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Gynecologic Oncology

The Prognostic Impact of Type 2 Diabetes Mellitus on Early Cervical Cancer in Asia

*

*

HUNG-YANG KUO,

a,

ZHONG-ZHE LIN,

b,c,

RAYMOND KUO,

g

WEN-YI SHAU,

h

CHIU-LIN LAI,

g

YEN-YUN YANG, g YU-YUN SHAO, b,e

CHIUN HSU, b,e WEN-FAN CHENG, d,e ANN-LII CHENG, b,c,e JAMES CHIH-HSIN YANG, b,e MEI-SHU LAI f,g,i

a Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu, Taiwan, Republic of China; Departments of b Oncology, c Internal Medicine, and d Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; e Graduate Institute of Oncology, College of Medicine, and f Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan, Republic of China; g Center for Comparative Effectiveness Research, National Center of Excellence for Clinical Trial and Research,Taipei,Taiwan, Republic of China; h Division of Health Technology Assessment, Center for Drug Evaluation, Taipei, Taiwan, Republic of China; i Taiwan Cancer Registry, Taipei, Taiwan, Republic of China

*

Contributed equally.

Disclosures of potential conflicts of interest may be found at the end of this article.

Key Words. Diabetes mellitus x Cervical cancer x Cancer registry x Cancer-specific survival x Prognosis

ABSTRACT

Background. Many studies have shown that type 2 diabetes

mellitus (DM) increases the risk for several types of cancer

but not

cervical cancer (CC).

Although DM and insulin-like

growth factor 1 have preclinical and clinical implications for CC, less is known about the prognostic impact of DM on patients with early stage CC.

Patients and Methods. We used the nationwide Taiwan Cancer Registry database to collect the characteristics of stage IIIA

cervical cancer patients diagnosed between 2004 and 2008. DM and other comorbidities were retrieved from the National Health

hazard ratios (HRs) for the effects of DM and other risk factors on mortality.

Results. A total of 2,946 patients had primary stage IIIA CC and received curative treatments, and 284 (9.6%) had DM.The 5-year CSS and OS rates for patients with DM were significantly lower than those without DM (CSS:

85.4% vs. 91.5%; OS: 73.9% vs. 87.9%). After adjusting for clinicopathologic variables and comorbidities, DM remained an independent unfavorable prognostic factor for CSS (adjusted HR: 1.46) and OS (adjusted HR: 1.55).

Insurance database.

Cervical cancer-specific survival (CSS)

and

Conclusion. In Asian patients with early cervical cancer, DM

overall survival (OS)

times of patients according to DM status

is an independent unfavorable prognostic factor influ-encing

were estimated using the Kaplan-Meier method. We used a Cox

both

OS

and

CSS, even after curative treatments.

The

proportional hazards model to calculate adjusted

Oncologist 2015;20:10511057

 

Implications for Practice:

Type 2 diabetes mellitus (DM) increases the incidence of several types of cancer but not cervical

cancer

(CC);

however, less is known about the impact of DM on patients who already have CC.

This study suggests that DM

may increase the risk of cancer recurrence and death for early stage CC patients, even after curative treatments.

Incorporating

DM control should be considered part of the continuum of care for early stage CC patients, and close surveillance during

routine follow-up in this population is recommended.

INTRODUCTION

Cervical cancer (CC) is a major health concern for women in

 

in developing countries [1]. Assisted by cytological and molec-

developing countries and remains the fourth most common

 

ular screening,

increasing numbers of patients have been

 

cancer in women worldwide

. Although the incidence rate of

 

diagnosed at an early stage. Surgery and radiotherapy are

CC has decreased gradually, 528,000 new cases and 266,000

treatments of choice for early stage CC and provide high cure

deaths were reported in 2012, with 85% of deaths occurring

rates;

however, certain patients still die of disease recurrence.

Correspondence: James Chih-Hsin Yang, M.D., Ph.D., Graduate Institute of Oncology and Cancer Research Centre, College of Medicine, National

Taiwan University, 5F, No.2, Xuzhou Road, Zhongzheng District,Taipei City 100,Taiwan, Republic of China.Telephone: 886-2-23123456, ext. 67511;

E-Mail: chihyang@ntu.edu.tw; or Mei-Shu Lai, M.D., Ph.D., Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Room 518, No. 17, Xuzhou Road, Taipei City 100, Taiwan, Republic of China. Telephone: 886-2-33668018; E- Mail: mslai@cph. ntu.edu.tw Received March 18, 2015; accepted for publication June 3, 2015; published Online First on August 3, 2015. ©AlphaMed Press 1083-7159/2015/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2015-0111

The Oncologist 2015;20:10511057 www.TheOncologist.com

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CME Figure 1. Patient flow diagram. Abbreviation: DM, diabetes mellitus. Prognostic factors including pelvic lymph node

Figure 1. Patient flow diagram. Abbreviation: DM, diabetes mellitus.

