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Rinnakkaistallenteet Terveystieteiden tiedekunta
2020
Perioperative Dexamethasone Is Associated With Higher Short-Term Mortality in Reconstructive Head and Neck Cancer Surgery
Kainulainen, Satu
Elsevier BV
Tieteelliset aikakauslehtiartikkelit
© 2020 American Association of Oral and Maxillofacial Surgeon CC BY-NC-ND https://creativecommons.org/licenses/by-nc-nd/4.0/
http://dx.doi.org/10.1016/j.joms.2020.05.004
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Perioperative dexamethasone is associated with higher short-term mortality in reconstructive head and neck cancer surgery
Kainulainen Satu, Aro Katri, Koivusalo Anna-Maria, Wilkman Tommy, Roine Risto, Aronen Pasi, Törnwall Jyrki, Lassus Patrik
PII: S0278-2391(20)30457-2
DOI: https://doi.org/10.1016/j.joms.2020.05.004 Reference: YJOMS 59209
To appear in: Journal of Oral and Maxillofacial Surgery Received Date: 23 July 2019
Revised Date: 27 April 2020 Accepted Date: 2 May 2020
Please cite this article as: Satu K, Katri A, Anna-Maria K, Tommy W, Risto R, Pasi A, Jyrki T, Patrik L, Perioperative dexamethasone is associated with higher short-term mortality in reconstructive head and neck cancer surgery, Journal of Oral and Maxillofacial Surgery (2020), doi: https://doi.org/10.1016/
j.joms.2020.05.004.
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© 2020 Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial Surgeons
Perioperative dexamethasone is associated with higher short-term mortality in reconstructive 1
head and neck cancer surgery 2
3
Kainulainen Satu1, Aro Katri2, Koivusalo Anna-Maria3, Wilkman Tommy4, Roine Risto5, 6, Aronen 4
Pasi7, Törnwall Jyrki8, Lassus Patrik9 5
6
1. Consultant, MD, DDS, Department of Oral and Maxillofacial Surgery, Helsinki University 7
Hospital, University of Helsinki, Helsinki, Finland 8
2. Consultant, MD, PhD, Department of Otorhinolaryngology-Head and Neck Surgery, 9
University of Helsinki, Helsinki, Finland 10
3. Consultant, MD, Docent, Department of Anesthesia and Intensive Care Unit, Helsinki 11
University Hospital, University of Helsinki, Helsinki, Finland 12
4. Consultant, MD, PhD, Department of Oral and Maxillofacial Surgery, Helsinki University 13
Hospital, Helsinki, Finland 14
5. Professor emeritus, MD, Department of Health and Social Management, University of 15
Eastern Finland, Kuopio, Finland 16
6. Professor emeritus, MD, Group Administration, University of Helsinki and Helsinki 17
University Hospital, Helsinki, Finland 18
7. Biostatistics Consulting, Department of Public Health, University of Helsinki and Helsinki 19
University Hospital, Helsinki, Finland 20
8. Consultant, MD, Docent, University of Helsinki, Helsinki, Finland 21
9. Department Head, MD, Docent, Department of Plastic Surgery, Helsinki University 22
Hospital, University of Helsinki, Helsinki, Finland 23
24 25 26 27 28 29
Corresponding author: Satu Kainulainen, Department of Oral and Maxillofacial Surgery, Helsinki 30
University Hospital, P.O. Box 220, FI-00029 HUS, Helsinki, Finland. Phone: +358504270208; E- 31
mail: satu.kainulainen@hus.fi (S. Kainulainen).
32
EudraCT number: 2008-000892-11 33
Abstract 34
35
Purpose 36
Studies of the impact of perioperative dexamethasone on oncological surgery are scarce. The first 37
aim of the present study was to clarify whether perioperative dexamethasone affects short-term 38
mortality in head and neck cancer (HNC) patients. The second aim was to analyze the causes of 39
death and predictors affecting long-term mortality.
40 41
Methods 42
This prospective, double-blind randomized controlled study included HNC patients with 43
microvascular reconstruction through 2008 – 2013. Patients were randomized into two groups; to 44
receive perioperative dexamethasone (DEX) over three days or to serve as controls (NON-DEX).
45
Patient data and causes of death were registered until the end of 2017. The primary cause of death 46
was used in the analyses.
