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Radiotherapy has a crucial role in the treatment of non-small cell lung cancer[1]. However, esophageal toxicity and pulmonary toxicity are common toxic side effects of radiotherapy and usually interrupt its planned course[2]. Acute esophageal toxicity during the course of treatment can disrupt normal activities, such as swallowing, drinking, and eating, of patients. Pulmonary toxicity causes coughing, aggravates sputum production, and induces posterior sternal pain. Thus, esophageal and pulmonary toxicities cause the life quality of patients to deteriorate.
Numerous drugs with the potential to protect normal tissues from intensive radiotherapy and/or chemotherapy while exerting the optimal therapeutic effect have been investigated over the past several decades. Amifostine is an organic thiophosphate pro-drug that is dephosphorylated in vivo into its active moiety, WR-1065(5); it has been developed to selectively protect normal tissues against the toxic effects of radiotherapy and/or chemotherapy by scavenging free radicals[3]. Some randomized controlled trials(RCTs) have demonstrated that amifostine could reduce the risk of esophageal toxicity and pulmonary toxicity in patients with lung cancer and receiving radiation or concomitant chemoradiotherapy[4-5]. However, some RCTs have shown that amifostine cannot reduce radiation toxicities[6-7]. Some investigators have even suggested that amifostine can reduce the therapeutic effects of radiation or chemotherapy by exerting tumor-protective effects[8].
Thus far, however, the radiotherapy and/or chemotherapy protection efficacy of amifostine lacks adequate statistical support. We performed this systematic review and meta-analysis to confirm whether amifostine can reduce the risk of radiotherapy and/or chemotherapy toxicities and to evaluate its therapeutic efficacy in lung cancer.
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Trials No. of patients
Ami/ControlStage
includedDaily ami
(dose)Administration Concomitant
chemotherapyRadiotherapy Zhao(2014)[5] 69/68 Ⅲ, Ⅳ 200 mg/m2 Ⅳ, 30 min before RT, q.d 54-66 Gy, 2 Gy/fraction, 5 fractions/week Lin(2013)[13] 21/23 Ⅱ, Ⅲ 300 mg/m2 Ⅳ, 15-30 min before RT, q.d 54 Gy, 1.8 Gy/fraction, 5 fractions weekly Liu(2015)[4] 25/25 Ⅲ 300 mg/m2 Ⅳ, 30 min before RT, q.d DDP (50 mg/m2) + E (50 mg/m2)daily for the first 4 weeks of RT. DDP (50 mg/m2) + E(50 mg/m2)/DDP(50 mg/m2) + V(50 mg/m2)/C(50 mg/m2) + P(50 mg/m2) daily for the second 4 weeks of RT 66 Gy, 16.5 Gy/week Li(2010)[14] 55/53 Ⅱ, Ⅲ, Ⅳ 200 mg/m2 Ⅳ, 30 min before RT, q.d 54-66 Gy, 2 Gy/fraction, 5 fractions/week Weng(2007)[15] 30/30 Ⅲ 300 mg/m2 Ⅳ, 30 min before RT, q.d P (135 mg/m2) days: 1 + DDP(50 mg/m2) days:1-3 50-60 Gy, 2 Gy/fraction, 5 fractions/week Movsas(2005)[6] 114/115 Ⅲ 500 mg, 4 times/ week Ⅳ, 15-30 min before RT q.d, on RT-onlydays; 180minbefore RT q.d, on CT + RT days P(225 mg/m2) + C(AUC6) days: 1, 22; P(50mg/m2) + C (AUC2) days:43, 50, 57, 64, 71, 78 69.6 Gy, 1.2 Gy bid, 5 days/week Komaki(2004)[16] 31/31 Ⅱ, Ⅲ 500 mg, 