- Email: [email protected]
Influence of Hyperglycemia on Treatment Outcomes of Oral Cavity Squamous Cell Carcinoma
Journal Pre-proof The influence of hyperglycemia on the treatment outcomes of oral cavity squamous cell carcinoma Kuang-Hsu Lien, MD, Chief Resident, Paula Francezca C. Padua, MD, Fellow, Ze Yun Tay, MD, Fellow, Huang-Kai Kao, MD, FACS, Professor, Shao-Yu Hung, MD, Lecturer, Yenlin Huang, MD, Assistant Professor, Ngan-Ming Tsang, MD, DSc, Professor, Kai-Ping Chang, MD, PhD, Professor, Division Head PII:
S0278-2391(20)30089-6
DOI:
https://doi.org/10.1016/j.joms.2020.01.018
Reference:
YJOMS 59053
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 10 November 2019 Revised Date:
9 January 2020
Accepted Date: 9 January 2020
Please cite this article as: Lien K-H, Padua PFC, Tay ZY, Kao H-K, Hung S-Y, Huang Y, Tsang NM, Chang K-P, The influence of hyperglycemia on the treatment outcomes of oral cavity squamous cell carcinoma, Journal of Oral and Maxillofacial Surgery (2020), doi: https://doi.org/10.1016/ j.joms.2020.01.018. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial Surgeons
The influence of hyperglycemia on the treatment outcomes of oral cavity squamous cell carcinoma
Kuang-Hsu Lien, MD (Chief Resident)1, #, Paula Francezca C. Padua, MD (Fellow)1, #, Ze Yun Tay, MD (Fellow)1, 2, #, Huang-Kai Kao, MD, FACS (Professor)3, 6, Shao-Yu Hung, MD (Lecturer)3, Yenlin Huang, MD (Assistant Professor)4, 6, Ngan-Ming Tsang, MD, DSc (Professor)5, Kai-Ping Chang, MD, PhD (Professor, Division Head)1, 6, *
1
Department of Otolaryngology - Head & Neck Surgery, Chang Gung Memorial
Hospital, Taoyuan, Taiwan. 2
Department of Otolaryngology, Sengkang General Hospital, Singapore.
3
Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital,
Taoyuan, Taiwan. 4
Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
5
Department of Radiation Oncology, Proton and radiation therapy center, Chang
Gung Memorial Hospital, Taoyuan, Taiwan. 6
College of Medicine, Chang Gung University, Taoyuan, Taiwan.
#
These authors contributed equally to this work.
*CORRESPONDING AUTHOR Professor. Kai-Ping Chang, MD, PhD Head, Division of Head & Neck Surgery, Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital & College of Medicine, Chang Gung University, Taoyuan, Taiwan No. 5 Fu-Hsing St. Kwei-Shan, Taoyuan, Taiwan, 33305. Email: [email protected]
ABSTRACT Purpose: The study aimed to investigate the association between perioperative hyperglycemia and the treatment/ survival outcomes of oral cavity squamous cell carcinoma (OSCC). Methods: From 2004 to 2016, 385 OSCC patients were enrolled and stratified into normoglycemic (<180 mg/dL) and hyperglycemic (>180 mg/dL) groups. The clinicopathological characteristics and treatment outcomes of OSCC were subsequently analyzed. Results: Of the 385 patients, 61 (15.8%) were in the hyperglycemic group. Hyperglycemia was significantly associated with pT status, pN status, overall pathologic stage, extranodal extension, albumin level, and tumor depth (p = 0.004, 0.042, 0.008, 0.001, 0.004, and 0.011, respectively). Patients with hyperglycemia were also found to have a longer hospital stay (p = 0.003). Five-year overall survival (OS) and disease specific survival (DFS) were poorer in the hyperglycemic compared to the normoglycemic group (p = 0.001 and p = 0.002, respectively). Multivariate analysis revealed that hyperglycemia is a significant adverse prognostic indicator for OSCC (hazard ratio: 1.709; 95% confidence interval: 1.003 – 2.912; p = 0.049). Conclusions: Hyperglycemia is associated with more advanced disease and poorer survival rates in OSCC patients. It correlates with adverse clinicopathological 1
characteristics and longer hospital stay. Screening for hyperglycemia and maintenance of normal glycemic status during the treatment course is imperative in the treatment of OSCC.
Keywords: hyperglycemia, oral cavity squamous cell carcinoma, OSCC, head and neck, cancer
2
INTRODUCTION Oral cavity cancer is one of the leading malignancies globally, accounting for 354,864 (2% of all sites) new cases and 177,384 (1.9% of all sites) deaths in 2018. In Asia alone, based on the World Health Organization statistics, it is the 11th most common cancer in 2018.1 Within Taiwan, oral cavity cancer is ranked sixth in terms of cancer incidence, and is the fifth leading cause of cancer death as of 2016.2 Furthermore, the incidence of this disease has seen an increase over the last three decades, with smoking, alcohol and betel quid consumption being the main risk factors.3 Within oral cavity cancer, the epithelium-derived oral cavity squamous cell carcinoma (OSCC) has been the most prevalent cancer subtype.4 Over the years, key prognostic factors have been identified;5 however, despite refinement in staging and management strategies, OSCC still results in significant morbidity and mortality for patients inflicted with this disease. Hyperglycemia has been shown to promote both tumorigenesis and tumor progression via diverse mechanisms and also found to be an adverse prognostic factor for several malignancies.6-9 In addition, hyperglycemia has been demonstrated to impact surgical treatment outcomes and is strongly associated with the development of post-operative complications.10-13 Despite this mounting evidence, there is limited literature on the relationship between hyperglycemia and OSCC clinicopathological 3
manifestations and treatment outcomes. Herein, the current study aimed to utilize a large cohort of OSCC patients to investigate the association between perioperative hyperglycemia and the treatment/ survival outcomes of oral cavity squamous cell carcinoma (OSCC).
METHODS This retrospective study reviewed the medical records of the OSCC patients consecutively diagnosed and enrolled at Chang Gung Memorial Hospital (Taoyuan, Taiwan) between July 2004 to July 2016. Patients with at least one of the following conditions were considered ineligible: unresectable or inoperable cancer, other concomitant primary cancer, recurrent cancer, distant metastasis at presentation, any prior history of malignancy, treatment with neoadjuvant therapy, and a medical contraindication for surgery. Data gathered included age, gender, body mass index, history of alcohol consumption (≥1 alcoholic beverage/week for at least 6 months), cigarette use (≥0.05 per pack year), site of lesion, and preoperative levels of serum albumin (g/dL), creatinine (mg/dL), and hemoglobin (g/dL). The primary outcomes of interest were length of hospital stay including intensive care unit admission, and survival data. Secondary outcomes studied were the adverse clinicopathological features associated with hyperglycemia. 4
Clinicopathological characteristics (TNM classification, overall stage, presence of extranodal extension, cell differentiation, lymphovascular invasion, and tumor depth) were recorded. Treatment-related factors gathered were history of adjuvant therapy (radiotherapy or concurrent chemoradiotherapy) and surgical margins. The patients were then stratified into two groups based on the random glucose measurements obtained prior to surgery, and/or the highest serum blood glucose level during the first 24 hours after surgery: normoglycemic group (<180 mg/dL) and hyperglycemic group (≥180 mg/dL). The serum blood sugar threshold of 180 mg/dL was based on the American Association of Clinical Endocrinologists and American Diabetes Association recommendation of random blood glucose target for non-critically ill patients.14 The medical records, including the pre-treatment work-ups, operative techniques and pathological reports were reviewed. Primary tumors were excised with clear margins, ascertained by frozen section controls, and defects were reconstructed, if necessary, by the plastic surgical team, with free flaps being most commonly utilized. The 7th edition of the American Joint Committee on Cancer Staging Manual (2010) was used to establish the final pathological TNM classification after surgical treatment.15 Adjuvant radiotherapy or chemoradiation was recommended based on institutional guidelines after reviewing each patient’s clinicopathological adverse features at a 5
multidisciplinary tumor board. Regular follow-up visits were arranged every 2 months for the first year, every 3 months for the second year, and at 6 month intervals thereafter, and all patients were followed until December 2018 or their demise. This study was approved by the ethics committee of the Chang Gung Memorial Hospital, Taiwan. Written consent was obtained from all surviving patients included in this study. In accordance with the ethics committee, the data from non-surviving patients were irreversibly anonymized for statistical evaluation. Continuous data are presented as means with standard deviations, while categorical data are presented as frequencies and percentages. The clinicopathological characteristics of OSCC were compared between the two groups using chi-square and Wilcoxon tests. Five-year survival analyses were plotted using the Kaplan-Meier method, and differences were evaluated using the log-rank test. A Cox regression model was used to perform the univariate and multivariate analyses for survival analyses. All calculations were performed using the SAS software (version 9.3; SAS Institute, Cary, NC). All p-values were two-sided and statistical significance was set at p < 0.05.
