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Antonia M.D. Churchhouse, Timothy J. Mathews, Olivia M.B. McBride, Joel Dunning, Does blood transfusion increase the chance of recurrence in patients undergoing surgery for lung cancer?, Interactive CardioVascular and Thoracic Surgery, Volume 14, Issue 1, January 2012, Pages 85–90, https://doi.org/10.1093/icvts/ivr025
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Abstract
A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether blood transfusion increases the chance of recurrence in patients undergoing surgery for lung cancer. Altogether 468 papers were found using the reported search, of which 21 represented the best evidence to answer the clinical question. The authors, journal date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. Nineteen cohort studies (two of which examined the same or similar data sets as two other studies already included), one comment article and one meta-analysis were identified. In total, the outcomes of 5378 patients undergoing surgical resection for lung cancer were analysed. The transfusion rate varied between 15 and 67%. The primary endpoints in all 21 papers were recurrence, survival or disease-free survival. We conclude that the research undertaken to examine the relationship between blood transfusion and lung cancer recurrence, survival and disease-free survival comes to no definite conclusion. Half of the papers relating to recurrence state that there is no significantly increased risk of recurrence with transfusion, whereas the other half state that there is. However, four of the five papers examining disease-free survival demonstrate a significant adverse relationship between this primary outcome and blood transfusion. With regard to survival, five of the papers reviewed showed no effect of blood transfusion, whereas five showed some form of adverse effect. Although there is no overwhelming agreement among the presented evidence, there is a slightly larger body of evidence supporting the theory that blood transfusions are associated with poorer outcomes in patients undergoing resection for lung cancer. However, whether this is a direct effect, or a surrogate marker for other factors such as anaemia, is unclear.
INTRODUCTION
A best evidence topic was constructed according to a structured protocol. This is fully described in Interactive CardioVascular and Thoracic Surgery [1].
THREE-PART QUESTION
In [patients undergoing surgery for lung cancer] does [blood transfusion] increase the chance of [recurrence].
CLINICAL SCENARIO
On your morning ward round, your House Officer points out to you that the haemoglobin of your 74-year old patient who underwent a left pneumonectomy for squamous cell carcinoma yesterday has dropped to 7.6 g/dl. His preoperative haemoglobin was 10.8 g/dl and blood loss in theatre was 250 ml. He is haemodynamically stable and his coagulation screen is normal but he looks pale and tired. In view of this, you wonder whether a transfusion of 2 units of red cell concentrate would be appropriate. However, you recall that a trusted colleague once told you to avoid perioperative transfusions in patients undergoing surgery for lung cancer as they lead to an increased risk of cancer recurrence. You wonder why this might be and you resolve to check the literature yourself.
SEARCH STRATEGY
Medline 1948 to June 2011 using OVID interface (transfusion.mp. or exp Blood Transfusion/ or exp Erythrocyte Transfusion/ or exp Blood Component Transfusion/) AND (exp Carcinoma, Non-Small-Cell Lung/ or exp Lung Neoplasms/ or exp Thoracic Neoplasms/ or thoracic malignancy.mp. or thoracic malignancies.mp.)
SEARCH OUTCOME
Four hundred and sixty-eight papers were found using the reported search. From these, 21 papers were identified that provided the best evidence to answer the question. Twenty of these papers were either cohort studies or meta-analyses; these are presented in Table 1.
