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. 2020 Sep 4;99(36):e21785. doi: 10.1097/MD.0000000000021785

Concurrent cisplatin or cetuximab with radiotherapy in patients with locally advanced head and neck squamous cell carcinoma

A meta-analysis

Wen-Hua Tang a,b, Wei Sun b, Guo-Xian Long b,∗
Editor: Surinder Kumar
PMCID: PMC7478598  PMID: 32899005

Supplemental Digital Content is available in the text

Keywords: head and neck carcinoma, cisplatin, cetuximab, radiation therapy, outcome

Abstract

Background:

Concurrent cisplatin with radiotherapy (CRT) or concurrent cetuximab with radiotherapy (BRT) improves outcomes in locally advanced head and neck squamous cell carcinoma (HNSCC) compared with radiotherapy alone. Nevertheless, a detailed comparison between CRT and BRT in locally advanced HNSCC is required due to inconclusive results.

Methods:

A comprehensive literature search was conducted on PubMed, Web of Science, Cochrane databases, and EMBASE. Studies that evaluated CRT vs BRT in locally advanced HNSCC were included. The primary outcome that was overall survival (OS), whereas the secondary outcomes were progression-free survival (PFS), locoregional control (LRC), and distant metastasis-free survival (DMFS). Pooled hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were used to evaluate prognosis. All the analyses were performed using Stata Statistical Software 12.0.

Results:

Twenty-three studies, with a total of 8701 patients, were considered eligible and included in this meta-analysis. Our results revealed that patients treated with CRT had longer OS (HR = 0.51, 95%CI, 0.41–0.64, P < .001), PFS (HR = 0.37, 95%CI, 0.23–0.60, P < .001), LRC (HR = 0.46, 95%CI, 0.37–0.57, P < .001), and DMFS (HR = 0.56, 95%CI, 0.40–0.77, P < .001) than those treated with BRT. Furthermore, the results of the subgroup analyses were consistent with the primary analysis.

Conclusions:

CRT has a better OS, PFS, LRC, and DMFS than BRT in locally advanced HNSCC, and should be the preferred treatment for patients with the disease.

1. Introduction

Head and neck cancers (HNC) are relatively common carcinomas, with approximately 600,000 new cases and 320,000 deaths annually.[1,2] The head and neck squamous cell carcinoma (HNSCC) have the highest morbidity, accounting for 85% death among all HNC.[3] Most patients have advanced locoregional disease at diagnosis and require combined treatment of radiotherapy (RT), surgery and systemic therapy.[4]

The established standard treatment for patients, which are unsuitable for surgical treatment is concurrent systemic therapy with RT. There are currently 2 common treatment strategies supported by guidelines, concurrent platinum, or cetuximab with RT. Platinum-based chemoradiotherapy is the standard of care for locally advanced HNSCC in many countries, and concurrent high-dose cisplatin is the preferred systemic agent recommended by National Comprehensive Cancer Network Guideline, which is used most widely in the world. Many large phase 3 trials and meta-analysis have shown that concurrent cisplatin with radiotherapy (CRT) improves overall survival (OS) compared with RT alone. However, CRT leads to numerous toxicities.[5–7] As patients may might develop serious toxicity of cisplatin, which could persist for a long time, and could affect their quality of life. Radiotherapy can induce the expression of epidermal growth factor receptor (EGFR) in HNC, leading to acquired resistance.[8] Cetuximab, a monoclonal antibody that targets the EGFR, is the first targeted treatment that shows therapeutic efficacy in HNC and may help to overcome this resistance. Similarly, some phase 3 trials have demonstrated that concurrent cetuximab with radiotherapy (BRT) improves OS, locoregional control (LRC), and the quality of life compared with RT alone.[9,10] Cetuximab has been increasingly used to treat patients who concern about the toxicity of platinum chemotherapy, such as elderly or frail patients. Recently, 2 randomized studies showed that BRT was inferior to CRT for patients with human papillomavirus (HPV) positive (+) oropharyngeal carcinoma.[9,10] However, except for its highly selected group, there are no randomized clinical trials to compare the efficacy of cisplatin and cetuximab head to head in patients with HPV negative (−) tumors, which comprises the majority in HNSCC. Furthermore, several studies suggest that EGFR inhibition might be more effective in HPV (−) disease than in HPV (+) disease.[13,14] Therefore, it is still unclear if the efficacy of BRT is similar to CRT in HPV (−) HNSCC.

Hence, this meta-analysis was conducted to comprehensively compare concurrent cisplatin or cetuximab with radiotherapy in locally advanced HNSCC, towards providing direction in decision making for treatment.

