Induction Chemoradiation Is Not Superior to Induction Chemotherapy Alone in Stage IIIA Lung Cancer

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1 Induction Chemoradiation Is Not Superior to Induction Chemotherapy Alone in Stage IIIA Lung Cancer Asad A. Shah, MD, Mark F. Berry, MD, Ching Tzao, MD, PhD, Mihir Gandhi, MS, Mathias Worni, MD, Ricardo Pietrobon, MD, MPH, and Thomas A. D Amico, MD Department of Surgery, Duke University Medical Center, Durham, North Carolina; Division of Thoracic Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Biostatistics, Singapore Clinical Research Institute, Singapore; Centre for Quantitative Medicine, Office of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore GENERAL THORACIC Background. The optimal treatment strategy for patients with operable stage IIIA (N2) non-small cell lung cancer is uncertain. We performed a systematic review and meta-analysis to test the hypothesis that the addition of radiotherapy to induction chemotherapy prior to surgical resection does not improve survival compared with induction chemotherapy alone. Methods. A comprehensive search of PubMed for relevant studies comparing patients with stage IIIA (N2) non-small cell lung cancer undergoing resection after treatment with induction chemotherapy alone or induction chemoradiotherapy was conducted using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standards. Hazard ratios were extracted from these studies to give pooled estimates of the effect of induction therapy on overall survival. Results. There were 7 studies that met criteria for analysis, including 1 randomized control trial, 1 phase II study, 3 retrospective reviews, and 2 published abstracts of randomized controlled trials. None of the studies demonstrated a survival benefit to adding induction radiation to induction chemotherapy versus induction chemotherapy alone. The meta-analysis performed on randomized studies (n 156 patients) demonstrated no benefit in survival from adding radiation (hazard ratio 0.93, 95% confidence interval 0.54 to 1.62, p 0.81), nor did the meta-analysis performed on retrospective studies (n 183 patients, hazard ratio 0.77, 95% confidence interval 0.50 to 1.19, p 0.24). Conclusions. Published evidence is sparse but does not support the use of radiation therapy in induction regimens for stage IIIA (N2). Given the potential disadvantages of adding radiation preoperatively, clinicians should consider using this treatment strategy only in the context of a clinical trial to allow better assessment of its effectiveness. (Ann Thorac Surg 2012;93: ) 2012 by The Society of Thoracic Surgeons Lung cancer is the most common cause of death by malignancy, both in the U.S. [1] and worldwide [2]. The role of surgery in treatment of stage IIIA (N2) nonsmall cell lung cancer (NSCLC) [3] remains controversial as there is not yet an agreement on the definition of operable versus nonoperable stage IIIA [4]. Induction chemotherapy followed by surgery has been demonstrated to improve survival in selected patients with stage IIIA NSCLC [4 7]. However, the use of radiation therapy in induction therapy regimens is less clear, and the survival benefits of induction chemoradiation therapy have not been clearly demonstrated [8]. Recently, a randomized clinical trial attempted to answer this question, but failed to be completed [9]. Examination and synthesis of the limited available data comparing induction chemotherapy and induction chemoradiotherapy may allow physicians to determine the optimal induction regimen for patients with IIIA (N2) disease. The objective of this study was to perform a systematic review and Accepted for publication March 8, Address correspondence to Dr D Amico, Section of Thoracic Surgery, Duke University Medical Center, DUMC Box 3496, Durham, NC 27710; damic001@mc.duke.edu. meta-analysis of available data to determine if induction chemoradiotherapy is superior to induction chemotherapy alone in patients with operable stage IIIA (N2) NSCLC. Patients and Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used as the basis for reporting the materials and methods of this study [10]. The PRISMA statement is a consensus document created by international authors and methodologists that provides an evidence-based guideline for reporting the results of systematic reviews and metaanalyses in a clear, accurate, and reliable manner [10]. Eligibility Criteria Studies containing potentially operable patients with stage IIIA (N2) NSCLC receiving induction chemotherapy and induction chemoradiotherapy were eligible for review. Studies focusing on particular groups of patients such as only the elderly, women, and those with tumors in particular locations only were excluded. Randomized, nonrandomized, and retrospective studies were all eligible for inclusion by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 GENERAL THORACIC 1808 SHAH ET AL Ann Thorac Surg INDUCTION THERAPY FOR LUNG CANCER 2012;93: Information Sources Studies were identified by searching electronic databases and examining references of relevant publications. PubMed was searched for English language articles meeting the eligibility criteria published between January 1, 1990 and December 28, The search was limited to studies in humans. The last search was performed on December 