RESULTS Patient Characteristics A total of 385 OSCC patients were included in our study, with a mean age of 53.2 6
years, ranging from 28.5 to 88.7 years. Among the patients, 353 (91.7%) were male, 271 (70.4%) were alcohol consumers, and 325 (84.4%) were cigarette smokers. The most common cancer site identified was from the buccal mucosa (37.9%), followed closely by tongue primaries (34.8%). Other sites such as the gingiva (12.7%), floor of mouth (7.3%), hard palate (3.6%), and lip (3.6%) occurred less frequently. Majority of the patients had a stage IV TNM classification (41.3%), followed by stage I (24.9%), stage II (23.4) and stage III (10.3%).
Association between hyperglycemia and clinicopathological characteristics The patients were classified into two groups, normoglycemic group (n = 324, 84.2%) and hyperglycemic group (n = 61; 15.8%). Hyperglycemia was found to be significantly associated with pre-operative albumin level (p = 0.004), pT status (p = 0.004), pN status (p = 0.042), overall pathologic stage (p = 0.008), ENE (p = 0.001), and tumor depth (p = 0.011). Length of hospital stay was also found to be significantly longer in the hyperglycemic group (p = 0.003). However, no significant difference was noted between the normoglycemic and hyperglycemic groups with regards to age, sex, body mass index, preoperative creatinine level, preoperative hemoglobin level, alcohol consumption, cigarette smoking, lesion site, pathological cell differentiation, lymphovascular invasion, adjuvant therapy, surgical margins and intensive care unit 7
admissions. These above statistics are shown in Table 1.
Association between hyperglycemia and survival outcomes The 5-year survival analysis (Figure 1) revealed significantly poorer survival rates for the hyperglycemic group in terms of locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), overall survival (OS), and disease-specific survival (DSS). Comparing the normoglycemic and hyperglycemic the groups, the 5-year LRFS were 77.2 vs 60.7 %, respectively (p = 0.002), 5-year DMFS were 76.9 vs 60.7 % respectively (p = 0.001), 5-year OS were 76.9 and 60.7 %, respectively (p =0.001), 5-year DSS were 79.9 vs 65.6 %, respectively (p = 0.002).
Association between survival and treatment-related factors The results of the univariate and multivariate analyzes are shown in Tables 2 and 3. Univariate analysis revealed that variables associated with poorer overall survival and disease-specific survival were advanced patient age (OS: p = 0.042; DSS: p = 0.043), higher overall pathological stage (OS: p <0.0001; DSS: p <0.0001), extranodal extension (OS: p <0.0001; DSS: p <0.0001), perineural invasion (OS: p <0.0001; DSS: p <0.0001), poor cancer differentiation (OS: p = 0.010; DSS: p = 0.011), lymphovascular invasion (OS: p <0.0001; DSS: p <0.0001), deeper tumor depth (OS: p 8
<0.0001; DSS: p = 0.0001) and presence of hyperglycemia (OS: p =0.002; DSS: p = 0.002). Multivariate analysis performed showed that overall pathological stage, extranodal extension and hyperglycemia were independent factors for poorer overall survival (p = 0.036, p = 0.003 and p = 0.048, respectively). For disease-specific survival, multivariate analysis also implicated the same independent prognostic factors including overall stage, extranodal extension and hyperglycemia (p = 0.032, p = 0.007, and p = 0.049, respectively).
DISCUSSION Hyperglycemia refers to a state where there is an elevated blood glucose level in the blood circulation. Its definition is however variable, depending on the context of the blood glucose measurement. Transient hyperglycemia is often benign and asymptomatic and may present in non-diabetic or prediabetic patients. However, chronic hyperglycemia may actually be a manifestation of diabetes mellitus. Based on the American Association of Clinical Endocrinologists and American Diabetes Association guidelines, perioperative hyperglycemia is defined as blood glucose level greater than 180 mg/dL in non-critically ill patients.14 A large scale study by Kwon et al demonstrated that perioperative hyperglycemia, based on the aforementioned cut-off, was associated with adverse outcomes in their patients undergoing general surgical procedures.12 Our study therefore has also adopted this criterion to define our 9
hyperglycemic cohort. There is increasing evidence to suggest that diabetic patients have higher risks of developing specific cancers, as well as have poorer cancer outcomes than their non-diabetic counterparts.16-17 Since hyperglycemia is a hallmark of diabetes mellitus, its role in cancer development has also been studied. In a meta-analysis by Crawley et al, a positive association between serum glucose and cancer risk was consistently demonstrated.18 Various mechanisms have been postulated to explain the association of cancer development and progression in hyperglycemia or diabetes mellitus. A chronic hyperinsulinemic state is seen in chronic hyperglycemia, leading to an elevated level of circulating free insulin-like growth factor-1 (IGF-1), which can promote tumor proliferation by stimulating mitogenesis and inhibiting apoptosis.19 Hyperglycemia can also directly stimulate tumor development and progression since glucose is a key substrate in cellular metabolism and cancer cells have been demonstrated to be able to up-regulate glucose transporters to facilitate glucose uptake.20 Persistent hyperglycemia, in the setting of diabetes mellitus, is also associated with a chronic systemic inflammatory state. This systemic inflammatory response is characterized by elevated levels of cytokines, such as IL-6 and TNF-α, which promote an environment for cancer development and progression.21 The influence of hyperglycemia on cancer survival has also been reported in the 10
literature. In a recent meta-analysis by Barua et al, hyperglycemia was shown to adversely affect overall survival and disease-free survival in various solid tumors, including breast, hepatocellular, pancreatic, gastric, esophageal, lung, cervical cancers and glioblastomas.22 Despite the wealth of evidence demonstrating the association of hyperglycemia and cancer risk, the literature is sparse with regards to the relationship between hyperglycemia and OSCC. To the best of our knowledge, our study is the first to evaluate the impact of hyperglycemia in OSCC treatment and survival outcomes. The results of our study revealed that hyperglycemia is associated with higher pT and pN statuses, and more advanced overall pathological stage. It is also significantly associated with more aggressive clinicopathologic features, including extranodal extension and increased tumor depth. These findings are compatible with the study results by Zaoui et al, in which a significant association was found between the presence of diabetes mellitus and larger tumor size and more advanced tumor grade in their cohort of head and neck squamous cell carcinoma patients.23 With regards to preoperative albumin levels, our cohort of hyperglycemia patients had significantly lower albumin levels than their counterparts who were normoglycemic. A plausible explanation is that this cohort of patients may be in a state of insulin deficiency, and since insulin stimulates the hepatic production of serum proteins including albumin, the lack of insulin in these patients therefore lead to hypoalbuminemia. 11
In our study, it was observed that patients in the hyperglycemic group had longer hospital admissions compared to the normoglycemic patients. This might imply that the OSCC patients with hyperglycemia may have a higher rate of postoperative complications, though the details of the complication were not specifically analyzed in this current study. This finding is consistent with existing literature, in that diabetic patients undergoing head and neck procedures had higher risks of postoperative infections, cardiac events and acute renal impairment.16 Similarly, in our recent investigation, we have also demonstrated that perioperative hyperglycemia is associated with an elevated risk of surgical site infections following microvascular head and neck reconstruction procedures.10 The impact of hyperglycemia or diabetes mellitus on cancer prognoses has been previously reported. A meta-analysis studying the association between hyperglycemia and cervical cancer prognosis showed that hyperglycemia was associated with poorer overall survival and locoregional recurrence-free survival.6 Another study observed that women with increasing blood glucose levels were at increased risk of both all-cause and breast cancer mortality.8 Similarly, a retrospective review of patients with glioblastoma revealed that poorer overall survival was found in patients with perioperative hyperglycemia.8 With regards to head and neck cancer or OSCC specifically, there is no existing literature to our knowledge that studied the influence of 12
hyperglycemia on survival outcomes, though Wu et al demonstrated that their cohort of diabetic patients with OSCC have poorer survival outcomes including recurrence-free survival.24 In our current study, poorer locoregional-recurrence free survival and distant metastases-free survival rates were observed in the hyperglycemic cohort, indicating that perioperative hyperglycemia can adversely affect the treatment outcomes with the higher probability of locoregional recurrence and distant metastasis. The hyperglycemic patients in our study also had inferior overall and disease-specific survival rates compared to their counterparts who were normoglycemic. These results could also be partially contributed by the higher rates of locoregional recurrences and distant metastases in these patients. Furthermore, the multivariate analyzes performed further affirmed hyperglycemia as an independent adverse prognostic factor for both overall survival and disease-specific survival in our study. Consequently, the current study results demonstrate the importance of the screening of hyperglycemic status and that maintenance of normoglycemia may reduce the hospital stay and improve the treatment outcome for OSCC patients.