Author, date, country, study type (level of evidence) . | Patient group . | Outcomes . | Key results . | Comments . |
---|---|---|---|---|
Keller et al., 1988, USA [2] Retrospective cohort study (level 2b) |
|
Recurrence (event-free survival) |
|
This retrospective audit showed that blood transfusion was not associated with an increased risk of recurrence, when patients with stage I and II NSCLC were followed up for a minimum of 36 months. |
Moores et al., 1989, USA [3] Cohort study (level 2b) |
|
Recurrence |
|
Significant adverse relationship between perioperative blood transfusion and recurrence and long-term survival in lung cancer patients (even after adjustment for extent of disease). |
Piantadosi et al., 1994, USA [4] Data reanalysed | Recurrence |
|
Similar to previously reported results. | |
Pena et al., 1992, USA [5] Retrospective cohort study (level 2b) |
|
Disease-free survival (table on recurrence) |
|
No significant correlation between perioperative blood transfusions and an increased risk of recurrence. |
Vamvakas, 1995, USA [7] Meta-analysis of cohort studies (level 2a) | Meta-analysis of observational studies in many types of cancer. | Recurrence |
|
RR 1.3 |
Pastorino et al., 1986, Italy [8] Retrospective cohort study (level 2b) |
|
Disease-free survival, Survival |
|
No effect of blood transfusion on survival or disease-free survival. |
Tartter et al., 1984, USA [9] Retrospective cohort study (level 2b) |
|
Disease-free survival |
|
Blood transfusion was a significant prognostic factor adversely affecting disease-free survival. |
Wu, 1989, USA [10] Cohort study (level 2b) |
|
Disease-free Survival | Disease-free survival: 43% transfused vs 78% non-transfused. |
|
Little et al., 1990, USA [11] Retrospective cohort study (level 2b) |
|
Disease-free survival |
|
Perioperative transfusion worsens a patient's prognosis. |
Nosotti et al., 2003, Italy [12] Prospective cohort study (level 2b) |
|
Disease-free survival |
|
Significant correlation between blood transfusion and both cancer recurrence and poor survival. |
Novak et al., 1994, Czech Republic [13] Cohort study (level 2b) |
|
Survival | Not able to prove the statistical difference between patients undergoing surgery with and without blood transfusions. |
|
Rzyman et al., 2003, Poland [14] Retrospective cohort study (level 2b) |
|
Survival |
|
No significant effect of blood transfusion and survival. |
Ghosh et al., 2004, UK [15] Retrospective cohort study (level 2b) |
|
Survival |
|
Long-term survival is independent of perioperative blood transfusion. |
Penalver et al., 2005, Spain [16] Retrospective cohort study (level 2b) |
|
Survival |
|
No difference in survival in patients requiring perioperative blood transfusion. |
Hyman et al., 1985, USA [17] Retrospective cohort study (level 2b) |
|
Survival |
|
Significantly poorer prognosis in patients receiving transfusion. |
Rainio et al., 1995, Finland [18] Retrospective cohort study (level 2b) |
|
Survival |
|
Only slight (but not a significant survival advantage on non-transfused patients. |
Panagopoulos et al., 2008, Greece [19] Prospective cohort study (level 2b) |
|
Survival |
|
Transfusion significantly associated with decreased survival, but only in patients with stage I disease. |
Zimmermann et al., 1993, Germany [20] Cohort study (level 2b) |
|
Survival |
|
|
Thomas et al., 2007, France [21] Retrospective cohort study (level 2b) |
|
Survival |
|
Blood transfusion confers poor prognosis in the immediate post-operative period, but not long-term survival. |
Berardi et al., 2005, Italy [22] Retrospective cohort study (level 2b) |
|
Survival |
|
Significant correlation between anaemia, but not blood transfusion, and poorer survival. |
Author, date, country, study type (level of evidence) . | Patient group . | Outcomes . | Key results . | Comments . |
---|---|---|---|---|
Keller et al., 1988, USA [2] Retrospective cohort study (level 2b) |
|
Recurrence (event-free survival) |
|
This retrospective audit showed that blood transfusion was not associated with an increased risk of recurrence, when patients with stage I and II NSCLC were followed up for a minimum of 36 months. |
Moores et al., 1989, USA [3] Cohort study (level 2b) |
|
Recurrence |
|
Significant adverse relationship between perioperative blood transfusion and recurrence and long-term survival in lung cancer patients (even after adjustment for extent of disease). |
Piantadosi et al., 1994, USA [4] Data reanalysed | Recurrence |
|
Similar to previously reported results. | |
Pena et al., 1992, USA [5] Retrospective cohort study (level 2b) |
|
Disease-free survival (table on recurrence) |
|
No significant correlation between perioperative blood transfusions and an increased risk of recurrence. |
Vamvakas, 1995, USA [7] Meta-analysis of cohort studies (level 2a) | Meta-analysis of observational studies in many types of cancer. | Recurrence |
|
RR 1.3 |
Pastorino et al., 1986, Italy [8] Retrospective cohort study (level 2b) |
|
Disease-free survival, Survival |
|
