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ORIGINAL ARTICLE
Year : 2019  |  Volume : 63  |  Issue : 1  |  Page : 31-35  

Cancer relapse in surgical patients who received perioperative transfusion of blood and blood products: A case-control study


1 Division of Anaesthesiology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
2 Division of Surgical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
3 Division of Cancer Epidemiology and Biostatistics, Regional Cancer Centre, Thiruvananthapuram, Kerala, India

Date of Web Publication10-Jan-2019

Correspondence Address:
Dr. R Subha
Department of Anaesthesiology, Regional Cancer Centre, Medical College P.O, Trivandrum - 695 011, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ija.IJA_409_18

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Background and Aims: Immunomodulatory consequences of allogeneic blood transfusion may outweigh the advantages of improved oxygen delivery and tissue perfusion, especially in patients with cancer. In colorectal cancer, there is evidence of cancer relapse in patients who received transfusion. This retrospective analysis was undertaken to evaluate the relationship between perioperative blood transfusion and cancer recurrence in patients undergoing oncosurgery. Methods: In this case-control study, we retrospectively analysed the case sheets of 194 patients who had perioperative transfusion and underwent cancer surgery from March to December 2013(Study group, Cases). They were compared with controls matched for cancer site and TNM staging who did not receive perioperative transfusions (Control Group, Controls). We intended to find out if the Study group had any increased risk of cancer relapse compared with the controls. Records from the institute cancer registry were analysed in 2018 to give a follow-up period of 5 years. Continuous variables were analysed using Student's T test and Mann Whitney U test for normally distributed and skewed data respectively. For Categorical data Fisher's exact test and Chi square test were applied. The risk for recurrence was estimated using odds ratio. Results: The recurrence rate in cases and controls was 53.09% and 19.59% respectively and the odds ratio, 4.647 (CI: 2.954, 7.309). In Cases, significant relapse was noted for carcinomas of ovary, colorectal, bladder, larynx, head of pancreas and liver. Conclusion: In surgical oncology patients, ABT is associated with greater rate of recurrence.

Keywords: Blood transfusion, immunosuppression, perioperative period, recurrence, retrospective studies


How to cite this article:
Subha R, Cherian K, Nair A, Koshy RC, Krishna J. Cancer relapse in surgical patients who received perioperative transfusion of blood and blood products: A case-control study. Indian J Anaesth 2019;63:31-5

How to cite this URL:
Subha R, Cherian K, Nair A, Koshy RC, Krishna J. Cancer relapse in surgical patients who received perioperative transfusion of blood and blood products: A case-control study. Indian J Anaesth [serial online] 2019 [cited 2019 Jan 21];63:31-5. Available from: http://www.ijaweb.org/text.asp?2019/63/1/31/249778




   Introduction Top


Perioperative allogeneic blood transfusion (ABT) is common in patients with cancer. ABT has an immune modulating effect. Nonspecific immunosuppression induced by transfusion might favour tumour growth.[1] Subsequent evidence suggests an adverse relationship between transfusion and survival after resection of colorectal cancer.[2] According to American Cancer Society, 'If cancer is found after treatment, or found after a period of time when the cancer could not be detected, it's called a cancer recurrence or relapse'. Hence, this study was done to evaluate the relationship between perioperative blood transfusion (PBT) and cancer recurrence in patients undergoing cancer surgeries.


   Methods Top


After institutional review board approval, we retrospectively analysed the case sheets of 194 patients who had PBT and underwent cancer surgery from March to December 2013. PBT was defined as the receipt of any blood or blood product (packed red blood cells, whole blood, fresh frozen plasma or single-donor plasma) within 24h before or 48 h after surgery.[3] The decision to administer blood and blood products was at the discretion of anaesthesiologist intraoperatively and attending surgeon and anaesthesiologist postoperatively with no institutional standardised transfusion threshold. Patients with cancer undergoing primary surgical resection of the tumour were included in the study. Patients were excluded if they underwent prior surgical diagnosis of their current cancer through laparoscopy or laparotomy, were undergoing surgery for recurrent disease or with distant metastases. The retrospective analysis of the case sheets was done in 2018 to determine the disease status after 5 years of follow-up.

