Clinical Investigation
Effect of Smoking During Radiotherapy, Respiratory Insufficiency, and Hemoglobin Levels on Outcome in Patients Irradiated for Non–Small-Cell Lung Cancer

https://doi.org/10.1016/j.ijrobp.2007.11.006Get rights and content

Purpose

To investigate the effect of smoking during radiotherapy (RT), respiratory insufficiency before RT, hemoglobin levels during RT, and additional factors on overall survival, locoregional control (LRC), and metastasis-free survival in non–small-cell lung cancer patients.

Methods and Materials

The following factors were investigated in 181 patients who underwent RT for non–small-cell lung cancer: age, gender, Karnofsky performance score, histologic type, grade, T/N stage, American Joint Committee on Cancer stage, surgery, chemotherapy, respiratory insufficiency before RT, pack-years, smoking during RT, and hemoglobin levels during RT. Additionally, in the 129 patients who did not undergo surgery, the effect of the equivalent dose in 2-Gy fractions (EQD2) (<60 Gy vs. 60 Gy vs. >60 Gy) on outcome was investigated.

Results

On multivariate analysis, improved overall survival was associated with a lower T stage (p = 0.004), lower N stage (p = 0.040), surgery (p = 0.010), and no respiratory insufficiency (p = 0.023). A Karnofsky performance score >70 achieved borderline significance (p = 0.056). Improved LRC was associated with a lower T stage (p = 0.007) and no smoking during RT (p = 0.029). Improved metastasis-free survival was associated with lower T stage (p < 0.001) and lower N stage (p < 0.001). In those patients who did not undergo surgery, an EQD2 of ≥60 Gy was associated with a better outcome than an EQD2 of <60 Gy. Furthermore, an EQD2 >60 Gy resulted in better LRC than did an EQD2 of ≤60 Gy.

Conclusions

Smoking during RT had a significant effect on LRC, but we did not find that hemoglobin levels or respiratory insufficiency significantly affected LRC or metastasis-free survival in our patient population. Furthermore, our data suggest a dose–effect relationship in those patients who did not undergo surgery.

Introduction

Tumor oxygenation is critically important to achieve maximal efficacy from radiotherapy (RT). Radiobiologic studies have demonstrated that tumor hypoxia is associated with an increased resistance to radiation-induced tumor cell kill because of the lower production of cytotoxic free radicals, resulting in less DNA damage (1). Furthermore, a biophysical model has suggested that tumor hypoxia might drive malignant cells to metastasize more readily and frequently (2). Tumor oxygenation can be affected by several factors such as the adequacy of the blood supply, microcirculation, and the oxygen-carrying capacity of the blood. The latter is represented to a certain extent by the total hemoglobin level. The hemoglobin levels during RT have been demonstrated to be associated with the clinical outcome for several tumors such as endometrial carcinoma, cervical cancer, and esophageal cancer 3, 4, 5.

However, the total hemoglobin level might not be the only important parameter for tumor oxygenation. Methemoglobin is altered hemoglobin and is unable to carry oxygen. Controversy exists regarding the question of whether smoking increases the methemoglobin level 6, 7, 8. However, it is well known that carboxyhemoglobin impairs the delivery of oxygen to the body. Furthermore, hemoglobin binds to carbon monoxide about 200 times more than it does to oxygen. Thus, carboxyhemoglobin will not release the carbon monoxide, and the hemoglobin is unable to carry oxygen to the tumor cells. It has been demonstrated that smoking increases carboxyhemoglobin levels 6, 7, 8, 9. Considering the half life (4–6 h) of carboxyhemoglobin in the blood, it could well be that smoking during RT increases the level of carboxyhemoglobin, resulting in poorer tumor oxygenation.

A negative effect of smoking during RT on outcome has been demonstrated for several tumors, including head-and-neck cancer, bladder cancer, and small-cell lung cancer 10, 11, 12, 13, 14, 15. Controversy exists regarding the prognostic effect of smoking during RT in patients with non–small-cell lung cancer (NSCLC). Two retrospective analyses suggested that smoking was adversely associated with outcome 16, 17. However, one of these analyses also included patients with small-cell lung cancer (17). A third retrospective analysis did not show a significant effect of smoking during RT on outcome (18).

The present study investigated 14 potential prognostic factors for overall survival (OS), locoregional control (LRC), and metastasis-free survival (MFS) in 181 patients with NSCLC. These factors included smoking during RT, respiratory insufficiency before RT, and hemoglobin levels during RT. All these factors could negatively effect tumor oxygenation but have not been previously related to the clinical outcome in NSCLC patients.

Section snippets

Methods and Materials

The data of 181 smokers (patients who were smokers at diagnosis) who had undergone RT at the University Hospital in Luebeck between January 2000 and December 2005 for nonmetastatic NSCLC were retrospectively evaluated. The patient characteristics are summarized in Table 1.

Radiotherapy was performed with a linear accelerator and 6–18-MV photons after computed tomography-based three-dimensional treatment planning. The target volume included the primary tumor and locoregional lymph nodes with a

Results

The patients were followed until death or for a median of 17 months (range, 12–64) in survivors. The median survival for the entire cohort was 12 months. The survival rate at 1 and 2 years was 49% and 33%, respectively. On univariate analysis, improved survival was significantly associated with KPS >70, lower T stage, lower N stage, AJCC Stage I-II, surgery, no or partial respiratory insufficiency before RT (Fig. 1), and hemoglobin levels during RT of ≥12 g/dL. The results of the univariate

Discussion

In the present study, smoking during RT was significantly associated with LRC on both univariate and multivariate analyses and must, therefore, be considered an independent prognostic factor for LRC. Nonsmokers during RT (so-called quitters) also had better survival rates. However, significance regarding OS was not achieved. Abstinence of smoking during RT did not improve MFS. Improvement of LRC in quitters was most likely a result of the enhanced efficacy of RT, which is a locoregional

Conclusions

Smoking during RT proved to be a negative independent prognostic factor for LRC in patients undergoing RT for NSCLC. Therefore, it is important to work with patients to stop smoking before RT. Respiratory insufficiency measured before RT was a negative independent prognostic factor for OS. We did not find that hemoglobin levels or respiratory insufficiency were independent predictors of LRC or MFS. Our data suggest that treatment results can be improved by convincing patients to quit smoking.

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