2. Methods

2.1. Search strategy

We performed a comprehensive literature search in PubMed, Web of Science, Cochrane databases, and EMBASE, up to 1st May 2019 using the following keywords “head and neck squamous cell carcinoma,” “cancers of the larynx,” “HNSCC,” “cancer of oropharynx,” “opc,” “cancer of hypopharynx,” “cancer of tongue,” “radiotherapy,” “cisplatin” and “cetuximab.” We also reviewed conference abstracts of the unpublished articles and searched the references list of relevant studies to find other potential studies. This meta-analysis was registered in PROSPERO (registration number: CRD42019123560), and the research was conducted according to the recommended items of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).[15]

2.2. Selection criteria

Studies were included in this meta-analysis if they fulfilled the following criteria: Studies

  • 1.

    that evaluated the efficacy of CRT and compared it with BRT in locally advanced HNSCC;

  • 2.

    with one or more outcomes, including OS, progression-free survival (PFS), LRC or distant metastasis-free survival (DMFS);

  • 3.

    that provided hazard ratio (HR) and its 95% confidence intervals (CI) or that can obtain the HR and 95% CI by statistical extraction; and

  • 4.

    that published latest data or largest data was included if a particular center published the same study severally.

Exclusion criteria:

  • 1.

    studies that patients were treated with cisplatin-based double or multiple concurrent agents;

  • 2.

    studies that included patients with nasopharyngeal carcinoma, and

  • 3.

    review articles.

No ethical review is needed in this study.

2.3. Data extraction

The following data was extracted from the included studies: first author's last name, publication year, country of origin, type of study, study period, therapy regimens, number of patients, number of both sexes, median age, cancer types, stage, median follow-up time, and survival data (HR and its 95% CI for OS, PFS, LRC, DMFS). If HR and the corresponding 95% CI could not be extracted directly from the text, then methods proposed by Tierney[16] and Parmar[17] were applied to calculate these statistical variables by using the available numerical data. Any disagreements were settled by consulting with the third author.

2.4. Study quality assessment

Three authors independently evaluated the quality of the included studies. The Newcastle-Ottawa Scale was used to evaluate the cohort studies,[18] and scores of 6 or greater showed the high quality of the study. The Cochrane Handbook for Systematic Reviews of Interventions was used to evaluate the randomized clinical trial.[19] Three categories, including “low risk,” “high risk” or “unclear” for bias, were performed judging from the risk of bias in the included studies for each domains.

2.5. Statistical analysis

The primary outcome was evaluated by the OS, defined as the time from diagnosis of locally advanced HNSCC to death from any cause. Other outcomes were evaluated by PFS, defined as the time from diagnosis of locally advanced HNSCC to tumor progression in any aspect or death from any cause; LRC, defined as the time from completion of RT to locoregional recurrence; and DMFS, defined as the time from completion of RT to distant metastasis. HR and its 95% CI were applied to investigate the treatment efficacy of CRT or BRT. The overall HR, integrated from individual HR, was shown with a forest plot. Pooled HR < 1, and 1 not included in the corresponding 95% CI (P < .05), was described as a better survival for the CRT group. Heterogeneity was assessed using the Cochran Q test and the Higgins I2 statistic test. When the case of I2 value ≥50% or P-value ≤.1 was considered as substantial heterogeneity,[20] a random effect model was applied; otherwise, a fixed-effect model was employed. Subgroup analyses were based on cancer types, HPV infection status, study types, and the type of therapy (induction chemotherapy or none induction chemotherapy). The funnel plot and Egger test[21] were used to identify potential publication biases. P-values <.05 were recognized as statistically significant, and all analyses were calculated using Stata Statistical Software 12.0. (Stata Corporation, College Station, TX).

3. Results

3.1. Literature selection and screening

As illustrated in Figure 1, a total of 2473 studies were identified based on the initial literature search, and 45 studies remained after screening the titles and abstracts. Subsequently, 22 studies were excluded after reading the full-text or abstracts, based on the following reasons: overlap with others studies (6), use of cisplatin-based double or multiple concurrent agents (12), inclusion of distant metastasis patients (2), a review article without original data (1), and inclusion of postoperative patients (1).

Figure 1.

Figure 1

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Flow chat of study selection.

3.2. Characteristics of included studies and quality assessment

Twenty-three studies with a total of 8701 patients were enrolled in this meta-analysis; and Table 1 summarizes the major characteristics of the enrolled studies. The eligible studies consisted of 18 retrospective trials[22–40] and 5 prospective studies,[11,12,41–43] including 2 randomized, multicenter, and phase 3 trials.[11,12] For the median age, patients treated with CRT were generally older than patients treated with BRT. All studies used the same cetuximab schedule with a loading dose of 400 mg/m2 and, subsequently, administration of 250 mg/m2 weekly. Regarding the therapeutic schedule, some studies included patients that received induction chemotherapy while others did not. Eighteen studies with 8007 patients were pooled to assess the impact of the treatment with OS. To evaluate the PFS, LRC, and DMFS, 4, 11, and 8 studies were pooled, respectively. The results of the quality assessment for the cohort studies are presented in Table 2. Five, 10, and 3 studies had quality scores of 6, 7, and 8, respectively. Each included randomized clinical trial and its quality score was shown in Figure 2. Most of them had low risk of bias.

