Prognostic Impact of Hyperglycemia in Patients with Locally Advanced Squamous Cell Carcinoma of Cervix Receiving Definite Radiotherapy 2016.04.08 KCCH 김문홍
DM and prediabetes in cancer Negative impact on survival in cancer patients receiving surgery and/or chemotherapy ; GI, breast, liver, pancreas, lung, and hematologic malignancies Little evaluation for survival impact in cancer treated primarily by radiation ; cervix, head and neck Nat Clin Pract Oncol 2(1): 48-53. Cancer 115(5): 1021-1027. Cancer 110(1): 96-102. J Clin Oncol 24(31): 5017-5024.
Cancer-associated systemic inflammation Neutrophilia and lymphopenia NLR: neutrophil lymphocyte ratio Association with tumor extent and aggressiveness Poor prognostic factor in most malignancy including cervical cancer Anticancer Res 32(4): 1555-1561. Int J Clin Oncol 20(5): 989-996.
Objective Survival impact of hyperglycemia in locally advanced cervical cancer treated by primary RT or CCRT
Methods Retrospective analysis Inclusion criteria Squamous cell carcinoma FIGO stage IIB IVA Year of diagnosis: 2004~2013 Glucose level at initial W/U Primary RT or CCRT Exclusion criteria Other malignancy within 5 years Incomplete treatment Primary surgery
Flow diagram for patients enrollment Locally Advanced Cervical Cancer Stage IIB ~ IVA Squamous cell carcinoma from January 2004 to December 2013 N=282 Primary RT N=260 Exclusion 1 Primary surgery: 8 Initially treated at other site: 4 Incomplete treatment: 8 Accompanying other cancer : 2 Exclusion 2 No initial glucose level: 4 No tumor size description: 2 F/U loss within 3 months: 13 N= 242
Random Plasma Glucose and NLR Measured as a initial W/U: CBC and admission panel Cut-off value Random plasma glucose: 126mg/dL NLR: 2.9 (median value) Diagnosis criteria for Diabetes (American Diabetes Association) A1C 6.5% Or Fasting plasma glucose (FPG) 126 mg/dl Or 2-h PG 200 mg/dl on 75gOGTT Or classic Sx & random plasma glucose 200 mg/dl
Methodology Survival analysis (PFS and OS) Glucose < 126mg/dL vs. 126 mg/dl In total patients In non-dm patients DM vs. non-dm Metformin vs. other drug for patients with DM NLR <2.9 vs. 2.9 Multivariate & Cox regression analysis for non-dm patients
Methodology PFS: From: date of diagnosis To: date of first recurrence or last f/u date OS: used survival data obtained from national database From: date of diagnosis To: date of death or January 1 st 2014 (date of confirmation for life or death or last f/u date)
General characteristics No. of patients 242 Age, years (range) 58* (30-88) Follow up duration, months (range) 52* (3.8-120.1) BMI, kg/m 2 23.8* (12.8-36.5) Hemoglobin, g/dl 11.8* (4.0-16.0) Random plasma glucose, mg/dl (range) 110* (69-364) Total cholesterol, mg/dl 177* (89-309) Albumin, g/dl 4.2* (1.9-5.1) NLR (neutrophil lymphocyte ratio) 2.9* (0.83-25.3) Tumor diameter, cm (range) 5* (1.5-10) SCC, ng/ml 8* (1-259) Diabetes mellitus (%) 28 (11.6) FIGO stage (%) IIB 168 (69.4) III 57 (23.6) IVA 17 (7.0) Treatment (%) RT only 48 (19.8) CCRT 194 (80.2) Lymph nodes enlargement (%) no 88 (36.4) yes 154 (63.6) Treatment result (%) Complete remission 215 (88.8) Persistent disease 27 (11.2) * median
Comparisons according to random plasma glucose Random plasma glucose, mg/dl <125 125 p No. of patients 162 80 Age, years 57.3 ± 12.1 59.0 ± 11.1 0.301 BMI, kg/m 2 23.8 ± 3.9 24.4 ± 3.9 0.262 Hemoglobin, g/dl 11.39 ± 2.21 11.30 ± 2.02 0.76 Total cholesterol, mg/dl 181.6 ± 41.5 177.9 ± 36.7 0.5 Albumin, g/dl 4.18 ± 0.48 4.10 ± 0.56 0.276 NLR (neutrophil lymphocyte ratio) 3.16 ± 1.58 3.90 ± 3.43 0.07 Tumor diameter, cm 53.3 ± 18.5 53.7 ± 17.5 0.885 SCC, ng/ml 20.0 ± 32.2 17.1 ±32.5 0.527 DM <0.001 no 154 (95.1) 60 (75.0) yes 8 (4.9) 20 (25.0) FIGO stage (%) 0.176 IIB 107 (66.0) 61 (76.3) III 43 (26.5) 14 (17.5) IVA 12 (7.4) 5 (6.3) Treatment (%) 0.999 RT only 32 (19.8) 16 (20.0) CCRT 130 (80.2) 64 (80.0)