28, References of relevant articles and book chapters were also searched. Search We used the following search strategy for searching PubMed: (non-small cell lung cancer) and (induction therapy or chemotherapy or radiation) and (resection or surgery). Limits included dates (January 1, 1990 to December 28, 2010), English language, and studies in humans. Study Selection Eligibility assessment was first performed by screening titles and abstracts identified by the previously described searches and sources. This was performed independently by 2 separate authors in an unblinded, standardized manner. Disagreements between reviewers were resolved by consensus. The full texts of shortlisted studies were reviewed and further assessed. All review authors decided on study inclusion. Data Collection Process We created a data extraction sheet to capture all data needed to assess the quality and eligibility of studies and perform a systematic review and meta-analysis. Data from eligible studies were extracted by 1 author and then independently by a second author. Disagreements were solved by discussion between the 2 authors. We attempted to contact authors of 6 of the studies [11 16] included in the systematic review to obtain sufficient data to perform the meta-analysis, as data available in these published manuscripts were insufficient to perform quantitative analyses. We received unpublished data from 4 of them [11, 12, 14, 15]. Data Items Variables for which data were sought included the following: patient-related information (number of patients overall and in each group, diagnosis, stage of disease, etc), inclusion and exclusion criteria of study, type of intervention (induction chemotherapy, induction radiotherapy, surgery, etc), and outcomes (median survival, 3-year survival, differences in survival between groups [percentages, hazard ratios, confidence intervals, p values], postoperative complications, etc). Recorded survival times and hazard ratios were based on intention-to-treat analyses when applicable. As data were directly obtained from some authors of included manuscripts, survival data were often updated when compared with published results. Additionally, we included survival data of patients specifically with stage IIIA (N2) disease undergoing neoadjuvant therapy followed by surgery, which was directly obtained from authors of included studies, as this was not specified in some of the published manuscripts. When hazard ratios and confidence intervals were not provided, they were extracted from life Fig 1. Flow diagram of patients included in systematic review and meta-analysis. tables provided by authors, or Kaplan-Meier curves and the maximum follow-up time reported in manuscripts [17]. Risk of Bias in Individual Studies Risk of bias in individual studies was assessed independently by 2 authors. Characteristics assessed by 2 authors included concealment of randomization sequence and proportion of patients lost to follow-up. Summary Measures and Synthesis of Results The primary outcome was hazard ratio of overall survival with induction chemotherapy versus chemoradiotherapy. Heterogeneity in clinical design was ascertained by examination of the table of characteristics of included studies. Statistical heterogeneity was quantified using the I 2 statistics and 2 -based tests. When warranted, pooling was made under a random effect model, in view of anticipated differences in clinical design [18]. Data were analyzed in the Revman Review Manager V5 software [19]. Results The initial PubMed search yielded 3,277 studies, and review of bibliographies revealed 2 additional studies (Fig 1). Thus, there were 3,279 studies that underwent initial review, but 3,271 were discarded after abstract and title review demonstrated they did not meet inclusion criteria. The full texts of the remaining 8 studies were further examined. One of these studies was eliminated as it reported preliminary data of an included study [20]. Thus, a total of 7 studies were included in the systematic review, including 1 randomized control trial, 1 phase II study, 3 retrospective reviews, and 2 published abstracts of randomized controlled trials (Table 1). Table 2 details the staging and treatment details for each of the studies. Individually, none of the studies demonstrated a survival benefit to adding induction radiation therapy to induction chemotherapy versus induction chemotherapy alone (Table 1). Four of these studies contained randomized patients to attempt to use in the meta-analysis [11 14]. However, we were unable to incorporate 2 of these studies into the

