Concurrent chemo-radiotherapy (CT-RT) is considered the standard treatment for patients with stage III NSCLC.
Patients with locally advanced NSCLC are technically curable, but the majority of these patients will die from distant metastatic disease.
There is a growing interest on the efficacy of maintenance chemotherapy to treat metastatic non-small cell lung cancer (NSCLC) and adjuvant chemotherapy to treat early stage NSCLC; however, the role of consolidation chemotherapy (CCT) after concurrent chemo-radiotherapy in locally advanced NSCLC (LA- NSCLC) is not as well understood.
The HOG study (Hanna et al., JCO, 2008) randomized patients with locally advanced NSCLC to 3 cycles of consolidation docetaxel vs. observation after definitive treatment with concurrent chemoradiation. There was no difference in overall or progression-free survival with or without consolidation docetaxel and the patients who received docetaxel had a higher incidence of hospitalization, pneumonitis, and treatment-related death
Similarly, a SWOG study (Kelley et al., JCO, 2008) randomized stage III NSCLC patients to gefitinib vs. placebo after treatment with definitive chemoradiation followed by consolidation therapy with docetaxel x 3 cycles. Again, no benefit was noted with additional consolidation/maintenance chemotherapy.
Despite the negative results in prior studies, studies are investigating the use of consolidation with different chemotherapy agents, given the strong need to improve distant failure and overall survival rates
The purpose of the current study is to determine whether consolidation chemotherapy is beneficial for patients with LA-NSCLC in terms of survival prolongation and toxicities.
Materials and Methods
This is a meta-analysis of phase II/III trials examining survival of locally-advanced NSCLC patients treated with concurrent chemo-radiotherapy between January 1, 1995 and October 31, 2011.
Median overall survival (mOS) and corresponding 95% confidence interval (CI), regimens of chemotherapy, radiation (RT) doses, delivery of treatment, study size, grade 3-5 toxicities and patient characteristics were collected from each study and pooled.
The authors extracted log-transformated hazard ratios and standard errors under the assumption that survival follows an exponential distribution, and computed a pooled mOS and its 95% CI using random-effect model.
Trial arms were divided into two groups by the presence of consolidation chemotherapy (CCT): Arm with CCT (CCT+) and without CCT (CCT-).
Forty-five studies were identified:
The 45 studies included a total of 3447 patients.
There were 9 phase III studies and 36 phase II studies with 51 arms (CCT+: 29, CCT-: 22)
Clinical data were comparable in clinical stage, performance status, cancer histology, gender, and median age between the two groups.
Chemotherapy regimens were cisplatin or carboplatin based.
The mean planned RT dose was 62.85 Gy in the in the CCT+ studies and 62.7 Gy in the CCT – studies (p = 0.958).
I2 values for assessing heterogeneity were 15.3, 9.1 and 24.2% in overall, CCT+ and CCT- studies, respectively.
There was no statistical difference in pooled mOS between CCT+ (18.5 month, 95%CI: 16.7-20.5) vs CCT- (18.1 month, 95%CI: 16.5-20.2).
Factors influencing median overall survival included:
Time period of study: mOS: 16.4 vs. 19.1 vs. 21.4 months for 1995-2000 vs. 2001-2005 vs. 2006-2011, respectively. P = 0.022
Geographic region: mOS: 21.12 vs. 17.65 months for Asian vs. Non-Asian regions, respectively. P = 0.035
After adjusting for these factors, there was still no difference in pooled mOS between CCT+ vs. CCT-
With regard to ? grade 3 toxicities (pneumonitis, esophagitis, and neutropenia) and treatment-related death, there was no difference between the two groups throughout the whole treatment courses.
The authors concluded that the pooled analysis on publication basis failed to provide evidence that consolidation chemotherapy yields significant survival benefit for locally advanced NSCLC. Therefore, consolidation chemotherapy after concurrent chemoradiation should not be recommended outside of a clinical trial.
These data, demonstrating no significant benefit in survival with consolidation chemotherapy, is consistent with prior studies evaluating the role of consolidation chemotherapy after definitive therapy with concurrent chemoradiation in locally advanced NSCLC.
The study is a large meta-analysis with 3447 patients and 45 studies. The inherent flaws of meta-analyses include the comparison of heterogeneous patient populations with heterogeneous treatments. Despite this, meta-analyses provide a means to compare large numbers of patients
The problem with using a meta-analysis to determine the role of consolidation chemotherapy is the dependence of treatment response on unique patient and tumor characteristics. Subgroups of patients that respond to treatment need to be identified. Therefore, a meta-analysis is not an optimal way to assess the question of the role of consolidation chemotherapy for specific patient sub-populations; still, the authors’ conclusion that consolidation chemotherapy should not be offered to NSCLC patients outside of a clinical trial is reasonable. Future trial may investigate the potential role of consolidation regimens for specific patient populations.
Systemic relapse in locally advanced NSCLC is an important issue and more well designed, phase III randomized trials are necessary to improve outcomes in these patients.
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