A series of recent studies and meta-analyses confirm

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1 Originl Reserch Clinicl Medicine & Reserch Volume 11, Number 4: Mrshfield Clinic clinmedres.org Brest nd Prostte Cncer Survivors in Dibetic Cohort: Results from the Living With Dibetes Study Adedyo A. Onitilo, MD, MSCR; Mri Donld, PhD; Rchel V. Stnkowski, PhD; Jessic M. Engel, DNP, FNP-BC; Gil Willims, MSc, PhD nd Suhil A. R. Doi, MD, PhD Objective: Dibetes is more common in cncer survivors thn in the generl popultion. The objective of the present study ws to determine cncer frequency in cohort of ptients with dibetes nd to exmine demogrphic, clinicl, nd qulity of life differences between cncer survivors nd their cncer-free peers to inform better individulized cre. Methods: Self-reported survey dt from 3,466 registrnts with type 2 dibetes from Austrli s Ntionl Dibetes Services Scheme (NDSS) were nlyzed to compre relevnt vribles between cncer survivors nd cncer-free ptients. Anlyses were focused on brest nd prostte cncer to reflect the most common cncers in women nd men, respectively. Results: Five percent of dibetic women reported history of brest cncer nd 4.2% of men reported history of prostte cncer. Dibetic ptients with history of brest or prostte cncer were older t time of survey nd dibetes dignosis, less likely to report metformin use (women), nd more likely to hve two or more comorbidities thn their cncer-free peers. More dibetic prostte cncer survivors lso reported problems with mobility nd performing usul tsks. However, cncerfree dibetic subjects reported lower dibetes-dependent qulity of life thn dibetic cncer survivors. There ws no ssocition between cncer survivorship nd durtion of dibetes, indices of glycemic control, obesity, or dibetic complictions. Conclusions: Cncer survivors comprise significnt minority of dibetic ptients tht re prticulrly vulnerble nd my benefit from interventions to increse screening nd tretment of other comorbidities nd promote helthy lifestyle. Keywords: Dibetes, Ptient chrcteristics; Metformin; Cncer; Cross-sectionl survey A series of recent studies nd met-nlyses confirm tht the risk for severl solid nd hemtologic mlignncies is elevted in dibetic ptients. 1 Conversely, higher frequency of dibetes is observed in cncer survivors thn in the generl popultion. 2 The frequency of dignosis is such tht even minor reciprocl influences between cncer nd dibetes my hve mjor impct on disese. 1 The ssocition between dibetes nd cncer risk is complex nd not welldefined, but is thought to occur s consequence of hyperglycemi nd/or through underlying biologic fctors tht lter cncer risk, such s insulin resistnce nd hyperinsulinemi. 3 Hyperglycemi nd hyperinsulinemi my lso be modulted by other risk fctors common to cncer nd dibetes, such s obesity or phrmcologicl gents for dibetes mngement. 3 Similrly, the ssocition between cncer survivorship nd dibetes my be relted to cncer tretment nd/or unhelthy lifestyle choices. 4,5 Corresponding Author: Adedyo A. Onitilo, MD, MSCR, FACP, Mrshfield Clinic Weston Center, 3501 Crnberry Boulevrd, Weston, WI 54476, Tel: , Fx: , Emil: onitilo.dedyo@ mrshfieldclinic.org 210 Received: Februry 13, st Revision: April 5, nd Revision: My 7, 2013 Accepted: My 9, 2013 doi: /cmr Funding: This study ws supported by Queenslnd Helth through the evlution of the Queenslnd Strtegy for Chronic Disese

