Avoiding perioperative dexamethasone may improve the outcome of patients with rectal cancer

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Avoiding perioperative dexamethasone may improve the outcome of patients with rectal cancer H.C. Yu a, Y.X. Luo a,b, H. Peng a, L. Kang a, M.J. Huang a, J.P. Wang a,b,* a

Department of Colorectal and Anal Surgery, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China b Gastrointestinal Institute, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China Accepted 29 January 2015 Available online 19 February 2015

Abstract Background: Perioperative administration of dexamethasone may augment recurrence and mortality after tumor resection possibly by immunosuppression, which, unfortunately, has never been noted. We therefore carried out a retrospective study in rectal cancer to validate the hypothesis. Methods: Five hundreds and fifteen patients with stage I to III rectal cancers who underwent a curative resection from June 2007 and June 2011 were enrolled in the current study. Patients who had been given intravenous (IV) dexamethasone (4e10 mg) postoperatively and/or intraoperatively were assigned to dexamethasone group. The outcome of dexamethasone group and non-dexamethasone group were compared. The primary outcome was disease-free survival (DFS) and overall survival (OS). Results: dexamethasone group had significant lower three-year DFS (62.3% vs 71.8%, P ¼ 0.026) and OS (74.1% vs 82.9%, P ¼ 0.031) rate in comparison to non-dexamethasone group, the hazard ratios (HRs) of which were 1.59 (95% CI 1.05e2.39, P ¼ 0.028) and 1.77 (95% CI 1.05e3.01, P ¼ 0.034), respectively. Multivariate analysis revealed that administration of systemic dexamethasone were independently associated with DFS [adjusted HR 1.60 (95% CI 1.03e2.49, p ¼ 0.039)], but for OS, dexamethasone didn’t remain significant in this model. In the analyses of a subgroup of 428 patients (55/428 in dexamethasone group) without perioperative blood transfusion, dexamethasone had independently impact on both DFS and OS. Conclusion: Patients not given dexamethasone had better three-year survival outcomes compared with patients given dexamethasone perioperatively. Our results indicate that rectal cancer patients treated with curative surgery may get survival benefit from avoiding low-dose perioperative dexamethasone. Ó 2015 Elsevier Ltd. All rights reserved.

Keywords: Rectal cancer; Dexamethasone; Survival; Immunosuppression

Introduction It has been well established that major operations may augment release of cancer cells into circulation1 and introduce immunosuppression that lasts for several days.2 This * Corresponding author. Department of Colorectal and Anal Surgery, Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, China. Tel.: þ86 20 38254955; fax: þ86 20 38254094. E-mail addresses: [email protected] (H.C. Yu), luoyx25@ mail.sysu.edu.cn (Y.X. Luo), [email protected], jpwanggz@ gmail.com (J.P. Wang). http://dx.doi.org/10.1016/j.ejso.2015.01.034 0748-7983/Ó 2015 Elsevier Ltd. All rights reserved.

process partially contributes to clinical recurrence and metastasis, but immune defenses are certainly a critical protection.3 Several studies showed that perioperative immunosuppression increases the risk of recurrence in cancer patients having surgery.4e6 Dexamethasone, similar to other corticosteroids, induces generalized immunosuppression.7 Perioperative administration of dexamethasone may therefore have a deleterious effect on the survival and recurrence after tumor resection, possibly because of immunosuppression. This possibility is supported by studies in animals in which tumor growth was enhanced after dexamethasone given.8 Unfortunately, the

