Influence of Technologic Advances on Outcomes in Patients With Unresectable, Locally Advanced Non–Small-Cell Lung Cancer Receiving Concomitant Chemoradiotherapy

Purpose

In 2004, our institution began using four-dimensional computed tomography (4DCT) simulation and then intensity-modulated radiotherapy (IMRT) (4DCT/IMRT) instead of three-dimensional conformal radiotherapy (3DCRT) for the standard treatment of non–small-cell lung cancer (NSCLC). This retrospective study compares disease outcomes and toxicity in patients treated with concomitant chemotherapy and either 4DCT/IMRT or 3DCRT.

Methods and Materials

A total of 496 NSCLC patients have been treated at M. D. Anderson Cancer Center between 1999 and 2006 with concomitant chemoradiotherapy. Among these, 318 were treated with CT/3DCRT and 91 with 4DCT/IMRT. Both groups received a median dose of 63 Gy. Disease end points were locoregional progression (LRP), distant metastasis (DM), and overall survival (OS). Disease covariates were gross tumor volume (GTV), nodal status, and histology. The toxicity end point was Grade ≥3 radiation pneumonitis; toxicity covariates were GTV, smoking status, and dosimetric factors. Data were analyzed using Cox proportional hazards models.

Results

Mean follow-up times in the 4DCT/IMRT and CT/3DCRT groups were 1.3 (range, 0.1–3.2) and 2.1 (range, 0.1–7.9) years, respectively. The hazard ratios for 4DCT/IMRT were <1 for all disease end points; the difference was significant only for OS. The toxicity rate was significantly lower in the IMRT/4DCT group than in the CT/3DCRT group. V20 was significantly higher in the 3DCRT group and was a significant factor in determining toxicity. Freedom from DM was nearly identical in both groups.

Conclusions

Treatment with 4DCT/IMRT was at least as good as that with 3DCRT in terms of the rates of freedom from LRP and DM. There was a significant reduction in toxicity and a significant improvement in OS.

Introduction

Radiotherapy is one of the most effective and commonly used treatments for solid malignancies, including lung cancer. Indeed, about 50% of patients with locally advanced lung cancer (1) including non–small-cell lung cancer, receive radiotherapy. Treatment of these patients with concomitant chemotherapy is constrained, however, by the sensitivity of normal lung tissue to radiation, which clinically takes the form of radiation pneumonitis (RP). Three factors make NSCLC, or any lung cancer, particularly difficult to treat with radiotherapy: respiratory motion, the presence of numerous neighboring organs with a low radiation tolerance, and dosimetric difficulties caused by the presence of tissue inhomogeneities.

Important technologic advances in radiotherapy treatment planning and delivery occurring in the past 5 years are changing this picture, however. These advances include imaging technologies such as functional imaging, radiation delivering technology such as three-dimensional conformal radiotherapy (3DCRT), respiratory gating, four-dimensional computed tomography (4DCT) simulation, intensity-modulated radiotherapy (IMRT), image-guided radiotherapy, stereotactic body irradiation, tomotherapy, image-guided adaptive radiotherapy, and proton beam therapy (2).

One of the most important technologic advances in radiotherapy has been the development of sophisticated 3DCRT treatment planning systems and computer-controlled radiation delivery systems that allow the delivery of higher radiation doses to properly defined target volumes but spare critical normal tissues surrounding the tumor. Because of its ability to likewise conform the radiation dose to the tumor, IMRT has also rapidly increased in popularity among radiation oncologists in the United States. However, this has occurred in the absence of standardized guidelines or careful prospective analyses evaluating its risks and benefits (3). In theory, these advanced technologies should have therapeutic benefits because of their ability to conform the radiation to the tumors; however, there are concerns about using IMRT for lung cancer because of the respiratory motion involved. This is because, unlike 3DCRT, IMRT irradiates only a portion of the target volume at a particular time. This creates the potential for significant dosimetric missing of the target volume, which may in turn have an unfavorable effect on locoregional control of the tumor. There is also concern that IMRT may be used excessively, despite a lack of evidence of real clinical benefit, because of its higher reimbursement from Medicare (4).

However, in the absence of prospective randomized trials of these new radiotherapeutic techniques, it is difficult to know their real benefits (5), but such trials are extremely difficult to carry out. A retrospective study done in a large number of patients, such as the numbers seen at The University of Texas M. D. Anderson, should, however, provide very reliable information. We therefore undertook such a study comparing 4DCT/IMRT and CT/3DCRT.

We started using 3DCRT for patients with lung cancer in 1999 and then switched to 4DCT simulation with IMRT in mid-2004. In a recent report (6) in which we analyzed the toxicity associated with 3DCRT in 222 patients and IMRT in 68 patients, the rate of Grade ≥3 RP (RP3) was only 8% in the IMRT group but 32% in the 3DCRT group, a difference that was statistically significant (6). Of particular note, this was despite the fact that the GTV was larger in the IMRT group; however, this leaves open the question of clinical outcomes, especially the probability of locoregional control in these patients. In the study we report here, we compared the effect of CT/3DCRT and 4DCT/IMRT on disease outcome in patients with unresectable, locally advanced NSCLC who received concomitant chemoradiotherapy. We also analyzed the toxicity associated with the two technologies in larger patient groups and with longer follow-up times than we had in our earlier study. We found that the locoregional progression-free survival and distant metastasis–free survival rates were at least as good in patients treated with 3DCRT as in patients treated with IMRT and that the overall survival (OS) and RP rates were significantly better in patients treated with IMRT. Therefore, IMRT appears to have an important place in the treatment of patients with advanced NSCLC and has clear advantages over 3DCRT.