No effect of blood transfusion on survival or disease-free survival. |
Tartter et al., 1984, USA [9] Retrospective cohort study (level 2b) |
|
Disease-free survival |
|
Blood transfusion was a significant prognostic factor adversely affecting disease-free survival. |
Wu, 1989, USA [10] Cohort study (level 2b) |
|
Disease-free Survival | Disease-free survival: 43% transfused vs 78% non-transfused. |
|
Little et al., 1990, USA [11] Retrospective cohort study (level 2b) |
|
Disease-free survival |
|
Perioperative transfusion worsens a patient's prognosis. |
Nosotti et al., 2003, Italy [12] Prospective cohort study (level 2b) |
|
Disease-free survival |
|
Significant correlation between blood transfusion and both cancer recurrence and poor survival. |
Novak et al., 1994, Czech Republic [13] Cohort study (level 2b) |
|
Survival | Not able to prove the statistical difference between patients undergoing surgery with and without blood transfusions. |
|
Rzyman et al., 2003, Poland [14] Retrospective cohort study (level 2b) |
|
Survival |
|
No significant effect of blood transfusion and survival. |
Ghosh et al., 2004, UK [15] Retrospective cohort study (level 2b) |
|
Survival |
|
Long-term survival is independent of perioperative blood transfusion. |
Penalver et al., 2005, Spain [16] Retrospective cohort study (level 2b) |
|
Survival |
|
No difference in survival in patients requiring perioperative blood transfusion. |
Hyman et al., 1985, USA [17] Retrospective cohort study (level 2b) |
|
Survival |
|
Significantly poorer prognosis in patients receiving transfusion. |
Rainio et al., 1995, Finland [18] Retrospective cohort study (level 2b) |
|
Survival |
|
Only slight (but not a significant survival advantage on non-transfused patients. |
Panagopoulos et al., 2008, Greece [19] Prospective cohort study (level 2b) |
|
Survival |
|
Transfusion significantly associated with decreased survival, but only in patients with stage I disease. |
Zimmermann et al., 1993, Germany [20] Cohort study (level 2b) |
|
Survival |
|
|
Thomas et al., 2007, France [21] Retrospective cohort study (level 2b) |
|
Survival |
|
Blood transfusion confers poor prognosis in the immediate post-operative period, but not long-term survival. |
Berardi et al., 2005, Italy [22] Retrospective cohort study (level 2b) |
|
Survival |
|
Significant correlation between anaemia, but not blood transfusion, and poorer survival. |
BET, best evidence topic; FFP, fresh frozen plasma; RBC, red blood cells; and SCC, squamous cell carcinoma.
Author, date, country, study type (level of evidence) . | Patient group . | Outcomes . | Key results . | Comments . |
---|---|---|---|---|
Keller et al., 1988, USA [2] Retrospective cohort study (level 2b) |
|
Recurrence (event-free survival) |
|
This retrospective audit showed that blood transfusion was not associated with an increased risk of recurrence, when patients with stage I and II NSCLC were followed up for a minimum of 36 months. |
Moores et al., 1989, USA [3] Cohort study (level 2b) |
|
Recurrence |
|
Significant adverse relationship between perioperative blood transfusion and recurrence and long-term survival in lung cancer patients (even after adjustment for extent of disease). |
Piantadosi et al., 1994, USA [4] Data reanalysed | Recurrence |
|
Similar to previously reported results. | |
Pena et al., 1992, USA [5] Retrospective cohort study (level 2b) |
|
Disease-free survival (table on recurrence) |
|
No significant correlation between perioperative blood transfusions and an increased risk of recurrence. |
Vamvakas, 1995, USA [7] Meta-analysis of cohort studies (level 2a) | Meta-analysis of observational studies in many types of cancer. | Recurrence |
|
RR 1.3 |
Pastorino et al., 1986, Italy [8] Retrospective cohort study (level 2b) |
|
Disease-free survival, Survival |
|
No effect of blood transfusion on survival or disease-free survival. |
Tartter et al., 1984, USA [9] Retrospective cohort study (level 2b) |
|
Disease-free survival |
|
Blood transfusion was a significant prognostic factor adversely affecting disease-free survival. |
Wu, 1989, USA [10] Cohort study (level 2b) |
|
Disease-free Survival | Disease-free survival: 43% transfused vs 78% non-transfused. |
|
Little et al., 1990, USA [11] Retrospective cohort study (level 2b) |
|
Disease-free survival |
|
Perioperative transfusion worsens a patient's prognosis. |
Nosotti et al., 2003, Italy [12] Prospective cohort study (level 2b) |
|
Disease-free survival |
|
Significant correlation between blood transfusion and both cancer recurrence and poor survival. |
Novak et al., 1994, Czech Republic [13] Cohort study (level 2b) |
|
Survival | Not able to prove the statistical difference between patients undergoing surgery with and without blood transfusions. |
|
Rzyman et al., 2003, Poland [14] Retrospective cohort study (level 2b) |
|
Survival |
|
No significant effect of blood transfusion and survival. |
Ghosh et al., 2004, UK [15] Retrospective cohort study (level 2b) |
|
Survival |
|
