# Treatment Protocols in the Efficacy and Safety of Anti-EGFR Medicines in Combination with Standard Therapy for Patients with Nasopharyngeal Cancer: A Meta-Analysis

Authors: Yakun Fang; Jinlei Fan; Chao Yan
Journal: BioMed Research International
 (2023)

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## Abstract

Objective. This study was conducted to compare the efficacy of standard therapy (radiotherapy/RT/CT) with that of antiepidermal growth factor receptor (anti-EGFR) monoclonal antibody (NPC) therapy in patients with advanced nasopharyngeal cancer. Methods. A meta-analysis was performed to meet the objective of this study. The English databases PubMed, Cochrane Library, and Web of Science were searched. The literature review compared anti-EGFR-targeted therapy with conventional therapy practices. The main outcome measure was overall survival (OS). Secondary goals were progression-free survival (PFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and adverse events (grade 3). Results. The database search resulted in 11 studies, with a total of 4219 participants. It was found that combining an anti-EGFR regimen with conventional therapy did not enhance OS (hazardratioHR=1.18; 95%confidenceintervalCI=0.51–2.40; p=0.70) or PFS appreciably (HR=0.95; 95%CI=0.51–1.48; p=0.88) in patients with nasopharyngeal carcinoma. While LRRFS increased considerably (HR=0.70; 95%CI=0.67–1.00; p=0.01), the combined regimen did not improve DMFS (HR=0.86; 95%CI=0.61–1.12; p=0.36). Treatment-related adverse events included haematological toxicity (RR=0.2; 95%CI=0.08–0.45; p=0.01), cutaneous reactions (RR=7.05; 95%CI=2.15–23.09; p=0.01), and mucositis (RR=1.96; 95%CI=1.58–2.09; p=0.01). Conclusions. Individuals who have nasopharyngeal cancer do not have an increased chance of surviving until a local recurrence of their disease if they get normal therapy in addition to an anti-EGFR regimen. However, this combination does not enhance overall survival. On the other hand, this factor adds to an increase in the number of adverse effects.


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## Body

## 1. Introduction

In 2018, more than 129,000 new cases of nasopharyngeal carcinoma (NPC) were recorded worldwide, with over 70% occurring in southern China and southeast Asia [1, 2], and they were commonly detected at an advanced stage [3]. Radiotherapy and chemotherapy are the main treatment options for NPC, and they considerably improve patient outcomes. However, recurrence and metastasis occur in 25% of cases, making them the most common reasons for treatment failure in advanced NPC cases [4]. Immune checkpoint therapy is now used to treat recurrent or metastatic nasopharyngeal carcinoma [5–7].The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein belonging to the epidermal growth factor (EGF) family [8], and increased EGFR expression has been linked to a poor prognosis and outcome for a variety of cancers [9]. Systemic anti-EGFR medicines, such as cetuximab (CXT) and nimotuzumab (NTZ), have shown modest efficacy in clinical trials for nasopharyngeal cancer [10], but the results have been inconsistent [11–13]. It is also unknown whether combining anti-EGFR medicines with standard therapy increases the risk of bad outcomes. Therefore, to explore the efficacy and safety of anti-EGFR in combination with standard therapy for nasopharyngeal cancer patients, a comprehensive search and meta-analysis of randomised controlled trials were conducted in this study with the aim of rereporting relevant data for future therapy recommendations and clinical trials.


## 2. Data and Methods

### 2.1. Literature Review

Two independent reviewers combed through PubMed, Cochrane Library, Web of Science, and Embase for relevant articles from the time the databases were conceived to May 2022. They followed references given in the literature to reduce the likelihood of omissions and searched for grey literature. Nasopharyngeal neoplasms, EGFR inhibitor, cetuximab, panitumumab, and nimotuzumab were popular keywords [14, 15].