CONCLUSIONS This study, the first in the literature evaluating the association of hyperglycemia and treatment and survival outcomes of OSCC patients, showed that hyperglycemia was associated with adverse clinicopathological features, such as more advanced overall 13
pathological stage, presence of extranodal extension, deeper tumor depth, and longer hospital admissions. Furthermore, hyperglycemia in OSCC patients may result in higher rates of locoregional recurrences and distant metastases, which can result in poorer survival outcomes in terms of both overall survival and disease-specific survival. Our study findings highlight the importance to screen and maintain normal glycemic status during the treatment course of oral cavity squamous cell carcinoma.
Acknowledgements The authors thank all the members of the Cancer Center, Chang Gung Memorial Hospital, for their invaluable help. This study was supported by the grant (CMRPG3H0851, CMRPG3J1251, CORPG3G0171, and CIRPG3B0014) from Chang Gung Memorial Hospital, Taiwan.
Authors' contributions Conception and design: KPC. Analysis and interpretation of data: All authors. Drafting the article or revising it critically for important intellectual content: All authors. Final approval of manuscript: All authors. Agreement to be accountable for all aspects of the work: All authors. First authors: Kuang-Hsu Lien, Paula Francezca C. Padua, and Ze Yun Tay. 14
Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests The authors declare that they have no competing interests.
15
References 1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A: Global cancer
statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394, 2018 2.
Ministry of Health and Welfare R. O. C. Statistics of General Health and Welfare
2016. 3.
Hsu W-L, Yu KJ, Chiang C-J, Chen T-C, Wang C-P: Head and Neck Cancer
Incidence Trends in Taiwan, 1980 ~ 2014. International Journal of Head and Neck Science 1:180, 2017 4.
Zini A, Czerninski R, Sgan-Cohen HD: Oral cancer over four decades:
epidemiology, trends, histology, and survival by anatomical sites. J Oral Pathol Med 39:299, 2010 5.
De Paz D, Kao HK, Huang Y, Chang KP: Prognostic Stratification of Patients
With Advanced Oral Cavity Squamous Cell Carcinoma. Curr Oncol Rep 19:65, 2017 6.
Chen S, Tao M, Zhao L, Zhang X: The association between
diabetes/hyperglycemia and the prognosis of cervical cancer patients: A systematic review and meta-analysis. Medicine (Baltimore) 96:e7981, 2017
16
7.
Storey S, Von Ah D, Hammer MJ: Measurement of Hyperglycemia and Impact
on Health Outcomes in People With Cancer: Challenges and Opportunities. Oncol Nurs Forum 44:E141, 2017 8.
Connor AE, Visvanathan K, Boone SD, Rifai N, Baumgartner KB, Baumgartner
RN: Fructosamine and diabetes as predictors of mortality among Hispanic and non-Hispanic white breast cancer survivors. NPJ Breast Cancer 5:3, 2019 9.
Zanders MM, Vissers PA, Haak HR, van de Poll-Franse LV: Colorectal cancer,
diabetes and survival: epidemiological insights. Diabetes Metab 40:120, 2014 10. Offodile AC, 2nd, Chou HY, Lin JA, Loh CYY, Chang KP, Aycart MA, Kao HK: Hyperglycemia and risk of adverse outcomes following microvascular reconstruction of oncologic head and neck defects. Oral Oncol 79:15, 2018 11. Link TW, Woodworth GF, Chaichana KL, Grossman SA, Mayer RS, Brem H, Weingart JD, Quinones-Hinojosa A: Hyperglycemia is independently associated with post-operative function loss in patients with primary eloquent glioblastoma. J Clin Neurosci 19:996, 2012 12. Kwon S, Thompson R, Dellinger P, Yanez D, Farrohki E, Flum D: Importance of perioperative glycemic control in general surgery: a report from the Surgical Care and Outcomes Assessment Program. Ann Surg 257:8, 2013
17
13. Fiorillo C, Rosa F, Quero G, Menghi R, Doglietto GB, Alfieri S: Postoperative hyperglycemia in nondiabetic patients after gastric surgery for cancer: perioperative outcomes. Gastric Cancer 20:536, 2017 14. Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D, Hellman R, Hirsch IB, Inzucchi SE, Ismail-Beigi F, Kirkman MS, Umpierrez GE, American Association of Clinical E, American Diabetes A: American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care 32:1119, 2009 15. Fan KH, Wang HM, Kang CJ, Lee LY, Huang SF, Lin CY, Chen EY, Chen IH, Liao CT, Chang JT: Treatment results of postoperative radiotherapy on squamous cell carcinoma of the oral cavity: coexistence of multiple minor risk factors results in higher recurrence rates. Int J Radiat Oncol Biol Phys 77:1024, 2010 16. Raikundalia MD, Fang CH, Spinazzi EF, Vazquez A, Park RC, Baredes S, Eloy JA: Impact of Diabetes Mellitus on Head and Neck Cancer Patients Undergoing Surgery. Otolaryngol Head Neck Surg 154:294, 2016 17. 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 159:1160, 2004
18