2 times/week Ⅳ, 20-30 min before CT q.d, days: 1, 8, 29, 36; 60-90 minbefore first fraction RT; 30-60 min before RT q.d, days: 2, 9, 30, 37 E(50mg/m2)days: 1-10, 29-38DDP(50mg/m2)days: 1, 8, 29, 36 69.6 Gy, 1.2 Gy bid, 5 days/week Leong (2003)[17] 30/30 Ⅲ 740 mg/m2 Ⅳ, 30 min before CT q.d P(175 mg/m2) + C (AUC6) days: 1, 22; P(60 mg/m2) days: 43, 50, 57, 64, 71, 78 60-66 Gy, 2 Gy fraction, 5 fractions/week Antonadou(2003)[18] 36/32 Ⅲ 300 mg/m2 Ⅳ, 15 min before RT and before CT on CT days q.d P(60 mg/m2) / C(AUC2) weekly before RT 55-60 Gy, 2 Gy fraction, 5 fractions/week Senzer(2002)[7] 24/25 Ⅲ 500 mg/ 200 mg q.d Ⅳ, 500 mg, 15-30 min weekly before CT; 200 mg/m2, 15 -30 min before RT (including the day of CT) q.d P(50 mg/m2) + C(AUC2) weekly +G(1000 mg/m2) days: 22, 29, 36+DDP(80 mg/m2) days: 29 beforeRT 64.8 Gy, 36 fractions over 7.5 weeks Antonadou(2001)[19] 44/53 Ⅲ 340 mg/m2 Ⅳ, 15 min before RT q.d 55-60 Gy, 2 Gy fraction, 5 fractions/week Koukourakis(2001)[20] 19/17 Ⅲ 500 mg IH, 20 min before RT q.d 64 Gy, 2 Gy/fraction, 5 fractions/week Notes: Ami=amifostine; IV=intravenous injection; IH=subcutaneously injected; RT=radiotherapy; C=carboplatin; G=gemcitabine; V=vinorelbine; DDP=cisplatin; P=paclitaxel; E=etoposide; AUC=area under the curve; qd=daily; bid=twice daily. Table 1. General characteristics of included radomized controlled trials
For the entire patient population, 1996 articles were retrieved through the initial search. After reviewing titles and abstracts, 1778 articles were removed. The full texts of the remaining 12 articles were reviewed for inclusion in the meta-analysis. All twelve trials were RCTs and published in English or Chinese[4-7, 13-20] in the period of 2000 to 2016. The included RCTs involved 1000 patients(604 and 563 in each treatment arm).
Methodological quality was evaluated with a seven-question instrument described in the Cochrane Reviews Handbook 5.1.0. Generally, the 12includedtrials were considered to be at moderate risk of bias. Although randomization was performed in all 12 trials, only two articles mentioned allocation concealment[16, 18]. In addition, all 12 trials performed an adequate sequence generation[4-7, 13-20]. Only one trial described blinding patients and physicians or evaluators. The outcome of methodological quality for each trial is presented in Fig. 2.
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Of the 12 trials, nine[4, 6-7, 13, 15-19] trials evaluated acute esophageal toxicity with evident heterogeneity between studies(I2=84%) (Fig. 3). The meta-analysis was performed using the random-effect model(Dersimonian-Laird method). Pooled analysis showed that the use of amifostine reduced acute esophageal toxicity by 44% (RR, 0.56; 95%CI, 0.39-0.81; P=0.002). Egger′s test revealed that publication bias was absent(P=0.206).Subgroup analysis indicated that the use of amifostine significantly reduced acute esophageal toxicity in patients receiving concurrent chemoradiation(RR, 0.67;95%CI, 0.49-0.93; P=0.020) and radiation only(RR, 0.20; 95%CI, 0.05-0.80; P=0.020)(Table 2).
