Inoperable locally advanced non-small cell lung cancer: Survival rates of Endostar, CCRT
Inoperable locally advanced non-small cell lung cancer (NSCLC): An Introduction
Accounting for approximately 80% of lung cancers, non-small cell lung cancer (NSCLC) is the most common subtype. Most NSCLC patients are diagnosed at an advanced stage with a mere 15-20% rate of 5-year survival. Several clinical studies have shown that the prognosis could be improved by neither induction chemotherapy nor consolidation chemotherapy in addition to concurrent chemoradiotherapy. Therefore, there remains a great need to develop effective treatment modalities involving novel therapeutic agents in combination with CCRT to improve the outcome of locally advanced NSCLC.
Tumor angiogenesis plays an important role in tumor growth and response to chemotherapy. Hence anti-tumor angiogenesis is one of the most hottest areas of studies. Endostar, an anti-angiogenic target drug, is found to be efficient in inhibiting tumor endothelial cell proliferation and suppressing primary tumor and metastatic growth in lung cancer with less side effects. Studies reported that Endostar combined with platinum-doublet chemotherapy can prolong the survival time for advanced NSCLC patients. Some studies also showed that the mode of administration of Endostar combined with radiotherapy may affect the efficacy and side effects in the treatment in patients with advanced NSCLC.
Therefore, a retrospective analysis was conducted to evaluate how anti-angiogenesis therapy can temporarily ‘normalize’ the tumor vasculature, as well as whether the fortnightly-administration of Endostar in combination with CCRT can improve the 5-year survival rate in locally advanced NSCLC patients.
The Study Background
A Phase II, randomized, prospective, multicentric trial showed that Endostar plus concurrent chemoradiotherapy (CCRT) can improve the overall survival (OS) in patients with inoperable locally advanced non-small cell lung cancer (NSCLC). This retrospective study compares the 5-year survival rate of NSCLC patients who received a combination of Endostar and CCRT to that of patients who received only CCRT.
Patients and Methods
Ethics and consent
The protocol of the present study was approved by the Ethics Committee of The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital) (No. ZJZLYY-2012-10-24). All participating patients signed informed consent before being enrolled in this retrospective study. The study protocol strictly followed the Declaration of Helsinki.
A total of 227 treatment-naive patients with inoperable locally advanced NSCLC who had long-term follow-up data from 2009 to 2015 were screened and enrolled in this study. Excluding the patients with a radiotherapy dose of <60 Gy, 193 patients were included in the analysis, with 104 cases in the CCRT + Endostar group and 89 cases in the CCRT group.
Three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) was applied to both CCRT + Endostar and CCRT groups, and the dose of radical radiotherapy was given, conventional fractionated 2 Gy/F, once a day, five times a week.
All participants received concurrent platinum-based 2-drug CCRT including,
- EP regimen (etoposide 50 mg/m2, D1–D5; cisplatin 50 mg/m2, D1 and D8, repeated every 4 weeks)
- DP/C regimen [docetaxel 65 mg/m2, D1; cisplatin 65 mg/m2 or carboplatin area under the curve (AUC) =5, D1, repeated every 4 weeks)
- TP/C regimen (paclitaxel 135–175 mg/m2, D1; cisplatin 65 mg/m2 or carboplatin AUC =5, D1, repeated every 4 weeks)
- NP regimen (vinorelbine 60 mg/m2, D1 and D8; cisplatin 65 mg/m2, D1, repeated every 4 weeks)
- AP regimen (pemetrexed 500 mg/m2,D1; cisplatin 65 mg/m2, D1, repeated every 4 weeks)
- GP regimen (gemcitabine 1,000 mg/m2, D1 and D8; cisplatin 65 mg/m2, D1, repeated every 4 weeks)
7.5 mg/m2 Endostar per day was continuously administered to the CCRT + Endostar group for 5-7 days. Endostar was given 5-7 days before radiotherapy, and fortnightly during radiotherapy. This was repeated every 2 weeks for a total of four cycles.
- The OS was calculated as the duration from the start of treatment to death due to any cause.
- Local progression-free survival (LPFS) was calculated as the duration from the start of treatment to local tumor progression, which also included the relapse time of the primary lesion and regional lymph nodes.
