Radiol med DOI 10.1007/s11547-015-0547-8
RADIOTHERAPY
Effectiveness of chemotherapy and radiotherapy for laryngeal preservation in advanced laryngeal cancer: a meta‑analysis and systematic review Xiao‑Ning Luo1 · Liang‑Si Chen1 · Si‑Yi Zhang1 · Zhong‑Ming Lu1 · Yan Huang1
Received: 1 March 2015 / Accepted: 28 April 2015 © Italian Society of Medical Radiology 2015
Abstract Purpose This meta-analysis compared the efficacy of laryngectomy and three larynx-preservation treatments in patients with advanced laryngeal cancer. Materials and methods Medline, Cochrane, EMBASE and Google Scholar databases were searched (until May 5, 2014) for studies that evaluated total laryngectomy followed by radiation and three larynx-preserving strategies in patients with advanced laryngeal cancer. The outcomes assessed were the 2- to 5-year overall survival (OS), disease-free survival (DFS), and laryngectomy-free survival (LFS) Results The search identified ten studies which were used for the meta-analysis (N = 2013 patients). The metaanalysis found that among different treatments, RT alone was associated with the highest rate of OS (71.6 %), DFS (57.8 %), and LFS (79.0 %). OS was similar among the following treatments: laryngectomy→RT vs. CT→RT [P = 0.402]; RT+CT vs. RT alone [P = 0.440]; and * Xiao‑Ning Luo [email protected]; [email protected] Liang‑Si Chen [email protected] Si‑Yi Zhang [email protected] Zhong‑Ming Lu [email protected] Yan Huang [email protected] 1
Department of Otorhinolaryngology‑Head and Neck Surgery, Guangdong General Hospital, Guangdong Academy of Medical Science, 106 Zhongshan 2nd Road, Guangzhou 510080, People’s Republic of China
RT+CT vs CT→RT [P = 0.588]. DFS rate was higher in patients receiving laryngectomy→RT than CT→RT (P = 0.001) and was similar for RT+CT compared with CT→RT (P = 0.590). Conclusion These findings suggest that of the larynxpreserving treatments, RT alone was associated with highest rates of OS, DFS, and LFS in patients with locally advanced cancer of the larynx and hypopharynx. Laryngectomy provided a better rate of DFS than CT and RT, but OS were similar across the different larynx-preserving treatments and laryngectomy. Keywords Chemotherapy · Laryngeal cancer · Laryngectomy · Meta-analysis · Radiotherapy
Introduction A key goal of treating patients with locoregional advanced laryngeal cancer is to preserve larynx function [1–4]. Advanced laryngeal cancer typically indicates stage III or IV cancer [3]. The treatment options for advance laryngeal cancer include surgery, radiation therapy, and chemoradiation therapy, or some combination of these [3]. Often surgery for advanced laryngeal cancer is a total laryngectomy which, although it offers good local control, has significant functional consequences and can greatly impact a patient’s quality of life [3, 5]. Over the past several years there has been a change in the strategies to treat locoregional advanced laryngeal cancer. There has been an increase in the number of patients treated with radiation therapy (RT) and chemotherapy (CT) and a decrease in the number of patients treated with surgery [3, 6]. Several well-designed randomized trials have evaluated the effects of a number of different
13
nonsurgical treatments that are aimed at optimizing larynx preservation [1, 2, 7–9]. Larynx-preserving treatment options include conservative surgery followed by radiation therapy (laryngectomy→RT), concurrent RT and CT (CT+RT), inductive CT followed by RT (CT→RT), and alternating CT and RT [5]. These trials have shown that CT+RT may be more effective than inductive CT→RT [6]. Based on a guideline by American Society of Clinical Oncology, a larynx-preserving approach is an appropriate treatment option for most patients with T3 or T4 laryngeal cancers without tumor invasion through cartilage into soft tissues [10]. They recommend that concomitant CT+RT is the standard of care for patients with T3–T4 laryngeal cancer and that preservation surgery is limited to selected patients [5]. However, at many institutions RT or CT is the treatment of choice for most T3 laryngeal cancer [3]. The use of RT or CT (alone, in combination, or sequentially) is associated with a high incidence of acute toxicity and disruption in laryngeal function, particularly in patients treated with concurrent RT and CT [11–14]. Concerns have also been raised regarding a decrease in overall survival following concurrent CT and RT therapy [3]. The current meta-analysis was performed to compare total laryngectomy followed by RT and three larynx-preserving strategies (RT→CT, RT+CT, or RT alone). We hypothesize that the different treatments may results in different treatment response. We evaluated overall survival (OS), disease-free survival (DFS), and laryngectomy-free survival (LFS). To our knowledge, this is the first metaanalysis to address this issue.