2 In 2009 study using the United Sttes Behviorl Risk Fctor Surveillnce System, the prevlence of dibetes in cncer survivors ws 16.7%. 6 In cncer survivors, incident or prevlent comorbid dibetes hs been demonstrted to negtively impct overll nd helth-specific qulity of life While severl studies hve reported the prevlence of dibetes in cncer survivors with the gol of understnding nd mnging dibetes s comorbidity in cncer survivors, the converse hs not been exmined. Understnding the rte of cncer survivorship in dibetic ptients will help to understnd the scope of the problem nd size of the dibetic community for which cncer survivorship is lso n issue. It is lso importnt to understnd how dibetic cncer survivors re different thn dibetic ptients in generl in order to optimize cre. The Living With Dibetes Study (LWDS) ws undertken to provide comprehensive exmintion of temporl trends in stisfction with cre, qulity of life, helth cre utiliztion, nd disese progression in people living with dibetes in Queenslnd, Austrli. 11 The objective of this study ws to use the stte-wide LWDS dtbse to report on the frequency of brest nd prostte cncer survivors in this cohort of dibetic ptients nd to exmine demogrphic, clinicl, nd qulity of life differences in dibetic ptients with nd without history of cncer. Becuse issues my be cncer-specific, we focused on the most common cncers in women nd men, nmely brest cncer in women nd prostte cncer in men. We hypothesize tht cncer survivors mke up smll, but significnt minority of dibetic ptients nd tht these ptients differ from their cncer-free peers with respect to demogrphics, clinicl chrcteristics, nd/or qulity of life. Identifying such differences cn help providers to focus on needs specific to this popultion. Methods Study design nd prticipnts The Living with Dibetes Study (LWDS) is n ongoing longitudinl study of people with dibetes living in Queenslnd, Austrli. Dt from this study re contributing to lrge scle evlution of the stte-wide Queenslnd Strtegy for Chronic Disese (QSCD) progrm whose gol is improvement of cre reltive to mjor chronic diseses, including dibetes. This pper reports on dt collected t bseline in 2008 concerning brest nd prostte cncer history mong ptients with dibetes. The smpling frme ws people with dibetes registered with Austrli s Ntionl Dibetes Services Scheme (NDSS), n inititive of the Austrlin Government dministered by Dibetes Austrli. The primry purpose of the NDSS is to deliver dibetes-relted products t subsidized prices to registrnts, who must hve verified dignosis for ccess. Eligibility criteri for study prticipnts included registrtion with the NDSS, physicl residence in Queenslnd with vlid postl ddress on record with the NDSS, ge 18 yers or older, dignosis of type 1 or type 2 dibetes, nd indiction of interest in prticiption in reserch opportunities upon NDSS registrtion. Persons with gesttionl dibetes were excluded. A smple of 14,439 registrnts of the NDSS ws invited to prticipte; ech ws miled questionnire, informtion sheet, consent form, nd reply-pid envelope. Completed questionnires were returned by 3,951 prticipnts, yielding prticiption rte t bseline of 27%. Ninety-five percent (N=3,761) of the prticipnts hd dignosis of type 2 dibetes. Becuse differences my be cncer-specific, we focused on brest nd prostte cncer, nd prticipnts reporting dignosis of ny other type of cncer were excluded from nlysis resulting in totl of 3,466 eligible subjects. Type of dibetes dignosis ws verified using NDSS registrtion dt. Individuls who took up the invittion to prticipte were lrgely similr to those who did not, with the exception tht individuls were more likely to prticipte if they were ged over 60 yers, nd Indigenous Austrlins were less likely to prticipte. The finl criterion, interest in receiving informtion bout opportunities to prticipte in reserch, reduced the vilble popultion for smpling by bout third. Three policy trget zones for the QSCD were over-smpled: n outer metropolitn re, new urbn development, nd costl griculturl community. 