- Distant metastasis-free survival (DMFS) was calculated as the duration from the start of treatment to the first appearance of distant metastasis.
- Kaplan-Meier method was used for survival analysis for patients with a radiation dose ≥60 Gy.
- Cox proportional-hazards regression model was used for univariate analysis.
- A P value of <0.05 was considered statistically significant.
Of the 227 patients with inoperable locally advanced non-small cell lung cancer screened from two prospective phase II clinical studies, 34 were excluded due to a Radiotherapy dose of <60 Gy. The 193 patients enrolled in the study were further divided into two groups: the CCRT + Endostar group with 104 patients and the CCRT group with 89 patients.
Baseline characteristics comparison of CCRT + Endostar & CCRT groups:
- Median age: 58 in CCRT + Endostar group and 56 years in CCRT group.
- Gender of participants: male – 84 (84.6%) in CCRT + Endostar group and 74 (83.1%) in CCRT group; females – 16 (15.4%) in in CCRT + Endostar group and 15 (16.9%) in CCRT group
- Active squamous cell carcinoma cases: 63 (60.6%) in CCRT + Endostar group and 40 (44.9%) in CCRT group.
- Stage IIIA and Stage IIIB: 33.7% and 66.3% in CCRT + Endostar group and 28.1% and 71.9% in CCRT group.
- Regimens of CCRT: EP regimen (61.5%) and DP regimen (38.5%) in CCRT + Endostar group; and a variety of platinum-based 2 drug chemotherapy regimens including TP/C regimen (53.9%), DP regimen (22.5%), EP regimen (3.4%), and (20.2%) of other regimens in CCRT group.
The observations and results of the survival analysis were as follows:
- The median follow-up times: 73.6 months (95% CI: 65.6 to 81.7 months) for the CCRT + Endostar group and 66.3 months (95% CI: 52.7 to 79.9 months) for the CCRT group.
- Participants died: CCRT + Endostar group: 72 participants (64 due to lung cancer progression, 5 due to other diseases, and 2 due to treatment complications, and 1 with unknown cause); CCRT group: 62 participants (60 due to lung cancer progression, and 2 due to other diseases).
- The median survival times: CCRT + Endostar group: 29.7 months (95% CI: 22.8 to 36.6 months); CCRT group: 21.3% (95% CI: 15.9 to 26.7 months).
- 5-year survival rates: CCRT + Endostar group: 34.7%; CCRT group: 23.6% (p=0.038)
Late-stage adverse reactions
Late-stage lung injury and esophageal injury were the predominant late-stage adverse reactions and were evaluated according to standards of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC).
There was no occurrence of grade 4–5 late-stage lung injury in both groups however a single case of grade 3 injury was reported in the CCRT + Endostar group.
The CCRT group showed higher incidence rates of grade 1 (33.7% ) and grade 2 (14.4%) lung injury than that in the CCRT + Endostar group which were 9.1% and 3.8% respectively (P=0.002).
The incidence rate of late-stage esophageal injury was 5.6% in the CCRT + Endostar group and 1.0% in the CCRT group.
CCRT is considered standard for care for inoperable locally advanced non-small cell lung cancer (NSCLC), but the optimal treatment strategies to improve the efficacy are still being studied. Tumor radiation resistance in NSCLC patients is also a major challenge. This retrospective analysis indicates that Endostar combined with radical CCRT presents a promising treatment modality in the treatment of inoperable locally advanced non-small cell lung cancer along with better efficacy and survival benefit.
The follow-up data available for the two study groups indicated a follow-up time of 5+years (73.6 months for CCRT + Endostar group and 66.3 months for the CCRT group). The median OS and 5-year OS rates of the CCRT + Endostar group were significantly higher than the CCRT group (29.7 vs. 21.3 months, 34.7% vs. 23.6%, respectively, P=0.038).