Clinicopathological variables recorded included body mass index, age, gender and duration of surgery, receipt of PBT and the number of transfused units, tumour stage and lymph node status. Tumour staging followed the 2009 American Joint Committee on Cancer/Union Internationale contre le cancer 7th edition TNM classification.

A total of 194 patients who had PBT and underwent cancer surgery from March to December 2013 (Study Group, Cases) were retrospectively compared against the same number of patients without any PBTs and who underwent cancer surgery during the same time period (Control Group, Controls), to determine whether the study group had any increased risk of cancer relapse compared with the patients in the control group. The control group included similar patients matched for cancer site and TNM staging (which was obtained from their clinical examination, biopsy results and imaging reports) as that of the study group. Records from the institute cancer registry were analysed in 2018 to determine the cancer relapse rates among the two groups.

For statistical analysis, the continuous variables [age, body mass index (BMI), duration of surgery] were summarised using mean and standard deviation. The categorical variables (relapse, group) were expressed in frequency and percentage. The association between two categorical variables was assessed using Chi-square or Fisher's exact test. The comparison between the cases and control on other continuous variables were tested using Student's t-test for normally distributed data; otherwise Mann–Whitney U-test was used. The odds for recurrence were estimated using odds ratio (OR) with 95% confidence interval (CI). A P value <0.05 was considered as significant, statistically. The site-wise sample size considered for the study was as follows –ovary: 100, colon: 110, liver: 12, lung: 12, larynx: 16, tongue: 16, buccalmucosa: 14, stomach: 20, breast: 10, oesophagus: 20, bladder: 24, kidney: 16 and head of pancreas 18.


   Results Top


The study was done in 194 patients with cancer which included the following types: colorectal, ovarian, urinary bladder, stomach, oesophagus, head of pancreas, kidney, tongue, larynx, buccal mucosa, lung, liver and breast [Figure 1]. The descriptive statistics of the demographics (age, BMI, duration of surgery) for cases and controls are given in [Table 1]. No statistical significant difference between the two groups was observed in the demographic variables [Table 1]. Compared to control group, the relapse rates are higher for cases in all the sites [Table 2]. The recurrence rate for all cancers put together in cases and controls is 53.09% and 19.59% respectively, OR 4.65 (CI: 2.95, 7.31), [P = 0.001]. In our study, significant relapse in terms of P value was noted for carcinomas of ovary (P value: 0.001), colorectal (P value: 0.004), urinary bladder (P value: 0.013), larynx (P value: 0.021), head of pancreas (P value: 0.046) and liver (P value: 0.046) cases and it was not significant for others [Table 2]. The estimated odds ratio was found to be higher for all cancer sites, colon 3.15 (CI: 1.430,6.931), lung 5.0 (CI: 0.34, 72.77), ovary 4.03 (CI: 1.71, 9.49), tongue 7.0 (CI: 0.57, 86.32), buccal mucosa 4.5 (CI: 0.34, 60.15), stomach 6.0 (CI: 0.53,67.65), oesophagus 6.0 (CI: 0.81, 44.35), urinary bladder 10.0 (CI: 1.44, 69.26), kidney 7.0 (CI: 0.57, 86.32), head of pancreas 10.0 (CI: 0.86,117.02). OR was statistically significant only for colon (P = 0.004), ovary (P = 0.001), urinary bladder (P = 0.020), [Table 3].
Figure 1: Study population

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Table 1: Site wise comparison of case and control with respect to Age, BMI & Duration of Surgery

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Table 2: Site wise case-control analysis with respect to relapse

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Table 3: Site wise odds ratio for case compared to control

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   Discussion Top


In the present study, cases and controls has been taken in the ratio 1: 1. High risk for relapse was observed in cases compared to control in all types of cancers. The odds ratio has shown statistical significance for ovary, colorectal, bladder and overall cancers and marginal significance for oesophagus and head of pancreas cancers at 5% level of significance. Even though all other sites are having higher odds ratio, they are not statistically significant (P value >0.05) may be due to the small sample size. Hence, we infer that in surgical oncology patients, ABTs are associated with greater rate of recurrence.