47 48
Results 49
There were 93 patients, 51 in the study group and 42 in the control group. Altogether 38 patients 50
died during the median follow-up time of 5.3 years. During the first year, more deaths occurred in 51
the DEX group than in the NON-DEX group: at one month 4% vs 0%, at 6 months 14% vs 0% and 52
at 12 months 22% vs 5% (p=0.043). Overall survival (OS) for all patients was 59%. HNC was the 53
primary cause of death in most of the deceased. In univariate analysis, deceased patients had more 54
advanced decease (higher T classification, p=0.002; and higher stage, p=0.008), need for 55
gastrostoma (p=0.002), received more often postoperative chemotherapy (p=0.005), and more often 56
locoregional (p=0.025) or distal metastases (P<0.001). In multivariate Cox model, the most 57
important long-term predictors of death were distant metastases (p<0.001), CCI 5-9 (p<0.001), and 58
the use of perioperative dexamethasone (p=0.004).
59 60
Conclusion 61
The use of perioperative dexamethasone was associated with higher short-term mortality in 62
reconstructive HNC surgery. The most important long-term predictors of death were DEX group, 63
distant metastases and CCI 5-9. Our data do not encourage routine utilization of perioperative 64
dexamethasone in this patient group.
65 66
Keywords: Head and neck cancer; dexamethasone; microvascular reconstruction; mortality;
67
survival 68
69
The clinical trial registration number: 2008-000892-11 70
71 72
Surgery for advanced head and neck cancer (HNC) is often mutilating, and large defects after tumor 73
resection require reconstruction with free flaps. Complex surgeries with possible complications 74
influence HNC survival. The five-year disease-specific survival of head and neck squamous cell 75
cancer (HNSCC) has improved during the last decades from 55 to 66% 1,2, but the overall five-year 76
survival is lower and is reported to be around 50-60% 3-5. With an ageing population, also HNC 77
patients undergoing surgery are getting older with an increasing toll of comorbidities.
78 79
Postoperative complications after free flap reconstruction for HNC impair survival 6-8. Perioperative 80
glucocorticoids (GC), mainly dexamethasone, are widely used in HNC surgery due to their anti- 81
inflammatory effects and numerous patients with HNC receive GCs for prevention of pain, 82
swelling, nausea and vomiting during their perioperative treatment although the safety of their use 83
remains unclear. Only a few studies have evaluated the influence of perioperative dexamethasone 84
on oncological surgery outcomes. De Oliveira et al. did not find a significant association between 85
perioperative administration of dexamethasone and tumor recurrence in 260 patients having surgery 86
for ovarian cancer 9. Yu et al. studied the effect of perioperative dexamethasone in 515 rectal cancer 87
patients treated with radical surgery and reported that patients who received dexamethasone had 88
significantly lower 3-year disease-free and overall survival (OS) 10. 89
90
We have previously shown that the use of perioperative dexamethasone increases the incidence of 91
major complications in HNC patients undergoing microvascular reconstruction, which might also 92
affect patient survival 11. The purpose of this study was to investigate whether the use of 93
perioperative dexamethasone influences HNC patients’ short-term survival. The second aim was to 94
assess the causes of death and the factors associated with mortality during long-term follow-up in 95
reconstructive HNC patients.
96
Methods 97
98
Study Design 99
100
To address the research purpose, the authors designed and implemented a prospective randomized 101
double-blind controlled study. The study population was composed of all patients presenting for 102
evaluation and management of HNC at the Department of Oral and Maxillofacial Surgery and the 103
Department of Plastic Surgery, Helsinki University Hospital between December 2008 and February 104
2013, and they were followed until the end of 2017. To be included in the study cohort, adult 105
patients had to require microvascular reconstruction. Patients were excluded if there was a history 106
of liver or kidney dysfunction, glaucoma, peptic ulcer, psychosis from use of steroids, allergy to any 107
constituent of the dexamethasone preparation used, or absence of written informed consent. The 108
multidisciplinary head and neck tumor board of Helsinki University Hospital determines 109
management for all HNC patients in our catchment area of 1.6 million people. This study followed 110
the Declaration of Helsinki on medical protocol and ethics and the Regional Ethical Review Board 111
of Helsinki University Hospital, Finland approved the study. The study was registered with 112
EudraCT (2008-000892-11). Written informed consent was obtained from all patients before 113
randomization.