11 Ethics pprovl for the study ws grnted by the University of Queenslnd s Behviourl nd Socil Sciences Ethicl Review Committee. Written informed consent ws obtined from ll study prticipnts. Mesures Of 347 primry vribles in the 2008 bseline dt file, the following demogrphic, clinicl, nd qulity of life chrcteristics were extrcted for this study: gender, ge, ge t dibetes dignosis, self-reported HbA1c result, ever smoked, lcohol intke, dibetes-relted complictions, metformin use (durtion of therpy ws not recorded), co-morbid conditions, durtion of dibetes, body mss index (BMI), qulity of life mesures, nd history of brest or prostte cncer. Although ge t cncer dignosis ws requested on the LWDS questionnire, it ws not relibly recorded or vilble for nlysis. Therefore, ll ptients with history of brest or prostte cncer were included, regrdless of whether cncer ws dignosed before or fter dibetes. We used the EuroQoL group s EQ-5D 12 to determine physicl nd mentl helth sttus nd the Audit of Dibetes Dependent Qulity of Life (ADDQoL) 13 to determine dibetes-specific qulity of life. Results of the former were scored in five dimensions nd expressed in terms of ny impirment (yes/ no) for ech of the five dimensions, while the ltter ws expressed in terms of n impct score tht cn rnge from -9 to +3 indicting mximum negtive to mximum positive impct on dibetes qulity of life. Sttisticl procedures A cross-sectionl nlysis ws performed on dt from questionnires completed in We compred groups with unpired Student s t-tests nd compred frequencies using χ 2 tests. Comprisons were lso djusted for current ge nd CM&R 2013 : 4 (December) Onitilo et l. 211

3 Tble 1: Bseline chrcteristics of dults with type 2 dibetes. N n (%) or medin (IQR) Cncer history (4.6) Brest cncer (5.0) Prostte cncer (4.2) Age (yers) (6.3) (31.5) (49.9) (12.3) High co-morbidity (2+) (48.3) No. of complictions (0 2) Durtion of dibetes (yers) (3 8) Mle Gender (55.4) Metformin use (yes) (57.3) HbA1c 2837 <6.5% 775 (27.3) 6.5-7% 885 (31.2) 7.1-8% 724 (25.5) >8% 453 (16.0) HbA1c result score b (1 3) Obesity (BMI > 30) (52.3) Risky/high risk lcohol use (6.6) Hve you ever smoked (yes) (53.6) BMI, body mss index; HbA1c, hemoglobin A1c Number of respondents for whom dt were vilble for ech vrible. b 1 6.5%; 2 = 6.5-7%; 3 = 7.1-8%; 4 8% durtion of dibetes to determine if differences were medited through such non-modifible fctors. Multivrible logistic regression nlysis ws pplied to model the ssocition between durtion of dibetes nd cncer survivorship s prior reserch suggests tht dibetes per se my be risk fctor for cncer. Sttisticlly non-significnt differences in confounders between durtion groups my still cuse n importnt confounding effect, nd thus vribles djusted for in the ltter nlysis were selected bsed on either being known risk fctors for cncer or relted to glycemic control. Oversmpling weights did not chnge the outcome of the finl model when djusted for, nd thus were not used in model building. We used SPSS version 19 (IBM, Armonk, NY, USA) for ll nlyses. Results The generl chrcteristics of the 3,466 subjects with type 2 dibetes re described in Tble 1. The mjority of ptients were in the 60 to 74-yer-old ge rnge, nd the medin durtion of dibetes ws 6 yers. Phrmcologicl use surveyed mong the subjects reveled tht 57.3% were currently using metformin. Among the reference popultion, 158 subjects (4.6%) hd history of brest or prostte cncer. There were 77 cses of brest cncer mong 1,547 women (5.0%), nd 81 cses of prostte cncer mong 1,919 men (4.2%). Compred to subjects with no history of cncer, women with history of brest cncer nd men with history of prostte cncer were significntly older t time of survey, older t time of dibetes dignosis (figure 1), less likely to report using metformin, nd were more likely to hve two or more comorbidities (tbles 2 nd 3). Brest cncer survivors were Figure 1. Box nd whiskers plot compring ge t dibetes onset in dibetic ptients with nd without history of prostte cncer (left) or brest cncer (right). 212 Dibetes nd cncer survivors CM&R 2013 : 4 (December)