Methods Search strategy and study selection Medline, Cochrane, EMBASE, and Google Scholar databases were searched (until May 5, 2014) for studies that evaluated total laryngectomy→RT and three larynxpreserving strategies in patients with advanced laryngeal cancer. The following search terms were used: larynx/ laryngeal cancer, hypopharyngeal cancer/carcinoma, chemoradiotherapy/chemotherapy/radiotherapy, preservation/preserving, larynx-preservation, laryngeal preservation, and organ-preserving. Randomized controlled and prospective comparative studies which evaluated patients with locally advanced laryngeal or hypopharyngeal cancer were included. Included studies had to have evaluated at least one larynx-preserving treatment. All included studies had to be published in English. Retrospective studies, case reports, comments, editorials,
13
Radiol med
letters, proceedings, and personal communications were excluded. Potential studies were identified and reviewed by two independent reviewers. If there was uncertainty regarding eligibility of a study, a third reviewer was consulted. The analysis was performed in adherence to the PRISMA guidelines. Data extraction Data were extracted by two independent reviewers and a third reviewer was consulted in the case of any uncertainty or disagreement. The following information/data were extracted from the included studies: the name of the first author, year of publication, study design, number of participants in each treatment group, participants’ age and gender, tumor location, cancer stages, patient performance status, treatment regimens, and outcomes of measures (OS, DFS, LFS rates). Quality assessment The quality of the studies and included data was evaluated using the Cochrane Risk of Bias Tool [15]. Similar to study inclusion and data extraction, two independent reviewers performed the quality assessment and a reviewer was consulted for any disagreement. Statistical analysis The outcomes assessed were 2- to 5-year rates of OS, DFS, and LFS. Patient demographic data and rates of OS, DFS, and LFS were presented descriptively. All outcomes with 95 % confidence intervals (95 % CIs) were calculated for given treatments for each study. Pooled OS, DFS, and LFS rates were presented with the corresponding 95 % CIs and P values. Comparisons of OS, DFS, and LFS rates between (1) larynectomy→RT vs. CT → RT, (2) RT alone vs. RT+CT, and (3) CT→RT vs. RT+CT were determined. The odds ratios (ORs) were derived for each study for each type of comparison, and the pooled odds ratio (OR) with 95 % CIs was estimated. Heterogeneity among the studies was assessed using the Cochran Q and the I2 statistics. Either a Q statistic with P 50 % indicated heterogeneity existed among the studies, and hence a random-effects model (DerSimonian-Laird method) of analysis was used. If no heterogeneity was apparent, a fixed-effects model (Mantel–Haenszel method) was used. Sensitivity analysis was performed using the leave-one-out approach. A P 60
Karnofsky performance scale ≥60
WHO performance status ≤2
Karnovsky performance scale ≥70
WHO performance status ≤1
N0, 54 %; N1, 18 %; Above 50 of Karnofsky N2, 11 %; and N3, 17 % Performance score
N0, 78 %; N1, 15 %; N2/ N3, 11 %; and N3, 7 %
N0, 48 %; N1, 34 %; N2, 17 %;
N0, 40 %; N1, 10 %; ≤2 on the ECOG scale N2, 24 %; and N3, 26 %
Above 70 of Karnofsky performance score
WHO 0–2
WHO 0–1 WHO performance status ≤1
At least 60 of Karnofsky performance score
Inclusion criteria perfor- Laryngectomy mance status (Karnofsky performance score or ECOG)
N0, 39 %; N1, 23 %; N2, 33 %; N3, 4 %
N0, 36 %; N1, 26 %; N2, 38 %
N0—resectable N3 N0, 67 %; N1, 12 %; N2, 20 %
N0, 50 %; N1, 21 %; N2, 28 %; and N3, 2 %
% of N
Radiol med
Radiol med