### 2.2. Admission and Exclusion Criteria

The eligibility criteria included the following: (i) articles examining the English language’s linguistics, (ii) studies on reported case size, (iii) comparing EGFR-targeted therapy with standard treatment for individuals with nasopharyngeal cancer, and (iv) researches that clearly provide overall survival (OS) [16–18].The exclusion criteria included the following: (i) publications that were not unique, (ii) publications we were unable to get the full text of, (iii) inadequate outcome indicators and evaluation standards, and (iv) indicators of result variability.


### 2.3. Information Gathering

The titles and abstracts of articles were examined, and duplicate articles and plainly unrelated or noncompliant literature were excluded. When the abstract and title were insufficient to determine whether the inclusion criteria were met, the entire content was scrutinised: the first author, year of publication, research stage, number of patients (per group), and outcomes (overall survival [OS], progression-free survival [PFS], locoregional recurrence-free survival [LRRFS], and distant metastasis-free survival [DMFS] as well as serious adverse events [SAEs]). The main result is OS, with PFS, LRRFS, and DMFS as supplementary endpoints [19–24]. Furthermore, various common SAEs between anti-EGFR drugs plus standard treatment and standard treatment alone were analysed. The data collection and analysis for this project were collaboratively performed by two researchers, with conflicts resolved through a consensus discussion or with the participation of a third researcher.


### 2.4. Statistical Methods

Data were collected and analysed using RevMan 5.3 software. The clinical heterogeneity of each included study was analysed first, followed by a chi-square examination of statistical heterogeneity. IfI2 was less than 50%, a fixed-effects model was used for the data analysis. Furthermore, if there was no statistical heterogeneity between studies when the p value was greater than 0.05, a random-effects model was used and the sources of heterogeneity addressed [25–27]. RevMan 5.3 was used to check for possible publication bias, and the results were visually depicted. Meta-analysis of the included 11 research literatures should exclude the following three research results: those of poor quality, those with high weighting, and those with results that differed from other investigations. If two outcomes were identical, the conclusions were deemed stable; otherwise, they were unstable.


## 2.1. Literature Review

Two independent reviewers combed through PubMed, Cochrane Library, Web of Science, and Embase for relevant articles from the time the databases were conceived to May 2022. They followed references given in the literature to reduce the likelihood of omissions and searched for grey literature. Nasopharyngeal neoplasms, EGFR inhibitor, cetuximab, panitumumab, and nimotuzumab were popular keywords [14, 15].


## 2.2. Admission and Exclusion Criteria

The eligibility criteria included the following: (i) articles examining the English language’s linguistics, (ii) studies on reported case size, (iii) comparing EGFR-targeted therapy with standard treatment for individuals with nasopharyngeal cancer, and (iv) researches that clearly provide overall survival (OS) [16–18].The exclusion criteria included the following: (i) publications that were not unique, (ii) publications we were unable to get the full text of, (iii) inadequate outcome indicators and evaluation standards, and (iv) indicators of result variability.


## 2.3. Information Gathering

The titles and abstracts of articles were examined, and duplicate articles and plainly unrelated or noncompliant literature were excluded. When the abstract and title were insufficient to determine whether the inclusion criteria were met, the entire content was scrutinised: the first author, year of publication, research stage, number of patients (per group), and outcomes (overall survival [OS], progression-free survival [PFS], locoregional recurrence-free survival [LRRFS], and distant metastasis-free survival [DMFS] as well as serious adverse events [SAEs]). The main result is OS, with PFS, LRRFS, and DMFS as supplementary endpoints [19–24]. Furthermore, various common SAEs between anti-EGFR drugs plus standard treatment and standard treatment alone were analysed. The data collection and analysis for this project were collaboratively performed by two researchers, with conflicts resolved through a consensus discussion or with the participation of a third researcher.