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prognosis after perioperative administration of systemic dexamethasone has never been noted in patients with cancer. As numerous patients with rectal cancer receive GCs for antiallergic intervention and prevention of pain, nausea and vomiting during their perioperative treatment,9e11 the effect of this clinical intervention on cancer outcomes represents an important clinical issue. We therefore conducted a retrospective study to define the association between perioperatively administration of systemic dexamethasone and oncological outcomes in rectal cancer treated with radical surgery. Methods The study design and protocol were approved by our institutional review board. Stage I to III rectal cancer patients who underwent a curative resection from June 2007 and June 2011 were identified using a database maintained by Sixth Affiliated Hospital of Sun Yat-Sen University. Rectal cancer was defined as histologically proven adenocarcinoma within 15 cm from the anal verge and was staged according to the 7th edition of the American Joint Committee on Cancer (AJCC) staging system. Exclusion criteria were as follows: patients who were on immunosuppressive therapy including recent steroid exposure, or with chronic inflammatory disease including inflammatory bowel disease (IBD); those diagnosed as familial adenomatous polyposis (FAP) and those with multiple primary cancers. Moreover, patients without comprehensive prescription records during perioperative treatment were excluded. Inpatient medical records and anesthesia notes were evaluated, and patients who had been given intravenous (IV) dexamethasone (4e10 mg) postoperatively and/or intraoperatively were assigned to dexamethasone group. The following data were extracted from patients’ medical records: demographic characteristics (age, height, and weight), tumor location, tumor staging, tumor’s histological features, presence or absence of blood transfusion, preoperative serum carcinoembryonic antigen (CEA) level, treatment regimen and time to recurrence and survival. Above all, dose, timing and frequency of IV dexamethasone given in the perioperative treatment were recorded. These data were compared between patients who were and were not given perioperative systemic dexamethasone. Dexamethasone was commonly administered to prevent or treat postoperative nausea and vomiting and allergic reaction to drugs and blood transfusion. Since no guidelines exist on how to deal with postoperative nausea and vomiting and there are several alternative approaches, such as promethazine, to treat allergic reaction to blood transfusion, provider preference was the driving force for administration of dexamethasone. Patients were followed up every three months for the first three years after surgery, every six months for the next two years, and yearly thereafter. Each visit included a medical history, a physical examination, including a rectal examination, and measurement of the serum CEA concentration. Routine radiological examinations consisting of

chest radiography, abdominopelvic computed tomography or ultrasonography, whole-body bone scintigraphy, and colonoscopy or double-contrast barium enema were performed six months after surgery and annually thereafter. The follow-up period for the study ended July 2014 with the interval of follow-up varying from three to seven years. The primary outcome was disease-free survival (DFS) and overall survival (OS). Cancer recurrence was detected by CEA > 5 ng/mL and/or a sequential computerized tomography scan with evidence of the disease followed by histopathological confirmation. DFS was defined as the time from the surgery until recurrence or death from any cause, and OS was defined as the time from the surgery to death. The intergroup comparisons of clinicopathologic variables were performed using the analysis of variance and KruskaleWallis tests for continuous variables (depending on the distribution of the continuous variables), and the chi-square and two-tailed Fisher’s exact tests for discrete variables. The OS and DFS rate were estimated and compared according to the KaplaneMeier method and log-rank test, respectively. A univariate screen of potential risk factors of mortality using the Cox proportional hazard model for each variable extracted from medical records was performed. Multivariate analyses using Cox’s proportional hazard model were used to identify the independent risk factors that influenced long-term survival. All tests were 2-sided, and p value < 0.05 was considered statistically significant. Data analyses were performed using SPSS version 19.0 for Windows (SPSS, Inc., Chicago, IL). The study was approved by the Medicine Ethics Committee of the Hospital in Sun Yat-sen University. There was no harm to patients, given that the data were collected retrospectively from database and medical records. All the necessary precautions were taken to secure the privacy of the human subjects in our database, allowing the medical records and databases to be used only by the investigators. Results Baseline characteristics A total of 515 patients matched the inclusion and exclusion criteria and were included in this study (Fig. 1). There were 297 male and 218 female patients, with the median age of 59 years (rang, 21e89 years). The AJCC staging among the patients was distributed as 26%, 32% and 42% for stages I, II and III, respectively. There were 75 patients in dexamethasone group, among which 50 (67%) patients were given intraoperatively, 25 (33%) patients were given postoperatively for once or twice and no patient given dexamethasone preoperatively was identified. Forty-eight patients were given 4e5 mg, and 27 patients were given 8e10 mg. Demographic, morphometric, therapeutic and tumor characteristics were not statistically different in patients given and not given dexamethasone, except for perioperative blood transfusion that had significantly higher

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Figure 1. CONSORT diagram. Patient disposition in the analysis of the effect of dexamethasone on survival.

rate (28% vs 15%, P ¼ 0.005) in dexamethasone group when compared with non-dexamethasone group. Overall, the recurrence rate was 24% (124/515), and patients in dexamethasone group had higher risk of recurrence compared with non-dexamethasone group [35% (26/75) vs 22% (98/440), P ¼ 0.020]. (Table 1).