3 Ann Thorac Surg SHAH ET AL 2012;93: INDUCTION THERAPY FOR LUNG CANCER Table 1. Studies Included in Systematic Review and Meta-Analyses Number of Patients Median Survival (months) 3-Year Survival (%) First Author Study Design Study Years Chemo Chemo RT Chemo Chemo RT Chemo Chemo RT 1809 p Value GENERAL THORACIC Thomas et al [14] Randomized control trial Sauvaget et al Randomized control trial [13] (abstract) Fleck et al [12] a Randomized control trial (abstract) Girard et al [11] Phase II trial b b b 0.40 Higgins et al [21] Retrospective review Pezzetta et al [15] Retrospective review Li et al [16] Retrospective review a Includes a minority of stage IIIB patients. b Arm B. Arm C not chosen given lack of available survival data. RT radiation therapy. meta-analysis due to lack of available data [12, 13]. The abstract by Fleck and colleagues [1] did not separate survival results for patients with stages IIIA versus IIIB who underwent surgery, and the abstract by Sauvaget and colleagues [13] did not specify the number of stage IIIA (N2) patients. Only 2 randomized studies were thus available for the quantitative meta-analysis [11, 14]. With only 2 studies, estimates of statistical heterogeneity were deemed imprecise. The estimated proportion of between-study variability (I 2 ) was 38% for the hazard ratio for survival of induction chemotherapy versus induction chemoradiotherapy. Based on the 2 test, no significant statistical heterogeneity was found, but this is likely due to low statistical power (Fig 2). Using a random effect model, pooling of data from both studies (n 156 patients) demonstrated no benefit to the addition of radiation to induction chemotherapy versus induction chemotherapy alone (hazard ratio 0.93, 95% confidence interval 0.54 to 1.62, p 0.81) as assessed for hazard ratio of overall survival. Given the limited number of studies with available randomized data on stage IIIA (N2) patients comparing induction chemotherapy to induction chemoradiotherapy, we performed a meta-analysis on the available retrospective studies comparing these 2 strategies. We were unable to use the study by Li et al [16] as insufficient data were available to extract a hazard ratio. A metaanalysis was thus performed on 2 retrospective studies (Fig 3) [15, 21]. The estimated proportion of betweenstudy variability (I 2 ) was 0% for the hazard ratio of survival for induction chemotherapy versus induction chemoradiotherapy. Using a random effect model, pooling of data from these 2 studies (n 183 patients) demonstrated no statistically significant benefit to the addition of induction radiation to induction chemotherapy versus induction chemotherapy alone (hazard ratio 0.77, 95% confidence interval 0.50 to 1.19, p 0.24) as assessed for hazard ratio of overall survival (Fig 3). Comment The optimal treatment approach for patients with stage IIIA (N2) NSCLC remains uncertain [4, 7, 22, 23]. Issues that are currently debated include whether surgery should be included in the regimen at all [4, 7, 22], whether patients considered eligible for resection should be restaged surgically to determine operability [4, 7, 24, 25] and whether induction regimens should include radiation therapy. While induction chemotherapy has been shown to improve overall survival in patients with operable stage IIIA NSCLC, the addition of radiation therapy to the regimens has not [4 7]. We chose to perform a systematic review and metaanalysis to determine if induction chemoradiotherapy is superior to induction chemotherapy alone in patients undergoing resection for stage IIIA (N2) NSCLC because the current available published studies have not uniformly answered this important question. Additionally, we chose this method because an exhaustive review of the literature on this topic has yet to be performed. Given the failure of numerous clinical trials attempting to answer this question as well as the small sample sizes of individual published studies on this topic, we attempted to evaluate and synthesize the available data to provide clinicians with summarized evidence-based information to guide them in taking care of patients with stage IIIA (N2) disease. There are several potential advantages of using chemotherapy alone in induction regimens. First, without radiation therapy it may be possible to have a higher delivery of preoperative chemotherapy. As most recurrences are distant, this may contribute to improved survival [7, 26]. Second, an important goal of induction therapy is to assess the biology of the tumor. The efficacy of chemotherapy may be assessed by restaging the mediastinum prior to resection [4, 7, 24, 25]; however, the accurate assessment of nodal downstaging solely as a result of chemotherapy administration is not possible if radiation is also given concurrently. As well, interrupting potentially curative definitive doses of chemoradiation therapy for surgical exploration is deleteri-

4 GENERAL THORACIC Table 2. Characteristics of Included Studies Study Thomas et al [14] Method of Mediastinal Staging PET Use Radiation Dose Chemo Regimen Mediastinoscopy Ch: 96% ChRT: 94% Method of Restaging After Induction Therapy Gy Cisplatin Etoposide Systematic LN dissection Ch: 62% ChRT: 58% LN sampling Ch: 29% ChRT: 33% Exploratory thoracotomy Ch: 8% ChRT: 8% Sauvaget et al [13] Gy Cisplatin Mitomycin Vinblastine Fleck et al [12] cgy in 15 fractions Girard et al [11] Higgins et al [21] Mediastinoscopy PET Mediastinoscopy or VATS (87%) Cisplatin Mitomycin Vinblastine Variable 46 Gy Cisplatin Gemcitabine Ch: 61% ChRT: 67% 45 Gy (median) Platinum doublet (97%) Progression-Free Survival Ch: 10 ChRT: 9 (median months, p 0.69) Complete Pathological Response Ch: 2% ChRT: 5% 5-Year Survival Ch: 12% ChRT: 23% Ch: 21% ChRT: 40% (3 year, p 0.04)... Ch: 16 ChRT: 13 (median months, P 0.31)... Ch: 27% ChRT: 28% (3 year, p 0.90) Pezzetta et al [15] Mediastinoscopy Variable 44 Gy Cisplatin Docetacel... Higher with ChRT (p 0.04) Ch: 0% ChRT: 6% Ch: 35% ChRT: 65% (p 0.02) Ch: 33% ChRT: 67% Ch: 36% ChRT: 24% Li et al [16] Chest CT None Gy Platinum-based Chest CT % Ch: 12% ChRT: 29% Ch chemotherapy; ChRT chemoradiotherapy; CT computerized tomography; Gy Gray; LN lymph node; PET positron emission tomography; VATS video-assisted thoracoscopic surgery SHAH ET AL Ann Thorac Surg INDUCTION THERAPY FOR LUNG CANCER 2012;93:

