In this trial, the PR rate and the objective effective response rate were both 72.4%, and the disease control rate was 93.1%, and no participants experienced a CR. In previous clinical trials of concurrent CRT the CR rate was 9–28%, the PR rate was 28–81%, and the objective effective response rate was 43–85% [2–11,14]. Among participants in previous studies who received radiotherapy only, or sequential chemotherapy and radiotherapy, the CR rate was 1.3–30%, the PR rate was 30–65%, and the objective effective response rate was 39–66%. Although none of the participants in our study experienced a CR, the PR rate and the objective effective response rate were comparable to those of previous studies.
The reason for the absence of any participants with a CR in this study may be attributable to: the high proportion of participants with stage Ⅲ B disease (76%); older age (50% were aged ≥65 years); high PTV (62% had a PTV volume >450 ml); the relatively small proportion of participants with adenocarcinoma (41%). The relatively high PR rate and objective effective response rate compared to previous studies may be attributable to the higher rates of completion of radiotherapy (97%) and targeted therapy (83%).
In the CALB30106 trial [12] the high-risk group (radiotherapy and gefitinib) had a MST of 19.0 months and median PFS of 13.4 months; while the low-risk group (concurrent CRT and gefitinib) had a MST of 13 months and a median PFS of 9.2 months. The survival time of high-risk patients who received sequential CRT with gefitinib is promising. Spanish researchers [15] studied 90 patients with locally advanced NSCLC. The MST was 11.4 months among those who received radiotherapy only, and 8.9 months among those who received radiotherapy with erlotinib, and the median PFS was 15.3 months and 12.9 months, respectively. Wang et al reported that EGFR-TKI concurrent with thoracic radiotherapy in treating stage ⅢB/Ⅳ NSCLC had local control rate of 96% for thoracic tumor and 1-year PFS rate of 42% [16]. Zheng et al reported that the 1-year PFS rate of 57.1%, the median PFS 13 months and the median time to progression of irradiated lesion 20.5 months in TIK combined with radiotherapy as first line treatment for patients with stage Ⅳ NSCLC harboring EGFR active mutations [17]. In the RTOG 9410 trial [4], the MST was 17 months among participants who received 60 Gy of CRT, and 15.6 months among those who received 70 Gy of CRT. Compared with radiotherapy only and concurrent CRT, the survival of participants who received radiotherapy combined with targeted therapy is comparable to that of the participants in our study.
In our study, the OS and PFS of participants with stage Ⅲ B disease was higher than that of participants with stage Ⅲ A disease. Possible reasons for this paradoxical result include: (1) participants with stage Ⅲ A disease had more risk factors than those with Ⅲ B disease including older age, greater weight loss, more comorbidities, less healthy lifestyles, and larger primary tumors; (2) participants with stage Ⅲ B disease were more likely to have adenocarcinoma and EGFR mutations than those with stage Ⅲ A disease; (3) participants with stage Ⅲ B disease received more induction chemotherapy; and (4) participants with stage Ⅲ A disease suffered more acute toxicities.
In our study, participants with the EGFR-activating mutation had a better MST than those with the EGFR wild-type and those with non-adeno carcinomatous tumors. This result suggests that there is an association between the EGFR mutation state and response to radiotherapy combined with targeted therapy. Previous studies have shown that among patients with NSCLC, approximately 80% have squamous cell carcinoma, and 65% of patients with adenocarcinomas have overexpression of EGFR protein, which is an important factor leading to radiation resistance [18–19]. A meta-analysis conducted in 2002 suggested that a high EGFR expression could be related to the prognosis of NSCLC [20]. However, the CALGB 30106 trial [12] did not find an association between the presence of EGFR mutations and the prognosis of NSCLC. Although the relationship between EFGR-mutation and prognosis in advanced lung adenocarcinoma was relatively clear, the heterogeneity was relatively large among participants with locally advanced lung adenocarcinoma who were able to receive radiotherapy and chemotherapy. For locally advanced lung cancer, there are no prospective studies that have assessed whether individuals with EGFR-activating mutations could benefit from targeted therapy as the first-line treatment. Our study suggests that radiotherapy combined with gefitinib could improve the survival of patients with locally advanced EGFR-activating mutation lung adenocarcinoma.
In this study, the majority of acute adverse events (93%) were grades 1 and 2; only 7% of participants experienced a grade 3 acute adverse event, and no participants experienced a grade 4 acute adverse event. These results indicate that radiotherapy combined with gefitinib was well tolerated.
Irradiation pneumonia is an important adverse event among patients treated with TRT. In our study, the incidence of grade 2 acute irradiation pneumonitis was 24%, but there were no cases of more than grade 3 acute irradiation pneumonitis. Compared with concurrent CRT (which has a reported rate of grade 3 acute irradiation pneumonitis of 0–18%) [2–11], targeted therapy combined with radiotherapy did not significantly increase the incidence of related adverse events. Although irradiation pneumonia did not cause any treatment-related deaths among participants in our study, the pulmonary toxicity associated with EGFR-TKIs is a cause for concern. Zheng et al reported that the most common grade 3 adverse events were radiation pneumonitis (20%) and rash (10%) in TIK combined with radiotherapy as first line treatment for patients with stage Ⅳ NSCLC harboring EGFR active mutations [17]. A study [21] of the relationship between radiotherapy combined with erlotinib and acute irradiation pneumonitis among 24 patients with NSCLC, suggested that 9 patients (37.5%) experienced greater than grade 2 acute irradiation pneumonitis. Other studies have shown that erlotinib can damage the lung stroma [22–23], and erlotinib combined with TRT may increase the occurrence of acute irradiation pneumonitis. Some small sample studies [24–25] also reported there was a higher incidence of acute irradiation pneumonitis among patients treated with erlotinib combined with TRT.
This trial had several limitations. First, some patients received induction chemotherapy, but the induction chemotherapy regimens and chemotherapy cycles were not standardized. Second, this study was a single-arm, phase Ⅱ clinical trial with no control group. Third, the sample was small.