Univariate and multivariate analyses of survival KaplaneMeier curves showed significant lower 3-year DFS (62.3% vs 71.8%, P ¼ 0.026) and OS (74.1% vs 82.9%, P ¼ 0.031) rate in dexamethasone group in comparison to non-dexamethasone group (Table 2, Fig. 2). The univariate analysis indicated that old age, advanced AJCC stages, low-grade differentiation, lymphovascular invasion, perineural invasion, elevated CEA, perioperative blood transfusion and IV dexamethasone were all significantly associated with increased mortality (Table 2). Specifically, dexamethasone group had lower three-year DFS and OS rate compared to non-dexamethasone group, the hazard ratios (HRs) of which were 1.59 (95% CI 1.05e2.39, P ¼ 0.028) and 1.77 (95% CI 1.05e3.01, P ¼ 0.034). Using the multivariate analysis, advanced AJCC stages, perineural invasion and IV dexamethasone [adjusted HR 1.60 (95% CI 1.03e2.49, p ¼ 0.039)] were still significantly associated with three-year DFS. Advanced AJCC stages, elevated CEA, low-degree differentiation and

adjuvant treatment had independently significant prediction value on three-year OS. Nevertheless, IV dexamethasone didn’t remain significant in this model.(Table 3). Additional analyses on subsets of patients Further subsets analyses were conducted to determine if the above correlation between dexamethasone and survival depends on blood transfusion. In the analyses of a subgroup of 428 patients without perioperative blood transfusion, IV dexamethasone (55/428,12.8%) was still associated with lower 3-year DFS (60.9% VS 73.0%, P ¼ 0.007) and OS (77.2% vs 85.0%, P ¼ 0.017) rate, the adjusted HRs of which were 2.06 (95% CI 1.27e3.33, P ¼ 0.003)] and 2.07 (95% CI 1.05e4.11, P ¼ 0.037) respectively in the Cox regression model. Next, to assess the correlation between timing of dexamethasone administration and survival, outcomes were compared between patients given dexamethasone intraoperatively and postoperatively. Logrank test showed that there was no significant difference of either OS (P ¼ 0.458) or DFS (P ¼ 0.468) rate between intraoperative group and postoperative group. Discussion In consistent with our hypothesis, there exist correlation between perioperative administration of 4e10 mg of IV

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Table 1 Baseline characteristics and distribution of clinicopathologic variables in dexamethasone and non-dexamethasone group. Characteristic

Age-yr, median(range) BMI, median(range) Sex Male Female TNM Stage, AJCC I II III Histology Mucinous Other adenocarcinomas Differentiation degree Low Moderate High Lymphovascular invasion Negative Positive Perineural invasion Negative Positive Preoperative CEA Negative Positive Distance from anal verge <5 cm 5e12 cm Blood transfusion No Yes Adjuvant treatment No Yes Neoadjuvant treatment No Yes Recurrence No Yes

Overall population (N ¼ 515)

IV dexamethasone No (N ¼ 440)

Yes(N ¼ 75)

p value

59 (21e89) 22.1 (13.3e33.8)

59 (21e89) 22.1 (14.0e33.8)

60 (25e88) 22.2 (13.3e29.0)

297 (58) 218 (42)

250 (57) 190 (43)

47 (63) 28 (37)

132 (26) 164 (32) 219 (42)

114 (26) 143 (32) 183 (42)

18 (24) 21 (28) 36 (48)

57 (11) 453 (89)

48 (11) 387 (89)

9 (12) 66 (88)

95 (19) 276 (56) 126 (25)