Prognostic factors including pelvic lymph node metastasis, stromal invasion, lymphovascular space invasion, and large tumor size affect the outcome of CC [2, 3]. The variability in recurrence-free and overall survival (OS) among patients with similar clinical and pathological characteristics implies in-completeness among the current prognostic factors.

In recent decades, numerous comprehensive cohort studies and meta-analyses have reported the consistent association

between diabetes mellitus (DM) and an increased risk of several types of cancer, including liver, pancreas, endometrium, colon,

   

and breast cancer [47]. The underlying mechanism affecting the association between DM and cancer remains elusive, and one of the most commonly adopted hypotheses involves insulin- like growth factor 1 (IGF-1). Hyperinsulinemia may increase the production of free IGF-1, which activates downstream pathways involved in proliferation, invasion, and metastasis after binding to IGF-1 receptors (IGF-1Rs) [8, 9]. Although researchers have reported preclinical and clinical implications of IGF-1 for early stage CC [10, 11], studies have not determined a significant correlation between the in-cidence of CC and DM [12, 13]. The impact of DM on OS and cancer- specific mortality of patients with early stage CC has never been addressed. Based on a comprehensive literature review,

this population-based study is the first to investigate the impact

of DM on cancer-specific survival (CSS) in CC.

We

analyzed

patient information by using the Taiwan Cancer Registry (TCR)

and National Health Insurance (NHI) databases

. Both databases

included almost all patients covered by man-datory national health insurance in Taiwan, hence this cohort study is highly representative.

MATERIALS AND METHODS

Data Source

Patients with primary CC who were newly diagnosed between

  • 2004 and 2008 were selected from the TCR database for this

nationwide population-based cohort study. The TCR database

©AlphaMed Press 2015

was

established

and

is

maintained by the Health Promotion

Administration (HPA)

, Ministry of Health and Welfare in Taiwan

[14, 15]. Major cancer care providers in Taiwan must report the data of newly diagnosed cancer patients to the TCR,thus the TCR database covers 97.6% of cancer patients in Taiwan [16]. The following information was obtained for final prognostic analysis:

patient demographics, clinicopathological status, treatment modality, and details regarding major treatment courses

Subsequently, we linked the data to the Taiwan NHI database to identify DM status and other comorbidities. The NHI program is a mandatory single-payer health insurance program that covers more than 99% of the residents of Taiwan [17]. This unified reimbursement system includes outpatient clinic and inpatient hospitalization services provided by both the private and public sectors. All medical claims are submitted and recorded electronically [18]. For our study, we linked the patient records to the National Death Registry (NDR) to identify mortality outcomes between 2004 and 2011.

Identities of patients were encrypted, and all data were an- alyzed anonymously to comply with personal electronic data pri- vacy regulations.The study data were approved for release by the data release review board of the HPA, and the protocol was ap- proved by the research ethics committee of the College of Public Health, National Taiwan University (protocol number 990205).

Study Population

Patients newly diagnosed with CC between 2004 and 2008 were identified using the following inclusion criteria: (a) an initial diagnosis of CC as a primary tumor, (b) the presence of stage IIIA disease according to the American Joint Cancer Committee on Cancer system (sixth edition) [19] and International Federation of Gynecology and Obstetrics staging system (1994) [20], and (c) age $40 years. Patients with the following characteristics were excluded: (a) had other cancers in the past; (b) exhibited multiple primary cancers; (c) exhibited pathology other than squamous cell carcinoma or adenocar-cinoma; (d) received treatment other than standard curative treatment (surgery, definitive radiotherapy, and concurrent chemoradiation), such as neoadjuvant chemotherapy, chemo- therapy alone, or unknown therapy (missing data); and (e) exhibited a positive or unknown surgical margin.

