Background
Gastric cancer is a major cause of cancer-associated mortality worldwide [
1]. Nearly half of the worldwide gastric cancer cases and deaths occur in China [
1,
2]. As reported by the GLOBOCAN 2012, approximately one million new gastric cancer cases and more than 700,000 cancer-related deaths occurred globally in 2012 [
3]. The treatment strategy for gastric cancer is still controversial [
4]. Surgical resection is preferred for patients without advanced-stage cancer [
4]. On the contrary, the benefits of surgical resection for patients with locally advanced gastric cancer are limited [
5‐
8]. Perioperative strategies and adjuvant therapies, such as chemotherapy, radiotherapy, chemoradiotherapy, and targeted therapy, have been used in clinical settings for years and proved to be effective [
4,
9‐
12].
Several clinical studies demonstrated that adjuvant therapies administered after surgical resection prolonged the survival of patients with locally advanced gastric cancer [
4,
10,
11,
13‐
18]. Adjuvant therapy, such as radiotherapy, significantly increased the survival of patients with gastric cancer and reduced the risk of recurrence [
15,
17]. However, the therapeutic benefits were accompanied by increased adverse events or toxicity [
17,
19].
The three-dimensional conformal radiation (3D-CRT) and intensity-modulated radiation therapy (IMRT) are gradually implemented in clinical studies to reduce radiation-related toxicity without the loss of treatment effectiveness. A previous study showed significant grade 3 toxicity in patients with resected gastric or gastroesophageal junction cancers treated with 3D-planned CRT [
20]. In recent years, several clinical trials have been performed to evaluate clinical outcomes and toxicity in patients with resected gastric cancer treated with IMRT versus 3D-CRT [
21‐
28]. Minn et al. [
29] compared the clinical efficacy and adverse events in patients with gastric cancer who received IMRT versus 3D-CRT. They did not find a significant difference between these two groups in terms of 2-year overall survival (OS) rate (
P = 0.5). Whether IMRT was associated with reduced toxicity compared with 3D-CRT was explored by Liu et al. [
26] who recruited 24 patients with stage IB–IIIB gastric cancer: 12 in the 3D-CRT group and 12 in the IMRT group. No significant differences in the OS and disease-free survival (DFS) rates were observed between 3D-CRT and IMRT, while similar toxicity was observed in these two groups. Due to the smaller sample size and nonsignificant differences observed in the aforementioned studies, this meta-analysis was performed to explore whether IMRT was more effective and safe compared with 3D-CRT in treating patients with gastric cancer.
Discussion
This meta-analysis examined the impact of IMRT versus 3D-CRT in patients with resectable gastric cancer by quantitatively summarizing the findings from nine different trials. The results showed that the use of IMRT was associated with a nearly 40% reduction in the risk of disease relapse and a 16% increase in the OS rate. Moreover, the risk of radiation-related toxicities was not increased in IMRT compared with 3D-CRT. Taken together, IMRT seemed to be a promising alternative in this clinical setting.
A meta-analysis [
16] assessed the impact of radiotherapy on both 3- and 5-year survival [overall survival (OS) and disease-free survival (DFS)] rates in patients with resectable gastric cancer by including 14 RCTs. The pooled result showed that the addition of radiotherapy after surgery improved the 3- (RR, 1.18; 95% CI, 1.01–1.38) and 5-year OS and DFS rates (RR, 1.38; 95% CI, 1.18–1.61). IMRT was widely used in recent studies, demonstrating promising efficacy and less toxicity. Therefore, comparing the efficacy and toxicity of IMRT with those of 3D-CRT in patients with gastric cancer was necessary. The findings of this meta-analysis indicated a significant improvement in patient’s outcomes after IMRT compared with 3D-CRT. Notably, IMRT significantly reduced the risk of loco-regional relapse, indicating its high clinical efficacy and potential as first-line adjuvant treatment for locally advanced or high-risk gastric cancer.
Reducing radiation toxicity and improving treatment compliance and quality of life of patients are serious issues in clinical practice. This meta-analysis showed that patients in the IMRT group did not experience increased radiation-related side effects compared with those in the 3D-CRT group. Recent studies showed that IMRT had a lower incidence of toxicity, especially grade 3 and 4 toxicities, compared with 3D-CRT. Murthy et al. [
37] showed that IMRT was more advantageous than 3D-CRT in terms of dose coverage and conformity. Ringash et al. [
38] also reported that the conformity and uniformity of IMRT were better than those of 3D-CRT; it was better in reducing the dose of liver radiation, thus decreasing liver toxicity. In addition, Wei Gang et al. [
39] also showed that the radiation field distribution, homogeneity, and conformity of IMRT were superior to those of 3D-CRT in reducing the normal tissue radiation dose. Wieland et al. [
40] showed that the radiation dose of the kidney and liver was lower in the IMRT group than in the 3D-CRT group. The results were consistent with those of previous IMRT studies, which paved the way for IMRT as the stand-alone radiotherapy treatment for gastric cancer.
Although a strict retrieving and analysis strategy was used for a comprehensive meta-analysis, some limitations should be highlighted. First, the included studies had uneven quality and a limited number of participants; some of them were retrospective studies, increasing the risk of selective reporting bias. Second, the included studies were limited to Chinese and English databases, leading to language bias. Third, the heterogeneity of IMRT or 3D-CRT in different studies led to clinical heterogeneity and reduced the statistical power. Fourth, the survival data were not provided by different age and staging of patients with gastric cancer, particularly the lymph node status after resection. Therefore, it was not appropriate to analyze the impact of IMRT versus 3D-CRT on patient survival by age and tumor staging. Finally, the detail and radiation fields of radiotherapy varied among studies, leading to different toxicities and efficacy. The radiation dose of IMRT was higher than that of 3D-CRT in the study by Liu et al. [
26], but severe toxicity was similar for the two. The present meta-analysis also showed similar toxicity for IMRT and 3D-CRT, which was consistent with previous findings. Despite the aforementioned limitations, the findings of this meta-analysis might guide adjuvant therapies for resected gastric cancer.
Conclusions
In summary, this meta-analysis showed that IMRT was associated with a slight increase in the 3-year OS rate and a significant increase in the local control rate, without affecting the DFS rate or increasing the clinical toxicity rate, compared with 3D-CRT. Further studies, such as more rigorous, high-quality RCTs, are required to validate the effectiveness of IMRT in treating gastric cancer. Moreover, a dose–response curve for the radiation dose and potential injuries at specific sites should be explored.
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