5 Ann Thorac Surg SHAH ET AL 2012;93: INDUCTION THERAPY FOR LUNG CANCER Study Log(Hazard Ratio) Girard Thomas Total SE Weight Hazard Ratio [95% CI] 30.3% 69.7% 100.0% 1.43 [0.61, 3.33] 0.78 [0.52, 1.16] 0.93 [0.54, 1.62] Hazard Ratio, 95% CI Favors chemoradiotherapy Favors chemotherapy 1811 GENERAL THORACIC Fig 2. Forest plot of overall survival of patients in randomized studies receiving induction chemotherapy versus induction chemoradiotherapy followed by resection. (CI confidence interval; SE standard error.) ous in patients who then prove to be unresectable [4]. Finally, although some studies have not shown an increased surgical risk when induction chemoradiation is used [14, 21], other studies have demonstrated a lower surgical complication rate when induction regimens include chemotherapy alone [27, 28, 29, 30]. Not only is there no demonstrable benefit to using radiation therapy, but there are significant potential disadvantages. Induction radiotherapy greater than 45Gy, when combined with induction chemotherapy, is predictive of postoperative complications [31]. Furthermore, radiation therapy is associated with its own complications, including radiation-induced pneumonitis and pulmonary fibrosis [32]. This may delay surgical resection or interfere with the administration of preoperative chemotherapy. Radiation therapy also causes cardiac dysfunction in up to 40% of patients [33], which may be a contributing factor to postoperative complications after pulmonary resection. Lastly, radiation is associated with significant economic costs [34] that may be unnecessary if induction radiation does not provide a survival benefit. We have demonstrated, using a systematic review and meta-analysis, that published data do not show that the addition of induction radiation therapy to induction chemotherapy improves survival over induction chemotherapy alone in operable patients with stage IIIA (N2) NSCLC. Although 2 of the randomized studies showed slightly improved median and 3-year survival with chemoradiation, the results were not statistically significant in either trial [12, 14] and 2 additional randomized studies demonstrated the opposite effect [11, 13]. In addition, the combined data in the metaanalysis did not show a statistically significant improvement. Unfortunately, in addition to this result, the most significant finding of our systematic review is the disappointing lack of studies that have investigated this subset of patients. Patients with stage IIIA (N2) disease constitute a minority but not insignificant number of lung cancer patients when the overall incidence of lung cancer is considered. The limited availability of randomized data has clearly decreased the power of our meta-analysis, though it is worth noting that no individual study even showed a survival benefit to the addition of induction radiotherapy. Although ongoing clinical trials may clarify the role of preoperative radiation therapy in patients with operable stage IIIA disease, at this time there is no evidence that potential benefits of adding radiation therapy to induction regimens outweigh potential risks. Clinicians who treat lung cancer should strive to develop formal protocols and participate in randomized studies that address this topic in order to address this critical shortage of evidence. Other limitations of this study are worth noting. We performed an additional meta-analysis of retrospective studies, and there are significant biases associated with this. However, we felt that given the severely limited randomized data available comparing these 2 induction regimens, synthesizing the available retrospective data in addition to synthesizing the randomized data was reasonable. In addition, we were unable to incorporate 2 randomized controlled trials into our meta-analysis as these were only available in abstract form, and we were unable to obtain the needed data directly from the authors. Lastly, the chemotherapy and radiation regimens used in these studies were heterogeneous and these could have an impact on survival. However, the included randomized trials were platinum-based and delivered radiation concurrently with chemotherapy. In conclusion, published evidence is limited but does not support the inclusion of radiation therapy in induction regimens for stage IIIA (N2) NSCLC. Given the potential disadvantages of adding radiation preoperatively, clinicians should consider using this treatment strategy only in the context of a clinical trial to allow better assessment of its effectiveness. Study Log(Hazard Ratio) SE Higgins Pezzetta Weight Hazard Ratio [95% CI] 58.2% 41.8% 0.87 [0.50, 1.54] 0.65 [0.34, 1.27] Hazard Ratio, 95% CI Total 100.0% 0.77 [0.50, 1.19] Favors chemoradiotherapy Favors chemotherapy Fig 3. Forest plot of overall survival of patients in retrospective studies receiving induction chemotherapy versus induction chemoradiotherapy followed by resection. (CI confidence interval; SE standard error.)

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