PBT is used to ensure optimal tissue oxygenation in patients undergoing surgery. ABT has an immune modulating effect which enhances cancer metastasis and recurrence.[4],[5] The demonstrated mechanisms in transfusion-related immune modulation are a decrease in interleukin 2 secretion, natural killer cell activity, macrophage function, CD4/CD8 ratios and delayed hypersensitivity responses.[6] Although transfusion aims at increasing the delivery of oxygen to the tissues, the physiological changes during RBC storage could limit this goal.[7]

In colorectal cancer, there is evidence of cancer relapse in patients who received PBT.[8] In other types of cancer, conclusive evidence is not available.[9],[10],[11],[12],[13],[14],[15],[16] The most probable reason for recurrence could be the immunosuppressive effect of surgery and anaesthesia, aggravated by administration of blood products. Tumour manipulation during surgical resection, volatile anaesthetics, opioids, stress response to surgery, inflammatory response to injury, hyperglycaemia and hypothermia cause a significant imbalance in defence responses, which may facilitate distal seeding of circulating cells and the growth of micrometastases into established clinical metastases.[17]

The circumstances under which PBT was given are likely to influence cancer recurrence. Preoperative nutrition, functional status and anaemia, degree of resectability, type and duration of anaesthesia, amount of blood loss, stress response and the presence of postoperative complications are some of these factors. It is difficult to understand the potential impacts of many of these important confounding factors on cancer recurrence from retrospective studies. The decision to transfuse should not be driven only by the haemoglobin concentration, and no single criterion can be used as an indication for transfusion. Clinical status of the patient should be of utmost consideration.

The recurrence or relapse of the cancer involves the surgical factors as well. Standard surgical procedure was done for the preoperatively staged malignancy. We have sub-specialised and the same surgeon operated the same cases. En bloc resection of the tumour including the draining lymph nodes was resected in all cases. The number of lymph nodes sampled was histopathologically assessed and was found to be comparable with American Joint Committee for Cancer standards.

This study has several limitations, the most important of which is it is a retrospective design, which means the results warrant further confirmation in well-defined prospective and randomised clinical trials. The second limitation was that we could not control for the variables of the number of units transfused, type of blood products given, preoperative haemoglobin levels, preoperative albumin value, intraoperative estimated blood loss, patient comorbidity or performance status which can act as confounding variables. Third, PBT was at the discretion of the anaesthesiologist/surgeon and because of the retrospective nature of the study, it is impossible to ascertain the exact reasons and indications for it, which also introduces a major bias to the conclusion. The small sample size for most of the sites resulted in higher odds ratio, also forms another limitation of the study.

Even though it is not clear from the study that a specific threshold can be recommended, it is important to stick to the current blood transfusion studies and avoid any unnecessary transfusions. Leukodepleted red blood cells (RBCs) and fresh blood are preferred if substitutes to ABT are not easily available. Meticulous selection of surgical cases, improving preoperative nutritional status, anaesthetic techniques that prevent tumour progression and surgical techniques that minimise blood loss are to be adopted.

Many substitutes exist for ABT. Autologous transfusion techniques including preoperative autologous donation, acute normovolaemic haemodilution, intraoperative and postoperative cell salvage and reinfusion are life-saving in high blood loss surgeries. The efficacy of these can be augmented by supplemental iron or erythropoietin. Tranexamic acid reduces bleeding and is safe and inexpensive. Further studies are needed to prove the safety and efficacy of artificial blood substitutes. Detailed discussion about these is beyond the scope of this article.

Patient blood management strategies to minimise ABTshould be undertaken, and focus should be more on the substitutes to it, and large prospective studies are required.