4 Tble 2: Comprisons between history of brest cncer nd ptient chrcteristics. Cncer History (Femles Only) Brest Cncer None (N = 77) (N = 1470) Vribles N n (%) or medin (IQR) n (%) or medin (IQR) P vlue Age (yers) 1547 < (0) 127 (8.6) (22.1) 504 (34.3) (49.3) 703 (47.8) (28.6) 136 (9.2) Age (yers, continuous) (60 76) 61 (54 68) Age t dibetes dignosis (52 68) 54 (52 68) <0.001 High comorbidity (2+) (67.5) 430 (29.2) <0.001 Comorbidities Chronic obstructive (13.0) 103 (7.0) pulmonry disese Kidney disese (6.5) 81 (5.5) Hert disese (27.3) 262 (17.8) Stroke (6.5) 66 (4.5) Arthritis (51.9) 516 (35.1) High blood pressure (59.7) 666 (45.3) Osteoporosis (23.4) 134 (9.1) <0.001 Number of dibetic complictions (0 1) 0 (0 1) Durtion of dibetes (3 9) 6 (3 8) Metformin use (yes) (42.9) 848 (57.9) HbA1c result score b (1 3) 2 (1 3) Obesity (BMI > 30) (54.8) 801 (46.9) Risky/high drinker lcohol use (8.1) 59 (4.1) Hve you ever smoked (yes) (48.5) 504 (39.1) Generl Qulity of Life Survey c Problems with mobility (35.1) 463 (31.9) Problems with self-cre (8.0) 94 (6.5) Problems with usul ctivities (32.5) 416 (28.7) Problems with pin (67.1) 863 (60.0) Problems with nxiety (32.0) 503 (35.2) Dibetes-dependent Qulity of Life d ( ) ( ) BMI, body mss index; HbA1c, hemoglobin A1c Dt ws not vilble for ll ptients for ll vribles b 1 6.5%; 2 = 6.5-7%; 3 = 7.1-8%; 4 8% c Reporting problems yes or no for the five domins of the Europen Qulity of Life Survey d Rnge from -9 to +3 representing mximum negtive to mximum positive impct of dibetes on qulity of life significntly more likely to report kidney disese, hert disese, rthritis, high blood pressure, nd osteoporosis thn their cncer-free dibetic peers (tble 2). Prostte cncer survivors were significntly more likely to report hert disese nd osteoporosis thn their cncer-free dibetic peers, nd there ws trend towrd n incresed rte of stroke s well (tble 3). Few differences were observed in generl qulity of life mesures; however, dibetic prostte cncer survivors were more likely to report problems with mobility nd problems performing usul ctivities thn dibetic ptients with no history of cncer (tble 3). There ws nonsignificnt trend towrd lower dibetes-dependent qulity of life score in ptients with no history of cncer compred to either brest or prostte cncer survivors (tbles 2 nd 3). When ll subjects were pooled, dibetes-dependent qulity of life ws significntly lower in dibetic subjects with no history of cncer (-1.00 IQR ) compred to brest or prostte cncer survivors (-0.71 IQR , P = 0.01). The significnt difference in ge between subjects with nd without history of cncer rised the possibility tht nonmodifible fctors like ge nd durtion of dibetes my be key mechnisms influencing differences observed between the two groups. Additionl nlyses djusted for ge nd durtion of dibetes demonstrted tht in women with history of brest cncer, incresed comorbidities, especilly osteoporosis nd rthritis, were independent of ge (tble 4). Similrly, in men with history of prostte cncer incresed comorbidities nd problems with mobility were lso independent of ge (tble 5). Femle subjects with history of brest cncer nd mle subjects with history of prostte cncer were divided into CM&R 2013 : 4 (December) Onitilo et l. 213

5 Tble 3: Comprisons between history of prostte cncer nd ptient chrcteristics. Cncer History (Mles Only) Prostte Cncer (N = 81) None (N = 1838) Vribles N n (%) or medin (IQR) n (%) or medin (IQR) P vlue Age (yers) 1919 < (0) 90 (4.9) (8.6) 566 (30.8) (48.1) 951 (51.7) (43.2) 231 (12.6) Age (yers, continuous) (66 79) 63 (56 70) <0.001 Age t dibetes dignosis ( ) 55 (48 63) <0.001 High co-morbidity (2+) (56.8) 407 (22.1) <0.001 Comorbidities Chronic obstructive (8.6) 108 (5.9) pulmonry disese Kidney disese (6.2) 97 (5.3) Hert disese (39.5) 479 (26.1) Stroke (12.3) 130 (7.1) Arthritis (333) 463 (25.2) High blood pressure (48.1) 770 (41.9) Osteoporosis (7.4) 38 (2.1) Number of dibetic complictions (0 3) 1 (0 2) Durtion of dibetes (4 9) 6 (3 9) Metformin use (yes) (46.9) 1067 (58.0) HbA1c result score b (1 3) 2 (1 3) Obesity (BMI > 30) (42.5) 802 (47.0) Risky/high drinker lcohol use (6.2) 158 (8.7) Hve you ever smoked (yes) (60.0) 1074 (64.8) Generl Qulity of Life Survey c Problems with mobility (51.2) 526 (29.0) <0.001 Problems with self-cre (7.5) 135 (7.5) Problems with usul ctivities (35.0) 447 (24.6) Problems with pin (57.0) 938 (51.9) Problems with nxiety (27.8) 556 (30.9) Dibetes-dependent Qulity of Life ( ) ( ) BMI, body mss index; HbA1c, hemoglobin A1c Dt ws not vilble for ll ptients for ll vribles b 1 6.5%; 2 = 6.5-7%; 3 = 7.1-8%; 4 8% c Five domins of the Europen Qulity of Life Survey tertiles bsed on durtion of dibetes. Subjects with dibetes durtion of 4 yers were included in the low tertile, ptients with dibetes durtion of 5 to 7 yers were included in the middle tertile, nd ptients with dibetes durtion of 8 yers were included in the high tertile. The undjusted odds rtio (OR) for brest or prostte cncer survivorship by durtion of dibetes ws not significnt. The OR for brest cncer survivorship in the upper tertile ws 1.03 (95% CI , P = 0.90) compred to the lower tertile. Similrly, the OR for prostte cncer survivorship in the upper tertile ws 1.49 (95% CI , P = 0.08) suggesting no ssocition. When potentil confounding vribles were djusted for using multivrible logistic regression model, there ws still no ssocition demonstrble between dibetes durtion nd brest or prostte cncer survivorship frequency. Vribles djusted for included ge, BMI, metformin use, lcohol use, smoking, number of complictions nd glycemic control s determined by self-reported hemoglobin A1C levels. 214 Dibetes nd cncer survivors Discussion There is cler evidence of n ssocition between dibetes nd cncer, 3 nd dt suggest tht there is n incresed frequency of dibetes in cncer survivors. 2 Here, we sought to better understnd the frequency of brest nd prostte cncer survivors in the dibetic community nd differences between dibetic ptients with nd without history of cncer. In defined cohort of individuls living with dibetes in Queenslnd, Austrli, we found tht the frequency of brest cncer survivorship mong women ws 5.0% nd the frequency of prostte cncer survivorship mong men ws 4.2%. Severl demogrphic, clinicl, nd qulity of life prmeters were exmined, nd dibetic ptients with history of cncer were older t the time of survey nd dibetes dignosis, less likely to report metformin use, hd more comorbidity, nd hd higher dibetes-dependent qulity of life thn their cncer-free peers, but were similr in terms of dibetes-specific indices compred to their cncer-free peers. Following djustment for ge nd dibetes durtion, CM&R 2013 : 4 (December)

6 significnt differences in comorbidity remined, suggesting tht the mechnism behind this difference ws not simply ge or dibetes durtion relted. The findings of this study re consistent with the literture suggesting tht the risk for brest nd prostte cncer increses with ge, 6 nd tht use of metformin reduces cncer risk. 14 Similrly, severl studies hve reported tht cncer survivors with dibetes hve more comorbidities thn cncer survivors without dibetes. 2 It is interesting tht the sme holds true for dibetic cncer survivors compred to dibetic subjects with no history of cncer nd my be relted to the lte-term effects of cncer nd/or cncer tretment. 15 In our study, vsculr risks were incresed in cncer ptients s evidenced by incresed rtes of kidney disese, hert disese, nd high blood pressure in brest cncer survivors nd incresed hert disese nd trend towrd incresed stroke in prostte cncer survivors. Vsculr risks were lso incresed in dibetes, suggesting tht surveillnce nd erly intervention my be especilly importnt for dibetic cncer survivors. Cncer therpy, especilly chemotherpy nd endocrine therpy, is known to contribute to osteoporosis 16 nd to crdiovsculr risk. 17,18 While some of these problems my be relted to cncer survivors being older, it does not detrct from the fct tht they need to be ddressed when deling with such ptients, regrdless of whether it is direct effect of cncer or not. The finding tht brest nd prostte cncer survivors were generlly dignosed with dibetes t n older ge is prticulrly interesting given the literture suggesting tht dibetes per se my be risk fctor for cncer. 