Study Variables and Endpoint Definitions

To determine whether the patients had DM, we used the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes derived from the NHI claims data to screen for comorbidities; a revised version of the mapping

algorithm by Quan et al. [21] was used. All comorbidities in the Deyo-Charlson Comorbidity Index were examined [22], and diagnosis codes from both the inpatient and outpatient clinics were included. A DM diagnosis was established only if it had been reported more than two times in outpatient clinics in different months or at least once during hospital admission within 1 year. Each comorbidity was coded and analyzed as a dichotomized variable (i.e., yes or no). The following ICD-9-CM codes were used: type 2 DM (ICD-9-CM code 250.x), congestive heart failure (ICD-9-CM codes 398.91, 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, 425.4-425.9, 428.x), cerebro- vascular disease (ICD-9-CM codes 362.34, 430.x-438.x), de-mentia (ICD-9-CM codes 290.x, 294.1, 331.2), renal disease

O

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Table 1. Patient characteristics

Characteristic

Total

With DM

Without DM

p value

Patients, n (%)

2,946

284(9.6)

2,662(90.4)

Age at diagnosis, mean (SD), range

56.7(12.1), 40102

66.2(11.3), 4293

55.7(11.7), 40102

,.001

Aged 4064 years, n (%)

2,142(72.7)

121(42.6)

2,021(75.9)

Aged $65 years, n (%)

804(27.3)

163(57.4)

641(24.1)

Tumor size, n (%) ,4 cm

966(32.8)

91(32.0)

875(32.9)

.85

$4 cm

343(11.6)

31(10.9)

312(11.7)

Unknown

1,637(55.6)

162(57.0)

1,475(55.4)

Lymph node, n (%)

N0

2,668(90.6)

250(88.3)

2,418(90.8)

.001

N1

64(2.2)

,3

63(2.4)

Unknown

214(7.3)

33(11.7)

181(6.8)

Histology, n (%) Adenocarcinoma

578(19.6)

43(15.1)

535(20.1)

.046

Squamous cell carcinoma

2,368(80.4)

241(84.9)

2,127(79.9)

Stage, n (%) Stage I

2,440(82.8)

228(80.3)

2,212(83.1)

.23

506(17.2)

56(19.7)

450(16.9)

Stage IIA Treatment group, n (%) Surgery

1,734(58.9)

109(38.4)

1,625(61.0)

,.001

Surgery plus adjuvant therapy

519(17.6)

50(17.6)

469(17.6)

Concurrent chemoradiation

349(11.8)

39(13.7)

310(11.7)

Radiotherapy

344(11.7)

86(30.3)

258(9.7)

Comorbidity, n (%) Congestive heart failure

65(2.2)

17(6.0)

48(1.8)

,.001

Cerebrovascular disease

97(3.3)

22(7.8)

75(2.8)

,.001

Dementia

17(0.6)

5(1.8)

12(0.5)

.006

Chronic pulmonary disease

126(4.3)

22(7.8)

104(3.9)

.002

Mild liver disease

134(4.5)

33(11.6)

101(3.8)

,.001

Renal disease

38(1.3)

16(5.6)

22(0.8)

,.001

Follow-up time (months), mean (SD), range

61.1(24.8), 0.595.7

55.0(21.0), 0.595.7

61.7, 1.495.7

,.001

Mortality, n (%) All-cause

422(14.3)

81(28.5)

341(12.8)

,.001

Cervical cancer-specific

274(9.3)

41(14.4)

233(8.8)

.002

Abbreviation: DM, diabetes mellitus.

(ICD-9-CM codes 403.01, 403.11, 403.91, 404.02, 404.03, 404.12,

using the Kaplan-Meier method and compared using the log-

404.13, 404.92, 404.93, 582.x, 583.0583.7, 585.x, 586.x, 588.0,

rank test.

We used a Cox proportional hazards model to esti-

V42.0, V45.1, V56.x), chronic pulmonary disease (ICD-9-CM

mate the adjusted hazard ratio (HR) and the associated 95%

codes 416.8, 416.9, 490.x505.x, 506.4, 508.1, 508.8), and mild liver disease (ICD-9-CM codes 571.2, 571.4571.6). Patients receiving postoperative chemoradiation or radiotherapy within 90 days of surgery were defined as having received adjuvant treatment.

confidence interval (CI), evaluating the impact of DM and other risk factors on mortality. Patient demographics, tumor stage, histology, lymph node involvement status, type of curative treatment, and comorbidities were all included in the Cox

Patients were followed from the day of CC diagnosis to death from

model

. Subgroup of age ($65 and 4064 years), tumor stage (I

CC (CSS), death resulting from any cause (OS), or the last follow-

or IIA), histology (squamous cell carcinoma or adenocarci-

up date in the NDR database (i.e., December 31, 2011).

noma), tumor size ($4 cm,

,

4 cm, or unknown), lymph node

stage (N0 or N1), and treatment (surgery, surgery followed by

Statistical Analysis

adjuvant therapy, chemoradiation, radiotherapy

) were analyzed

The mean or frequency of the baseline characteristics of the two

study groups at the time of CC diagnosis were compared using one-way analysis of variance for continuous variables and a chi-

square test for categorical variables.