80 (19) 229 (54) 114 (27)

15 (20) 47 (64) 12 (16)

470 (91) 45 (9)

404 (92) 36 (8)

66 (88) 9 (12)

464 (90) 51 (10)

397 (90) 43 (10)

67 (89) 8 (11)

355 (72) 138 (28)

305 (72) 120 (28)

50 (73) 18 (27)

193 (38) 309 (62)

163 (38) 266 (62)

30 (41) 43 (59)

428 (83) 87 (17)

374 (85) 66 (15)

54 (72) 21 (28)

250 (49) 261 (51)

215 (49) 222 (51)

35 (47) 39 (53)

447 (87) 68 (13)

385 (87) 55 (13)

62 (83) 13 (17)

391 (76) 124 (24)

342 (78) 98 (22)

49 (65) 26 (35)

0.092 0.064 0.343

0.572

0.915

0.141

0.279

0.811

0.763

0.615

0.005

0.762

0.253

0.020

dexamethasone and 3-year survival rate in rectal cancer after curative surgery. These findings were confirmed after we stratified patients and only looked into the tumors without perioperative blood transfusion. Our results thus suggest that doses of dexamethasone commonly used for anesthesia and postoperative complications, such as nausea and vomiting, do increase the risk of mortality in patients having surgery for rectal cancer and are needed to be limited in that patient population. Glucocorticoids (GCs), such as dexamethasone and prednisone, are widely applied in antitumor therapy. In leukemia and lymphoma, GCs are used as anticancer drugs due to their antitumor effects in hematopoetic malignancies.12,13 In contrast, solid tumors are completely resistant to GC-induced apoptosis and thus GCs are given to

alleviate adverse effects.9,14e16 The adjuvant use of GCs during therapy of solid tumors is under debate, since GCs have been shown to undermine the efficacy of chemotherapy both in vitro, as well as in certain clinical trials of solid tumors.13,17,18 Perioperative administration of dexamethasone augment cancer-related death after curative cancer surgery through several possible ways. Systematic dexamethasone have an effect of corticosteroid-induced generalized immunosuppression.7 Specifically, dexamethasone inhibits natural killer cell function,19 which is a most important component of tumor cytotoxicity. Moreover, GCs were shown to induce proliferation in normal cells, such as fibroblasts and erythroid progenitor cells,20,21 and few studies indicate very low concentrations of dexamethasone also induce

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Table 2 Univariate analysis of prognostic factors for DFS and OS. Factors

DFS 3-year rate (%)

Age e TNM Stage, AJCC I 83.7 II 75.6 III 59.8 Differentiation degree Low 59.6 Moderate 71.9 High 75.9 Lymphovascular invasion Positive 54.1 Negative 72.1 Perineural invasion Positive 33.8 Negative 73.4 Preoperative CEA >5 ng/ml 60.6 0e5 ng/ml 75.9 Perioperative blood transfusion Yes 65.6 No 71.3 Adjuvant treatment Yes 75.4 No 65.8 IV dexamethasone Yes 62.3 No 71.8

OS HR (95% CI)

p value

3-year rate (%)

HR (95% CI)

p value

e

1.04 (1.02e1.06)

<0.001

1.01 (0.99e1.02)