19 We therefore took prticulr interest in determining if durtion of dibetes ws independently ssocited with cncer survivorship nd found tht this ws not the cse. This ltter finding suggests tht dibetes-relted fctors of control nd complictions my not be key fctors influencing cncer survivorship but contribute simply to the burden of comorbidities. This is consistent with our observtion tht trditionl risk fctors for both dibetes nd cncer, including obesity nd glycemic control, were not significntly different in dibetic subjects who were or were not brest or prostte cncer survivors. Similrly, there ws no difference in the rte of dibetes complictions in either group. This suggests tht mngement of dibetes is similr regrdless of cncer history, nd tht worsening mesures of glycemic control re more relted to incresed dibetes durtion thn to whether or not ptients hve history of cncer. It hs been suggested tht some cncer survivors my be so focused on recurrence tht other spects of their helth my be neglected, including lifestyle chnges tht my contribute to the development of dibetes nd mngement of existing dibetes. 10 Among cncer survivors, those with comorbid conditions, including dibetes, report higher rte of disbility nd overll poorer helth thn those without comorbidities. 10 In generl, cncer survivors with dibetes re more likely to report tht cncer hs ffected their overll helth nd re more likely to suffer from severl other comorbid conditions including rthritis, ctrcts, circultion problems, dizziness, strokes, hering impirment, nd hert, kidney, liver, nd thyroid problems thn cncer survivors without dibetes. 2 For Tble 4: Age nd dibetes-durtion djusted logistic regression for brest cncer. Vribles Odds Rtio (OR) 95% CI P vlue Age t dibetes dignosis High co-morbidity (2+) <0.001 Comorbidities Chronic obstructive pulmonry disese Kidney disese Hert disese Stroke Arthritis High blood pressure Osteoporosis Number of dibetic complictions Metformin use (yes) Obesity (BMI > 30) Risky/high drinker lcohol use Hve you ever smoked (yes) Generl Qulity of Life Survey Problems with mobility Problems with self-cre Problems with usul ctivities Problems with pin Problems with nxiety Dibetes-dependent Qulity of Life BMI, body mss index; CI, confidence intervl Five domins of the Europen Qulity of Life Survey CM&R 2013 : 4 (December) Onitilo et l. 215

7 Tble 5: Age nd dibetes-durtion djusted logistic regression for prostte cncer. Vribles Odds Rtio (OR) 95% CI P vlue Age t dibetes dignosis High co-morbidity (2+) <0.001 Comorbidities Chronic obstructive pulmonry disese Kidney disese Hert disese Stroke Arthritis High blood pressure Osteoporosis Number of dibetic complictions Metformin use (yes) Obesity (BMI > 30) Risky/high drinker lcohol use Hve you ever smoked (yes) Generl Qulity of Life Survey Problems with mobility Problems with self-cre Problems with usul ctivities Problems with pin Problems with nxiety Dibetes-dependent Qulity of Life BMI, body mss index; CI, confidence intervl Five domins of the Europen Qulity of Life Survey exmple, using helth utility score s mesure of qulity of life, Ko et l 7 reported tht helth utility scores incresed over time following cute illness with brest cncer. However, dibetes ws predictive of lower helth utility score. 7 Similrly, Thong et l 9 reported tht men with dibetes dignosed either before or fter prostte cncer dignosis hve poorer generl helth nd lower helth-relted qulity of life thn prostte cncer survivors without dibetes. In the present study, dibetic prostte cncer survivors were more likely to report problems with mobility nd performing usul ctivities thn dibetic men with no history of cncer. We did not, however, observe ny difference in generl qulity of life between dibetic brest cncer survivors nd dibetic women with no history of cncer. Interestingly, dibetic subjects with no history of cncer hd lower dibetes-dependent qulity of life score thn dibetic cncer survivors, suggesting tht cncer survivors perceive dibetes to hve lesser impct on their qulity of life. It is possible tht this reflects difference in perspective relted to cncer survivl, whereby dibetes is overshdowed by decrese in qulity of life s result of cncer. Cncer survivors pper to hold unique position s significnt minority of the overll dibetic popultion. Evidence suggests tht individuls with dibetes re t higher risk for cncer thn those without dibetes. 