18. Crawley DJ, Holmberg L, Melvin JC, Loda M, Chowdhury S, Rudman SM, Hemelrijck MV: Serum glucose and risk of cancer: a meta-analysis. BMC Cancer 19:985, 2014 19. Emily Jane Gallagher DL: The proliferating role of insulin and insulin-like growth factors in cancer. Trends in Endocrinology and Metabolism 21:610, 2010 20. Rachel E. Airley AM: Hypoxic Regulation of Glucose Transport, Anaerobic Metabolism and Angiogenesis in Cancer: Novel Pathways and Targets for Anticancer Therapeutics Chemotherapy 53:233, 2007 21. Gallagher EJ, LeRoith D: Epidemiology and Molecular Mechanisms Tying Obesity, Diabetes, and the Metabolic Syndrome With Cancer. DIABETES CARE 36:S233, 2013 22. Barua R, Templeton AJ, Seruga B, Ocana A, Amir E, Ethier JL: Hyperglycaemia and Survival in Solid Tumours: A Systematic Review and Meta-analysis. Clin Oncol (R Coll Radiol) 30:215, 2018 23. Zaoui K, Doll J, Stiebi P, Federspil P, Plinkert PK, Hess J: Diabetes mellitus as a prognostic marker in oropharyngeal and laryngeal squamous cell carcinoma. HNO 64:479, 2016 24. Hagan K, Bhavsar S, Arunkumar R, Grasu R, Dang A, Carlson R, Cowles C, Arnold B, Potylchansky Y, Rahlfs TF, Lipski I, Walsh C, Jimenez F, Nguyen AT, 19
Feng L, Cata JP: Association Between Perioperative Hyperglycemia and Survival in Patients With Glioblastoma. J Neurosurg Anesthesiol 29:21, 2017
20
Table 1. Clinicopathological characteristics and treatment-related factors. Characteristic (n (%) or mean ± SD)
Hyperglycemia (BG ≥ 180mg/dL) (-)
(+)
Patients
324 (84.2)
61 (15.8)
Age, y
53.0 ± 10.6
54.3 ± 9.8
Sex, n (%)
p
0.236 0.121
Male
294 (76.4)
59 (15.3)
30 (7.8)
2 (0.5)
BMI (kg/m )
26.3 ± 21.4
30.0 ± 23.4
0.335
Creatinine (mg/dL)
0.85 ± 0.23
0.84 ± 0.31
0.307
Albumin(g/dL)
4.4 ± 0.3
4.2 ± 0.4
0.004a
Hemoglobin(g/dL)
14.3 ± 1.9
13.9 ± 2.0
0.203
Alcoholic beverage drinkers
229 (59.5)
42 (10.9)
0.774
Cigarette smoking
275 (72.2)
50 (13)
0.566
Female 2
Lesion site Buccal mucosa
0.168 127 (33)
19 (4.9)
23 (6)
5 (1.3)
Gingiva
35 (9.1)
14 (3.6)
Hard palate
11 (2.9)
1 (0.3)
Lip
13 (3.4)
3 (0.8)
115 29.9)
19 (4.9)
Mouth floor
Tongue
0.004 a
pT status I/II
212 (55.1)
28 (7.3)
III/IV
112 (29.1)
33 (8.6) 0.042 a
pN status N0
219 (56.9)
33 (8.6)
N+
105 (27.3)
28 7.3) 0.008 a
Overall Pathological Stage I/II III/IV Extranodal extension
166 (43.1)
20 (5.2)
158 (41)
41 (10.6)
58 (15.1)
22 (5.7)
Cell Differentiation W-D/ M-D
0.001 a 0.652
288 (74.8)
53 (13.8)
36 (9.4)
8 (2.1)
25 (6.5)
8 (2.1)
0.167
Tumor Depth (mm)
12.3 ± 12.0
15.2 ± 11.6
0.011 a
Adjuvant therapyb
159 (41.3)
35 (9.1)
0.234
5.5 ± 2.9
5.9 ± 2.3
0.133
15.7 ± 11.7
18.6 ± 9.0
0.003 a
7.0 ± 1.8
7.3 ± 4.5
0.213
P-D Lymphovascular invasion
Surgical margin (mm) Hospital stay (days) ICU stay (days) a
p-values are significant
b
Adjuvant therapy may be radiotherapy or concurrent chemoradiotherapy
Abbreviation: BG, blood glucose level; BMI, body mass index; W-D, well-differentiated, M-D, moderately-differentiated; P-D, poorly-differentiated squamous cell carcinoma; ICU, intensive care unit
21
Table 2. Univariate and multivariate analyses of clinicopathological characteristics on overall survival after treatment. Variables HR
Univariate 95% CI
p
Adjusted HR
Multivariate 95% CI
p
Reference 0.657
0.439–0.984
0.042a
Reference 0.788
0.519–1.197
0.264
Reference 0.884
0.445–1.758
0.726
Reference 0.817
0.390–1.712
0.593
Reference 4.610
2.789–7.621
<0.0001a
Reference 1.995
1.048–3.801
0.036a
3.204–7.211
<0.0001
a
Reference 2.170
1.311–3.589
0.003a
<0.0001
a
Reference 1.499
0.923–2.433
0.102
Reference 1.266
0.739–2.170
0.391
Reference 1.083
0.598–1.959
0.793
Reference 0.844
0.546–1.305
0.446
Reference 1.674
0.716–3.918
0.235
Reference 1.648
1.004–2.707
0.048a
b
Age (Years) ≤51.1 >51.1 Sex Male Female Overall Pathological Stage I/II III/IV Extranodal extension No Yes Perineural Invasion No Yes Cell Differentiation W-D/ M-D P-D Lymphovascular invasion No Yes Margin (mm) <5 ≥5 Tumor Depth (mm) <5 ≥5 Hyperglycemiac No Yes
Reference 4.807 Reference 3.164 Reference 1.971 Reference 3.112 Reference 0.725 Reference 4.426 Reference 2.107
2.111–4.744
1.178–3.296
1.860–5.204
0.010
<0.0001
0.480–1.095
2.145–9.130
a
a
0.126
<0.0001
1.325–3.350
0.002
a
a
a
p-values are significant.
b
median age of all patients
c
Hyperglycemia is defined as perioperative blood glucose level ≥180mg/dL.
Abbreviation: HR, hazards ratio; CI, confidence interval; W-D, well-differentiated; M-D, moderately-differentiated; P-D, poorly-differentiated squamous cell carcinoma
22
Table 3. Univariate and multivariate analyses of clinicopathological characteristics on disease-specific survival after treatment. Variables
Univariate HR
Ageb (Years) ≤51.1
Multivariate
95% CI
p
Adjusted HR
Reference
>51.1
0.642
95% CI
p
0.486–1.200
0.242
0.336-1.675
0.483
1.068-4.320
0.032a
1.222–3.643
0.007a
0.859-2.445
0.165
0.734-2.342
0.361
0.609-2.215
0.650
0.527–1.355
0.484a
0.642-3.995
0.312
1.003–2.912
0.049a
Reference 0.418–0.987
0.043
a
0.764
Sex Male
Reference
Female
0.748
Reference 0.374–1.493
0.410
0.750
2.850–8.465
<0.0001a
3.253–7.702
<0.0001
a
2.098–4.965
<0.0001
a
1.182–3.522
0.011a
Overall Pathological Stage I/II
Reference
III/IV
4.911
Reference 2.148
Extranodal extension No
Reference
Yes
5.006
Reference 2.110
Perineural Invasion No
Reference
Yes
3.227
Reference 1.449
Cell Differentiation W-D/ M-D
Reference
P-D
2.040
Reference 1.311
Lymphovascular invasion No
Reference
Yes
3.490
Reference 2.047–5.949
<0.0001
a
1.161
Margin (mm) <5
Reference
≥5
0.741
Reference 0.478–1.148
0.179
2.071-9.747
0.0001a
0.845
Tumor Depth (mm) <5
Reference
≥5
4.493
Hyperglycemia
Reference 1.602
c
No Yes
Reference 2.131
Reference 1.299–3.495
0.002
a
a
p-values are significant.
b
median age of all patients
c
Hyperglycemia is defined as perioperative blood glucose level ≥180mg/dL.