114 115
Study Variables 116
117
For the survival analysis, the primary predictor variable was treatment group, classified as DEX or 118
NON-DEX depending on whether patients had received dexamethasone. Patients were followed 119
until the end of 2017, and the causes of death for deceased patients were obtained from the death 120
certificates of Statistics Finland. In Finland, the causes of death are classified as immediate, 121
intermediate or contributing causes of death and categorized as “disease”, “occupational causes”, 122
“trauma”, “medical complications”, “homicide”, “suicide”, “war” or “unclear”. The classification 123
for causes of death was made according to the Finnish Cause of Death Registry 12. The intermediate 124
cause of death refers to a condition which leads from the underlying cause to an immediate cause of 125
death. The primary (intermediate) cause of death was used to divide deaths into three categories:
126
HNC, non-HNC, and other cause of death. Additional variables that included data on patients’ free 127
flap type, tumor location and stage, American Society of Anesthesiologists (ASA) score, Charlson 128
Comorbidity Index (CCI), body mass index (BMI), alcohol use, smoking (smoking status was 129
recorded during the time of primary surgery but not during follow-up), postoperative radiation 130
therapy (intensity-modulated radiotherapy (IMRT) after primary surgery approximately 60-66 Gy 131
to the primary site and neck) and/or chemotherapy, number of complications, number of surgeries 132
and possible tumor recurrence or metastasis were collected from patient records. Surgical 133
complications were classified according to the classification suggested by Dindo et al. and all 134
patients with major complications required additional surgery within three weeks. 13,14. 135
136
Data Collection methods 137
138
Patients were randomly allocated into two groups; DEX and NON-DEX. The patients in the study 139
group received dexamethasone (Oradexon®) 10 mg intravenously three times a day at the first day, 140
two times at the second day and one dose at the third day adding up to a total dose of 60 mg (DEX 141
group). The patients in the control group did not receive dexamethasone at all (NON-DEX). The 142
randomization was done by a person not participating in the study. The information of the patient 143
allocation was given in a sealed envelope to the anesthesiologist, and they administered all doses to 144
the patient. The surgeons did not know of the patient assignment to groups.
145 146
Data Analyses 147
148
Descriptive statistics are reported as means and standard deviations (SD), medians or percentages.
149
The statistical significance of the differences between the groups was tested by Chi-square test or 150
independent samples t-test. The analysis of short-term survival of DEX vs NON-DEX groups was 151
carried out with univariate analysis. Factors associated with long-term death were assessed using 152
univariate and multivariate Cox’s proportional hazard models and the results are reported as hazard 153
ratios (HR). Variables for the multivariate model were selected using variables that were significant 154
in the univariate model and/or have clinical relevance, and least absolute shrinkage and selection 155
operator 15. In addition, a Kaplan-Meier plot was used to compare survival in the two study groups.
156
Two-sided p values < 0.05 were regarded as statistically significant. Power analysis to determine 157
the number of patients needed was performed in our previous study with the same patient cohort 11. 158
Statistical analysis was performed using the SPSS for Windows statistical software version 22 159
(SPSS, Inc., Chicago, IL, USA) and R 3.6.1 software (R Core Team (2019). R: A language and 160
environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria 16. 161
162
Results 163
164
Demographic data 165
166
Initially, a total of 110 consecutive HNC patients were included in the study and were randomized 167
into two groups, 55 in each. After inclusion criteria assessment 13 patients were excluded from the 168
study population. Further four patient were excluded since three of them had intraoperative 169
cancellation of free flap reconstruction and one patient had administed an additional 170
dexamethasone. This left 93 patients who formed the study cohort. Ultimately, 51 patients had 171
received dexamethasone (DEX), and 42 patients served as controls (NON-DEX). The discrepancy 172
in the size of the two groups is explained by the effect of chance in the randomization. Most (92%) 173
of the tumors were HNSCCs. The only statistically significant difference between the groups at the 174
baseline regarding preoperative data was the proportion of major alcohol users (DEX 16% vs NON- 175
DEX 32%, p=0.038). Alcohol use was defined as moderate if drinking was weekly or less and 176
major if it occurred daily. Perioperative management of the airway was different in the groups 177
(p=0.047). None of the patients had radiologically diagnosed distant metastasis before the primary 178
surgery. The demographic data and their associations with the treatment group are given in Table 1.
179
In total, 18% of the patients developed a major complication. Second primary HNC rate was 17%
180
(16 patients, diagnosis made between days 32 and 3363, median 612). Locoregional metastasis on 181
the neck occurred in 14% (13 patients, diagnosis made between days 52 and 1982, median 600) and 182
distant metastasis in 14% (13 patients, diagnosis made between days 32 and 1982, median 244) 183
during follow-up (Table 2). In addition, four patients developed another cancer besides HNC during 184
follow-up.
