Does blood transfusion increase the chance of recurrence ... - CiteSeerX

BEST EVIDENCE TOPIC

Interactive CardioVascular and Thoracic Surgery 14 (2012) 85–90 doi:10.1093/icvts/ivr025 Advance Access publication 15 November 2011

Does blood transfusion increase the chance of recurrence in patients undergoing surgery for lung cancer? Antonia M.D. Churchhousea,*, Timothy J. Mathewsa, Olivia M.B. McBridea and Joel Dunningb a b

Department of Cardiothoracic Surgery, Royal Infirmary of Edinburgh, Edinburgh, UK Department of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough, UK

* Correspondence author. Tel: +44-7962-152150; e-mail: [email protected] Received 3 August 2011; received in revised form 9 September 2011; accepted 16 September 2011

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.

A best evidence topic was constructed according to a structured protocol. This is fully described in Interactive CardioVascular and Thoracic Surgery [1].

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.

THREE-PART QUESTION

SEARCH STRATEGY

In [ patients undergoing surgery for lung cancer] does [blood transfusion] increase the chance of [recurrence].

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-SmallCell Lung/ or exp Lung Neoplasms/ or exp Thoracic Neoplasms/ or thoracic malignancy.mp. or thoracic malignancies.mp.)

INTRODUCTION

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

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.

© The Author 2011. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

THORACIC ONCOLOGIC

Keywords: Review • Blood transfusion • Lung neoplasms • Recurrence

A.M.D. Churchhouse et al. / Interactive CardioVascular and Thoracic Surgery

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Table 1: Best evidence papers Author, date, country, study type (level of evidence)

Patient group

Outcomes

Key results

Comments

Keller et al., 1988, USA [2]

Looked at 352 stage I and II nonsmall cell lung cancer (NSCLC) resections at one centre 1974– 1981. Transfusion was defined as whole blood or packed cells. Plasma expanders, fresh frozen plasma (FFP) and platelets were not included. There is no mention of time-frame of transfusion. Patients were excluded if they had incomplete resection or underwent chemotherapy or radiotherapy. Minimum of 36-month follow-up. Pneumonectomy, bilobectomy, lobectomy and wedge resections included. 39% transfused.

Recurrence (event-free survival)

32 recurrences in 119 transfused stage I patients; 47 recurrences in 186 non-transfused stage I patients (P = 0.58). No values given for the number of recurrences in transfused and non-transfused stage II resections. However, 24 recurrences in total/47 resections and any difference between the two groups was not significant (P = 0.14). Transfusion was not associated with recurrence, based on log-rank test adjusting for stage (P = 0.48) or the likelihood ratio test adjusting for the selected subset of prognostic variables (stage, year, procedure) without the interaction term (P = 0.13) and with the interaction term (stage; P = 0.21). Also looked at the lobectomy subgroup—229 patients (to compare with a recent study)— no difference in recurrence (P = 0.74). RR stage I: 1.24 (NS) and RR stage II: 1.92 (NS). No difference in event-free survival as a whole or when the lobectomy subgroup analysed.

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.

330 NSCLC patients (433 but data not available for 103) taken from control arms of three separate studies carried out by the North American Lung Cancer Study Group. Transfusion was defined as red blood cells (RBC), whole blood or FFP 24 h before or 48 h after operation. Patients were included if they had complete resection and no adjuvant therapy. Mean follow-up 3.6 years. Prospective follow-up for recurrence. Retrospective transfusion history. Time to cancer recurrence included second primaries. All stages considered. 51% transfused.

Recurrence

90 recurrences in the transfused group (169 patients-53%) and 74 recurrences in the non-transfused group (161 patients-46%) (without adjusting for confounding variables, P = 0.04). When adjusted for tumour node (TN) status and histology, risk of recurrence did not achieve significance (log rank). Time to recurrence was shorter for patients receiving transfusion (P = 0.035) but became less significant when adjusted for both cell type and stage. Cox model: a significant predictor of recurrence (hazard ratio = 1.44, P = 0.11). Acknowledges may be surrogates for more extensive disease/ differences due to unknown or incompletely controlled prognostic factors.

Significant adverse relationship between perioperative blood transfusion and recurrence and long-term survival in lung cancer patients (even after adjustment for extent of disease).

Recurrence

Multiple regression analysis employed. The hazard ratio of 1.62 (P = 0.01).

Similar to previously reported results.