WHO performance status of ≤2, and two used the ECOG scale (either ≤2 or >2). Treatment regimens differed across the studies and are summarized in Table 2. OS, DFS, and LFS decreased with greater number of years following treatment both for the randomized controlled trials, which compared different treatments regimens, and the single arm studies (Table 3). Of the randomized controlled studies, the range in overall survival rate for 2 years was from 50 to 92 %, for 3 years was from 40 to 75 %, and for 5 years was from 77 to 48.5 %. Only one study looked at 10-year OS, which ranged from 27.5 % for RT+CT, 31.5 % for RT alone, and 38.8 % for CT→RT [2]. Similarly, the DFS and LFS rates decreased with increasing length of time from treatment. The single-arm studies showed similar trends as that of the randomized control trials (Table 3). Meta‑analysis Overall survival Three of the ten studies included in the meta-analysis reported data for the rate of OS for patients receiving laryngectomy [1, 19, 20], all ten studies reported data for patients receiving CT→RT, five studies reported data for patients receiving concomitant RT+CT [2, 9, 17, 18, 23], and three reported data for patients receiving RT alone (Fig. 2) [2, 17, 21]. Analysis of the data indicated the presence of heterogeneity for OS rates among the studies for each of the treatments (laryngectomy: I2 = 62.17 %, Q value = 10.575, P = 0.032; CT→RT: I2 = 77.12 %, Q value = 39.33, P
RADIOTHERAPY
Effectiveness of chemotherapy and radiotherapy for laryngeal preservation in advanced laryngeal cancer: a meta‑analysis and systematic review Xiao‑Ning Luo1 · Liang‑Si Chen1 · Si‑Yi Zhang1 · Zhong‑Ming Lu1 · Yan Huang1
Received: 1 March 2015 / Accepted: 28 April 2015 © Italian Society of Medical Radiology 2015
Abstract Purpose This meta-analysis compared the efficacy of laryngectomy and three larynx-preservation treatments in patients with advanced laryngeal cancer. Materials and methods Medline, Cochrane, EMBASE and Google Scholar databases were searched (until May 5, 2014) for studies that evaluated total laryngectomy followed by radiation and three larynx-preserving strategies in patients with advanced laryngeal cancer. The outcomes assessed were the 2- to 5-year overall survival (OS), disease-free survival (DFS), and laryngectomy-free survival (LFS) Results The search identified ten studies which were used for the meta-analysis (N = 2013 patients). The metaanalysis found that among different treatments, RT alone was associated with the highest rate of OS (71.6 %), DFS (57.8 %), and LFS (79.0 %). OS was similar among the following treatments: laryngectomy→RT vs. CT→RT [P = 0.402]; RT+CT vs. RT alone [P = 0.440]; and * Xiao‑Ning Luo [email protected]; [email protected] Liang‑Si Chen [email protected] Si‑Yi Zhang [email protected] Zhong‑Ming Lu [email protected] Yan Huang [email protected] 1
Department of Otorhinolaryngology‑Head and Neck Surgery, Guangdong General Hospital, Guangdong Academy of Medical Science, 106 Zhongshan 2nd Road, Guangzhou 510080, People’s Republic of China
RT+CT vs CT→RT [P = 0.588]. DFS rate was higher in patients receiving laryngectomy→RT than CT→RT (P = 0.001) and was similar for RT+CT compared with CT→RT (P = 0.590). Conclusion These findings suggest that of the larynxpreserving treatments, RT alone was associated with highest rates of OS, DFS, and LFS in patients with locally advanced cancer of the larynx and hypopharynx. Laryngectomy provided a better rate of DFS than CT and RT, but OS were similar across the different larynx-preserving treatments and laryngectomy. Keywords Chemotherapy · Laryngeal cancer · Laryngectomy · Meta-analysis · Radiotherapy