185 186
Short-term survival 187
188
Two patients died within 33 days; both were in the DEX group. There were seven deaths in the 189
DEX group during the first six months and none in the NON-DEX group. After one year 11 patients 190
have died in the DEX-group and two in the NON-DEX group (Chi-square test p=0.043) (Fig 1).
191
Five out of seven (71%) DEX group patients that died during the first six months, experienced 192
postoperative complications (two numerous operations due to rapid spread of cancer, one 193
pneumonia, one local infection, one venous thrombosis). The primary cause of death was HNC for 194
all deceased patients during the first 12 postoperative months.
195 196
Long-term survival 197
198
For the whole cohort, the median follow-up time was 5.3 years (range, 0.07 - 9 years). The OS for 199
all patients was 59% (55/93), and the primary cause of death was HNC in most of the deceased 200
patients in the whole cohort (30/38; 79%). Three patients died because of non-HNC (one prostate 201
cancer, one colon cancer, and one bladder cancer). Five patients died due to other causes (four 202
suffered from cardiovascular disease, and one had preoperatively undiagnosed alcoholic liver 203
cirrhosis). Even though there were more deaths in DEX groups during the whole follow-up period, 204
according to the Kaplan-Meier curve and log-rank test, there was no statistically significant 205
difference in long-term survival between the treatment groups. (Fig 2).
206 207
In the long-term follow-up, deceased patients were more likely to have had more advanced decease 208
(higher T classification, p=0.002; and higher stage, p=0.008), need for gastrostoma (p=0.002), 209
received more often postoperative chemotherapy (p=0.005), and more often locoregional (p=0.025) 210
or distal metastases (P<0.001) in the follow-up (Table 2).
211 212
For an initial multivariate Cox model, we identified 13 confounders. From these three variables 213
(chemotherapy, BMI and alcohol use) had one or two missing observations that we imputed using 214
random imputation. After adjustement, contrary to the univariate analysis, the use of 215
dexamethasone predicted excess risk of mortality (p=0.004). Also, the reduced model suggests, that 216
the other statistically significant long-term predictors of death and poor OS during follow-up were 217
CCI 5-9 and presence of distant metastasis. Global Schoenfeld test indicated that the proportional 218
hazard assumption holds in multivariate Cox model 17,18 (Table 3).
219 220
Discussion 221
222
The first purpose of this prospective randomized double-blind controlled study was to investigate 223
the association of perioperative use of dexamethasone and short-term survival following free flap 224
surgery in HNC patients. The second aim was to clarify the causes of death and the long-term 225
predictors affecting long-term mortality. To our knowledge, this is the first study to examine the 226
effect of GCs on mortality in major microvascular reconstruction patients. We hypothesized that 227
dexamethasone might also have an effect on cancer patients’ short-term survival as it causes major 228
complications and also induces immunosuppression.
229 230
Our previous study showed a higher number of complications in patients who received 231
perioperative dexamethasone 19. In the present study, the use of perioperative dexamethasone was 232
associated with higher short-term mortality. All patients who died within six months and 85% of 233
those who died within 12 months postoperatively were in the DEX group. Almost all patients who 234
died within one year had had postoperative complications. In this study, the most important 235
predictors associated with long-term mortality were the DEX group, CCI 5-9, and the presence of 236
distant metastases and deceased patients were associated with more advanced initial oncological 237
status.
238 239
The use of free flaps has enabled radical ablative surgery. Radical surgery with negative surgical 240
margins is an independent predictor of local recurrence and patients’ survival 4,20. In this study, we 241
did not analyze the impact of surgical margins on deaths. The multidisciplinary head and neck 242
tumor board of the Helsinki University Hospital provides recommendations for the management for 243
all HNC patients in our institution. In our cohort, none of the deceased patients required additional 244
surgery or developed a recurrence at the primary site. Most HNC patients requiring free flaps have 245
more advanced stage disease. This might be expected to influence patients’ survival independent of 246
the reconstructive method.