0.100

0.22 (0.12e0.41) 0.52 (0.35e0.77) 1

<0.001 0.001

92.4 81.5 75.6

0.17 (0.07e0.42) 0.62 (0.38e1.02) 1

<0.001 0.062

2.39 (1.39e4.09) 1.32 (0.80e2.17) 1

0.002 0.276

73.1 82.5 88.5

3.73 (1.68e8.31) 1.96 (0.92e4.20) 1

0.001 0.082

2.18 (1.41e3.37) 1

<0.001

68.9 82.7

1.97 (1.08e3.58) 1

0.026

3.43 (2.17e5.42) 1

<0.001

68.9 82.9

2.53 (1.33e4.84) 1

0.005

1.61 (1.12e2.31) 1

0.010

70.6 88.0

2.32 (1.45e3.71) 1

<0.001

1.14 (0.74e1.75) 1

0.549

70.4 84.0

2.06 (1.26e3.36) 1

0.004

0.80 (0.57e1.13) 1

0.212

86.2 76.6

0.58 (0.37e0.91) 1

0.017

1.59 (1.05e2.39) 1

0.028

74.1 82.9

1.77 (1.05e3.01) 1

0.034

cancer cell proliferation in vitro, including glioma,22 astrocytoma23 and Kaposi’s sarcoma,24 but lack signaling data. In our studies, each dose of dexamethasone used perioperatively (4e10 mg) was far below than that in anticancer therapy.25,26 As very low concentrations of dexamethasone induce proliferation in vitro8 and as dexamethasone is metabolized with a long half-life in humans (9  3 h),27 we conclude that unfavorable serum concentrations of dexamethasone might persist for prolonged periods of time in patients with rectal cancer and the poor survival outcomes in our series validate it. Inversely, several factors may contribute to protective effect of dexamethasone on rectal cancer. Low-dose dexamethasone (8 mg) can decrease the perioperative stress response10 that has been shown to impair immune function.28 It is possible that these protective effects are insufficient to offset the aforementioned detrimental effects of dexamethasone on immune function to result in an overall positive effect. In addition, dexamethasone has been demonstrated as a proapoptotic co-medication to prolong survival time in certain types of breast cancer.29 However, since the effects in solid tumor are diverse, we speculate that only specific rectal cancer would benefit from certain dose of dexamethasone. The question of perioperatively low-dose dexamethasone-related immunosuppresion affecting cancer outcomes

has been examined by another investigator. De Oliveira et al.30 demonstrated that dexamethasone given perioperatively had no impact on recurrence in patients with ovarian cancer, but lack survival data. The results are in distinct contrast to our study. According to the conclusion of a systematic review of the clinical effect of glucocorticoids on nonhematologic malignancy,17 glucocorticoids have a beneficial effect in breast and prostate cancer as monotherapy, while in GI cancer, they most likely have a neutral effect. In lung cancer, glucocorticoids might have a deleterious effect. Moreover, high dose continuous glucocorticoids decrease survival in patients with nonhematologic malignancy. The aforementioned studies suggested that the primary site of tumor, as well as dose, timing and frequency of dexamethasone administration, may be responsible for different outcomes of dexamethasone. Therefore, further studies will be necessary to validate the detrimental effects of dexamethasone on other tumors. In present study, the patients were given IV dexamethasone either because of their disease or because given was necessary during blood transfusion. Although perioperative blood transfusion is a well known risk factor of poor prognosis in colorectal cancer,31,32 multivariate Cox regression and analyses of a subset of patients without blood transfusion confirmed the independently negative impact of dexamethasone on survival. However, the question still remains

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indicated are ethically unacceptable, this retrospective study would be an optimal surrogate. Despite all this, the detrimental effects of perioperative dexamethasone on rectal cancer should be validated in other cohorts. Conclusion Patients not given dexamethasone had better three-year survival outcomes compared with patients given dexamethasone perioperatively. Our results indicate that rectal cancer patients treated with curative surgery may get survival benefit from avoiding low-dose perioperative dexamethasone. However, the detrimental effects of dexamethasone on rectal cancer or other tumors should be validated in further studies.

Acknowledgments Support for these studies was provided by a Program of Introducing Talents of Discipline to Universities of China (B12003, JW) and International Science & Technology Cooperation Program of China (2011DFA32570, JW), National Natural Science Foundation of China (81172040, JW; 81201920, YL). Figure 2. The KaplaneMeier curves showed significant lower 3-year DFS (A) and OS (B) in the dexamethasone group compared to the nondexamethasone group.

whether the relation between IV dexamethasone and poor prognosis is causal or coincidental. The need for IV dexamethasone could be an indicator of other risk factors that are difficult to identify or quantify. We cannot avoid selection bias in our retrospective analysis, for instance, clinicians may have withheld dexamethasone from patients with hepatitis B. A randomized trial is the best way to validate the correlation, however, randomization between dexamethasone and non-dexamethasone is difficult to realize. Since that giving IV dexamethasone when there is no medical indication and withholding IV dexamethasone that are

Author contributions Conceived and designed the study: Jianping Wang and Huichuan Yu. Acquisition of data: Huichuan Yu, Liang Kang and Meijin Huang. Analysis and interpretation of data: Huichuan Yu and Yanxin Luo. Drafting the manuscript: Huichuan Yu, Yanxin Luo and Hui Peng. Revising manuscript critically for important intellectual content: Jianping Wang. All the authors have approved the submitted manuscript. Conflicts of interest None.