   Conclusion Top


In surgical oncology patients, ABTs are associated with greater rate of cancer recurrence.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Gantt CL. Red blood cells for cancer patients. Lancet 1981;2:363.  Back to cited text no. 1
    
2.
Blumberg N, Agarwal MM, Chuang C. Relation between recurrence of cancer of the colon and blood transfusion. Br Med J 1985;290:1037.  Back to cited text no. 2
    
3.
Warner LL, Dowdy SC, Martin JR, Lemens MA, McGree ME, WeaverAL,et al. The impact of perioperative packed red blood cell transfusion on survival in epithelial ovarian cancer. Int J Gynecol Cancer 2013;23:1612-9.  Back to cited text no. 3
    
4.
Shortt J, Polizzotto MN, Waters N, Borosak M, Moran M, Comande M,et al. Assessment of the urgency and deferability of transfusion to inform emergency blood planning and triage: The Bloodhound prospective audit of red blood cell use. Transfusion 2009;49:2296-303.  Back to cited text no. 4
    
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Watkins T, Surowiecka MK, McCullough J. Transfusion indications for patients with cancer. Cancer Control 2015;22:38-46.  Back to cited text no. 5
    
6.
Vamvakas EC, Bordin JO, Blajchman MA. Immunomodulatory and proinflammatory effects of allogenic blood transfusion. In: Simon TL, McCullough J, Snyder EL, Solheim BG, Strauss RG, editors. Rossi's Principles of Transfusion Medicine. 5th ed. United Kingdom: John Wiley and Sons Ltd; 2016. p. 695-710.  Back to cited text no. 6
    
7.
Lelubre C, Piagnerelli M, Vincent JL. Association between duration of storage of transfused red blood cells and morbidity and mortality in adult patients: Myth or reality? Transfusion 2009;49:1384-94.  Back to cited text no. 7
    
8.
Acheson AG, Brookes MJ, Spahn DR. Effects of allogeneic red blood cell transfusions on clinical outcomes in patients undergoing colorectal cancer surgery. A systematic review and meta-analysis. Ann Surgery 2012;256:235-44.  Back to cited text no. 8
    
9.
De Oliveira GS Jr, Schink JC, Buoy C, Ahmad S, Fitzgerald PC, McCarthy RJ. The association between allogeneic perioperative blood transfusion on tumour recurrence and survival in patients with advanced ovarian cancer. Transfus Med 2012;22:97-103.  Back to cited text no. 9
    
10.
Hanazaki K, Kajikawa S, Shimozawa N, Matsushita A, Machida T, Shimada K,et al. Perioperative blood transfusion and survival following curative hepatic resection for hepatocellular carcinoma. Hepatogastroenterology 2005;52:524-29.  Back to cited text no. 10
    
11.
Swisher SG, Holmes EC, Hunt KK, Gornbein JA, Zinner MJ, McFadden DW. Perioperative blood transfusions and decreased long-term survival in esophageal cancer. J Thorac Cardiovasc Surg 1996;112:341-8.  Back to cited text no. 11
    
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Linder BJ, Frank I, Cheville JC, Tollefson MK, Thompson RH, Tarrell RF, et al. The impact of perioperative blood transfusion on cancer recurrence and survival following radical cystectomy. Eur Urol 2013;63:839-45.  Back to cited text no. 12
    
13.
van de Watering LM, Brand A, Houbiers JG, Klein Kranenbarg WM, Hermans J, van de Velde C, et al. Perioperative blood transfusions, with or without allogeneic leukocytes, relate to survival, not to cancer recurrence. Br J Surg 2001;88:267-72.  Back to cited text no. 13
    
14.
Moores DW, Piantadosi S, McKneally MF. Effect of perioperative blood transfusion on outcome in patients with surgically resected lung cancer. Ann Thorac Surg 1989;47:346-51.  Back to cited text no. 14
    
15.
Edna TH, Vada K, Hesselberg F, Mjolnerod OK. Blood transfusion and survival following surgery for renal carcinoma. Br J Urol 1992;70:135-8.  Back to cited text no. 15
    
16.
Heiss MM, Allgayer H, Gruetzner KU, Tarabichi A, Babic R, Mempel W, et al. Prognostic influence of blood transfusion on minimal residual disease in resected gastric cancer patients. Anticancer Res 1997;17:2657-61.  Back to cited text no. 16
    
17.
Cata JP, Wang H, Gottumukkala V, Reuben J, Sessler DI. Inflammatory response, immunosuppresion, and cancer recurrence after perioperative blood transfusions. Br J Anaesth. 2013;110:690-701.  Back to cited text no. 17
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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