Is consolidation chemotherapy after concurrent chemo-radiotherapy beneficial for patients with locally advanced non-small cell lung cancer?

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1 Is consolidation chemotherapy after concurrent chemo-radiotherapy beneficial for patients with locally advanced non-small cell lung cancer? ~A pooled analysis of the literature~ Satomi Yamamoto 1, Kazuyuki Tsujino 2, Masahiko Ando 3, Tomoya Kawaguchi 1, Akihito Kubo 4, Shunichi Isa 1, Yoshikazu Hasegawa 5, Sai-Hong Ignatius Ou 6, Minoru Takada 7, Takayasu Kurata 8 1 National Hospital Organization Kinki-Chuo Chest Medical Center, 2 Osaka University Graduate School of Medicine, 3 Nagoya University Hospital, 4 Aichi Medical University School of Medicine, 5 Kishiwada City Hospital, 6 Chao Family Comprehensive Cancer Center, University of California Irvine, 7 Sakai Hospital Kinki University Faculty of Medicine, 8 Kinki University School of Medicine

2 Background-1 Approximately 30% of patients with NSCLC present with stage III locally advanced disease (LA-NSCLC). Patients with LA-NSCLC who have a good Performance Status (PS) and adequate organ function have a chance of long-term survival and could be potentially cured. Clinical trials demonstrated that concurrent administration of 2 cycles of chemotherapy with thoracic radiotherapy (TRT) improved overall survival compared with RT alone and/or sequential chemoradiotherapy. The standard treatment for patients with LA-NSCLC is concurrent chemoradiotherapy. Despite recent progress, the prognosis for the vast majority of LA-NSCLC patients remains poor.

3 Background-2 New strategies such as radiation methods, radiation dose, optimal chemotherapy regimen, prophylactic cranial irradiation, and molecular targeted agents, are needed to improve clinical outcome. Consolidation chemotherapy is an attractive approach, but, until now, few randomized studies have been reported. The Hoosier Oncology Group performed a randomized phase III study and reported that consolidation chemotherapy with docetaxel increased toxicities with no survival benefit. 1) There is insufficient evidence indicating that consolidation chemotherapy improves survival without increasing toxicities. 1) Hanna N et al; J Clin Oncol 26: , 2008.

4 Objective The purpose of this study is to determine whether consolidation chemotherapy is beneficial for patients with LA-NSCLC in terms of survival prolongation and toxicities.

5 Literature search We systematically searched PubMed for phase II or phase III trials published between January 1, 1995 and October 31, 2011, examining survival of concurrent chemo-radiotherapy for LA-NSCLC. The key words for systematic search were: non-small cell lung cancer, radiation or radiotherapy, concurrent or concomitant and phase II or phase III. All search was limited to English language and studies with more than 30 patients per arm. Studies with no survival data were excluded.

6 Data collection For each trial arm, the following data were collected. Median overall survival (OS) Regimens of chemotherapy Radiation doses Delivery of treatment Study size Grade 3-5 toxicities Patient characteristics, e.g., ethnicity, gender, age and PS

7 Statistical analysis To calculate a pooled median OS from survival data in individual study arms, we extracted log-transformed hazards and its standard errors under the assumption that survival follows an exponential distribution, and computed a pooled median OS and its 95% Confidence interval (CI) using a random-effect model. We used Student t-test, Kruskal-Wallis test, or Pearson Chi-square test to examine a difference in the distribution of targeted values among trial arms, or in the proportion of targeted trial arms.

