Perioperative anemia and blood transfusions as prognostic factors in patients undergoing resection for non-small cell lung cancers

doi:10.1016/j.lungcan.2005.04.011

Lung Cancer

Volume 49, Issue 3, September 2005, Pages 371-376

https://doi.org/10.1016/j.lungcan.2005.04.011 Get rights and content

Summary

We hypothesised that anemia could represent an important prognostic factor and perioperative blood transfusions do not reduce the risk of relapse. In order to explore this topic, we assessed the correlation of preoperative anemia and blood transfusions with survival in patients with resected non-small cell lung cancer (NSCLC).

Patients who underwent radical surgery for NSCLC at the Department of Thoracic Surgery of Università Politecnica delle Marche from January 1996 through December 2001, were included in our study.

Four hundred and thirty-nine patients were eligible for our analysis. Survival appeared worse in patients with haemoglobin (Hb) ≤10 g/dl versus Hb >10 g/dl (p = 0.012). Stratifying patients in three groups on their Hb level (group 1: Hb ≤10 g/dl; group 2: Hb = 10–12 g/dl; group 3: Hb ≥12 g/dl), we observed a worse prognosis in patients with lower Hb levels, too (p = 0.0325) and also in the transfused population (p = 0.046). At multivariate analysis, only the age of patients, pathological stage and Hb levels resulted indicators of prognosis.

Our results suggested that anemia could represent an important prognostic factor in resected NSCLC and correction of anemia in the perioperative setting does not reduce the risk of relapse.

Introduction

Complete surgical resection of the primary tumor and metastatic lymph nodes remains the only potentially curative treatment for patients with NSCLC [1]. Although a role for prognostic factors such as histology, leukocyte count and carcinoembryonic antigen (CEA) level has been suggested, only tumor size and nodal involvement are commonly accepted and used as prognostic indicators in the daily clinical practice [2].

Emerging evidence over the past decade has suggested that anemia may be related to poor clinical outcomes, including survival. The importance of Hb level as a prognostic and predictive factor for outcome has been examinated in a variety of solid tumors. A low Hb level was found to be prognostic for overall survival especially in patients with head and neck cancer and with cervical cancer [3].

Furthermore, several studies examined the prognostic influence of anemia on advanced NSCLC [4], [5].

More recently, Pradier et al. showed that the Hb levels prior to radio-chemotherapy have an influence on prognosis of NSCLC, where lower levels were associated with worse outcome [6].

In patients with lung cancer, the prevalence of anemia is high (50–60% with Hb levels <11 g/dl) [7], [8], and approximately 43% of this patient population receive blood transfusions, compared with only 19% of patients with breast carcinoma cases [9].

After the initial publication by Burrows an Tartter [10] showing a detrimental effect of perioperative blood transfusions given to patients that had undergone apparently curative resection for colon cancer, multiple studies have attempted to elucidate this correlation, its dependency upon the type of cancer and its clinical significance [11], [12], [13], [14], [15], [16], [17], [18], [19], [20].

It is suspected that an immune mechanism could be involved in this phenomenon. In fact, an immune disorder caused by blood transfusion is well described in the medical literature and goes by the name of “allogeneic blood transfusion-associated immunomodulation” (TRIM) [21]. This mechanism is the same one considered responsible for improved survival of kidney allografts in transplanted patients receiving preoperative blood transfusions [22]. It has been postulated that a state of non-specific immunosuppression induced by the transfused blood allows the kidney recipient to better tolerate the transplanted organ, with subsequent decreases in rejection episodes and improved survival [23].

In a similarly way, immunosuppression may be produced in cancer patients who have received blood transfusions perioperatively, thus resulting in the possible proliferation of residual tumor cells that had not been resected after the “curative” surgery [24].

However, the hypothetically negative effect of blood transfusions in solid tumors may be simply the consequence of the anemic status of the patients, and its role may be overestimated. Nevertheless it is also possible that blood transfusion request could only represent an epiphenomenon for a deeper alteration in tumor angiogenic pathways caused by anemia.

In order to explore the clinical implications of anemia as indicator of prognosis, we therefore assessed the correlation of preoperative anemia with survival in patients with resected NSCLC, and finally to assess the role of anemia and blood transfusion, respectively, in the determination of the prognosis of the patients.

Section snippets

Patients selection

The study includes all the consecutive patients who underwent radical surgery for NSCLC at the Department of Thoracic Surgery of Universita Politecnica delle Marche from January 1996 to December 2001.

Data for patients entered onto the analysis included age, sex, type of surgery, histological type, pathological stage of disease, risk factor (smoking), preoperative Hb levels, whether preoperative transfusions were administered and the number of transfusions were also reported.

Transfusions were

Results

From January 1996 through December 2001, 439 patients underwent radical surgery for NSCLC at the Department of Thoracic Surgery of Università Politecnica delle Marche. Median age at surgery was 68 years (range 37–84); male/female ratio was 374/65.