Table 1.

Characteristics of studies included in the meta-analysis.

3.2.

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Table 2.

Ottawa Quality Assessment Scale: cohort studies.

3.2.

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Figure 2.

Figure 2

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Cochrane Collaboration's risk of bias: randomized clinical trial.

3.3. Survival analysis

The OS, PFS, LRC, and DMFS, were used as outcomes in this study. As regards OS, the pooled HR was 0.51 (95%CI, 0.41–0.64, P < .001, Fig. 3A), indicating that patients treated with CRT compared with BRT had a longer OS in locally advanced HNSCC. Similarly, this study demonstrated that patients treated with CRT had better PFS (HR = 0.37, 95%CI 0.23–0.60, P < .001, Fig. 3B), LRC (HR = 0.46, 95%CI, 0.37–0.57, P < .001 Fig. 3C) and DMFS (HR = 0.56, 95%CI, 0.40–0.77, P < .001, Fig. 3D).

Figure 3.

Figure 3

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Forrest plot of HR assessing the risk of cisplatin-based chemoradiotherapy vs cetuximab-based bioradiotherapy for locally advanced HNSCC. A, Forrest plot for 18 studies considering overall survival (OS). B, Forrest plot for 4 studies considering progression-free survival. C Forrest plot for 11 studies considering locoregional control. D, Forrest plot for 8 studies considering distant metastasis-free survival. CI = confidence interval, HR = hazard ratio.

3.4. Subgroup analysis

Further subgroup analyses also had similar results to those of the primary analysis. In the subgroup of HPV (+) HNSCC, the combined HR for OS was 0.53 (95%CI, 0.41–0.69, P < .001, Fig. 4A). Similarly, we observed that HPV (+) HNSCC treated with CRT had better PFS (HR = 0.58, 95%CI, 0.47–0.76, P < .001, Fig. 4B), LRC (HR = 0.43, 95%CI, 0.32–0.59, P < .001, Fig. 4C) and DMFS (HR = 0.46, 95%CI, 0.24–0.86, P < .001, Fig. 4D). For oropharynx cancer regardless of HPV condition, CRT showed better OS (HR = 0.46, 95%CI, 0.37–0.57, P < .001, Fig. 5A), PFS (HR = 0.37, 95%CI, 0.23–0.60, P = .009, Fig. 5B), LRC (HR = 0.46, 95%CI, 0.37–0.57, P < .001, Fig. 5C) and DMFS (HR = 0.51, 95%CI, 0.41–0.64, P < .001, Fig. 5D) than BRT. Furthermore, as shown in Table 3, we also observed longer OS in patients treated with CRT than in patients treated with BRT, irrespective of the study type, retrospective or prospective, and the type of therapy (induction chemotherapy or none induction chemotherapy).

Figure 4.

Figure 4

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Forrest plot of HR assessing the risk of cisplatin-based chemoradiotherapy vs cetuximab-based bioradiotherapy for HPV positive (+) HNSCC. A, Forrest plot for 7 studies considering overall survival. B, Forrest plot for 2 studies considering progression-free survival. C, Forrest plot for 5 studies considering locoregional control. D, Forrest plot for 3 studies considering distant metastasis-free survival. CI = confidence interval, HPV = human papillomavirus, HR = hazard ratio.

Figure 5.

Figure 5

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Forrest plot of HR assessing the risk of cisplatin-based chemoradiotherapy vs cetuximab-based bioradiotherapy for human papillomavirus positive (+) HNSCC. A, Forrest plot for 8 studies considering overall survival. B, Forrest plot for 3 studies considering progression-free survival. C, Forrest plot for 4 studies considering locoregional control. D, Forrest plot for 2 studies considering distant metastasis-free survival. CI = confidence interval, HR = hazard ratio.

Table 3.

Subgroup analyses overall survival.

3.4.

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3.5. Publication bias

We evaluated publication bias by assessing the asymmetry of the funnel plot visually and quantitatively performing Egger test. No apparent asymmetry was observed from the visual evaluation of the funnel plot, and there was no publication bias using the Egger test (P = .127 for OS, P = .089 for PFS, P = .79 for LRC, P = .609 for DMFS) as illustrated in Figure 6.

Figure 6.

Figure 6

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Funnel plot for the assessment of publication bias in this study. A, Funnel plot for 18 studies considering overall survival. B, Funnel plot for 4 studies considering progression-free survival. C, Funnel plot for 11 studies considering locoregional control. D, Funnel plot for 8 studies considering distant metastasis-free survival.