Retrospective cohort study (level 2b)

Moores et al., 1989, USA [3] Cohort study (level 2b)

Piantadosi et al., 1994, USA [4] Data reanalysed

Continued


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Author, date, country, study type (level of evidence)

Patient group

Outcomes

Key results

Comments

Pena et al., 1992, USA [5]

127 patients undergoing surgery for stage I and II NSCLC. Transfusion defined as up to 24 h prior to or 48 h after surgery. If transfusion occurred outside of this time period, patients were excluded. Follow-up period for recurrence data not stated. 24% transfused.

Disease-free survival (table on recurrence)

Recurrence in transfused patients (7 of 28; 23.3%) and recurrence in non-transfused patients (33 of 97; 34%). No statistical analysis of recurrence data.

No significant correlation between perioperative blood transfusions and an increased risk of recurrence.

Meta-analysis of observational studies in many types of cancer.

Recurrence

RR 1.3 for lung cancer (raw RR not accounting for confounding variables). Also includes data form papers excluded from best evidence topic BET assessment. No statistical analysis carried out. Emphasis on colorectal cancer.

RR 1.3

283 patients undergoing surgery for stage Ia NSCLC at one centre 1974–1979. Transfusion defined as whole blood or packed red cells pre-, intraand post-operatively up to 8 days from operation. 55% transfused.

Disease-free survival, Survival

No effect of blood transfusion on Survival at 8 years: 40% transfused survival or disease-free survival. vs 41% non-transfused. Relapse-free survival: 36% transfused vs 34% non-transfused. Lobectomy subgroup survival: 41% for both transfused and non-transfused patients.

165 consecutive patients with resections for stage I (N0) lung cancer under one operator 1966– 1980. Minimum follow-up 24 months. 56% transfused.

Disease-free survival

Transfused patients had a 62% 5-year survival vs 76% non-transfused patients (P = 0.01). Analysed patients undergoing lobectomy as a separate group: survival 68 vs 77% (P = 0.08).

Blood transfusion was a significant prognostic factor adversely affecting disease-free survival.

53 patients with stage 1 (N0) lung cancer 1970–1986. 57% transfused.

Disease-free Survival

Disease-free survival: 43% transfused vs 78% non-transfused.

Perioperative blood transfusions adversely affect the survival of stage I (N0) lung cancer patients. Read as abstract only

117 patients at two centres with stage I NSCLC between 1977 and 1986. Transfusion defined as whole blood or packed cells within 30 days of operation. Mean follow-up 50 months. 50% transfused.


Perioperative transfusion worsens 5-year disease-free survival 53% in a patient’s prognosis. transfused patients vs 81% in non-transfused patients (P = 0.006). Significant correlation in multivariate analysis (P = 0.03), but does not include the stage as a confounding variable.

281 patients undergoing lobectomy for stage I NSCLC at one centre between 1995 and 2000. Transfusion defined as any type of blood product given during operation and up to 7 days after surgery. Patients definitely needing perioperative blood (low haemoglobin or platelets) excluded. Only stage I, treated by lobectomy via thoracotomy considered. Median follow-up 34 months. 25% transfused.


Transfused patients had a significantly lower disease-free interval (P < 0.005) and survival (P < 0.2) rate compared with non-transfused patients. Cox modelling showed transfusion to be a significant predictor of tumour relapse (P = 0.017) and mortality (P = 0.045).


Vamvakas, 1995, USA [7] Meta-analysis of cohort studies (level 2a)

Pastorino et al., 1986, Italy [8] Retrospective cohort study (level 2b)

Tartter et al., 1984, USA [9] Retrospective cohort study (level 2b) Wu, 1989, USA [10] Cohort study (level 2b) Little et al., 1990, USA [11] Retrospective cohort study (level 2b)

Nosotti et al., 2003, Italy [12] Prospective cohort study (level 2b)

Significant correlation between blood transfusion and both cancer recurrence and poor survival.

Continued

THORACIC ONCOLOGIC

Table 1: Continued


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Table 1: Continued Author, date, country, study type (level of evidence)

Outcomes

Key results

Comments

Novak et al., 1994, 143 patients undergoing resection over a 5-year period. Czech Republic [13] 59% transfused. Cohort study (level 2b)

Survival

Not able to prove the statistical difference between patients undergoing surgery with and without blood transfusions.

No difference in survival due to perioperative blood transfusion. Read as abstract only.

Rzyman et al., 2003, Poland [14]

493 patients undergoing thoracotomy for NSCLC at one centre from December 1993 to February 1997. Three cohorts: no transfusion, allogenic transfusion, autologous transfusion. Transfusion: whole blood or packed red cells. Median follow-up 46 months. 67% transfused.

Survival

Univariate analysis: poorer survival in transfused vs non-transfused group (P = 0.017). Cox model: no significant survival difference in transfused vs non-transfused patients. When only stages I and II analysed, no survival difference found on univariate analysis. When only lobectomy or sublobar resection analysed, no survival difference found on multivariate analysis.