Patient survival times (CSS

and OS) according to DM status were estimated

 

to determine whether the effects of DM on mortality were

consistent among the patient populations. A two-sided p value

#0.05 was considered statistically significant. We used SAS

version 9.2 (SAS Institute Inc, Cary, NC, http://www.sas.com) to perform the analyses.

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1.032.08; p 5 .032) (Table 2) and OS probability (adjusted HR: 1.55; 95% CI: 1.212.00; p 5 .0007) (Table 2).

RESULTS Patient Characteristics The TCR registered 21,352 patients with newly diagnosed CC between 2004 and 2008.
RESULTS
Patient Characteristics
The TCR registered 21,352 patients with newly
diagnosed CC between 2004 and 2008. In total,
Subgroup analyses demonstrated the consistent prognostic influence of
DM among the various subgroups including age, tumor size and stage, node
stages, histology, modalities of curative treatment, and comorbidities. No
strong heteroge-neity between the HRs of the subgroups was found. The
ranges of the adjusted HRs were 0.89–3.14 for CC-specific mortality and
2946 patients with stage I–IIA primary CC
1.13–2.97 for overall mortality among the subgroups (Fig. 3).
underwent curative treatment and satisfied the
eligibility criteria of this study (Fig. 1). A total of
284 patients (9.6%) had DM, and they were older
compared with patients without DM (mean age:
66.2 vs. 55.7 years; p , .001). Patients with DM
were more likely to have squamous cell carcinoma
(p 5.046) (Table 1), unknown nodal stage (p 5.001)
and other comorbidities (congestive heart failure,
cerebro-vascular disease, dementia, chronic
pulmonary disease, mild liver disease, and renal
disease). DM patients were also more likely to
receive definitive radiotherapy instead of curative
surgery (p , .001). Tumor sizes and stages differed
non-significantly between the two study groups.
Survival Analysis
During the follow-up period (mean: 61.1 months), 81
patients (28.5%) in the DM group and 41 (14.4%) in

the non-DM group died. Patients in the DM group exhibited shorter OS times than did patients without DM, and the difference was significant (p ,.0001) (Fig. 2A).The OS rates for patients with and without DM were 85.6% and 94.8%, respectively, at 2 years and 73.9% and 87.9%, respectively, at 5 years. Patients in the DM group also exhibited significantly shorter CSS times than did those in the non-DM group (p 5.0003) (Fig. 2B).The CSS rates for patients with and without DM were 90.9% and 95.9%, respectively, at 2 years and 85.4% and 91.5%, respectively, at 5 years.

Selama masa tindak lanjut (rata-rata: 61,1
Selama
masa
tindak
lanjut
(rata-rata:
61,1

bulan), 81 pasien (28,5%) pada kelompok DM dan 41 (14,4%) pada kelompok non-DM

meninggal.
meninggal.

Pasien dalam kelompok DM

menunjukkan waktu OS lebih pendek daripada pasien tanpa DM, dan perbedaannya signifikan (p, .0001) (Gambar 2A). Tingkat OS untuk pasien dengan dan tanpa DM adalah 85,6% dan 94,8%, masing-masing, pada 2 tahun dan 73,9% dan 87,9%, masing-masing, pada 5 tahun. Pasien dalam kelompok DM juga menunjukkan waktu CSS yang lebih pendek dibandingkan pada kelompok non-DM (p5,53) (Gambar 2B). Tingkat CSS untuk pasien dengan dan tanpa DM adalah 90,9% dan 95,9%, masing-masing, pada 2 tahun dan 85,4% dan 91,5%, masing-masing, pada 5 tahun.

DISCUSSION

In this comprehensive population-based study, we demon-strated that DM was an independent adverse prognostic factor for patients in Taiwan who received curative treatment for early stage CC. The prognostic impact of DM was significant according to multivariate analysis, and it remained consistent among various subgroups differentiated by age, stage, tumor size, histology, and treatment modality. Patients with DM exhibited significantly shorter CSS times than did those without DM (p 5 .0003; CSS rates: 85.4% vs. 91.5% at 5 years), and DM remained an independent predictor of lower CSS probability (adjusted HR: 1.46; 95% CI: 1.032.08; p 5 .032) according to multivariate analysis.

