1045 12122090
• Not checked yetcites [88] Ederer F Geisser MS Mongin SJ Church TR Mendel JS Colorectal cancer deaths as determined by expert committee and from death certification: a comparison J Clin Epidemiol 1999 52 5 447 452 10360340
• Not checked yetcites [89] Welch HG Black WC Are deaths within 1 month of cancer-directed surgery attributed to cancer? J Natl Cancer Inst 2002 94 14 1066 1070 12122097
• Not checked yetcites [90] Lu TH Shih TP Lee MC Chou MC Lin CK Diversity in death certification: a case vignette approach J Clin Epidemiol 2001 54 11 1086 1093 11675159

In the paper

“Fifth, the diagnosis and treatment of cancer may distract both the patient and the health care team from appropriate management of glycemia, blood pressure, and lipids, proven to reduce morbidity and mortality in diabetic adults.”

In the paper

“Titles, abstracts, and articles were reviewed by at least 2 independent readers.”

In the paper

“and the microvascular and macrovascular damage it causes likely accumulates to some extent regardless of cancer status.”

In the paper

“First, cancer patients with diabetes may have increased tumor cell proliferation and metastases in a physiologic environment of hyperinsulinemia and hyperglycemia.10”

What the sources say

• Not checked yetcites [10] Richardson LC Pollack LA Therapy insight: influence of type 2 diabetes on the development, treatment and outcomes of cancer Nat Clin Pract Oncol 2005 2 1 48 53 16264856

In the paper

“If several estimates were reported in the same article, we chose the most fully adjusted estimate (ie, multivariate regression was selected over univariate regression, which was selected over unadjusted Kaplan-Meier analysis).”

In the paper

“Another potential pathway is that acute exposure to hyperglycemia may increase endothelial cell permeability due to increased generation of reactive oxidative species and structural changes in the basement membrane, increasing the likelihood of metastasis.80”

What the sources say

• Not checked yetcites [80] Morss AS Edel ER Glucose modulates basement membrane fibroblast growth factor-2 via alterations in endothelial cell permeability J Biol Chem 2007 282 19 14635 14644 17327226

In the paper

“To avoid overlapping patient populations, we compared data on recruitment years, data source, and geographic location. If a patient population was found to overlap, we included the article with the most comprehensive population or most adjusted estimate of risk associated with preexisting diabetes. This resulted in the exclusion of 12 articles from our systematic review.12-23”

What the sources say

• Not checked yetcites [12] Janssen-Heijnen ML Maas HA Houterman S Lemmens VE Rutten HJ Coebergh JW Comorbidity in older surgical cancer patients: influence on patient care and outcome Eur J Cancer 2007 43 15 2179 2193 17681780
• Not checked yetcites [13] Lemmens VE Janssen-Heijnen ML Verheij CD Houterman S Repelaer van Driel OJ Coebergh JW Co-morbidity leads to altered treatment and worse survival of elderly patients with colorectal cancer Br J Surg 2005 92 5 615 623 15779071
• Not checked yetcites [14] Tanisada K Teshima T Ikeda H Prognostic factors for patients with esophageal cancer treated with radiation therapy in PCS: a preliminary study Radiat Med 1998 16 6 461 468 9929147
• Not checked yetcites [15] Nagasue N Kohno H Tachibana M Yamanoi A Ohmori H El-Assal ON Prognostic factors after hepatic resection for hepatocellular carcinoma associated with Child-Turcotte class B and C cirrhosis Ann Surg 1999 229 1 84 90 9923804 PMC1191612
• Not checked yetcites [16] Huo TI Wu JC Lui WY Diabetes mellitus is a recurrence-independent risk factor in patients with hepatitis B virus-related hepatocellular carcinoma undergoing resection Eur J Gastroenterol Hepatol 2003 15 11 1203 1208 14560154
• Not checked yetcites [17] Hanbali A Al-Khasawneh K Cole-Johnson C Divine G Ali H Protective effect of diabetes against metastasis in patients with non-small cell lung cancer Arch Intern Med 2007 167 5 513 17353502
• Not checked yetcites [18] Merrick GS Butler WM Wallner KE Galbreath RW Allen ZA Adamovich E Androgen-deprivation therapy does not impact cause-specific or overall survival after permanent prostate brachytherapy Int J Radiat Oncol Biol Phys 2006 65 3 669 677 16682149
• Not checked yetcites [19] Kouvaris J Kouloulias V Loghis C Sykiotis C Balafouta M Vlahos L Prognostic factors for survival in invasive squamous cell vulvar carcinoma: a univariate analysis Gynecol Obstet Invest 2001 51 4 262 265 11408738
• Not checked yetcites [20] Janssen-Heijnen ML Lemmens VE van den Borne BE Biesma B Oei SB Coebergh JW Negligible influence of comorbidity on prognosis of patients with small cell lung cancer: a population-based study in the Netherlands Crit Rev Oncol Hematol 2007 62 2 172 178 17197191
• Not checked yetcites [21] Maas HA Kruitwagen RF Lemmens VE Goey SH Janssen-Heijnen ML The influence of age and co-morbidity on treatment and prognosis of ovarian cancer: a population-based study Gynecol Oncol 2005 97 1 104 109 15790445