Comparisons according to NLR NLR <2.9 2.9 p No. of patients 119 123 Age, years 59.9±11.1 55.9±12.3 0.008 BMI, kg/m 2 24.9±4.1 23.2±3.6 0.001 Hemoglobin, g/dl 11.9±1.6 10.8±2.4 <0.001 Random plasma glucose, mg/dl 118.5±35.6 129.3±49.4 0.052 Total cholesterol, mg/dl 188.9±39.7 172.0±38.4 0.001 Albumin, g/dl 4.3±0.4 4.0±0.6 <0.001 Tumor diameter, cm 4.8±1.6 5.9±1.8 <0.001 SCC, ng/ml 17.0±32.9 20.9±31.6 0.36 DM 0.621 no 104 (87.4) 110 (89.4) yes 15 (12.6) 13 (10.6) FIGO stage (%) 0.004 IIB 92 (77.3) 76 (61.8) III 23 (19.3) 34 (27.6) IVA 4 (3.4) 13 (10.6) Treatment (%) 0.245 RT only 99 (83.2) 95 (77.2) CCRT 20 (16.8) 28 (22.8)
KM-survival curves Random plasma glucose in total patients (n=242) 126mg/dL 126mg/dL < 126mg/dL < 126mg/dL P=0.039 P=0.009
KM-survival curves Random plasma glucose in non-dm patients (n=214) 126mg/dL 126mg/dL < 126mg/dL < 126mg/dL P=0.053 P=0.035
KM-survival curves DM vs. non-dm in total patients (n=242) DM DM Non-DM Non-DM P=0.618 P=0.084
KM-survival curves Metformin vs. other drug in DM patients (n=28) Metformin Metformin Other drugs Other drugs P=0.618 P=0.174
PFS for non-dm patients (n=214) Progression-free survival Factor Number Univariate Multivariate HR P HR P Age >57 97 0.709 0.165 0.721 0.241 BMI>25 76 1.035 0.889 1.362 0.225 Albumin<3.5g/dL 22 1.142 0.723 Total cholesterol 200 45 0.717 0.294 Tumor size > 5cm 106 1.612 0.049 1.436 0.149 Glucose 126 mg/dl 60 0.566 0.057 0.552 0.049 NLR 2.9 110 2.040 0.004 1.924 0.014 FIGO stage III or IV 67 1.273 0.338 CCRT 174 0.646 0.127 0.519 0.038
OS for non-dm patients (n=214) Overall survival Factor Number Univariate Multivariate HR P HR P Age >57 97 1.095 0.696 0.832 0.508 BMI>25 76 0.586 0.039 0.726 0.232 Albumin<3.5g/dL 22 0.706 0.414 Total cholesterol 200 45 0.798 0.446 Tumor size > 5cm 106 1.287 0.276 1.358 0.221 Glucose 126 mg/dl 60 0.550 0.038 0.606 0.087 NLR 2.9 110 1.353 0.194 1.192 0.492 FIGO stage III or IV 67 1.314 0.256 CCRT 174 0.325 <0.001 0.306 <0.001
Metabolism and Cancer Cancer cells depend on glycolysis rather than oxydative phosphorylation due to hypoxic microenvironment. Tumor hypoxia causes resistance to radiation.
Transiently reducing oxygen consumption is a highly effective way to reduce tumor hypoxia. (Secomb et al., 1995) Attacking hypoxia by pharmacologically reducing oxygen demand is a highly innovative paradigm shift High dose glucose can modestly downregulate mitochondrial function in experimental tumors through the induction of the Crabtree effect.(snyder et al., 2001) A bolus of glucose can shift cellular energetics to glycolysis away from oxidative phosphorylation J Clin Oncol 32(26): 2871-2878.
Our hypothesis Cancer cell s dependence on glycolysis may be an adaptation response to tissue hypoxia not an inherited characteristics. Inducing glycolysis may have positive effect on radiation sensitivity by reducing oxygen consumption There may be an association between glucose concentration and radiation sensitivity
Limitation Selection bias -> prospective study Random plasma glucose Using mean value of multiple measurements during RT prospective study using fasting plasma glucose
Conclusion Hyperglycemia was associated with improved PFS in patients with locally advanced squamous cell carcinoma of cervix treated with primary RT or CCRT Hyperglycemia is suggested to enhance sensitivity to radiotherapy Mild obesity seems to be associated with improved overall survival NLR, a marker representing systemic inflammation, is associated with extent of disease and PFS