Previous studies have reported DM as a poor prognostic factor of early stage liver and breast cancers [23, 24] because it

©AlphaMed Press 2015

After adjustment for age, tumor size and stage, nodal stage, histology, modalities of curative treatment, and comorbidities, DM remained an independent predictor of a lower CSS probability (adjusted HR: 1.46; 95% CI:

Abbreviation: DM, diabetes mellitus.

increases cancer-specific mortality. Our study reveals a similar result in early CC. One of the common characteristics of these cancers is a high level of IGF-1R overexpression [2527]. The association between the IGF-1 level and CC has been reported [28], and high-grade expression of IGF-1R can be used to predict the high risk of death and disease recurrence in early CC [29]. Hyperglycemia and hyperinsulinemia in patients with DM may reduce the hepatic production of IGF binding protein 1 and increase the free IGF-1 level [30, 31]. An increased IGF-1 level in DM patients and overexpression of IGF-1R in CCcells activates the IGF axis and possibly results in poor prognosis. The subgroup analyses (Fig. 3) demonstrated that the impact of DM was consistent for OS and CSS among all subgroups. The negative impact of DM was more prominent in adenocarcinoma compared with squamous cell carcinoma. Nearly all cancers (pancreas, endometrium, liver, colon, and breast) with a positive association with DM are adenocarcinoma in pathology. The difference of the IGF-1 and IGF-1R axis between adenocarcinoma and squamous cell carcinoma remains unclear, and more studies are warranted to clarify the systems role in the metastasis of CC, particularly adenocarcinoma.

Figu

re 2.

Surv

ival

of

stag

e

I

IIA

cerv

ical

canc

er

patie

nts

by

diab

etes

mell

itus

diag

nosi

s

statu

s.

(A):

Ove

rall

surv

ival.

(B):

Cerv

ical

canc

er-

spec

ific

surv

ival.

Treatment modalities other than surgery alone were asso-ciated with less favorable OS and CSS. Patients for whom sur-gery is contraindicated might exhibit unfavorable risk factors, such as poor performance or inadequate control of DM, which

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Table 2. Cox regression model for stage IIIA

Overall mortality

Cancer-specific mortality

Variable

Adjusted HR (95% CI)

p value

Adjusted HR (95% CI)

p value

DM

No

Ref.

Ref.

Yes

1.55 (1.212.00)

.0007

1.46 (1.032.08)

.0320

Age

1.04 (1.031.05)

,.0001

1.02 (1.011.03)

.0005

Tumor size

,4 cm

Ref.

Ref.

$4 cm

1.40 (1.061.86)

.0183

1.59 (1.142.23)

.0066

Unknown

0.85 (0.681.06)

.1459

0.85 (0.641.12)

.2500

Lymph node

N0

Ref.

Ref.

N1

4.71 (3.117.13)

,.0001

4.97 (3.157.84)

,.0001

Unknown

0.99 (0.731.33)

.9328

1.00 (0.671.49)

.9939

Histology Squamous cell carcinoma

Ref.

Ref.

Adenocarcinoma

1.77 (1.382.27)

,.0001

2.12 (1.582.83)

,.0001

Stage

Stage I

Ref.

Stage IIA

1.49 (1.201.85)

,.0001

1.75 (1.342.29)

,.0001

Treatment Surgery

Ref.

Ref.

Surgery plus adjuvant therapy

1.75 (1.312.34)

.0002

1.90 (1.352.66)

.0002

Concurrent chemoradiation

2.16 (1.582.96)

,.0001

2.37 (1.623.47)

,.0001

Radiotherapy

2.52 (1.843.46)

,.0001

2.30 (1.523.47)

,.0001

Comorbidity Congestive heart failure

1.30 (0.802.11)

.2843

1.32 (0.672.62)

.4281

Cerebrovascular disease

1.18 (0.791.76)

.4154

1.34 (0.782.29)

.2901

Dementia

1.68 (0.873.25)

.1247

0.77 (0.193.19)

.7218

Chronic pulmonary disease

1.16 (0.791.69)

.4463

1.26 (0.772.06)

.3592

Mild liver disease

1.38 (0.961.99)

.0817

0.97 (0.561.68)

.9145

Renal disease

1.88 (1.083.27)

.0248

0.68 (0.222.15)