Introduction A key goal of treating patients with locoregional advanced laryngeal cancer is to preserve larynx function [1–4]. Advanced laryngeal cancer typically indicates stage III or IV cancer [3]. The treatment options for advance laryngeal cancer include surgery, radiation therapy, and chemoradiation therapy, or some combination of these [3]. Often surgery for advanced laryngeal cancer is a total laryngectomy which, although it offers good local control, has significant functional consequences and can greatly impact a patient’s quality of life [3, 5]. Over the past several years there has been a change in the strategies to treat locoregional advanced laryngeal cancer. There has been an increase in the number of patients treated with radiation therapy (RT) and chemotherapy (CT) and a decrease in the number of patients treated with surgery [3, 6]. Several well-designed randomized trials have evaluated the effects of a number of different
13
nonsurgical treatments that are aimed at optimizing larynx preservation [1, 2, 7–9]. Larynx-preserving treatment options include conservative surgery followed by radiation therapy (laryngectomy→RT), concurrent RT and CT (CT+RT), inductive CT followed by RT (CT→RT), and alternating CT and RT [5]. These trials have shown that CT+RT may be more effective than inductive CT→RT [6]. Based on a guideline by American Society of Clinical Oncology, a larynx-preserving approach is an appropriate treatment option for most patients with T3 or T4 laryngeal cancers without tumor invasion through cartilage into soft tissues [10]. They recommend that concomitant CT+RT is the standard of care for patients with T3–T4 laryngeal cancer and that preservation surgery is limited to selected patients [5]. However, at many institutions RT or CT is the treatment of choice for most T3 laryngeal cancer [3]. The use of RT or CT (alone, in combination, or sequentially) is associated with a high incidence of acute toxicity and disruption in laryngeal function, particularly in patients treated with concurrent RT and CT [11–14]. Concerns have also been raised regarding a decrease in overall survival following concurrent CT and RT therapy [3]. The current meta-analysis was performed to compare total laryngectomy followed by RT and three larynx-preserving strategies (RT→CT, RT+CT, or RT alone). We hypothesize that the different treatments may results in different treatment response. We evaluated overall survival (OS), disease-free survival (DFS), and laryngectomy-free survival (LFS). To our knowledge, this is the first metaanalysis to address this issue.
Methods Search strategy and study selection Medline, Cochrane, EMBASE, and Google Scholar databases were searched (until May 5, 2014) for studies that evaluated total laryngectomy→RT and three larynxpreserving strategies in patients with advanced laryngeal cancer. The following search terms were used: larynx/ laryngeal cancer, hypopharyngeal cancer/carcinoma, chemoradiotherapy/chemotherapy/radiotherapy, preservation/preserving, larynx-preservation, laryngeal preservation, and organ-preserving. Randomized controlled and prospective comparative studies which evaluated patients with locally advanced laryngeal or hypopharyngeal cancer were included. Included studies had to have evaluated at least one larynx-preserving treatment. All included studies had to be published in English. Retrospective studies, case reports, comments, editorials,
13
Radiol med