247 248
Our results support the hypothesis that perioperatively administered dexamethasone can be harmful 249
for the patients as it can increase postoperative complications and thus cause more serious side 250
effects. Impaired wound healing is a considerable disadvantage of GCs and may increase the risk of 251
postoperative complications. Another concern is that dexamethasone might have an effect on 252
patients’ survival as it induces immunosuppression and can suppress cell proliferation and promote 253
resistance to apoptosis in tumor cells 21,22. Khuri et al. studied the determinants of 30-day 254
postoperative mortality and long-term survival after eight different types of major surgery, 255
including vascular reconstructive surgery, in the US Veterans Administration 23. That study showed 256
that the most important determinant of decreased postoperative survival was the occurrence of 257
complications within 30 days postoperatively. Imai et al. evaluated the effect of preoperative GC 258
administration in major surgery for HNC as a part of Enhanced Recovery After Surgery (ERAS) 259
and compared the outcomes to a control group that underwent surgery before the implementation of 260
the protocol to those who did not receive GCs. They did not find an increase in the number of 261
complications relating to GC use. However, in that retrospective study, the number of patients was 262
limited to 28 24. de Cássia et al. studied clinical factors and morbidity and mortality among 530 oral 263
and oropharyngeal cancer patients and found that local complication (wound infection) and 264
systemic complications independently worsened 5-year OS (p < 0.001) 25. In our cohort, after 265
adjustment for confounding factors, we observed a difference in long-term survival and treatment 266
group, which was evident througout follow-up (Table 3, Fig 2). In our institute, we have already 267
discontinued the use of perioperative dexamethasone in HNC patients because our previous study 268
indicated that its use causes more harm than benefit 11,19. 269
There is limited knowledge on the causes of death after microvascular reconstruction in HNC.
271
Tanaka et al. analyzed 1249 HNC patients treated with free flaps and found short-term (30-day) 272
mortality to be 0.88%, but long-term survival was not analyzed 26. Lahtinen et al. analyzed 273
retrospectively survival and causes of death in 146 head and neck free flap patients with a median 274
follow-up time of three years. HNC was the primary cause of death in most (73%) patients 27, which 275
is in line with the results of the present study (79%). Our patient cohort had a 5.9-year OS of 59%
276
which is relatively good. Lidman and Niklasson studied 139 reconstructive HNC patients and found 277
a 5-year OS of 57%: In that study, causes of death, however, were studied only for those who died 278
within two months after surgery 28. De Vicente et al. analyzed 98 HNC patients (49 with free flap 279
reconstruction), and the OS rate was 59% at five years 29. 280
281
The strength of the present study is its double-blinded, randomized and prospective nature, although 282
the number of patients remained relatively small. The median follow-up time was more than five 283
years, which also provides long-term results of HNC mortality in patients requiring microvascular 284
reconstructive surgery.
285 286
Conclusion 287
288
In our study, perioperative use of dexamethasone was associated with higher short-term mortality in 289
HNC patients undergoing microvascular reconstruction. All of the patients who died during the first 290
six months, and most of those who died during the first year, had received perioperative 291
dexamethasone and had had postoperative complications. The most important long-term predictors 292
of death were DEX group, distant metastases and CCI 5-9. We conclude that it is not safe to use 293
perioperative dexamethasone in reconstructive HNC surgery, and we recommend that the potential 294
harm of perioperative dexamethasone should also be investigated in other surgically treated cancers 295
by randomized prospective studies.
296 297
Declaration of interests 298
The authors declare no conflicts of interest.
299 300
Funding 301
302
This study was supported by the Helsinki University Hospital Research Fund.
303 304
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388 389 390
Figure captions:
391 392
Fig 1. The percentage of deceased patients at different time points in follow-up, categorized by 393
treatment group 394
395
Footnote Fig 1:
396
Dex: Dexamethasone group 397
Non-dex: Control group 398
N/A: Statistical methods not available 399
400 401
Fig 2. Kaplan-Meyer overall survival curve for patients in dexamethasone (DEX) and non- 402
dexamethasone (NON-DEX) groups 403
404
Footnote Fig 2: Survival curves. There was 24 events (hazard=0.115) in DEX group, and 14 events 405
(hazard=0.0673) in NON-DEX group. Log-rank statistic was 0.094 for the whole follow-up, and 406
0.019 for the first 12 months.
