Effectiveness of image-guided radiotherapy for locally advanced lung cancer patients treated with definitive concurrent chemoradiotherapy

Introduction

Lung cancer is the major cause of cancer mortality around the world.¹ Definitive concurrent chemoradiotherapy (dCCRT) is the standard of care for unresectable locally advanced small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC) with good performance status^{2, 3} although consolidative immunotherapy had been recommended for NSCLC since September 2017.⁴

Image-guided radiotherapy (IGRT) is an advanced auxiliary technique used to improve the accuracy of radiotherapy delivery.^{5, 6} IGRT uses images (mainly x-ray) to verify and adjust the position of the radiotherapy target. Conceptually, this improvement in radiotherapy delivery accuracy improves the clinical outcome, as advocated in the literature or textbooks,^{5, 6} and as also reported in our previous nonrandomized study utilizing data from the Taiwan Cancer Registry (TCR) for lung cancer patients diagnosed during 2007–2010.⁷

However, a recent randomized study in 2018 for prostate cancer patients treated with conventional fractionated radiotherapy via either IGRT or routine care (no daily IGRT) reported a statistically significant worse overall survival for those treated with IGRT, although side effects and disease control were improved.⁸ Theoretically, the extra-radiotherapy dose due to xray-IGRT may have contributed to the increased risk of other cancer (10% vs. 5%) or cardiovascular mortality (6/236 vs. 1/234) observed in this study and led to the impaired overall survival.⁸ This raises a concern regarding the effectiveness of IGRT for other scenarios such as dCCRT for lung cancer.

Since 2011, additional prognostic factors such as body mass index (BMI), use of alcohol or betel nuts or smoking, and performance status (PS) have been prospectively collected in the TCR. Because these potential confounders were not adjusted in our previous study due to data limitation at that time, here we aimed to investigate the effectiveness of IGRT for locally advanced lung cancer (LALC) patients treated with dCCRT in this updated analysis with consideration of the above potential confounders.

Methods

Study population and study design

The study flow chart (Fig 1) was designed to conform to the STROBE statement,¹⁰ and depicted our main study population. We included nonoperated LALC adult (age ≥ 18) patients diagnosed between 2011 and 2016 who received curative concurrent systemic therapy and external beam radiotherapy 50–70 Gy using conventional fractionation via image-guided radiotherapy (IGRT) or non-IGRT, but excluded patients with other cancer(s). The explanatory variable of interest (IGRT vs. non-IGRT), the primary outcome of interest (overall survival [OS]) and other supplementary outcomes (incidence of lung cancer mortality [ILCM], other cancer mortality [IOCM] and cardiovascular mortality [ICVM]) were determined via the recordings in the TCR or the death registry. We defined the date of diagnosis as the index date and calculated the OS or other endpoints from the index date to the date of death or 31 December 2018 (censoring date of the death registry). The covariates (see next section “Other explanatory covariates”) were modified from our experiences in clinical care and TCR studies^{7, 11, 12} to adjust for potential nonrandomized treatment selection.

Results

Primary analysis

After a median follow-up of 21 months (range 3–95), death was observed for 141 patients in the IGRT group and for 458 patients in the non-IGRT group. The overlap weights adjusted OS curve are shown in Fig 2. The five-year OS rates for both groups were 19.61% (IGRT) and 19.96% (non-IGRT), respectively. When IGRT was compared to non-IGRT, the HR of death was 0.96 (95% confidence interval [95% CI]: 0.79–1.15, P = 0.65). The observed HR could be explained by an unmeasured confounder associated with the selection of treatment (IGRT or non-IGRT) and survival by a risk ratio of 1.20 (E-value) fold each, but weaker confounding factors could not do so. The results were also not significantly different for ILCM (HR = 0.92, P = 0.55) and IOCM (HR = 2.23, P = 0.37). The crude ICVM was around 1% (7/605) in the non-IGRT group and even lower in the IGRT group (exact number not reported per HWDC policy).