1.709
Abbreviation: HR, hazards ratio; CI, confidence interval; W-D, well-differentiated; M-D, moderately-differentiated; P-D, poorly-differentiated squamous cell carcinoma
23
Figure legends Figure 1. Kaplan-Meier plots of 5-year outcomes of normoglycemic (blue line) and hyperglycemic (red line) patients with OSCC. (a) Locoregional recurrence-free survival. (b) Distant metastasis-free survival. (c) Overall survival. (d) Disease-specific survival.
24
S0278-2391(20)30089-6
DOI:
https://doi.org/10.1016/j.joms.2020.01.018
Reference:
YJOMS 59053
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 10 November 2019 Revised Date:
9 January 2020
Accepted Date: 9 January 2020
Please cite this article as: Lien K-H, Padua PFC, Tay ZY, Kao H-K, Hung S-Y, Huang Y, Tsang NM, Chang K-P, The influence of hyperglycemia on the treatment outcomes of oral cavity squamous cell carcinoma, Journal of Oral and Maxillofacial Surgery (2020), doi: https://doi.org/10.1016/ j.joms.2020.01.018. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial Surgeons
The influence of hyperglycemia on the treatment outcomes of oral cavity squamous cell carcinoma
Kuang-Hsu Lien, MD (Chief Resident)1, #, Paula Francezca C. Padua, MD (Fellow)1, #, Ze Yun Tay, MD (Fellow)1, 2, #, Huang-Kai Kao, MD, FACS (Professor)3, 6, Shao-Yu Hung, MD (Lecturer)3, Yenlin Huang, MD (Assistant Professor)4, 6, Ngan-Ming Tsang, MD, DSc (Professor)5, Kai-Ping Chang, MD, PhD (Professor, Division Head)1, 6, *
1
Department of Otolaryngology - Head & Neck Surgery, Chang Gung Memorial
Hospital, Taoyuan, Taiwan. 2
Department of Otolaryngology, Sengkang General Hospital, Singapore.
3
Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital,
Taoyuan, Taiwan. 4
Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
5
Department of Radiation Oncology, Proton and radiation therapy center, Chang
Gung Memorial Hospital, Taoyuan, Taiwan. 6
College of Medicine, Chang Gung University, Taoyuan, Taiwan.
#
These authors contributed equally to this work.
*CORRESPONDING AUTHOR Professor. Kai-Ping Chang, MD, PhD Head, Division of Head & Neck Surgery, Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital & College of Medicine, Chang Gung University, Taoyuan, Taiwan No. 5 Fu-Hsing St. Kwei-Shan, Taoyuan, Taiwan, 33305. Email: [email protected]
ABSTRACT Purpose: The study aimed to investigate the association between perioperative hyperglycemia and the treatment/ survival outcomes of oral cavity squamous cell carcinoma (OSCC). Methods: From 2004 to 2016, 385 OSCC patients were enrolled and stratified into normoglycemic (<180 mg/dL) and hyperglycemic (>180 mg/dL) groups. The clinicopathological characteristics and treatment outcomes of OSCC were subsequently analyzed. Results: Of the 385 patients, 61 (15.8%) were in the hyperglycemic group. Hyperglycemia was significantly associated with pT status, pN status, overall pathologic stage, extranodal extension, albumin level, and tumor depth (p = 0.004, 0.042, 0.008, 0.001, 0.004, and 0.011, respectively). Patients with hyperglycemia were also found to have a longer hospital stay (p = 0.003). Five-year overall survival (OS) and disease specific survival (DFS) were poorer in the hyperglycemic compared to the normoglycemic group (p = 0.001 and p = 0.002, respectively). Multivariate analysis revealed that hyperglycemia is a significant adverse prognostic indicator for OSCC (hazard ratio: 1.709; 95% confidence interval: 1.003 – 2.912; p = 0.049). Conclusions: Hyperglycemia is associated with more advanced disease and poorer survival rates in OSCC patients. It correlates with adverse clinicopathological 1
characteristics and longer hospital stay. Screening for hyperglycemia and maintenance of normal glycemic status during the treatment course is imperative in the treatment of OSCC.
Keywords: hyperglycemia, oral cavity squamous cell carcinoma, OSCC, head and neck, cancer
2
INTRODUCTION Oral cavity cancer is one of the leading malignancies globally, accounting for 354,864 (2% of all sites) new cases and 177,384 (1.9% of all sites) deaths in 2018. In Asia alone, based on the World Health Organization statistics, it is the 11th most common cancer in 2018.1 Within Taiwan, oral cavity cancer is ranked sixth in terms of cancer incidence, and is the fifth leading cause of cancer death as of 2016.2 Furthermore, the incidence of this disease has seen an increase over the last three decades, with smoking, alcohol and betel quid consumption being the main risk factors.3 Within oral cavity cancer, the epithelium-derived oral cavity squamous cell carcinoma (OSCC) has been the most prevalent cancer subtype.4 Over the years, key prognostic factors have been identified;5 however, despite refinement in staging and management strategies, OSCC still results in significant morbidity and mortality for patients inflicted with this disease. Hyperglycemia has been shown to promote both tumorigenesis and tumor progression via diverse mechanisms and also found to be an adverse prognostic factor for several malignancies.6-9 In addition, hyperglycemia has been demonstrated to impact surgical treatment outcomes and is strongly associated with the development of post-operative complications.10-13 Despite this mounting evidence, there is limited literature on the relationship between hyperglycemia and OSCC clinicopathological 3
manifestations and treatment outcomes. Herein, the current study aimed to utilize a large cohort of OSCC patients to investigate the association between perioperative hyperglycemia and the treatment/ survival outcomes of oral cavity squamous cell carcinoma (OSCC).
METHODS This retrospective study reviewed the medical records of the OSCC patients consecutively diagnosed and enrolled at Chang Gung Memorial Hospital (Taoyuan, Taiwan) between July 2004 to July 2016. Patients with at least one of the following conditions were considered ineligible: unresectable or inoperable cancer, other concomitant primary cancer, recurrent cancer, distant metastasis at presentation, any prior history of malignancy, treatment with neoadjuvant therapy, and a medical contraindication for surgery. Data gathered included age, gender, body mass index, history of alcohol consumption (≥1 alcoholic beverage/week for at least 6 months), cigarette use (≥0.05 per pack year), site of lesion, and preoperative levels of serum albumin (g/dL), creatinine (mg/dL), and hemoglobin (g/dL). The primary outcomes of interest were length of hospital stay including intensive care unit admission, and survival data. Secondary outcomes studied were the adverse clinicopathological features associated with hyperglycemia. 4
Clinicopathological characteristics (TNM classification, overall stage, presence of extranodal extension, cell differentiation, lymphovascular invasion, and tumor depth) were recorded. Treatment-related factors gathered were history of adjuvant therapy (radiotherapy or concurrent chemoradiotherapy) and surgical margins. The patients were then stratified into two groups based on the random glucose measurements obtained prior to surgery, and/or the highest serum blood glucose level during the first 24 hours after surgery: normoglycemic group (<180 mg/dL) and hyperglycemic group (≥180 mg/dL). The serum blood sugar threshold of 180 mg/dL was based on the American Association of Clinical Endocrinologists and American Diabetes Association recommendation of random blood glucose target for non-critically ill patients.14 The medical records, including the pre-treatment work-ups, operative techniques and pathological reports were reviewed. Primary tumors were excised with clear margins, ascertained by frozen section controls, and defects were reconstructed, if necessary, by the plastic surgical team, with free flaps being most commonly utilized. The 7th edition of the American Joint Committee on Cancer Staging Manual (2010) was used to establish the final pathological TNM classification after surgical treatment.15 Adjuvant radiotherapy or chemoradiation was recommended based on institutional guidelines after reviewing each patient’s clinicopathological adverse features at a 5
multidisciplinary tumor board. Regular follow-up visits were arranged every 2 months for the first year, every 3 months for the second year, and at 6 month intervals thereafter, and all patients were followed until December 2018 or their demise. This study was approved by the ethics committee of the Chang Gung Memorial Hospital, Taiwan. Written consent was obtained from all surviving patients included in this study. In accordance with the ethics committee, the data from non-surviving patients were irreversibly anonymized for statistical evaluation. Continuous data are presented as means with standard deviations, while categorical data are presented as frequencies and percentages. The clinicopathological characteristics of OSCC were compared between the two groups using chi-square and Wilcoxon tests. Five-year survival analyses were plotted using the Kaplan-Meier method, and differences were evaluated using the log-rank test. A Cox regression model was used to perform the univariate and multivariate analyses for survival analyses. All calculations were performed using the SAS software (version 9.3; SAS Institute, Cary, NC). All p-values were two-sided and statistical significance was set at p < 0.05.