407 408 409
410
Table 1. Patient data
DEX (N=51)
NON-DEX
(N=42) Total (N=93)
p value
Gender (n, %) 0.8781
Female 19 (37.3) 15 (35.7) 34 (36.6)
Male 32 (62.7) 27 (64.3) 59 (63.4)
BMI § 0.3312
Median (Range) 25.5 (15.8-
42.7)
24.5 (17.0- 32.6)
24.9 (15.8- 42.7)
ASA (n, %) 0.3441
1 3 (5.9) 3 (7.1) 6 (6.5)
2 10 (19.6) 13 (31.0) 23 (24.7)
3 27 (52.9) 22 (52.4) 49 (52.7)
4 11 (21.6) 4 (9.5) 15 (16.1)
History of alcohol use (n, %) §§ 0.0381
Major 8 (15.7) 13 (31.7) 21 (22.8)
Moderate 23 (45.1) 21 (51.2) 44 (47.8)
No 20 (39.2) 7 (17.1) 27 (29.3)
History of smoking (n, %) † 0.5831
Yes No
19 (37.3) 32 (62.7)
18 (42.9) 24 (57.1)
37 (39.8) 56 (60.2)
CCI (n, %) 0.3631
0-1 24 (47.1) 25 (59.5) 49 (52.7)
2-4 19 (37.3) 10 (23.8) 29 (31.2)
5-9 8 (15.7) 7 (16.7) 15 (16.1)
Median age at operation (years, range) 65.4 (39.2- 92.8)
64.7 (34.2- 87.6)
65.2 (34.2- 92.9)
0.5372 Airway access for mechanical
ventilation (n, %)
0.0471
Intubation 30 (58.8) 16 (38.1) 46 (49.5)
Tracheostomy 21 (41.2) 26 (61.9) 47 (50.5)
PEG (n, %) 0.2281
Yes 19 (37.3) 23 (54.8) 42 (45.2)
No 28 (54.9) 16 (38.1) 44 (47.3)
Later 4 (7.8) 3 (7.1) 7 (7.5)
Reconstruction type (n, %) 0.7451
Bone 5 (9.8) 5 (11.9) 10 (10.8)
Soft tissue 46 (90.2) 37 (88.1) 83 (89.2)
Site of the primary lesion (n, %) 0.6991
Maxilla 9 (17.6) 6 (14.3) 15 (16.1)
Mandible 14 (27.5) 12 (28.6) 26 (28.0)
Tongue 13 (25.5) 14 (33.3) 27 (29.0)
Floor of mouth 8 (15.7) 3 (7.1) 11 (11.8)
Buccal mucosa 5 (9.8) 4 (9.5) 9 (9.7)
Tonsil 1 (2.0) 2 (4.8) 3 (3.2)
Palate 1 (2.0) 0 (0.0) 1 (1.1)
Larynx - hypopharynx 0 (0.0) 1 (2.4) 1 (1.1)
Flap type (n, %) 0.4401
ALT 15 (29.4) 17 (40.5) 32 (34.4)
Forearm flap 31 (60.8) 20 (47.6) 51 (54.8)
Other †† 5 (9.8) 5 (11.9) 10 (10.8)
Neck dissection (n, %) 0.2071
Unilateral 45 (88.2) 33 (78.6) 78 (83.9)
Bilateral 6 (11.8) 9 (21.4) 15 (16.1)
Neck dissection levels (n, %) 0.2011
Sentinel node biopsy 7 (13.7) 3 (7.1) 10 (10.8)
1-3 18 (35.3) 10 (23.8) 28 (30.1)
1 - 4/5 or radical 26 (51.0) 29 (69.0) 55 (59.1)
DEX: Dexamethasone group
NON-DEX: Non-dexamethasone group N: number
BMI: Body Mass Index
ASA: American Society of Anesthesiologists CCI: Charlson Comorbidity Index
PEG: Percutaneous endoscopic gastrotomy
§ Data are missing from one patient
§§ Alcohol use was defined as moderate if drinking was weekly or less and major if it occurred daily, Data are missing from two patients
† Patients were defined as smokers if they smoked before surgery
ALT: Anterolateral Thigh Perforator flap
†† Other: 4 DCIA (the deep circumflex iliac artery bone flap), 1 fibular flap, 1 LD (Latissimus dorsi muscle flap), 2 Scapular + LD flap and 1 Scapular + parascapular flap
p < 0.05 (significant)
1: Pearson′s Chi-squared test
2: Kruskal-Wallis rank sum test
Table 2. Comparison of study variables and survival data in follow-up (median 5.3 years)
Survived (N=55)
Deceased
(N=38) Total (N=93) p value