letters, proceedings, and personal communications were excluded. Potential studies were identified and reviewed by two independent reviewers. If there was uncertainty regarding eligibility of a study, a third reviewer was consulted. The analysis was performed in adherence to the PRISMA guidelines. Data extraction Data were extracted by two independent reviewers and a third reviewer was consulted in the case of any uncertainty or disagreement. The following information/data were extracted from the included studies: the name of the first author, year of publication, study design, number of participants in each treatment group, participants’ age and gender, tumor location, cancer stages, patient performance status, treatment regimens, and outcomes of measures (OS, DFS, LFS rates). Quality assessment The quality of the studies and included data was evaluated using the Cochrane Risk of Bias Tool [15]. Similar to study inclusion and data extraction, two independent reviewers performed the quality assessment and a reviewer was consulted for any disagreement. Statistical analysis The outcomes assessed were 2- to 5-year rates of OS, DFS, and LFS. Patient demographic data and rates of OS, DFS, and LFS were presented descriptively. All outcomes with 95 % confidence intervals (95 % CIs) were calculated for given treatments for each study. Pooled OS, DFS, and LFS rates were presented with the corresponding 95 % CIs and P values. Comparisons of OS, DFS, and LFS rates between (1) larynectomy→RT vs. CT → RT, (2) RT alone vs. RT+CT, and (3) CT→RT vs. RT+CT were determined. The odds ratios (ORs) were derived for each study for each type of comparison, and the pooled odds ratio (OR) with 95 % CIs was estimated. Heterogeneity among the studies was assessed using the Cochran Q and the I2 statistics. Either a Q statistic with P 50 % indicated heterogeneity existed among the studies, and hence a random-effects model (DerSimonian-Laird method) of analysis was used. If no heterogeneity was apparent, a fixed-effects model (Mantel–Haenszel method) was used. Sensitivity analysis was performed using the leave-one-out approach. A P 60
Karnofsky performance scale ≥60
WHO performance status ≤2
Karnovsky performance scale ≥70
WHO performance status ≤1
N0, 54 %; N1, 18 %; Above 50 of Karnofsky N2, 11 %; and N3, 17 % Performance score
N0, 78 %; N1, 15 %; N2/ N3, 11 %; and N3, 7 %
N0, 48 %; N1, 34 %; N2, 17 %;
N0, 40 %; N1, 10 %; ≤2 on the ECOG scale N2, 24 %; and N3, 26 %
Above 70 of Karnofsky performance score
WHO 0–2
WHO 0–1 WHO performance status ≤1
At least 60 of Karnofsky performance score
Inclusion criteria perfor- Laryngectomy mance status (Karnofsky performance score or ECOG)
N0, 39 %; N1, 23 %; N2, 33 %; N3, 4 %
N0, 36 %; N1, 26 %; N2, 38 %
N0—resectable N3 N0, 67 %; N1, 12 %; N2, 20 %
N0, 50 %; N1, 21 %; N2, 28 %; and N3, 2 %
% of N
Radiol med
Radiol med
WHO performance status of ≤2, and two used the ECOG scale (either ≤2 or >2). Treatment regimens differed across the studies and are summarized in Table 2. OS, DFS, and LFS decreased with greater number of years following treatment both for the randomized controlled trials, which compared different treatments regimens, and the single arm studies (Table 3). Of the randomized controlled studies, the range in overall survival rate for 2 years was from 50 to 92 %, for 3 years was from 40 to 75 %, and for 5 years was from 77 to 48.5 %. Only one study looked at 10-year OS, which ranged from 27.5 % for RT+CT, 31.5 % for RT alone, and 38.8 % for CT→RT [2]. Similarly, the DFS and LFS rates decreased with increasing length of time from treatment. The single-arm studies showed similar trends as that of the randomized control trials (Table 3). Meta‑analysis Overall survival Three of the ten studies included in the meta-analysis reported data for the rate of OS for patients receiving laryngectomy [1, 19, 20], all ten studies reported data for patients receiving CT→RT, five studies reported data for patients receiving concomitant RT+CT [2, 9, 17, 18, 23], and three reported data for patients receiving RT alone (Fig. 2) [2, 17, 21]. Analysis of the data indicated the presence of heterogeneity for OS rates among the studies for each of the treatments (laryngectomy: I2 = 62.17 %, Q value = 10.575, P = 0.032; CT→RT: I2 = 77.12 %, Q value = 39.33, P