Discussion

In this updated nonrandomized study using real world data with additional potential confounders, we found that the OS of LALC patients treated with dCCRT was not statistically different between those treated with IGRT versus those without IGRT. However, the observed HR for death in our study was less than unity (ie, in favor of IGRT), in contrast to the HR 2.12 (P = 0.042) observed in the RCT for prostate cancer.⁸ However, it should be noted that OS was the second but not primary outcome of this RCT,⁸ so the significance regarding the difference in OS or other outcomes may be false positive²⁵ and should be interpreted with caution. Furthermore, although this RCT⁸ failed to show superiority in its primary endpoint (recurrence-free survival, HR 0.81 P = 0.33), post hoc analyses did show a benefit to IGRT in biochemical progression-free, clinical progression-free interval, and rectal toxicity.

From the viewpoint of evidence-based medicine, our finding was not a high level evidence^{15, 26} and should be cautiously interpreted due to the nonrandomized study design.¹⁵ Although OS was obviously the most important endpoint in cancer treatment, it may not be the most relevant endpoint for IGRT, and our study lacked the data on local control or toxicity which might be better endpoints for IGRT. However, when we searched the clinical trial registry (https://clinicaltrials.gov/) in March 2020 using keywords “(image-guided radiation therapy) or (image-guided radiotherapy) or (IGRT) | lung cancer | Phase 2, 3, Not Applicable”, we found no RCT regarding IGRT for LALC patients treated with dCCRT. Therefore, our study provided a reasonable tentative evidence in the lack of RCT as suggested in the literature.¹⁵

We also looked for relevant studies by searching PubMed in May 2020 using the following keywords “(IGRT) or (image-guided radiation therapy) or (image*) and (guid*) and (radiotherapy) or (radiation therapy) and survival and (lung cancer)”and found two subsequent institutional studies from the United States in addition to our previous study.^{7, 27, 28} Kilburn et al. used data of 169 NSCLC patients and found similar OS (P = 0.63) although better locoregional control and less grade III acute toxicity for IGRT.²⁷ Deek et al. retrospectively reviewed 91 patients with NSCLC and reported daily KV image IGRT was associated with longer OS (P = 0.01) as well as less locoregional failure when compared to weekly MV image.²⁸ In contrast, our current study was a population based study from Asia with a much larger number of cases (797 vs. [91 or 169] in the previous studies).

There were several limitations in our study. First, the treatment assignment in our study (IGRT or not) was not randomized and potential unmeasured confounders are always a limitation of a nonrandomized study as seen in our previous study⁷ and the current study. Although we had included additional covariates in the current study, there were still possible unmeasured confounders. For example, use of invasive mediastinal staging, organ at risk dose, the planning target volume (PTV) margin or volume, dose calculation algorithms, or systematic therapy details might be different for those treated with IGRT or not and if imbalanced between groups may impact our results, but this information was not available in the TCR. Furthermore, accessibility (IGRT may not be available in some institutes [nor provided by the TCR in HWDC]) issues may also be possible because IGRT is a relatively recent technology. Therefore, we reported E-value to quantify the potential impact of unmeasured confounder(s) as suggested in the literature. Second, locoregional control or side effects but not OS might be more relevant endpoints as reported in previous studies.^{27, 28} However, we did not include these endpoints as we felt the recording of relapse pattern in TCR was relatively immature for lung cancer. Third, the implication regarding IGRT for current practice may be unclear in the era of immunotherapy because consolidative immunotherapy (durvalumab) has been the standard of care for locally advanced NSCLC treated with definitive CCRT since 2017.²⁹ Finally, the intervention (IGRT) in our study was not homogenous. To our knowledge, several different forms of xray-based IGRT are available in Taiwan including, but not limited to, cone beam computed tomography, KV imaging, and MV imaging, which could not be differentiated in the TCR. However, it is unclear whether these various technologies lead to different clinical benefits,³⁰ although, to our knowledge, the modern xray-free magnetic resonance image guided IGRT³¹ was not available in Taiwan for our study population. The quality of IGRT may also be a concern³² but could not be assessed in our study due to study limitations.

In conclusion, in this updated nonrandomized study using real world data with additional potential confounders, we found that the OS of LALC patients treated with dCCRT was not statistically different between those treated with IGRT versus those without IGRT, with the hazard ratio less than unity ie, in favor of IGRT. The results should be interpreted with caution given the nonrandomized design. Studies regarding toxicity, local control, or designed as RCT are needed to clarify the role of IGRT.

Disclosure

The authors have not published or submitted the manuscript elsewhere. The authors declare there are no conflicts of interest.