Figure 3. Forest plot of acute esophageal toxicity(all grades) in patients with lung cancer who received radiotherapy or concomitant chemoradiation
Subgroup Acute esophageal P Acute pulmonary P Late pulmonary P RR 95%CI RR 95%CI RR 95%CI Chemoradiation 0.67 0.49-0.93 0.020 0.44 0.21-0.95 0.040 0.84 0.48-1.46 0.540 Radiation only 0.20 0.05-0.80 0.020 0.38 0.25-0.58 0.001 Table 2. Subgroup analysis of radiation-induced side effects in accordance with treatment strategy
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Nine articles[4-7, 13-14, 16, 18-19] reported the number of patients who developed acute pulmonary toxicity in both treatment arms. Heterogeneity was observed among trials. Pooled analysis with the random-effect model demonstrated that amifostine reduced all grades ofacute pulmonary toxicity in patients with lung cancer (RR, 0.42; 95%CI, 0.25-0.70; P=0.001)(Fig. 4). Egger′s test revealed the absence of publication bias (P=0.244). Subgroup analysis revealed that the use of amifostine significantly reduced acute pulmonary toxicity in patients treated with concurrent chemoradiation(RR, 0.44; 95%CI, 0.21-0.95; P=0.040) and radiation only (RR, 0.38; 95% CI, 0.25-0.58; P < 0.001)(Table 2).
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Late pulmonary toxicity was reported in three trials[6, 18-19] with heterogeneity among studies (I2=59%). Meta-analysis showed that the risk (RR, 0.74; 95%CI, 0.45-1.19; P=0.210) of late pulmonary toxicity was not significantly lower in the amifostine group than that in the control treatment (Fig. 5). Publication bias was not observed by Egger′s test (P=0.052). Subgroup analysis also showed that the use of amifostine did not reduce the risk of pulmonary toxicity in lung cancer patients treated with concurrent chemoradiation (RR, 0.84; 95%CI, 0.48-1.46; P=0.540) (Table 2).
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Data on hematological toxicity, including neutropenia and thrombocytopenia, were extracted from five articles[6, 15-18]. Studies involving neutropenia exhibited heterogeneity (I2=74%). However, studies involving thrombocytopenia were not heterogeneous(I2=0%). Meta-analysis showed that the incidences of neutropenia (RR, 1.02; 95%CI, 0.61-1.71; P=0.940) in the amifostine and control groups were not significantly different. Egger′s test revealed no publication bias in this subset analysis(P=0.182). The use of amifostine significantly reduced the incidence of thrombocytopenia(RR, 0.45; 95%CI, 0.21-0.94; P=0.030)(Fig. 6).
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Nine articles provided response rates[4-6, 13, 15, 17-20]. No statistical heterogeneity among studies was found in both complete(I2=0%) and partial(I2=0%) response analysis. The pooled RR estimate for partial response was 0.98(95%CI, 0.83-1.15; P=0.800) (Fig. 6), which was not statistically significant. Publication bias was not observed through Egger′s test(P=0.138). The pooled RR estimate for the complete response was 1.50(95%CI, 1.03-2.18; P=0.030) and was statistically significant (Fig. 7). However, publication bias was observed through Egger′s test (P=0.000).
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Three articles reported overall survival rates[6, 16-17]. No statistical heterogeneity among studies was found in both one-year overall survival(I2=0%) and two-year overall survival(I2=0%) analysis. The pooled RR estimate for the one-year overall survival was 0.94(95%CI, 0.81-1.09; P=0.400). Publication bias was not observed through Egger′s test(P=0.555). The pooled RR estimate for two-year overall survival was 1.06(95%CI, 0.81-1.39; P=0.680) (Fig. 8). Publication bias was not observed through Egger′s test(P=0.732). Neither one-year overall survival nor two-year overall survival reached statistical significance (Fig. 8).
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Six studies[14-19] described amifostine toxicity. The most common amifostine-related side effects included nausea, vomiting, and transient hypotension with average incidence rates of 11%, 14%, and 24%, respectively. However, amifostine toxicity can be controlled through clinical treatment or resting.