Group (n, %) 0.2591
DEX 27 (49.1) 24 (63.2) 51 (54.8)
NON-DEX 28 (50.9) 14 (36.8) 42 (45.2)
Gender (n, %) 0.6281
Female 19 (34.5) 15 (39.5) 34 (36.6)
Male 36 (65.5) 23 (60.5) 59 (63.4)
BMI § 0.2842
Median (Range) 24.7 (16.0-
39.4)
25.6 (15.8- 42.7)
24.9 (15.8- 42.7)
ASA (n, %) 0.6211
1 5 (9.1) 1 (2.6) 6 (6.5)
2 14 (25.5) 9 (23.7) 23 (24.7)
3 28 (50.9) 21 (55.3) 49 (52.7)
4 8 (14.5) 7 (18.4) 15 (16.1)
History of alcohol use (n, %) §§ 0.1371
Major 13 (23.6) 8 (21.6) 21 (22.8)
Moderate 30 (54.5) 14 (37.8) 44 (47.8)
No 12 (21.8) 15 (40.5) 27 (29.3)
History of smoking (n, %) † 0.7041
Yes 21 (38.2) 16 (42.1) 37 (39.8)
No 34 (61.8) 22 (57.9) 56 (60.2)
CCI (n, %) 0.0821
0-1 32 (58.2) 17 (44.7) 49 (52.7)
2-4 18 (32.7) 11 (28.9) 29 (31.2)
5-9 5 (9.1) 10 (26.3) 15 (16.1)
Median age at operation (years, range)
64.7 (39.2- 87.7)
66.0 (34.2- 92.8)
65.2 (34.2- 92.8)
0.5222
Airway access for mechanical
ventilation (n, %) 0.2381
Intubation 30 (54.5) 16 (42.1) 46 (49.5)
Tracheostomy 25 (45.5) 22 (57.9) 47 (50.5)
PEG (n, %) 0.0021
Yes 19 (34.5) 23 (60.5) 42 (45.2)
No 34 (61.8) 10 (26.3) 44 (47.3)
Later 2 (3.6) 5 (13.2) 7 (7.5)
Reconstruction type (n, %) 0.5341
Bone 5 (9.1) 5 (13.2) 10 (10.8)
Soft tissue 50 (90.9) 33 (86.8) 83 (89.2)
Site of the primary lesion (n, %) 0.4281
Maxilla 8 (14.5) 7 (18.4) 15 (16.1)
Mandible 11 (20.0) 15 (39.5) 26 (28.0)
Tongue 17 (30.9) 10 (26.3) 27 (29.0)
Floor of mouth 8 (14.5) 3 (7.9) 11 (11.8)
Buccal mucosa 7 (12.7) 2 (5.3) 9 (9.7)
Tonsil 2 (3.6) 1 (2.6) 3 (3.2)
Palate 1 (1.8) 0 (0.0) 1 (1.1)
Larynx - hypopharynx 1 (1.8) 0 (0.0) 1 (1.1)
Flap type (n, %) 0.0531
ALT 17 (30.9) 15 (39.5) 32 (34.4)
Forearm flap 35 (63.6) 16 (42.1) 51 (54.8)
Other †† 3 (5.5) 7 (18.4) 10 (10.8)
Neck dissection (n, %) 0.2831
Unilateral 48 (87.3) 30 (78.9) 78 (83.9)
Bilateral 7 (12.7) 8 (21.1) 15 (16.1)
Neck dissection levels (n, %) 0.5061
Sentinel node biopsy 6 (10.9) 4 (10.5) 10 (10.8)
1-3 19 (34.5) 9 (23.7) 28 (30.1)
1 - 4/5 or radical 30 (54.5) 25 (65.8) 55 (59.1)
pT‡ (Mean (SD)) 2.07 (1.36) 2.97 (1.21) 2.44 (1.37) 0.0023
Stage (n, %) ‡‡ 0.0081
1 24 (43.6) 4 (10.8) 28 (30.4)
2 4 (7.3) 3 (8.1) 7 (7.6)
3 5 (9.1) 4 (10.8) 9 (9.8)
4 22 (40.0) 26 (70.3) 48 (52.2)
Radiation therapy postoperatively (n,
%)
0.0761
No 32 (58.2) 15 (39.5) 47 (50.5)
Yes 23 (41.8) 23 (60.5) 46 (49.5)
Chemotherapy postoperatively (n, %)
# 0.0051
No 47 (85.5) 22 (59.5) 69 (75.0)
Yes 8 (14.5) 15 (40.5) 23 (25.0)
Major complication (n, %) 0.0961
No 48 (87.3) 28 (73.7) 76 (81.7)
Yes 7 (12.7) 10 (26.3) 17 (18.3)
Second primary in follow-up (n, %) 0.4141
No 47 (85.5) 30 (78.9) 77 (82.8)
Yes 8 (14.5) 8 (21.1) 16 (17.2)
Distant metastasis in follow-up (n, %)
<0.0011
No 54 (98.2) 26 (68.4) 80 (86.0)
Yes 1 (1.8) 12 (31.6) 13 (14.0)
Locoregional metastasis in follow-up (n, %)
0.0251
No 51 (92.7) 29 (76.3) 80 (86.0)
Yes 4 (7.3) 9 (23.7) 13 (14.0)