## 2.4. Statistical Methods

Data were collected and analysed using RevMan 5.3 software. The clinical heterogeneity of each included study was analysed first, followed by a chi-square examination of statistical heterogeneity. IfI2 was less than 50%, a fixed-effects model was used for the data analysis. Furthermore, if there was no statistical heterogeneity between studies when the p value was greater than 0.05, a random-effects model was used and the sources of heterogeneity addressed [25–27]. RevMan 5.3 was used to check for possible publication bias, and the results were visually depicted. Meta-analysis of the included 11 research literatures should exclude the following three research results: those of poor quality, those with high weighting, and those with results that differed from other investigations. If two outcomes were identical, the conclusions were deemed stable; otherwise, they were unstable.


## 3. Results

### 3.1. Literature Retrieval

Initially, 1952 related literatures were separately evaluated by title and abstract. After consolidation, 12 duplicate articles, 1650 animal-related studies, 189 meta-analyses, 12 inaccessible full-text articles, and 11 articles were eliminated from the full-text browsing synthesis (see Figure1).Figure 1
Selection procedure flowchart illustration.The inclusion criteria were met by 4129 observations (study subjects reported between 2007 and 2019, see Table1). Nine publications were tested for heterogeneity; I2=0<50%, and Q-test p=1>0.05 revealed that there was no substantial heterogeneity, due to which the meta-analysis was conducted using a fixed-effects model.Table 1
Characteristics of included studies.
Author (yr)Age (years), median (range)Median follow-upAnti-EGFRControlAnti-EGFRControlWu (2014)36 (26-57)47 (32-63)RT+h-R3RTMei (2018)45 (25-68)44 (15-67)CTX/NTX+CCRTIC+CCRTYou (2017)45 (12-69)46 (15-74)CTX/NTX+CCRTCCRTMao (2019)44 (17-72)43 (13-73)NTX/CTX+CRTCRTHao (2018)42 (36-51)44 (36-51)CTX/NTX+ICICWu (2007)36 (26-57)47 (32+63)RT+h-R3RTWang (2019)44 (34-55)44 (32-55)NTZ+IMRTIMRTLi (2016)60 (25-68)60 (25-67)RT+h-R3RT+CDDPXia (2017)44 (32-52)44 (32-52)CTX+CCRTCCRTYang (2017)46 (25-64)46 (28-66)CTX+CCRTCCRTYou (2017)46 (18-75)47 (15-74)CTX/NTX+IMRTIMRT+CDDPNote: anti-EGFR: anti-epidermal growth factor receptor. CTX; NTX; h-R3; IMRT; CDDP.


### 3.2. Overall Survival

Individuals with nasopharyngeal cancer who underwent anti-EGFR in addition to conventional therapy were found to have better survival rates, but the difference was not statistically significant (HR=1.18; 95%CI=0.52–2.40; p=0.7). Figure 2 presents a comparison between the OS rates of anti-EGFR therapy combined with standard therapy and standard therapy alone. The funnel plot comparing the two treatment approaches has the goal of assessing overall survival (OS). The symmetric funnel plot in this research demonstrates that there is no publishing bias (see Figure 3).Figure 2
Forest diagram: anti-EGFR regimen plus standard therapy and standard therapy alone. Results: overall survival (OS).Figure 3
Comparison funnel chart: anti-EGFR regimen plus standard therapy and standard therapy alone; results: overall survival (OS).


### 3.3. Progression-Free Survival and Local Control

In the heterogeneity tests, eight studies were included in this study, and after heterogeneity test,I2=0<50%, and Q-test p=0.99>0.05, which indicated that there was no obvious heterogeneity among the literatures included in this study, so the fixed-effects model was selected for meta-analysis. PFS did not improve significantly among patients receiving anti-EGFR in addition to conventional therapy (HR=0.95; 95%CI=0.51–1.88; p=0.88) (Figure 4).Figure 4
Forest diagram: anti-EGFR regimen plus standard treatment and standard treatment alone. Results: progression-free survival (PFS).This meta-analysis included eight LRRFS trials. A heterogeneity test revealed that the included literature was heterogeneous (I2=53%>50% and Q-test p=0.1>0.05); accordingly, a random-effects model was employed for the meta-analysis (see Figure 5). It means that compared with the control group, the survival time of local recurrence increased by 70% when anti-EGFR drugs were added to the standard treatment. The random-effects model revealed that adding anti-EGFR agents to standard therapy increased patients’ local area recurrence survival (HR=0.70; 95%CI=0.67–1.02; p=0.01) (Figure 5) as well as local survival by local survival area (HR=0.70; 95%CI=0.67–1.02; p=0.01). After omitting Hao et al. [20] publication from the sensitivity analysis, heterogeneity test I2=0<50%; thus, a random-effects model was chosen.Figure 5
Forest diagram: anti-EGFR regimen plus standard treatment and standard treatment alone. Results: locoregional recurrence-free survival (LRRFS) rate.