RESULTS Patient Characteristics A total of 385 OSCC patients were included in our study, with a mean age of 53.2 6
years, ranging from 28.5 to 88.7 years. Among the patients, 353 (91.7%) were male, 271 (70.4%) were alcohol consumers, and 325 (84.4%) were cigarette smokers. The most common cancer site identified was from the buccal mucosa (37.9%), followed closely by tongue primaries (34.8%). Other sites such as the gingiva (12.7%), floor of mouth (7.3%), hard palate (3.6%), and lip (3.6%) occurred less frequently. Majority of the patients had a stage IV TNM classification (41.3%), followed by stage I (24.9%), stage II (23.4) and stage III (10.3%).
Association between hyperglycemia and clinicopathological characteristics The patients were classified into two groups, normoglycemic group (n = 324, 84.2%) and hyperglycemic group (n = 61; 15.8%). Hyperglycemia was found to be significantly associated with pre-operative albumin level (p = 0.004), pT status (p = 0.004), pN status (p = 0.042), overall pathologic stage (p = 0.008), ENE (p = 0.001), and tumor depth (p = 0.011). Length of hospital stay was also found to be significantly longer in the hyperglycemic group (p = 0.003). However, no significant difference was noted between the normoglycemic and hyperglycemic groups with regards to age, sex, body mass index, preoperative creatinine level, preoperative hemoglobin level, alcohol consumption, cigarette smoking, lesion site, pathological cell differentiation, lymphovascular invasion, adjuvant therapy, surgical margins and intensive care unit 7
admissions. These above statistics are shown in Table 1.
Association between hyperglycemia and survival outcomes The 5-year survival analysis (Figure 1) revealed significantly poorer survival rates for the hyperglycemic group in terms of locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), overall survival (OS), and disease-specific survival (DSS). Comparing the normoglycemic and hyperglycemic the groups, the 5-year LRFS were 77.2 vs 60.7 %, respectively (p = 0.002), 5-year DMFS were 76.9 vs 60.7 % respectively (p = 0.001), 5-year OS were 76.9 and 60.7 %, respectively (p =0.001), 5-year DSS were 79.9 vs 65.6 %, respectively (p = 0.002).
Association between survival and treatment-related factors The results of the univariate and multivariate analyzes are shown in Tables 2 and 3. Univariate analysis revealed that variables associated with poorer overall survival and disease-specific survival were advanced patient age (OS: p = 0.042; DSS: p = 0.043), higher overall pathological stage (OS: p <0.0001; DSS: p <0.0001), extranodal extension (OS: p <0.0001; DSS: p <0.0001), perineural invasion (OS: p <0.0001; DSS: p <0.0001), poor cancer differentiation (OS: p = 0.010; DSS: p = 0.011), lymphovascular invasion (OS: p <0.0001; DSS: p <0.0001), deeper tumor depth (OS: p 8
<0.0001; DSS: p = 0.0001) and presence of hyperglycemia (OS: p =0.002; DSS: p = 0.002). Multivariate analysis performed showed that overall pathological stage, extranodal extension and hyperglycemia were independent factors for poorer overall survival (p = 0.036, p = 0.003 and p = 0.048, respectively). For disease-specific survival, multivariate analysis also implicated the same independent prognostic factors including overall stage, extranodal extension and hyperglycemia (p = 0.032, p = 0.007, and p = 0.049, respectively).
DISCUSSION Hyperglycemia refers to a state where there is an elevated blood glucose level in the blood circulation. Its definition is however variable, depending on the context of the blood glucose measurement. Transient hyperglycemia is often benign and asymptomatic and may present in non-diabetic or prediabetic patients. However, chronic hyperglycemia may actually be a manifestation of diabetes mellitus. Based on the American Association of Clinical Endocrinologists and American Diabetes Association guidelines, perioperative hyperglycemia is defined as blood glucose level greater than 180 mg/dL in non-critically ill patients.14 A large scale study by Kwon et al demonstrated that perioperative hyperglycemia, based on the aforementioned cut-off, was associated with adverse outcomes in their patients undergoing general surgical procedures.12 Our study therefore has also adopted this criterion to define our 9
hyperglycemic cohort. There is increasing evidence to suggest that diabetic patients have higher risks of developing specific cancers, as well as have poorer cancer outcomes than their non-diabetic counterparts.16-17 Since hyperglycemia is a hallmark of diabetes mellitus, its role in cancer development has also been studied. In a meta-analysis by Crawley et al, a positive association between serum glucose and cancer risk was consistently demonstrated.18 Various mechanisms have been postulated to explain the association of cancer development and progression in hyperglycemia or diabetes mellitus. A chronic hyperinsulinemic state is seen in chronic hyperglycemia, leading to an elevated level of circulating free insulin-like growth factor-1 (IGF-1), which can promote tumor proliferation by stimulating mitogenesis and inhibiting apoptosis.19 Hyperglycemia can also directly stimulate tumor development and progression since glucose is a key substrate in cellular metabolism and cancer cells have been demonstrated to be able to up-regulate glucose transporters to facilitate glucose uptake.20 Persistent hyperglycemia, in the setting of diabetes mellitus, is also associated with a chronic systemic inflammatory state. This systemic inflammatory response is characterized by elevated levels of cytokines, such as IL-6 and TNF-α, which promote an environment for cancer development and progression.21 The influence of hyperglycemia on cancer survival has also been reported in the 10
literature. In a recent meta-analysis by Barua et al, hyperglycemia was shown to adversely affect overall survival and disease-free survival in various solid tumors, including breast, hepatocellular, pancreatic, gastric, esophageal, lung, cervical cancers and glioblastomas.22 Despite the wealth of evidence demonstrating the association of hyperglycemia and cancer risk, the literature is sparse with regards to the relationship between hyperglycemia and OSCC. To the best of our knowledge, our study is the first to evaluate the impact of hyperglycemia in OSCC treatment and survival outcomes. The results of our study revealed that hyperglycemia is associated with higher pT and pN statuses, and more advanced overall pathological stage. It is also significantly associated with more aggressive clinicopathologic features, including extranodal extension and increased tumor depth. These findings are compatible with the study results by Zaoui et al, in which a significant association was found between the presence of diabetes mellitus and larger tumor size and more advanced tumor grade in their cohort of head and neck squamous cell carcinoma patients.23 With regards to preoperative albumin levels, our cohort of hyperglycemia patients had significantly lower albumin levels than their counterparts who were normoglycemic. A plausible explanation is that this cohort of patients may be in a state of insulin deficiency, and since insulin stimulates the hepatic production of serum proteins including albumin, the lack of insulin in these patients therefore lead to hypoalbuminemia. 11
In our study, it was observed that patients in the hyperglycemic group had longer hospital admissions compared to the normoglycemic patients. This might imply that the OSCC patients with hyperglycemia may have a higher rate of postoperative complications, though the details of the complication were not specifically analyzed in this current study. This finding is consistent with existing literature, in that diabetic patients undergoing head and neck procedures had higher risks of postoperative infections, cardiac events and acute renal impairment.16 Similarly, in our recent investigation, we have also demonstrated that perioperative hyperglycemia is associated with an elevated risk of surgical site infections following microvascular head and neck reconstruction procedures.10 The impact of hyperglycemia or diabetes mellitus on cancer prognoses has been previously reported. A meta-analysis studying the association between hyperglycemia and cervical cancer prognosis showed that hyperglycemia was associated with poorer overall survival and locoregional recurrence-free survival.6 Another study observed that women with increasing blood glucose levels were at increased risk of both all-cause and breast cancer mortality.8 Similarly, a retrospective review of patients with glioblastoma revealed that poorer overall survival was found in patients with perioperative hyperglycemia.8 With regards to head and neck cancer or OSCC specifically, there is no existing literature to our knowledge that studied the influence of 12
hyperglycemia on survival outcomes, though Wu et al demonstrated that their cohort of diabetic patients with OSCC have poorer survival outcomes including recurrence-free survival.24 In our current study, poorer locoregional-recurrence free survival and distant metastases-free survival rates were observed in the hyperglycemic cohort, indicating that perioperative hyperglycemia can adversely affect the treatment outcomes with the higher probability of locoregional recurrence and distant metastasis. The hyperglycemic patients in our study also had inferior overall and disease-specific survival rates compared to their counterparts who were normoglycemic. These results could also be partially contributed by the higher rates of locoregional recurrences and distant metastases in these patients. Furthermore, the multivariate analyzes performed further affirmed hyperglycemia as an independent adverse prognostic factor for both overall survival and disease-specific survival in our study. Consequently, the current study results demonstrate the importance of the screening of hyperglycemic status and that maintenance of normoglycemia may reduce the hospital stay and improve the treatment outcome for OSCC patients.