.5103

Abbreviations: CI, confidence interval; DM, diabetes mellitus; HR, hazard ratio; Ref., reference.

could imply unfavorable prognosis. A large retrospective study performed by MD Anderson Cancer Center revealed that obese cervical cancer patients were more likely to be treated with primary radiotherapy rather than surgery and had poorer survival compared with healthy-weight patients [32].They found that obesity is also an independent poor prognostic factor for cervical cancer patients. DM patients also tend to have obesity, and that potentially leads to inadequate treatment dose in several respects that could impair outcomes. Inaccuracy in radiation dose calculationespecially for lateral or oblique treatment fields [33], inadequate pelvis penetration even by high-energy radiation beams, and deviation in daily setup due to skin folds [34]contributes to difficulties in delivering radiotherapy to obese patients. In addition, up to 40% of obese patients still receive smaller doses of chemotherapy than expected by their actual body weight, although interna-tional guidelines suggest giving full-weight-based cytotoxic chemotherapy doses for obese patients [35]. Without surgery, subclinical metastatic lymph nodes could impair survival in

patients who receive underdosing of radiotherapy and che- motherapy. Although we do not have body mass index data in this study because of limitations in our database, morbid obesity is less commonly seen in Asian populations and may play a minor role in this study. In addition, only patients exhibiting unfavorable pathological factors receive adjuvant treatment; therefore, they have a higher risk of disease recurrence and death.

For this nationwide population-based study, we used data from the Taiwan NHI database, thereby reducing the patient selection bias commonly found in institute-based studies; however, the study was retrospective, and several limitations were present. First, nonsurgical patients were not issued pathological reports documenting tumor size; therefore, inac- curacy in or lack of records of the clinical tumor size resulted in unknown tumor sizes. Except for the unknown parts of the data, distribution of tumor size was similar between the two groups. Second, we could not analyze several aforementioned crucial prognostic factors that may affect the choice of

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Diabetes Mellitus and Prognosis of Cervical Cancer

Diabetes Mellitus and Prognosis of Cervical Cancer Figure 3. Subgroup analysis of adjusted hazard ratios of

Figure 3. Subgroup analysis of adjusted hazard ratios of mortality for patients with and without diabetes mellitus using the Cox proportional hazards model.

Abbreviations: CCRT, chemoradiotherapy; CI, confidence interval; DM, diabetes mellitus; HR, hazard ratio; OP, surgery; RT, radiotherapy

curative treatment modality. Although there are many limi-tations, DM remained an independent prognostic factor for OS and CSS after adjusting confounding factors by multivariate analysis.

 

In conclusion, we demonstrated that early stage CC patients with DM exhibited less favorable OS and CSS

after curative treatment.

The prognostic impact of DM remained significant after adjustment for patient

demographics and other comor-bidities. We should continue to search for more accurate prognostic factors and to determine which would justify more frequent surveillance in high-risk groups for early detection of curable disease recurrence. To confirm the role of the IGF axis for cancer survival in humans, more clinical trials of IGF-targeted agents for CC patientsparticularly those with DM or adenocarcinomaare required.

ACKNOWLEDGMENTS

Taiwan, for providing the database. This study was supported by the Bureau of National Health Insurance, Department of Health, Taiwan (DOH96-NH-1003) and the Science and Technology Unit, Department of Health, Taiwan (DOH99-TD-B- 111001, DOH100-TD-B-111001).

AUTHOR CONTRIBUTIONS

Conception/Design: Hung-Yang Kuo, Zhong-Zhe Lin, Yu-Yun Shao, Chiun Hsu, Ann-Lii Cheng, James Chih-Hsin Yang, Mei-Shu Lai Provision of study material or patients: Raymond Kuo, Wen-Yi Shau, Chiu-Lin Lai, Yen-Yun Yang Collection and/or assembly of data: Raymond Kuo, Wen-Yi Shau, Chiu-Lin Lai, Yen-Yun Yang Data analysis and interpretation: Hung-Yang Kuo, Zhong-Zhe Lin, Raymond Kuo, Chiu-Lin Lai, Yen-Yun Yang Manuscript writing: Hung-Yang Kuo, Zhong-Zhe Lin

Final approval of manuscript: Hung-Yang Kuo, Zhong-Zhe Lin, Raymond Kuo, Wen-Yi Shau, Chiu-Lin Lai, Yen-Yun Yang, Yu-Yun Shao, Chiun Hsu, Wen-Fan Cheng,