### 3.4. Survival Is Achievable in the Absence of Distant Metastases

The DMFS meta-analysis involved nine investigations. Based on the results of a heterogeneity test (I2=84%>50% and Q-test p=0.01>0.05), which demonstrated heterogeneity across the included studies, a random-effects model was chosen for the meta-analysis. No statistically significant improvement was seen in disease-free survival among patients who took anti-EGFR medicine in addition to undergoing standard therapy (HR=0.86; 95%CI=0.61–1.16; p=0.36) (Figure 6). Sensitivity analysis, arbitrarily rejecting the literature in this study, will not affect the results of this study. It means that the calculation results of the above random effects are stable and reliable.Figure 6
Forest plots of survival without distant metastases. Forest diagram: anti-EGFR regimen plus standard treatment and standard treatment alone. Results: survival without distant metastasis (DMFS).


### 3.5. Serious Adverse Events

Anti-EGFR plus conventional therapy was compared to conventional therapy alone (DMFS). The addition of anti-EGFR to conventional patient care resulted in haematological toxicity, skin responses, and mucositis, among others. Since the combined haematological toxicity data indicated heterogeneity, a random-effects model was constructed. Excluding the data from You’s [17] sensitivity analysis caused I2 to reduce from 89% to 32%. Anti-EGFR medication was linked with an increased incidence of haematotoxicity (RR=0.22; 95%CI=0.08–0.45; p=0.01) (Figure 7). Variations in the data were determined (I2=91%, p=0.01), confirming the suitability of the random-effects model. Anti-EGFR therapy was linked with a greater frequency of skin toxicity (relativeriskRR=7.05; 95%CI=2.15–23.0; p=0.01) (Figure 8) and an increase in the incidence of severe mucositis (RR=1.96; 95%CI=1.58–2.00; p=0.01) (Figure 9). Figure 7 depicts the forest plots for the hepatotoxic consequences among patients who underwent an anti-EGFR regimen in addition to conventional treatment compared to those treated with conventional treatment alone. A forest plot comparison of the two treatment approaches in terms of skin poisoning as a consequence is given in Figure 8. Figure 9 shows a comparison of forest plots for induced mucosal reactivity.Figure 7
Forest diagram: results of anti-EGFR regimen plus standard treatment and standard treatment alone: blood toxicity.Figure 8
Forest diagram: anti-EGFR regimen plus standard treatment and standard treatment alone. Results: skin toxicity.Figure 9
Forest diagram: anti-EGFR regimen plus standard treatment and standard treatment alone. Results: mucosal reaction.