Effect of Amifostine on Patients with Lung Cancer Treated with Radiotherapy or Concomitant Chemoradiotherapy:A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Effect of Amifostine on Patients with Lung Cancer Treated with Radiotherapy or Concomitant Chemoradiotherapy:A Systematic Review and Meta-Analysis of Randomized Controlled Trials
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Abstract:
ObjectiveAmifostine is clinically used as a chemical radioprotector. Nevertheless, its efficacy as a radioprotector remains controversial. MethodsPubMed, Cochrane Central Register of Controlled Trials, EMBASE, China National Knowledge Infrastructure, and the references of the published results of trials on the efficacy of amifostine in patients with lung cancer and who received radiotherapy or concomitant chemoradiotherapy were searched. The pooled radiation protection efficacy, treatment response, and side effects of amifostine were calculated using RevMan software. ResultsTwelve randomized controlled trials involving 1000 patients with lung cancer were ultimately analyzed. Results of meta-analysis revealed that the use of amifostine reduced the risk of acute esophageal toxicity(RR, 0.56; 95% CI, 0.39-0.81; P=0.002) and pulmonary toxicity(RR, 0.42; 95% CI, 0.25-0.70; P=0.001). Subgroup analysis also demonstrated that the risk of acute esophageal toxicity and pulmonary toxicity significantly reduced in patients who received chemoradiation concurrent with amifostine or radiation only. Pooled data showed that the use of amifostine did not significantly decrease the risk of late pulmonary toxicity(RR, 0.74; 95% CI, 0.45-1.19; P=0.210). Moreover, subgroup analysis demonstrated that the risk oflate pulmonary toxicity did not significantly decrease in patients who received chemoradiotherapy concomitant with amifostine(RR, 0.84; 95% CI, 0.48-1.46; P=0.540). Amifostine did not exert tumor-protective effects in partial response(RR, 0.98; 95% CI, 0.83-1.15; P=0.800) but improved complete response(RR, 1.50; 95% CI, 1.03-2.18; P=0.030), although publication bias was observed through Egger's test(P=0.000). Moreover, amifostine had no effect on one-year overall survival (RR, 0.94; 95% CI, 0.81-1.09; P=0.400) and two-year overall survival(RR, 1.06; 95% CI, 0.81-1.39; P=0.680) rates. The incidence of neutropenia, a hematologic side effect of amifostine, was not significantly different(RR, 1.02; 95% CI, 0.61-1.71; P=0.940) between the amifostine and control group. The use of amifostine, however, significantly decreased the incidence of thrombocytopenia(RR, 0.45; 95% CI, 0.21-0.94; P=0.030). The most common amifostine-related side effects were nausea, vomiting, and hypotension with average incidence rates of 11%, 14%, and 24%, respectively. ConclusionsThis systematic review showed that the concurrent administration of amifostine with radiotherapy to patients with lung cancer significantly reduced the risks of acute esophageal toxicity and acute pulmonary toxicity and decreased the incidence of thrombocytopenia without tumor-protecting effects. In addition, the toxicities of amifostine were generally controllable through clinical treatment or resting. -