CONCLUSIONS This study, the first in the literature evaluating the association of hyperglycemia and treatment and survival outcomes of OSCC patients, showed that hyperglycemia was associated with adverse clinicopathological features, such as more advanced overall 13
pathological stage, presence of extranodal extension, deeper tumor depth, and longer hospital admissions. Furthermore, hyperglycemia in OSCC patients may result in higher rates of locoregional recurrences and distant metastases, which can result in poorer survival outcomes in terms of both overall survival and disease-specific survival. Our study findings highlight the importance to screen and maintain normal glycemic status during the treatment course of oral cavity squamous cell carcinoma.
Acknowledgements The authors thank all the members of the Cancer Center, Chang Gung Memorial Hospital, for their invaluable help. This study was supported by the grant (CMRPG3H0851, CMRPG3J1251, CORPG3G0171, and CIRPG3B0014) from Chang Gung Memorial Hospital, Taiwan.
Authors' contributions Conception and design: KPC. Analysis and interpretation of data: All authors. Drafting the article or revising it critically for important intellectual content: All authors. Final approval of manuscript: All authors. Agreement to be accountable for all aspects of the work: All authors. First authors: Kuang-Hsu Lien, Paula Francezca C. Padua, and Ze Yun Tay. 14
Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests The authors declare that they have no competing interests.
15
References 1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A: Global cancer
statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394, 2018 2.
Ministry of Health and Welfare R. O. C. Statistics of General Health and Welfare
2016. 3.
Hsu W-L, Yu KJ, Chiang C-J, Chen T-C, Wang C-P: Head and Neck Cancer
Incidence Trends in Taiwan, 1980 ~ 2014. International Journal of Head and Neck Science 1:180, 2017 4.
Zini A, Czerninski R, Sgan-Cohen HD: Oral cancer over four decades:
epidemiology, trends, histology, and survival by anatomical sites. J Oral Pathol Med 39:299, 2010 5.
De Paz D, Kao HK, Huang Y, Chang KP: Prognostic Stratification of Patients
With Advanced Oral Cavity Squamous Cell Carcinoma. Curr Oncol Rep 19:65, 2017 6.
Chen S, Tao M, Zhao L, Zhang X: The association between
diabetes/hyperglycemia and the prognosis of cervical cancer patients: A systematic review and meta-analysis. Medicine (Baltimore) 96:e7981, 2017
16
7.
Storey S, Von Ah D, Hammer MJ: Measurement of Hyperglycemia and Impact
on Health Outcomes in People With Cancer: Challenges and Opportunities. Oncol Nurs Forum 44:E141, 2017 8.
Connor AE, Visvanathan K, Boone SD, Rifai N, Baumgartner KB, Baumgartner
RN: Fructosamine and diabetes as predictors of mortality among Hispanic and non-Hispanic white breast cancer survivors. NPJ Breast Cancer 5:3, 2019 9.
Zanders MM, Vissers PA, Haak HR, van de Poll-Franse LV: Colorectal cancer,
diabetes and survival: epidemiological insights. Diabetes Metab 40:120, 2014 10. Offodile AC, 2nd, Chou HY, Lin JA, Loh CYY, Chang KP, Aycart MA, Kao HK: Hyperglycemia and risk of adverse outcomes following microvascular reconstruction of oncologic head and neck defects. Oral Oncol 79:15, 2018 11. Link TW, Woodworth GF, Chaichana KL, Grossman SA, Mayer RS, Brem H, Weingart JD, Quinones-Hinojosa A: Hyperglycemia is independently associated with post-operative function loss in patients with primary eloquent glioblastoma. J Clin Neurosci 19:996, 2012 12. Kwon S, Thompson R, Dellinger P, Yanez D, Farrohki E, Flum D: Importance of perioperative glycemic control in general surgery: a report from the Surgical Care and Outcomes Assessment Program. Ann Surg 257:8, 2013
17
13. Fiorillo C, Rosa F, Quero G, Menghi R, Doglietto GB, Alfieri S: Postoperative hyperglycemia in nondiabetic patients after gastric surgery for cancer: perioperative outcomes. Gastric Cancer 20:536, 2017 14. Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D, Hellman R, Hirsch IB, Inzucchi SE, Ismail-Beigi F, Kirkman MS, Umpierrez GE, American Association of Clinical E, American Diabetes A: American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care 32:1119, 2009 15. Fan KH, Wang HM, Kang CJ, Lee LY, Huang SF, Lin CY, Chen EY, Chen IH, Liao CT, Chang JT: Treatment results of postoperative radiotherapy on squamous cell carcinoma of the oral cavity: coexistence of multiple minor risk factors results in higher recurrence rates. Int J Radiat Oncol Biol Phys 77:1024, 2010 16. Raikundalia MD, Fang CH, Spinazzi EF, Vazquez A, Park RC, Baredes S, Eloy JA: Impact of Diabetes Mellitus on Head and Neck Cancer Patients Undergoing Surgery. Otolaryngol Head Neck Surg 154:294, 2016 17. 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 159:1160, 2004
18
18. Crawley DJ, Holmberg L, Melvin JC, Loda M, Chowdhury S, Rudman SM, Hemelrijck MV: Serum glucose and risk of cancer: a meta-analysis. BMC Cancer 19:985, 2014 19. Emily Jane Gallagher DL: The proliferating role of insulin and insulin-like growth factors in cancer. Trends in Endocrinology and Metabolism 21:610, 2010 20. Rachel E. Airley AM: Hypoxic Regulation of Glucose Transport, Anaerobic Metabolism and Angiogenesis in Cancer: Novel Pathways and Targets for Anticancer Therapeutics Chemotherapy 53:233, 2007 21. Gallagher EJ, LeRoith D: Epidemiology and Molecular Mechanisms Tying Obesity, Diabetes, and the Metabolic Syndrome With Cancer. DIABETES CARE 36:S233, 2013 22. Barua R, Templeton AJ, Seruga B, Ocana A, Amir E, Ethier JL: Hyperglycaemia and Survival in Solid Tumours: A Systematic Review and Meta-analysis. Clin Oncol (R Coll Radiol) 30:215, 2018 23. Zaoui K, Doll J, Stiebi P, Federspil P, Plinkert PK, Hess J: Diabetes mellitus as a prognostic marker in oropharyngeal and laryngeal squamous cell carcinoma. HNO 64:479, 2016 24. Hagan K, Bhavsar S, Arunkumar R, Grasu R, Dang A, Carlson R, Cowles C, Arnold B, Potylchansky Y, Rahlfs TF, Lipski I, Walsh C, Jimenez F, Nguyen AT, 19