No significant effect of blood transfusion and survival.

329 patients undergoing resection for squamous cell carcinoma (SCC) or adenocarcinoma 1996– 2003 at one centre. Wedge resections excluded. Mean follow-up 23 months. 36% transfused.

Survival

1-, 3- and 5-year survival adenocarcinoma transfused: 81, 46 and 35%. 1-, 3- and 5-year survival adenocarcinoma untransfused: 79, 31 and 19% (P = 0.08). 1-, 3- and 5-year survival SCC transfused: 85, 57 and 36%. 1-, 3- and 5-year survival SCC untransfused: 81, 52 and 34% (P = 0.16). Blood transfusion not a significant factor in multivariate analysis.

Long-term survival is independent of perioperative blood transfusion.

856 patients undergoing resection for stage I NSCLC 1969–2000. Transfusion: whole blood or packed red cells. Mean follow-up 17 years. 15% transfused.

Survival

2-, 5- and 10-year survival transfused: 78, 63 and 54%. 2-, 5- and 10-year survival non-transfused: 73, 59 and 46%. No relationship between transfusion and survival on multivariate regression analysis.

No difference in survival in patients requiring perioperative blood transfusion.

155 patients resected for carcinoma of lung between 1971 and 1979 at one centre. Transfusion: whole blood or packed red cells. Stage I, II and III patients. 47% transfused.

Survival

In resection for cure patients (stages Significantly poorer prognosis in patients receiving transfusion. I and II), 5-year survival 44% in non-transfused vs 37% transfused patients, even when adjusted for confounding variables. Relative risk of transfusion (the Cox model) 1.2 (P = 0.02).

208 patients with resection for lung cancer from 1978 to 1980. Transfusion: whole blood or packed cells. Follow-up: up to 15 years. 46% transfused.

Survival

Transfused patients had poorer 10-year survival (Kaplan–Meier), but this lost significance in multivariate (Cox) analysis. Relative risk of blood transfusion 1.1 (P = 0.074).

Only slight (but not a significant survival advantage on non-transfused patients.

331 consecutive NSCLC patients undergoing surgery at one centre 1995–2003. Mean follow-up 27 months. 26% transfused.

Survival

5-year survival 25% in transfused patients and 37% in non-transfused patients (P = 0.001). Transfusion not an independent predictor of survival in multivariate analysis overall. Transfusion was an independent predictor of survival in multivariate analysis of the selected group of patients (stage I NSCLC)

Transfusion significantly associated with decreased survival, but only in patients with stage I disease.


Ghosh et al., 2004, UK [15] Retrospective cohort study (level 2b)

Penalver et al., 2005, Spain [16] Retrospective cohort study (level 2b) Hyman et al., 1985, USA [17] Retrospective cohort study (level 2b) Rainio et al., 1995, Finland [18] Retrospective cohort study (level 2b) Panagopoulos et al., 2008, Greece [19] Prospective cohort study (level 2b)

Patient group

Continued


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Table 1: Continued Author, date, country, study type (level of evidence)

Patient group

Outcomes

Key results

Comments

Survival

2-year survival: 74% non-transfused and 59% transfused. 5-year survival: 43% transfused and non-transfused.

Poorer short-term, but not longer– term, survival in patients receiving perioperative blood transfusions. Read as abstract only.

432 consecutive patients undergoing pneumonectomy from May 1993 to December 2002. Transfusion: red cell, plasma, platelets, cryoprecipitate, factor VIII within 30 days of surgery. Malignant diseases requiring pneumonectomy, including thymoma, mesothelioma, lymphoma and metastases. Variety of surgical procedures. Neoadjuvant chemo/radiotherapy included. 42% transfused.

Survival

30-day mortality 19 vs 2% in transfused vs non-transfused patients (P < 0.0001) retains significance at multivariate analysis (similar figures for 90-day mortality). 5-year survival in patients with primary lung cancer; 28 vs 39% in transfused vs non-transfused. Cox model: when adjusting for stage and other variables, blood transfusion did not achieve significance when examining 5-year survival.

Blood transfusion confers poor prognosis in the immediate post-operative period, but not long-term survival.

439 consecutive patients undergoing surgery for NSCLC at one centre January 1996 to December 2001. ‘All-comer’ population: stages I–III. 23% transfused.

Survival

Survival worse in patients with lower Significant correlation between haemoglobin levels. anaemia, but not blood Poorer outcome in transfused transfusion, and poorer survival. patients, but NOT demonstrated when multivariate analysis conducted accounting for blood haemoglobin levels. The hazard ratio of transfusion 0.94.