Table 3 Multivariate analysis of prognostic factors for DFS and OS. Predictors

Survival HR (95% CI)

DFS AJCC Stage III Perineural invasion IV dexamethasone OS AJCC Stage III Preoperative CEA > 5 ng/ml Low-degree differentiation Adjuvant treatment

References p value

3.91 (2.00e7.62) 2.20 (1.32e3.65) 1.60 (1.03e2.49)

<0.001 0.002 0.039

8.16 1.78 3.63 0.37

0.001 0.023 0.008 <0.001

(2.41e27.60) (1.08e2.92) (1.40e9.39) (0.21e0.64)

1. Lundy J. Anesthesia and surgery: a double-edged sword for the cancer patient. J Surg Oncol 1980;14:61–5. 2. Shakhar G, Ben-Eliyahu S. Potential prophylactic measures against postoperative immunosuppression: could they reduce recurrence rates in oncological patients. Ann Surg Oncol 2003;10:972–92. 3. Colacchio TA, Yeager MP, Hildebrandt LW. Perioperative immunomodulation in cancer surgery. Am J Surg 1994;167:174–9. 4. Shakhar G, Abudarham N, Melamed R, Schwartz Y, Rosenne E, BenEliyahu S. Amelioration of operation-induced suppression of marginating pulmonary NK activity using poly IC: a potential approach to reduce postoperative metastasis. Ann Surg Oncol 2007;14:841–52.

H.C. Yu et al. / EJSO 41 (2015) 667e673 5. Heaney A, Buggy DJ. Can anaesthetic and analgesic techniques affect cancer recurrence or metastasis. Br J Anaesth 2012;109(Suppl. 1):i17– 28. 6. Kavanagh T, Buggy DJ. Can anaesthetic technique effect postoperative outcome. Curr Opin Anaesthesiol 2012;25:185–98. 7. Kunicka JE, Talle MA, Denhardt GH, Brown M, Prince LA, Goldstein G. Immunosuppression by glucocorticoids: inhibition of production of multiple lymphokines by in vivo administration of dexamethasone. Cell Immunol 1993;149:39–49. 8. Gundisch S, Boeckeler E, Behrends U, Amtmann E, Ehrhardt H, Jeremias I. Glucocorticoids augment survival and proliferation of tumor cells. Anticancer Res 2012;32:4251–61. 9. De Oliveira Jr GS, Castro-Alves LJ, Ahmad S, Kendall MC, McCarthy RJ. Dexamethasone to prevent postoperative nausea and vomiting: an updated meta-analysis of randomized controlled trials. Anesth Analg 2013;116:58–74. 10. Karaman K, Bostanci EB, Aksoy E, et al. Effects of dexamethasone and pheniramine hydrogen maleate on stress response in patients undergoing elective laparoscopic cholecystectomy. Am J Surg 2013;205: 213–9. 11. Schwiebert LM, Beck LA, Stellato C, Bickel CA, Bochner BS, Schleimer RP. Glucocorticosteroid inhibition of cytokine production: relevance to antiallergic actions. J Allergy Clin Immunol 1996;97: 143–52. 12. Frankfurt O, Rosen ST. Mechanisms of glucocorticoid-induced apoptosis in hematologic malignancies: updates. Curr Opin Oncol 2004;16:553–63. 13. Herr I, Buchler MW, Mattern J. Glucocorticoid-mediated apoptosis resistance of solid tumors. Results Probl Cell Differ 2009;49:191– 218. 14. De Oliveira Jr GS, Ahmad S, Fitzgerald PC, et al. Dose ranging study on the effect of preoperative dexamethasone on postoperative quality of recovery and opioid consumption after ambulatory gynaecological surgery. Br J Anaesth 2011;107:362–71. 15. Aapro MS. Corticosteroids as antiemetics. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 1988;108:102–11. 16. Vecht CJ, Hovestadt A, Verbiest HB, van Vliet JJ, van Putten WL. Dose-effect relationship of dexamethasone on Karnofsky performance in metastatic brain tumors: a randomized study of doses of 4, 8, and 16 mg per day. Neurology 1994;44:675–80. 17. Keith BD. Systematic review of the clinical effect of glucocorticoids on nonhematologic malignancy. BMC Cancer 2008;8:84. 18. Thatcher N, Wagstaff J, Wilkinson P, Palmer M, Crowther D. Intermittent high-dose cyclophosphamide with and without prednisolone: a