Key words:
- Amifostine /
- Lung neoplasms /
- Radiotherapy /
- Concomitant chemoradiotherapy /
- Meta-analysis
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Table 1. General characteristics of included radomized controlled trials
Trials No. of patients
Ami/ControlStage
includedDaily ami
(dose)Administration Concomitant
chemotherapyRadiotherapy Zhao(2014)[5] 69/68 Ⅲ, Ⅳ 200 mg/m2 Ⅳ, 30 min before RT, q.d 54-66 Gy, 2 Gy/fraction, 5 fractions/week Lin(2013)[13] 21/23 Ⅱ, Ⅲ 300 mg/m2 Ⅳ, 15-30 min before RT, q.d 54 Gy, 1.8 Gy/fraction, 5 fractions weekly Liu(2015)[4] 25/25 Ⅲ 300 mg/m2 Ⅳ, 30 min before RT, q.d DDP (50 mg/m2) + E (50 mg/m2)daily for the first 4 weeks of RT. DDP (50 mg/m2) + E(50 mg/m2)/DDP(50 mg/m2) + V(50 mg/m2)/C(50 mg/m2) + P(50 mg/m2) daily for the second 4 weeks of RT 66 Gy, 16.5 Gy/week Li(2010)[14] 55/53 Ⅱ, Ⅲ, Ⅳ 200 mg/m2 Ⅳ, 30 min before RT, q.d 54-66 Gy, 2 Gy/fraction, 5 fractions/week Weng(2007)[15] 30/30 Ⅲ 300 mg/m2 Ⅳ, 30 min before RT, q.d P (135 mg/m2) days: 1 + DDP(50 mg/m2) days:1-3 50-60 Gy, 2 Gy/fraction, 5 fractions/week Movsas(2005)[6] 114/115 Ⅲ 500 mg, 4 times/ week Ⅳ, 15-30 min before RT q.d, on RT-onlydays; 180minbefore RT q.d, on CT + RT days P(225 mg/m2) + C(AUC6) days: 1, 22; P(50mg/m2) + C (AUC2) days:43, 50, 57, 64, 71, 78 69.6 Gy, 1.2 Gy bid, 5 days/week Komaki(2004)[16] 31/31 Ⅱ, Ⅲ 500 mg, 2 times/week Ⅳ, 20-30 min before CT q.d, days: 1, 8, 29, 36; 60-90 minbefore first fraction RT; 30-60 min before RT q.d, days: 2, 9, 30, 37 E(50mg/m2)days: 1-10, 29-38DDP(50mg/m2)days: 1, 8, 29, 36 69.6 Gy, 1.2 Gy bid, 5 days/week Leong (2003)[17] 30/30 Ⅲ 740 mg/m2 Ⅳ, 30 min before CT q.d P(175 mg/m2) + C (AUC6) days: 1, 22; P(60 mg/m2) days: 43, 50, 57, 64, 71, 78 60-66 Gy, 2 Gy fraction, 5 fractions/week Antonadou(2003)[18] 36/32 Ⅲ 300 mg/m2 Ⅳ, 15 min before RT and before CT on CT days q.d P(60 mg/m2) / C(AUC2) weekly before RT 55-60 Gy, 2 Gy fraction, 5 fractions/week Senzer(2002)[7] 24/25 Ⅲ 500 mg/ 200 mg q.d Ⅳ, 500 mg, 15-30 min weekly before CT; 200 mg/m2, 15 -30 min before RT (including the day of CT) q.d P(50 mg/m2) + C(AUC2) weekly +G(1000 mg/m2) days: 22, 29, 36+DDP(80 mg/m2) days: 29 beforeRT 64.8 Gy, 36 fractions over 7.5 weeks Antonadou(2001)[19] 44/53 Ⅲ 340 mg/m2 Ⅳ, 15 min before RT q.d 55-60 Gy, 2 Gy fraction, 5 fractions/week Koukourakis(2001)[20] 19/17 Ⅲ 500 mg IH, 20 min before RT q.d 64 Gy, 2 Gy/fraction, 5 fractions/week Notes: Ami=amifostine; IV=intravenous injection; IH=subcutaneously injected; RT=radiotherapy; C=carboplatin; G=gemcitabine; V=vinorelbine; DDP=cisplatin; P=paclitaxel; E=etoposide; AUC=area under the curve; qd=daily; bid=twice daily. Table 2. Subgroup analysis of radiation-induced side effects in accordance with treatment strategy
Subgroup Acute esophageal P Acute pulmonary P Late pulmonary P RR 95%CI RR 95%CI RR 95%CI Chemoradiation 0.67 0.49-0.93 0.020 0.44 0.21-0.95 0.040 0.84 0.48-1.46 0.540 Radiation only 0.20 0.05-0.80 0.020 0.38 0.25-0.58 0.001 -
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