Zimmermann et al., 224 patients undergoing resection. 1993, Germany [20] 53% transfused. Cohort study (level 2b) Thomas et al., 2007, France [21] Retrospective cohort study (level 2b)

Berardi et al., 2005, Italy [22] Retrospective cohort study (level 2b)

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 nontransfused 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 nontransfused 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]

THORACIC ONCOLOGIC

BET, best evidence topic; FFP, fresh frozen plasma; RBC, red blood cells; and SCC, squamous cell carcinoma.

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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 diseasefree 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.

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[4] Piantadosi S, Moores DWO, McKneally MF. The adverse effect of perioperative blood transfusion in lung cancer. Chest 1994;106: 382S–4S. [5] Pena CM, Rice TW, Ahmad M, Medendorp SV. Significance of perioperative blood transfusions in patients undergoing resection of stage I and II non-small-cell lung cancers. Chest 1992;102:84–8. [6] Piantadosi S. The adverse effect of blood transfusion in lung cancer. Chest 1992;102:6–8. [7] Vamvakas EC. Perioperative blood transfusion and cancer recurrence: meta-analysis for explanation. Transfusion 1995;35:760–8. [8] Pastorino U, Valtente M, Cataldo I, Lequaglie C, Ravasi G. Perioperative blood transfusion and prognosis of stage Ia lung cancer. Eur J Clin Oncol 1986;22:1375–8. [9] Tartter PL, Burrows L, Kirschner P. Perioperative blood transfusion adversely affects prognosis after resection of stage I (subset N0) non-oat cell lung cancer. J Thorac CardioVasc Surg 1984;88:659–62. [10] Wu HS. Influence of blood transfusion on post-operative prognosis of stage I (N0) lung cancer. Chinese J Oncol 1989;11:297–9. [11] Little AG, Wu H-S, Ferguson MK, Ho C-H, Bowers VD, Segalin A et al. Perioperative blood transfusion adversely affects prognosis of patients with stage I non-small-cell lung cancer. Am J Surg 1990;160: 630–3. [12] Nosotti M, Rebulla P, Riccardi D, Baisi A, Bellaviti N, Rosso L et al. Correlation between perioperative blood transfusion and prognosis of patients subjected to surgery for stage I lung cancer. Chest 2003;124: 102–7. [13] Novak K, Vodicka J, Pesek M. Survival after surgery for bronchogenic carcinoma in relation to blood transfusion. Rozhledy V Chirurgii 1994; 73:110–3. [14] Rzyman W, Dziadziuszko R, Skokowski J, Wilimski R, Raiter A, Szymanowska A et al. The influence of blood transfusion on survival in operated non-small cell lung cancer patients. J Thor CardioVasc Surg 2003;126:755–60. [15] Ghosh S, Ahmed K, Hopkinson DN, Vaughan R. Pulmonary adenocarcinoma is associated with poor long-term survival after surgical resection. Effect of allogeneic blood transfusion. Cancer 2004;101: 2058–66. [16] Penalver JC, Padilla J, Jorda C, Escriva J, Ceron J, Calvo V et al. Use of blood products in patients treated surgically for stage I non-small cell lung cancer. Arch Bronconeumol 2005;41:484–8. [17] Hyman NH, Foster RS, De Meules JE, Costanza MC. Blood transfusions and survival after lung cancer resection. Am J Surg 1985;149:502–7. [18] Rainio P, Bloigu R, Satta J, Pokela R, Paakko P. Ten-year survival after resection for lung carcinoma. Effect of blood transfusion and tumour stage on outcome. Scand J Thor CardioVasc Surg 1996;30:87–91. [19] Panagopoulos ND, Karakantza M, Koletsis E, Apostolakis E, Sakellaropoulos GC, Filos KS et al. Influence of blood transfusions and preoperative anemia on long-term survival in patients operated for nonsmall cell lung cancer. Lung Cancer 2008;62:273–80. [20] Zimmermann T, Dobroschke J, Becker C, Kelm C, Padberg WM. Effect of perioperative donor blood transfusion on prognosis of bronchial cancer. Lagenbecks Archiv fur Chirurgie 1993;378:145–9. [21] Thomas P, Michelet P, Barlesi F, Thirion X, Doddoli C, Giudicelli R et al. Impact of blood transfusions on outcome after pneumonectomy for thoracic malignancies. Eur Respir J 2007;29:565–70. [22] Berardi R, Brunelli A, Tamburrano T, Verdecchia L, Onofri A, Zuccatosta L et al. Perioperative anemia and blood transfusions as prognostic factors in patients undergoing resection for non-small cell lung cancers. Lung Cancer 2005;49:371–6.