Long-term survival is independent of perioperative blood transfusion. |
Penalver et al., 2005, Spain [16] Retrospective cohort study (level 2b) |
|
Survival |
|
No difference in survival in patients requiring perioperative blood transfusion. |
Hyman et al., 1985, USA [17] Retrospective cohort study (level 2b) |
|
Survival |
|
Significantly poorer prognosis in patients receiving transfusion. |
Rainio et al., 1995, Finland [18] Retrospective cohort study (level 2b) |
|
Survival |
|
Only slight (but not a significant survival advantage on non-transfused patients. |
Panagopoulos et al., 2008, Greece [19] Prospective cohort study (level 2b) |
|
Survival |
|
Transfusion significantly associated with decreased survival, but only in patients with stage I disease. |
Zimmermann et al., 1993, Germany [20] Cohort study (level 2b) |
|
Survival |
|
|
Thomas et al., 2007, France [21] Retrospective cohort study (level 2b) |
|
Survival |
|
Blood transfusion confers poor prognosis in the immediate post-operative period, but not long-term survival. |
Berardi et al., 2005, Italy [22] Retrospective cohort study (level 2b) |
|
Survival |
|
Significant correlation between anaemia, but not blood transfusion, and poorer survival. |
Author, date, country, study type (level of evidence) . | Patient group . | Outcomes . | Key results . | Comments . |
---|---|---|---|---|
Keller et al., 1988, USA [2] Retrospective cohort study (level 2b) |
|
Recurrence (event-free survival) |
|
This retrospective audit showed that blood transfusion was not associated with an increased risk of recurrence, when patients with stage I and II NSCLC were followed up for a minimum of 36 months. |
Moores et al., 1989, USA [3] Cohort study (level 2b) |
|
Recurrence |
|
Significant adverse relationship between perioperative blood transfusion and recurrence and long-term survival in lung cancer patients (even after adjustment for extent of disease). |
Piantadosi et al., 1994, USA [4] Data reanalysed | Recurrence |
|
Similar to previously reported results. | |
Pena et al., 1992, USA [5] Retrospective cohort study (level 2b) |
|
Disease-free survival (table on recurrence) |
|
No significant correlation between perioperative blood transfusions and an increased risk of recurrence. |
Vamvakas, 1995, USA [7] Meta-analysis of cohort studies (level 2a) | Meta-analysis of observational studies in many types of cancer. | Recurrence |
|
RR 1.3 |
Pastorino et al., 1986, Italy [8] Retrospective cohort study (level 2b) |
|
Disease-free survival, Survival |
|
No effect of blood transfusion on survival or disease-free survival. |
Tartter et al., 1984, USA [9] Retrospective cohort study (level 2b) |
|
Disease-free survival |
|
Blood transfusion was a significant prognostic factor adversely affecting disease-free survival. |
Wu, 1989, USA [10] Cohort study (level 2b) |
|
Disease-free Survival | Disease-free survival: 43% transfused vs 78% non-transfused. |
|
Little et al., 1990, USA [11] Retrospective cohort study (level 2b) |
|
Disease-free survival |
|
Perioperative transfusion worsens a patient's prognosis. |
Nosotti et al., 2003, Italy [12] Prospective cohort study (level 2b) |
|
Disease-free survival |
|
Significant correlation between blood transfusion and both cancer recurrence and poor survival. |
Novak et al., 1994, Czech Republic [13] Cohort study (level 2b) |
|
Survival | Not able to prove the statistical difference between patients undergoing surgery with and without blood transfusions. |
|
Rzyman et al., 2003, Poland [14] Retrospective cohort study (level 2b) |
|
Survival |
|
No significant effect of blood transfusion and survival. |
Ghosh et al., 2004, UK [15] Retrospective cohort study (level 2b) |
|
Survival |
|
Long-term survival is independent of perioperative blood transfusion. |
Penalver et al., 2005, Spain [16] Retrospective cohort study (level 2b) |
|
Survival |
|
No difference in survival in patients requiring perioperative blood transfusion. |
Hyman et al., 1985, USA [17] Retrospective cohort study (level 2b) |
|
Survival |
|
Significantly poorer prognosis in patients receiving transfusion. |
Rainio et al., 1995, Finland [18] Retrospective cohort study (level 2b) |
|
Survival |
|
Only slight (but not a significant survival advantage on non-transfused patients. |
Panagopoulos et al., 2008, Greece [19] Prospective cohort study (level 2b) |
|
Survival |
|
Transfusion significantly associated with decreased survival, but only in patients with stage I disease. |
Zimmermann et al., 1993, Germany [20] Cohort study (level 2b) |
|
Survival |
|
|
Thomas et al., 2007, France [21] Retrospective cohort study (level 2b) |
|
Survival |
|
Blood transfusion confers poor prognosis in the immediate post-operative period, but not long-term survival. |
Berardi et al., 2005, Italy [22] Retrospective cohort study (level 2b) |
|
Survival |
|
Significant correlation between anaemia, but not blood transfusion, and poorer survival. |
BET, best evidence topic; FFP, fresh frozen plasma; RBC, red blood cells; and SCC, squamous cell carcinoma.