20 It follows tht cncer survivors with dibetes my hve greter risk for cncer recurrence thn cncer survivors without dibetes. Unfortuntely, dibetic ptients re less likely to undergo regulr cncer screening, including mmmogrphy, thn their non-dibetic counterprts. 21,22 Additionlly, findings from the 216 Dibetes nd cncer survivors present study suggest tht dibetic subjects with history of brest or prostte cncer hve greter number of comorbidities thn those with no history of cncer, nd dt from the Surveillnce Epidemiology End Results (SEER) dtbse strongly suggests tht cncer survivors die of noncncer cuses t higher rte thn the generl popultion. 4 Therefore, dibetic cncer survivors my be prticulrly vulnerble popultion nd my benefit gretly from helth nd lifestyle interventions, such s promotion of helthful diet nd ctive, non-smoking lifestyle, s described by Stull et l, 4 nd trgeted cncer screening. One importnt limittion of the present study is n unknown dte of cncer dignosis. It is impossible to know if subjects hd prevlent dibetes t the time of cncer dignosis or incident dibetes tht ws dignosed fter the cncer dignosis. Even if cncer dignosis dte were known, determining whether cncer occurred before or fter dibetes onset is still imprecise s hyperinsulinemi nd progressive hyperglycemi re lso present in the pre-dibetes phse. However, in study by Thong et l, 9 dibetes ws found to negtively impct on helth-relted qulity of life in prostte cncer survivors whether dibetes onset occurred before or fter prostte cncer dignosis, lthough incident dibetes hd lesser effect. Additionl study limittions include crosssectionl design, dt collection by self-report, survivorship bis, nd helthy subject bis. The cross-sectionl study design mkes the directionlity of ny ssocitions difficult to estblish. The fct tht we did not demonstrte link between incresing durtion of dibetes nd cncer survivorship is complicted by the long preclinicl predibetic stte with CM&R 2013 : 4 (December)

8 similr metbolic nd physiologic internl environment s in n overt dibetic stte. Thus, exct durtion of exposure is difficult to scertin. The effect nd durtion of dibetic tretments, such s metformin, further complictes mtters. Findings re lso limited by the fct tht mediction regimens nd co-morbid dignoses were self-reported nd, therefore, relint on recll. Self-report in generl presents difficulties. Hewitt et l 23 found tht self-report tends to underestimte the prevlence of cncer compred to use of tumor registry by pproximtely 14% for mles with prostte cncer nd 20% for women with brest cncer. Furthermore, the response rte for subjects consenting to prticipte in reserch ws low, yet consistent with reserch showing tht prticiption rtes in lrge cohort studies pper to be declining from bout 80% to 30% or 40% over the pst severl decdes. 24 It is possible tht prevlence estimtes of the collected vribles underestimted cncer rtes in the entire LWDS popultion. However, nlysis of self-report response ptterns in the Prostte Cncer Outcomes Study suggest tht with respect to comorbid conditions, including dibetes, response consistencies s high s 92% were obtined, nd consistency tended to be better in ptients tking prescription mediction for their condition. 