## 3.1. Literature Retrieval

Initially, 1952 related literatures were separately evaluated by title and abstract. After consolidation, 12 duplicate articles, 1650 animal-related studies, 189 meta-analyses, 12 inaccessible full-text articles, and 11 articles were eliminated from the full-text browsing synthesis (see Figure1).Figure 1
Selection procedure flowchart illustration.The inclusion criteria were met by 4129 observations (study subjects reported between 2007 and 2019, see Table1). Nine publications were tested for heterogeneity; I2=0<50%, and Q-test p=1>0.05 revealed that there was no substantial heterogeneity, due to which the meta-analysis was conducted using a fixed-effects model.Table 1
Characteristics of included studies.
Author (yr)Age (years), median (range)Median follow-upAnti-EGFRControlAnti-EGFRControlWu (2014)36 (26-57)47 (32-63)RT+h-R3RTMei (2018)45 (25-68)44 (15-67)CTX/NTX+CCRTIC+CCRTYou (2017)45 (12-69)46 (15-74)CTX/NTX+CCRTCCRTMao (2019)44 (17-72)43 (13-73)NTX/CTX+CRTCRTHao (2018)42 (36-51)44 (36-51)CTX/NTX+ICICWu (2007)36 (26-57)47 (32+63)RT+h-R3RTWang (2019)44 (34-55)44 (32-55)NTZ+IMRTIMRTLi (2016)60 (25-68)60 (25-67)RT+h-R3RT+CDDPXia (2017)44 (32-52)44 (32-52)CTX+CCRTCCRTYang (2017)46 (25-64)46 (28-66)CTX+CCRTCCRTYou (2017)46 (18-75)47 (15-74)CTX/NTX+IMRTIMRT+CDDPNote: anti-EGFR: anti-epidermal growth factor receptor. CTX; NTX; h-R3; IMRT; CDDP.


## 3.2. Overall Survival

Individuals with nasopharyngeal cancer who underwent anti-EGFR in addition to conventional therapy were found to have better survival rates, but the difference was not statistically significant (HR=1.18; 95%CI=0.52–2.40; p=0.7). Figure 2 presents a comparison between the OS rates of anti-EGFR therapy combined with standard therapy and standard therapy alone. The funnel plot comparing the two treatment approaches has the goal of assessing overall survival (OS). The symmetric funnel plot in this research demonstrates that there is no publishing bias (see Figure 3).Figure 2
Forest diagram: anti-EGFR regimen plus standard therapy and standard therapy alone. Results: overall survival (OS).Figure 3
Comparison funnel chart: anti-EGFR regimen plus standard therapy and standard therapy alone; results: overall survival (OS).


## 3.3. Progression-Free Survival and Local Control

In the heterogeneity tests, eight studies were included in this study, and after heterogeneity test,I2=0<50%, and Q-test p=0.99>0.05, which indicated that there was no obvious heterogeneity among the literatures included in this study, so the fixed-effects model was selected for meta-analysis. PFS did not improve significantly among patients receiving anti-EGFR in addition to conventional therapy (HR=0.95; 95%CI=0.51–1.88; p=0.88) (Figure 4).Figure 4
Forest diagram: anti-EGFR regimen plus standard treatment and standard treatment alone. Results: progression-free survival (PFS).This meta-analysis included eight LRRFS trials. A heterogeneity test revealed that the included literature was heterogeneous (I2=53%>50% and Q-test p=0.1>0.05); accordingly, a random-effects model was employed for the meta-analysis (see Figure 5). It means that compared with the control group, the survival time of local recurrence increased by 70% when anti-EGFR drugs were added to the standard treatment. The random-effects model revealed that adding anti-EGFR agents to standard therapy increased patients’ local area recurrence survival (HR=0.70; 95%CI=0.67–1.02; p=0.01) (Figure 5) as well as local survival by local survival area (HR=0.70; 95%CI=0.67–1.02; p=0.01). After omitting Hao et al. [20] publication from the sensitivity analysis, heterogeneity test I2=0<50%; thus, a random-effects model was chosen.Figure 5
Forest diagram: anti-EGFR regimen plus standard treatment and standard treatment alone. Results: locoregional recurrence-free survival (LRRFS) rate.


## 3.4. Survival Is Achievable in the Absence of Distant Metastases

The DMFS meta-analysis involved nine investigations. Based on the results of a heterogeneity test (I2=84%>50% and Q-test p=0.01>0.05), which demonstrated heterogeneity across the included studies, a random-effects model was chosen for the meta-analysis. No statistically significant improvement was seen in disease-free survival among patients who took anti-EGFR medicine in addition to undergoing standard therapy (HR=0.86; 95%CI=0.61–1.16; p=0.36) (Figure 6). Sensitivity analysis, arbitrarily rejecting the literature in this study, will not affect the results of this study. It means that the calculation results of the above random effects are stable and reliable.Figure 6
Forest plots of survival without distant metastases. Forest diagram: anti-EGFR regimen plus standard treatment and standard treatment alone. Results: survival without distant metastasis (DMFS).