RESULTS
Nineteen cohort studies (two of which examined the same or similar data sets as two other studies already included), one comment article and one meta-analysis were identified. In total, the outcomes of 5378 patients undergoing surgical resection for lung cancer were analysed. The transfusion rate varied between 15 and 67%. The primary endpoints in all 21 papers were recurrence, survival or disease-free survival.
Five papers looked at recurrence. In 1988, Keller et al. [2] conducted a retrospective clinical audit of 352 patients undergoing resection for stage I and II non-small cell lung cancer (NSCLC). They documented a 27% recurrence rate in stage I transfused patients and a 25% recurrence rate in stage I non-transfused patients (P = 0.58). To avoid the bias linked to the type of resection, Keller et al. also looked at a subgroup of patients only undergoing lobectomy (229 in total). There was no difference between transfused and non-transfused groups (P = 0.74).
Moores et al. [3] examined the outcomes of 330 NSCLC patients in 1989. They documented a 53% recurrence rate in their transfused group and a 46% recurrence rate in their non-transfused group (P = 0.04). However, this risk of recurrence did not achieve significance when adjusted for the tumour node (TN) stage and histology (log rank). The authors were, however, able to demonstrate a significant transfusion hazard ratio of 1.44 (P = 0.11) using the Cox proportional hazards regression model. In 1994, the Moores group (as Piantadosi et al. [4]) re-examined their data and confounding factors. Using the same data set, they used a multiple regression analysis to recalculate a hazard ratio of 1.62 (P = 0.01).
Pena et al. [5] briefly looked at cancer recurrence in their 1992 paper on disease-free survival in patients undergoing surgical resection. In total, they looked at the outcomes of 127 patients with stage I and II NSCLC. They state that the rate of recurrence in patients who received transfusion was 23%, yet in non-transfused patients, this was 34%, but no statistical analysis was performed. In a review of these data, however, Piantadosi [6] states that the sample size and the event rate are too small to detect any statistical significance.
In 1995, Vamvakas [7] conducted a meta-analysis to examine the relationship between perioperative blood transfusion and lung cancer recurrence. He included six separate papers in his analysis of the relationship between transfusion and lung cancer. The author calculates a relative risk for recurrence associated with transfusion as 1.3. However, this does not account for confounding variables and no statistical analysis is performed.
A further five papers examined the effect of transfusion on disease-free survival. One of these papers [8] reported no adverse effect of transfusion. However, the other four [9–12] reported a significantly poorer disease-free survival period for patients receiving perioperative blood transfusions.
Ten papers looked at the association of blood transfusion and survival. Four of these papers [13–16] found no evidence that blood transfusion is associated with decreased survival, whereas one [17] demonstrated a much poorer prognosis in patients receiving perioperative blood. The five remaining papers make conclusions somewhere along the spectrum of opinion; Rainio et al. [18] demonstrate only a slight (but not significant) survival advantage in non-transfused patients. Panagopoulos et al. [19] observed a poorer survival, but only in transfused patients with stage I disease. Two papers [20, 21] concluded that short-term, but not long-term, survival was affected by perioperative blood transfusion. Finally, one paper by Berardi et al. [22] concludes that in fact anaemia, rather than blood transfusion itself, is related to poorer survival.
CLINICAL BOTTOM LINE
The research undertaken to examine the relationship between blood transfusion and lung cancer recurrence, survival and disease-free survival comes to no definite conclusion. Half of the papers relating to recurrence state that there is no significantly increased risk of recurrence with transfusion, whereas the other half state that there is. However, four of the five papers examining disease-free survival demonstrate a significant adverse relationship between this primary outcome and blood transfusion. With regard to survival, five of the papers reviewed showed no effect of blood transfusion, whereas five showed some form of adverse effect.
Although there is no overwhelming agreement among the presented evidence, there is a slightly larger body of evidence supporting the theory that blood transfusions are associated with poorer outcomes in patients undergoing resection for lung cancer. However, whether this is a direct effect, or a surrogate marker for other factors such as anaemia, is unclear.
Conflict of interest: none declared.