DEX: Dexamethasone group
NON-DEX: Non-dexamethasone group N: Number
BMI: Body Mass Index
ASA: American Society of Anesthesiologists CCI: Charlson Comorbidity Index
PEG: Percutaneous endoscopic gastrotomy
§ Data are missing from one patient
§§ Alcohol use was defined as moderate if drinking was weekly or less and major if it occurred daily, data are missing from two patients
† Patients were defined as smokers if they smoked before surgery ALT: Anterolateral Thigh Perforator flap
†† Other: 4 DCIA (the deep circumflex iliac artery bone flap), 1 fibular flap, 1 LD (Latissimus dorsi muscle flap), 2 Scapular + LD flap and 1 Scapular + parascapular flap
‡ pT=Pathological tumor classification, data are missing from two patients
‡‡ Data are missing from two patients
# Data are missing from two patients p < 0.05 (significant)
1: Pearson′s Chi-squared test
2: Kruskal-Wallis rank sum test
3: Linear Model ANOVA (Mann-Whitney with two groups)
Table 3. Factors affecting long-term mortality in follow-up (5.3 years)
Overall survival All HR (multivariable) HR (multivariable reduced)
Group DEX 51 - -
NON-DEX 42 0.22 (0.09-0.56, p=0.001)
0.31 (0.14-0.69, p=0.004)
pT § 1 38 - -
2 15 3.07 (0.77-12.26,
p=0.111)
2.58 (0.74-9.03, p=0.137)
3 3 5.16 (0.83-32.00,
p=0.078)
3.13 (0.56-17.59, p=0.196)
4 37 4.22 (1.47-12.09,
p=0.007)
2.56 (0.98-6.71, p=0.055)
PEG Yes 42 - -
No 44 0.22 (0.06-0.74,
p=0.015)
0.37 (0.14-1.04, p=0.059)
Later 7 2.74 (0.61-12.34,
p=0.188)
2.09 (0.58-7.51, p=0.256)
Major complication (n) No 76 - -
Yes 17 0.94 (0.30-2.90,
p=0.910)
1.59 (0.65-3.89, p=0.312)
CCI 0-1 49 - -
2-4 29 3.79 (1.14-12.59,
p=0.029)
1.57 (0.64-3.83, p=0.322)
5-9 15 7.29 (2.33-22.83,
p=0.001)
5.82 (2.26-14.98, p<0.001) History of alcohol use (n)
§§
Major 22 - -
Moderate 44 0.81 (0.26-2.51, p=0.721)
0.84 (0.32-2.18, p=0.722)
No 27 2.35 (0.74-7.45,
p=0.146)
1.53 (0.54-4.34, p=0.421) Radiation therapy
postoperatively (n)
No 47 - -
Yes 46 0.83 (0.27-2.59,
p=0.752) - Age at operation Mean (SD) 65.3
(11.0)
1.00 (0.96-1.05, p=0.848)
-
Gender (n) Female 34 - -
Male 59 0.72 (0.28-1.80,
p=0.478) -
BMI Mean (SD) 25.6
(4.9)
1.05 (0.96-1.14, p=0.277)
- Second primary in follow-
up (n)
No 77 - -
Yes 16 0.51 (0.14-1.77,
p=0.286) -
Distant metastasis in No 80 - -
follow-up (n)
Yes 13 16.10 (5.13-50.52,
p<0.001)
10.41 (3.99-27.13, p<0.001) Locoregional metastasis in
follow-up (n)
No 80 - -
Yes 13 2.82 (1.00-7.94,
p=0.050) - Chemotherapy
postoperatively (n) #
No 69 - -
Yes 23 1.83 (0.51-6.54,
p=0.352) -
DEX: Dexamethasone group
NON-DEX: Non-dexamethasone group N = number
§ pT=Pathological tumor classification, data are missing from one patient CCI: Charlson Comorbidity Index
§§ Alcohol use was defined as moderate if drinking was weekly or less and major if it occurred daily, data are missing from two patients
BMI: Body Mass Index
# Data are missing from two patients