## 3.5. Serious Adverse Events

Anti-EGFR plus conventional therapy was compared to conventional therapy alone (DMFS). The addition of anti-EGFR to conventional patient care resulted in haematological toxicity, skin responses, and mucositis, among others. Since the combined haematological toxicity data indicated heterogeneity, a random-effects model was constructed. Excluding the data from You’s [17] sensitivity analysis caused I2 to reduce from 89% to 32%. Anti-EGFR medication was linked with an increased incidence of haematotoxicity (RR=0.22; 95%CI=0.08–0.45; p=0.01) (Figure 7). Variations in the data were determined (I2=91%, p=0.01), confirming the suitability of the random-effects model. Anti-EGFR therapy was linked with a greater frequency of skin toxicity (relativeriskRR=7.05; 95%CI=2.15–23.0; p=0.01) (Figure 8) and an increase in the incidence of severe mucositis (RR=1.96; 95%CI=1.58–2.00; p=0.01) (Figure 9). Figure 7 depicts the forest plots for the hepatotoxic consequences among patients who underwent an anti-EGFR regimen in addition to conventional treatment compared to those treated with conventional treatment alone. A forest plot comparison of the two treatment approaches in terms of skin poisoning as a consequence is given in Figure 8. Figure 9 shows a comparison of forest plots for induced mucosal reactivity.Figure 7
Forest diagram: results of anti-EGFR regimen plus standard treatment and standard treatment alone: blood toxicity.Figure 8
Forest diagram: anti-EGFR regimen plus standard treatment and standard treatment alone. Results: skin toxicity.Figure 9
Forest diagram: anti-EGFR regimen plus standard treatment and standard treatment alone. Results: mucosal reaction.


## 4. Discussion

This study assessed the efficacy and safety of combining anti-EGFR medication with standard NPC treatment. It was found that anti-EGFR therapy improves LRRFS but has no effect on OS, PFS, or DMFS and that treatment-related adverse effects increase. Consistent anticancer efficacy has been seen when anti-EGFR medication is paired with conventional therapy for EGFR-expressing cancers, such as non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), and colorectal cancer [10]. However, conflicting results were found in this meta-analysis, indicating that additional factors are at play. For tumour cells to be susceptible to drugs that target the DNA repair mechanism, this targeting process must be active. Anti-EGFR medications and conventional combination therapy drugs (e.g., platinum) may induce radiosensitivity by inhibiting the repair of radiation-induced DNA damage. Sensitivity to radiation and chemotherapy is generally affected by cancer cells and tumour microenvironments. Anti-EGFR or chemotherapy might have a greater impact on tumour cells than on tumour microenvironments. Thus, with an increase in radiotherapy/chemotherapy resistance, the use of chemotherapy, anti-EGFR, or both in combination with radiotherapy can eradicate the vast majority of cancer cell molecules in a more efficient manner. Using medications that target the vascular endothelial growth factor and thus change tumour microenvironments is the only way to make the remaining cells more receptive to treatment following CRT. It is important to note that pairing anti-EGFR therapy with conventional treatment results in increased haematotoxicity, mucositis, and radiation dermatitis.Our research still has some limitations. When exploring alternate treatments, it is critical to boost prediction findings and the quality of long-term survival. More research, especially prospective research, is required.


## 5. Conclusions

Individuals who have nasopharyngeal cancer do not have an increased chance of surviving until a local recurrence of their disease if they get normal therapy in addition to an anti-EGFR regimen. However, this combination does not enhance overall survival. On the other hand, this factor adds to an increase in the number of adverse effects.



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*Source: 9477442-2023-02-06.xml*