19.

20.

21.

22.

23. 24.

25.

26.

27.

28.

29.

30.

31.

32.

673

study of the relationships between toxicity, response and survival in metastatic lung cancer. Cancer 1982;50:1051–6. Bush KA, Krukowski K, Eddy JL, Janusek LW, Mathews HL. Glucocorticoid receptor mediated suppression of natural killer cell activity: identification of associated deacetylase and corepressor molecules. Cell Immunol 2012;275:80–9. Li S, Mawal-Dewan M, Cristofalo VJ, Sell C. Enhanced proliferation of human fibroblasts, in the presence of dexamethasone, is accompanied by changes in p21Waf1/Cip1/Sdi1 and the insulin-like growth factor type 1 receptor. J Cell Physiol 1998;177:396–401. Ganguli G, Back J, Sengupta S, Wasylyk B. The p53 tumour suppressor inhibits glucocorticoid-induced proliferation of erythroid progenitors. EMBO Rep 2002;3:569–74. Langeveld CH, van Waas MP, Stoof JC, et al. Implication of glucocorticoid receptors in the stimulation of human glioma cell proliferation by dexamethasone. J Neurosci Res 1992;31:524–31. Freshney RI. Effects of glucocorticoids on glioma cells in culture. Minireview on cancer research. Exp Cell Biol 1984;52:286–92. Guo WX, Antakly T. AIDS-related Kaposi’s sarcoma: evidence for direct stimulatory effect of glucocorticoid on cell proliferation. Am J Pathol 1995;146:727–34. Brady ME, Sartiano GP, Rosenblum SL, Zaglama NE, Bauguess CT. The pharmacokinetics of single high doses of dexamethasone in cancer patients. Eur J Clin Pharmacol 1987;32:593–6. Petersen KB, Jusko WJ, Rasmussen M, Schmiegelow K. Population pharmacokinetics of prednisolone in children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 2003;51:465–73. Charles B, Schild P, Steer P, Cartwright D, Donovan T. Pharmacokinetics of dexamethasone following single-dose intravenous administration to extremely low birth weight infants. Dev Pharmacol Ther 1993;20:205–10. Lai R, Peng Z, Chen D, et al. The effects of anesthetic technique on cancer recurrence in percutaneous radiofrequency ablation of small hepatocellular carcinoma. Anesth Analg 2012;114:290–6. Khan S, Lopez-Dee Z, Kumar R, Ling J. Activation of NFkB is a novel mechanism of pro-survival activity of glucocorticoids in breast cancer cells. Cancer Lett 2013;337:90–5. De Oliveira Jr GS, McCarthy R, Turan A, Schink JC, Fitzgerald PC, Sessler DI. Is dexamethasone associated with recurrence of ovarian Cancer. Anesth Analg 2014;118(6):1213–8. Busch OR, Hop WC, van Papendrecht MAH, Marquet RL, Jeekel J. Blood transfusions and prognosis in colorectal cancer. N Engl J Med 1993;328:1372–6. Hodgson WJ, Lowenfels AB. Blood transfusion and recurrence rates in colonic malignancy. Lancet 1982;2:1047.