A phase III randomized, double-blind, study by Zhou Q, Chen M, Wu G, et al in stage III unrespectable inoperable locally advanced non-small cell lung cancer (NSCLC) patients reported the median follow-up time to be 52 months, the median OS 15 months, the 3-year survival rate 17%, and the 5-year survival rate 15%. According to a two-center retrospective study using cetuximab combined with CCRT to treat stage III NSCLC patients, the median follow-up time was 32 months, and the median OS was 25.2 months. The RTOG 0617 study compared and determined the efficacy of cetuximab for stage III non-small-cell lung cancer (NSCLC). The median follow-up time was 5.1 years, the median survival time was 28.7 and 20.3 months, and the 5-year OS rate was 32.1% and 23%, respectively.
The PACIFIC study using durvalumab after chemo-radiotherapy in stage III non-small-cell lung cancer reported the median follow-up time to be 25.2 months. The progression-free survival was significantly longer with durvalumab and the safety was similar between the placebo and the group that received durvalumab. For this reason, durvalumab consolidation immunotherapy after CCRT became the new standard treatment for LA-NSCLC. Based on this H Ma et. al did not further carry out a prospective RT to compare the efficacy of neither CCRT nor CCRT + Endostar. Since the PACIFIC study only had participants who had no disease progression after CCRT, challenges remained to overcome radiation resistance in patients.
Recent studies have also shown that vascular-normalizing lower doses of anti-VEGF receptor 2 (VEGFR2) antibody can reprogram the tumor microenvironment away from immunosuppression thereby increasing the efficacy of immunotherapies. Endostar, an antiangiogenic drug, has a better safety profile than that of other antiangiogenic drugs. Recombinant human endostatin (rhE, Endostar), a C-terminal fragment naturally derived from type XVIII collagen can specifically inhibit the activity of vascular endothelial growth factor to block angiogenesis as well as induce cancer cell apoptosis and, this could simulate the roles of endostatin tumor suppression in vivo. However, more studies remained to be conducted to further confirm the link between Endostar’s low dosage and its safety profile.
Besides Endostar, bevacizumab and Anlotinib were the most applied anti-angiogenic drugs. Previous studies showed that Endostar still has an edge over the other drugs as it is better suited for a variety of pathologic types, has wider patient coverage, and is less toxic. The reported side effects of anti-angiogenic drugs include vascular events, cardiovascular toxicity, proteinuria, delayed wound healing, intestinal perforation, and esophagotracheal fistula. Studies also showed a 31% risk of pulmonary hemorrhage for squamous cell carcinoma and a 4% risk of pulmonary hemorrhage for other pathological subtypes.
When administered fortnightly, Endostar showed better tolerance in the prospective phase II clinical study. The researchers found no serious anti-angiogenesis drug-related bleeding adverse reactions except for one case of grade 5 hemoptysis. The most common acute toxicity was attributed to the chemoradiotherapy side effects, including blood toxicity, esophagitis, and pneumonia. The incidence rate was lower or similar to that reported from the previous CCRT studies for inoperable locally advanced non-small cell lung cancer. In this study, the incidence rate of grade 3–5 acute radiation pneumonitis was 6.8% in Endostar + CCRT group, which was still lower than that reported by Cancer and Leukemia Group B (CALGB) 30407.
In this study, except for one case of grade 3 late-stage lung injury in the CCRT + Endostar group, there were mainly grade 1 and grade 2 lung injuries in two groups. The incidence rate of the CCRT + Endostar group was only 19.2% whereas the CCRT group had an incidence rate of 42.8%. Among 4 participants in the CCRT group who received the GP regimen, 2 patients developed grade 1 late-stage lung injury, 1 developed grade 2 lung injury, and no patient developed ≥ grade 3 lung injury. It was also observed that the incidence rate of late-stage radiation-induced lung injury was not higher than other chemotherapy regimens.
This study has several limitations. Firstly, this was a retrospective study with small sample size. Secondly, the heterogeneity of the participants should be further considered in the future to reduce potential selective bias. Thirdly, the current results suggest that Endostar combined with CCRT is effective; however, the differences in efficacy and safety in relation to dosage, frequency, and course of treatment should be further investigated. Further well-designed prospective randomized controlled clinical trials (RCTs) are warranted to reach definitive conclusions.
The combination of fortnightly-administration of endostar and concurrent chemoradiotherapy significantly improved the median OS and 5-year survival rate for patients with inoperable locally advanced non-small cell lung cancer.
The side effects were significantly lower than those of patients received radical CCRT.
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