8 Classification of studies examined Without consolidation chemotherapy (CCT-) PL+A TRT PL+A With consolidation chemotherapy (CCT+) PL+A TRT PL+A Continuation consolidation chemotherapy (CCCT) PL+A B Chemotherapy Thoracic radiotherapy PL: platinum A, B: cytotoxic agent Switch consolidation chemotherapy (SCCT)

9 Results of systematic search Systematic search using key words (n=1,209) Potentially relevant references identified and screened for retrieval (n=506) Not English-language (n=144), Not phase II or phase III (n=559) Not clinical trials (n=98). Non NSCLC (n=40). Not concurrent chemoradiotherapy (n=26). Not phase II or phase III (n=102). Including Surgery or induction chemotherapy (n=105). No survival endpoint (n=15). Not platinum doublet chemotherapy (n=44). Small study size (n=14). Potentially appropriate trials to be included (n=62) OS did not reach to median (n=3). Including patients with Stage I/II/IV (n=5). Limiting to poor PS, poor risk, or elderly patients (n=8). Excluding patients with progressive diseases after chemoradiotherapy (n=3). Reanalyzed studies which are already included (n=2). 41 studies (7 PIII studies and 34 PII studies) with 45 arms. Without CCT (CCT-): 20 arms (No. of patients: 1,740) With CCT (CCT+): 25 arms (CCCT: 21 arms, SCCT: 4 arms) (No. of patients: 1,707)

10 Patient characteristics between two groups CCT- CCT+ mean SD mean SD p Age median age Gender % of female Histology % of Squamous cell carcinoma % of Adenocarcinoma Stage % of Stage IIIA % of Stage IIIB Performance Status (PS) % of PS % of PS % of PS There were no statistical differences between two groups.

11 Treatment administrations CCT- CCT+ mean SD mean SD p Concurrent phase Planned TRT dose (Gy) % of patients who completed TRT % of patients who completed chemotherapies Consolidation phase Number of planned CCT cycles Median number of delivered CCT cycles Mean number of delivered CCT cycles The planned doses of thoracic radiotherapy were comparable between two groups. In concurrent phases, % of patients had completed radiotherapy/chemotherapy in both groups.

12 Factors influencing on median overall survival Median OS (month) Study characteristics Total No. mean SD p Clinical trial Phase II Phase III Chemo regimen CDDP CBDCA Period Region Asian Non-Asian No significant difference was found in the distribution of clinical trial, chemo regimen, period, and region between CCT- and CCT+ (p 0.182).

13 Standard Errors Funnel plots based on survival data All study arms CCT- 0.0 CCT log-transformed hazards Hazard was calculated as log(2)/median OS. These data indicates that there is no evidence of publication bias.

14 Individual and pooled median OS month CCT- CCT (95%CI: ) 18.5 (95%CI: ) HR= 0.98 (95%CI: ) p= *Adjusted HR= 0.95 (95%CI: ) p= * Adjusted for period and region. I 2 values for assessing heterogeneity were 15.3% in all studies.

15 Subgroup analysis of hazard ratio (Comparison between CCT+ and CCT-) Period Region Asian Non-Asian Clinical Trial Phase II Phase III Total Hazard ratio (95%CI) 1.15 ( ) 0.96 ( ) 0.91 ( ) 0.84 ( ) 1.01 ( ) 1.03 ( ) 0.94 ( ) 0.98 ( ) p Favors CCT+ 1 2 Favors CCT-

16 Toxicities between two groups CCT- CCT+ Grade 3-5 toxicities mean SD mean SD p Neutropenia (%) Leukopenia (%) Esophagitis (%) Pneumonitis (%) Treatment-related death (%) Toxicities throughout the whole treatment courses were comparable.

17 Discussion Although there are some potential limitations including heterogeneity among selected studies, this pooled analysis showed that consolidation chemotherapy did not improve median overall survival. Consolidation chemotherapy after concurrent chemoradiotherapy should not be recommended outside of a clinical trial. Unexpectedly, toxicities throughout treatment courses between two groups were comparable. One possible explanation may be that the number of delivered courses of consolidation chemotherapy was lower than planned. Incorporation of molecular targeted agents based on gene alterations could be one option in designing clinical trials.

18 Conclusions This pooled analysis on publication basis failed to provide evidence that consolidation chemotherapy improves overall survival in patients with LA-NSCLC. Clinical trials to evaluate the impact of consolidation chemotherapy are warranted.