Two hundreds and thirteen patients (48.5%) were diagnosed with adenocarcinoma, 172 patients (39.2%) with squamous cell carcinoma and 25 patients (5.7%) had undifferentiated carcinoma.

Pathologic stage of disease was as follows: IA in 77 patients

Discussion

Anemia has been demonstrated to be a prognostic indicator for lower survival probability in patients with advanced lung cancer receiving a chemotherapy and/or radiotherapy. Results from a number of studies suggest that better outcomes are associated with Hb levels ≥11–12 g/dl [26], [27], [28], [29].

The results of the present study seem to indicate that anemia is a prognostic factor even for radically resected lung cancer patients. In fact our analysis revealed a significant difference in

Acknowledgement

Supported by CNR-MIUR—Lex 449/97.

References (33)

D.E. Van Raemdonck et al.
Surgical treatment for higher stage non-small cell lung carcinoma
Ann Thorac Surg
(1992)
L. Burrows et al.
Effect of blood transfusions on colonic malignancy recurrence rate
Lancet
(1982)
P.I. Tartter et al.
Perioperative blood transfusion adversely affects prognosis after resection of stage I (subset NO) non-oat cell lung cancer
J Thorac Cardiovasc Surg
(1984)
N.H. Hyman et al.
Blood transfusions and survival after lung cancer resection
Am J Surg
(1985)
R. MacRae et al.
Declining hemoglobin during chemoradiotherapy for locally advanced non-small cell lung cancer is significant
Radiother Oncol
(2002)
M. Nosotti et al.
Correlation between perioperative blood transfusion and prognosis of patients surgery for stage I lung cancer
Chest
(2003)
G. Opelz et al.
Induction of high kidney graft survival rate by multiple transfusion
Lancet
(1981)
M.J. Van Acht et al.
The prognostic value of hemoglobin and a decrease in hemoglobin during radiotherapy in laringeal carcinoma
Radiother Oncol
(1992)
A. Becker et al.
Severe anemia is associated with poor tumor oxygenation in head and neck squamous cell carcinomas
Int J Radiat Oncol Biol Phys
(2000)
G.L. Semenza
HIF-1 and tumor progression: pathophysiology and therapeutics
Trends Mol Med
(2002)

M.H. Gail et al.

A report from the Lung Cancer Study Group

Cancer

(1984)

L.B. Harrison et al.

Impact of tumor hypoxia and anemia on radiation therapy outcomes

Oncologist

(2002)

C. Ohlhauser et al.

Prognostic factors for survival in inoperable non-small-cell lung cancer: a multivariate regression analysis of 456 patients with radiation therapy

Onkologie

(1997)

S. Ylisirnio et al.

Serum type I collagen degradation markers, ICTP and CrossLaps, are factors for poor survival in lung cancer

Anticancer Res

(1999)

O. Pradier et al.

Concurrent low-dose cisplatin and thoracic radiotherapy in patients with inoperable stage III non-small cell lung cancer: a phase II trial with special reference to the hemoglobin level as prognostic parameter

J Cancer Res Clin Oncol

(2004)

D.A. Fein et al.

Pretreatment hemoglobin levels influences local control and survival of T1–T2 squamous cell carcinomas of the glottic larynx

J Clin Oncol

(1995)

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Outcomes assessed included perioperative mortality, 90-day mortality, and overall survival. Multivariate logistic and Cox regression analyses were used to assess the impact of preoperative anemia on 90-day mortality and overall survival, respectively. Overall, preoperatively, 24.0% (n = 1207) of patients were anemic. The 90-day mortality for anemic and nonanemic patients was 5.6% and 3.1%, respectively (p < 0.001). After multivariate adjustment, preoperative anemia was not associated with increased 90-day mortality. However, a log-rank analysis demonstrated reduced overall survival for anemic patients (p < 0.001). After multivariate adjustment, preoperative anemia was found to be independently associated with reduced overall survival (hazard ratio 1.287, 95% confidence interval 1.141-1.451, p < 0.001).
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But, it is not known how ABT affects the treatment outcomes in patients treated with immunotherapy, thus further studies are needed on this issue. So far, studies on this area have remained limited and included only early-stage operated patients [6,17,18,21–28]. Unlike other studies, our study included metastatic NSCLC patients at diagnosis, but even so our study had some limitations as follows; 1- It had retrospective nature, 2- We could not reach the data regarding the number of transfusions performed before treatment period or during treatment period, thus we do not know how this condition affects survival, 3- We don't exactly know after which cycle we performed transfusion.
To investigate the prognostic effects of Allogeneic Blood Transfusion (ABT) in patients with metastatic Non-Small Cell Lung Cancer (NSCLC) receiving Chemotherapy (CT) in the first-line treatment, comparing untransfused patients to those receiving blood transfusion during treatment period or before treatment period.
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