25 Finlly, cncer nd its tretment is often ccompnied by significnt morbidities tht my ffect individul interest in survey prticiption, thus creting helthy subject bis, which my ct towrd decresing cncer prevlence rte. Similrly, this study is limited to comprison of cncer survivors, rther thn those with cncer dignoses, becuse mortlity of subjects before study commencement s result of cncer my result in survivorship bis. This bis mkes comprison of cncer versus no cncer difficult since helthier subjects who hve survived longer re more likely to be included. Implictions Cncer survivors hve n older ge t dibetes onset nd more comorbidity. Specificlly, vsculr risks re incresed in dibetes nd cncer, nd this popultion my require incresed surveillnce nd erly intervention. There ws less metformin use seen in women, nd given tht metformin decreses insulin resistnce nd is ssocited with reduced risk of cncer, its use should be encourged in the elderly dibetic popultions. Better dibetes-dependent QoL ws seen in women, nd this could be becuse dibetes my be overshdowed by cncer-relted decrese in qulity of life. Finlly, similr dibetes durtion, glycemic control, body mss index, nd number of complictions suggest tht dibetes-specific indices re comprble; therefore, older ge t onset nd increse comorbidity re independent of glycemic control or obesity. Finlly, brest or prostte cncer survivorship is concern for s mny s 5% to 10% of people living with dibetes, nd therefore preventive nd risk reduction mesures, s well s erly dignosis nd tretment of other medicl conditions such s crdiovsculr disese or osteoporosis in cncer survivors with dibetes should be encourged. We conclude tht cncer survivors comprise significnt minority of dibetic ptients tht re prticulrly vulnerble nd my benefit from helth interventions to increse screening nd tretment of other comorbidities nd promote helthy lifestyle. Acknowledgements The uthors thnk Mrie Fleisner of the Mrshfield Clinic Reserch Foundtion s Office of Scientific Writing nd Publiction for editoril ssistnce in the preprtion of this mnuscript. References 1. Vigneri P, Frsc F, Scicc L, Pndini G, Vigneri R. Dibetes nd cncer. Endocr Relt Cncer 2009;16: Stv CJ, Beck ML, Feng L, Lopez A, Busidy N, Vssilopoulou-Sellin R. Dibetes mellitus mong cncer survivors. 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9 15. Khn NF, Mnt D, Crpenter L, Formn D, Rose PW. Longterm helth outcomes in British cohort of brest, colorectl nd prostte cncer survivors: dtbse study. Br J Cncer 2011;105:S29 S Pfeilschifter J, Diel IJ. Osteoporosis due to cncer tretment: Pthogenesis nd mngement. J Clin Oncol 2000: Yeh ET, Tong AT, Lenihn DJ, Yusuf SW, Swfford J, Chmpion C, Durnd JB, Gibbs H, Zfrmnd AA, Ewer MS. Crdiovsculr complictions of cncer therpy: dignosis, pthogenesis, nd mngement. Circultion 2004;109: Nguyen PL, Je Y, Schutz FA, Hoffmn KE, Hu JC, Prekh A, Beckmn JA, Choueiri TK. Assocition of ndrogen deprivtion therpy with crdiovsculr deth in ptients with prostte cncer: met-nlysis of rndomized trils. JAMA 2011;306: Onitilo AA, Engel JM, Glurich I, Stnkowski RV, Willims GM, Doi SA. Dibetes nd cncer II: role of dibetes medictions nd influence of shred risk fctors. Cncer Cuses Control 2012;23: Chowdhury TA. Dibetes nd cncer. QJM. 2010;103: Lipscombe LL, Hux JE, Booth GL. Reduced screening mmmogrphy mong women with dibetes. Arch Intern Med 2005;165: Jimenez-Grci R, Hernndez-Brrer V, Crrsco-Grrido P, Gil A. Prevlence nd predictors of brest nd cervicl cncer screening mong Spnish women with dibetes. Dibetes Cre 2009;32: Hewitt M, Breen N, Deves S. Cncer prevlence nd survivorship issues: nlyses of the 1992 Ntionl Helth Interview Survey. J Ntl Cncer Inst 1999;91: Nohr EA, Frydenberg M, Henriksen TB, Olsen J. Does low prticiption in cohort studies induce bis? Epidemiology 2006;17: Klbunde CN, Reeve BB, Hrln LC, Dvis WW, Potosky AL. Do ptients consistently report comorbid conditions over time?: results from the prostte cncer outcomes study. Med Cre 2005;43: Author Affilitions Adedyo A. Onitilo, MD, MSCR *, ; Mri Donld, PhD * ; Rchel V. Stnkowski, PhD ; Jessic M. Engel, DNP, FNP-BC ; Gil Willims, MSc, PhD * nd Suhil A. R. Doi, MD, PhD * * School of Popultion Helth, University of Queenslnd, Brisbne, Queenslnd, Austrli Deprtment of Hemtology/Oncology, Mrshfield Clinic, Weston Center, Weston, Wisconsin, USA Mrshfield Clinic Reserch Foundtion, Mrshfield, Wisconsin, USA Mrshfield Clinic Cncer Cre t St. Michel s, Stevens Point, Wisconsin USA 218 Dibetes nd cncer survivors CM&R 2013 : 4 (December)