Feng L, Cata JP: Association Between Perioperative Hyperglycemia and Survival in Patients With Glioblastoma. J Neurosurg Anesthesiol 29:21, 2017
20
Table 1. Clinicopathological characteristics and treatment-related factors. Characteristic (n (%) or mean ± SD)
Hyperglycemia (BG ≥ 180mg/dL) (-)
(+)
Patients
324 (84.2)
61 (15.8)
Age, y
53.0 ± 10.6
54.3 ± 9.8
Sex, n (%)
p
0.236 0.121
Male
294 (76.4)
59 (15.3)
30 (7.8)
2 (0.5)
BMI (kg/m )
26.3 ± 21.4
30.0 ± 23.4
0.335
Creatinine (mg/dL)
0.85 ± 0.23
0.84 ± 0.31
0.307
Albumin(g/dL)
4.4 ± 0.3
4.2 ± 0.4
0.004a
Hemoglobin(g/dL)
14.3 ± 1.9
13.9 ± 2.0
0.203
Alcoholic beverage drinkers
229 (59.5)
42 (10.9)
0.774
Cigarette smoking
275 (72.2)
50 (13)
0.566
Female 2
Lesion site Buccal mucosa
0.168 127 (33)
19 (4.9)
23 (6)
5 (1.3)
Gingiva
35 (9.1)
14 (3.6)
Hard palate
11 (2.9)
1 (0.3)
Lip
13 (3.4)
3 (0.8)
115 29.9)
19 (4.9)
Mouth floor
Tongue
0.004 a
pT status I/II
212 (55.1)
28 (7.3)
III/IV
112 (29.1)
33 (8.6) 0.042 a
pN status N0
219 (56.9)
33 (8.6)
N+
105 (27.3)
28 7.3) 0.008 a
Overall Pathological Stage I/II III/IV Extranodal extension
166 (43.1)
20 (5.2)
158 (41)
41 (10.6)
58 (15.1)
22 (5.7)
Cell Differentiation W-D/ M-D
0.001 a 0.652
288 (74.8)
53 (13.8)
36 (9.4)
8 (2.1)
25 (6.5)
8 (2.1)
0.167
Tumor Depth (mm)
12.3 ± 12.0
15.2 ± 11.6
0.011 a
Adjuvant therapyb
159 (41.3)
35 (9.1)
0.234
5.5 ± 2.9
5.9 ± 2.3
0.133
15.7 ± 11.7
18.6 ± 9.0
0.003 a
7.0 ± 1.8
7.3 ± 4.5
0.213
P-D Lymphovascular invasion
Surgical margin (mm) Hospital stay (days) ICU stay (days) a
p-values are significant
b
Adjuvant therapy may be radiotherapy or concurrent chemoradiotherapy
Abbreviation: BG, blood glucose level; BMI, body mass index; W-D, well-differentiated, M-D, moderately-differentiated; P-D, poorly-differentiated squamous cell carcinoma; ICU, intensive care unit
21
Table 2. Univariate and multivariate analyses of clinicopathological characteristics on overall survival after treatment. Variables HR
Univariate 95% CI
p
Adjusted HR
Multivariate 95% CI
p
Reference 0.657
0.439–0.984
0.042a
Reference 0.788
0.519–1.197
0.264
Reference 0.884
0.445–1.758
0.726
Reference 0.817
0.390–1.712
0.593
Reference 4.610
2.789–7.621
<0.0001a
Reference 1.995
1.048–3.801
0.036a
3.204–7.211
<0.0001
a
Reference 2.170
1.311–3.589
0.003a
<0.0001
a
Reference 1.499
0.923–2.433
0.102
Reference 1.266
0.739–2.170
0.391
Reference 1.083
0.598–1.959
0.793
Reference 0.844
0.546–1.305
0.446
Reference 1.674
0.716–3.918
0.235
Reference 1.648
1.004–2.707
0.048a
b
Age (Years) ≤51.1 >51.1 Sex Male Female Overall Pathological Stage I/II III/IV Extranodal extension No Yes Perineural Invasion No Yes Cell Differentiation W-D/ M-D P-D Lymphovascular invasion No Yes Margin (mm) <5 ≥5 Tumor Depth (mm) <5 ≥5 Hyperglycemiac No Yes
Reference 4.807 Reference 3.164 Reference 1.971 Reference 3.112 Reference 0.725 Reference 4.426 Reference 2.107
2.111–4.744
1.178–3.296
1.860–5.204
0.010
<0.0001
0.480–1.095
2.145–9.130
a
a
0.126
<0.0001
1.325–3.350
0.002
a
a
a
p-values are significant.
b
median age of all patients
c
Hyperglycemia is defined as perioperative blood glucose level ≥180mg/dL.
Abbreviation: HR, hazards ratio; CI, confidence interval; W-D, well-differentiated; M-D, moderately-differentiated; P-D, poorly-differentiated squamous cell carcinoma
22
Table 3. Univariate and multivariate analyses of clinicopathological characteristics on disease-specific survival after treatment. Variables
Univariate HR
Ageb (Years) ≤51.1
Multivariate
95% CI
p
Adjusted HR
Reference
>51.1
0.642
95% CI
p
0.486–1.200
0.242
0.336-1.675
0.483
1.068-4.320
0.032a
1.222–3.643
0.007a
0.859-2.445
0.165
0.734-2.342
0.361
0.609-2.215
0.650
0.527–1.355
0.484a
0.642-3.995
0.312
1.003–2.912
0.049a
Reference 0.418–0.987
0.043
a
0.764
Sex Male
Reference
Female
0.748
Reference 0.374–1.493
0.410
0.750
2.850–8.465
<0.0001a
3.253–7.702
<0.0001
a
2.098–4.965
<0.0001
a
1.182–3.522
0.011a
Overall Pathological Stage I/II
Reference
III/IV
4.911
Reference 2.148
Extranodal extension No
Reference
Yes
5.006
Reference 2.110
Perineural Invasion No
Reference
Yes
3.227
Reference 1.449
Cell Differentiation W-D/ M-D
Reference
P-D
2.040
Reference 1.311
Lymphovascular invasion No
Reference
Yes
3.490
Reference 2.047–5.949
<0.0001
a
1.161
Margin (mm) <5
Reference
≥5
0.741
Reference 0.478–1.148
0.179
2.071-9.747
0.0001a
0.845
Tumor Depth (mm) <5
Reference
≥5
4.493
Hyperglycemia
Reference 1.602
c
No Yes
Reference 2.131
Reference 1.299–3.495
0.002
a
a
p-values are significant.
b
median age of all patients
c
Hyperglycemia is defined as perioperative blood glucose level ≥180mg/dL.
1.709
Abbreviation: HR, hazards ratio; CI, confidence interval; W-D, well-differentiated; M-D, moderately-differentiated; P-D, poorly-differentiated squamous cell carcinoma
23
Figure legends Figure 1. Kaplan-Meier plots of 5-year outcomes of normoglycemic (blue line) and hyperglycemic (red line) patients with OSCC. (a) Locoregional recurrence-free survival. (b) Distant metastasis-free survival. (c) Overall survival. (d) Disease-specific survival.
24