4. Discussion

CRT and BRT are both the standard of treatment for patients with inoperable locally advanced HNSCC. Since there were no randomized phase 3 trials to compare these two strategies for a long time, the opinion that BRT was comparable to CRT has been challenged all the time. Some clinical studies and meta-analyses that have addressed this issue have conflicting conclusions. Fausto et al conducted a meta-analysis to evaluate the efficacy of platinum-based chemoradiotherapy compared with cetuximab-based bioradiotherapy in locally advanced HNSCC,[44] and they found cisplatin had better OS and PFS. However, the risk ratio was defined as the primary measurement of treatment outcome in this study, but the outcome of time-to-event was not considered. A meta-analysis by Huang et al observed a better OS in patients with HPV (+) HNSCC and better PFS in patients with oropharyngeal cancer treated with BRT than in patients treated with CRT,[45] including studies containing patients treated with cisplatin-based dual or multiple concurrent drugs. A pivotal limitation of this study was that negative numbers were included when calculating the HR in some included studies. The HR in survival analysis is described as the ratio of the hazard rate, and the hazard rates correspond to the conditions that are described by 2 levels of an explanatory variable. The negative numbers are often not included. Thus, we observed that there were different conclusions in the two meta-analyses as regards the OS of HPV (+) HNSCC patients and the PFS of patients with oropharyngeal cancer. Hence, we conducted this meta-analysis employing the latest researches to settle the dispute. The studies included in this meta-analysis were selected based on strict selected criteria. Since concurrent high-dose cisplatin is the preferred systemic agent recommended by National Comprehensive Cancer Network Guideline and has been used most commonly in clinic, our meta-analysis compared concurrent cetuximab with concurrent cisplatin only, excluding studies using other platinum-based chemoradiotherapy such as carboplatin plus paclitaxel, cisplantin plus 5-fluorouracil and cisplantin plus 5-fluorouracil/hydorxyurea,[46–50] the studies were excluded. Moreover, the latest updated results of some duplicate studies were accepted and the previous reports were excluded.[51–58] Eighteen studies were included in this analysis to assess the impact of treatment on OS. The combined HR for OS was 0.53 (95%CI, 0.41–0.69, P < .001), suggesting that patients treated with CRT compared with BRT had a longer OS in locally advanced HNSCC. Moreover, patients treated with CRT also had better PFS (HR = 0.37, 95%CI 0.23–0.60, P < .001), LRC (HR = 0.46, 95%CI, 0.37–0.57, P < .001) and DMFS (HR = 0.56, 95%CI, 0.40–0.77, P < .001). These results indicated that cetuximab could not replace the role of cisplatin in locally advanced HNSCC.

The above 2 meta-analyses drew inconsistent conclusions regarding OS in HPV (+) HNSCC patients and the PFS in patients with oropharyngeal cancer. Our subgroup analysis, limited to the HPV (+) HNSCC patients, showed that the CRT group had better OS (HR = 0.53, 95%CI, 0.41–0.69, P < .001), PFS (HR = 0.58, 95%CI, 0.47–0.76, P < .001), LRC (HR = 0.43, 95%CI, 0.32–0.59, P < .001) and DMFS (HR = 0.46, 95%CI, 0.24–0.86, P < .001). Similarly, when limited to oropharynx cancer, we found that CRT was associated with better OS (HR = 0.46, 95%CI, 0.37–0.57, P < .001), PFS (HR = 0.37, 95%CI, 0.23–0.60, P = .009), LRC (HR = 0.46, 95%CI, 0.37–0.57, P < .001) and DMFS (HR = 0.51, 95%CI, 0.41–0.64, P < .001). Conclusively, this analysis suggests that HPV (+) HNSCC and oropharyngeal cancer patients could benefit much more from concurrent cisplatin than BRT.

Given that in the clinical stages, radiotherapy regimens, and patients receiving induction chemotherapy is related to a patient's survival, we designed subgroup analyses in our study. Considering the nine studies that focused on stage III-IV patients and other studies that included all the clinical stages, we could not perform subgroup analysis on clinical stages. Similarly, subgroup analysis of the radiotherapy technique was not performed also because intensity-modulated radiation therapy was used in ten studies, the radiotherapy technology was not given in other studies. The combined HR for OS was 0.54 (95%CI, 0.33–0.90, P = .180) for three studies that employed induction chemotherapy, and 0.46 (95%CI, 0.33–0.65, P < .001) in the fourteen studies without induction chemotherapy. The OS and PFS cox model analysis from a phase II-III trial found that after induction, concurrent chemoradiotherapy had a similar survival to BRT. However, BRT had a better OS after induction chemotherapy than concurrent chemoradiotherapy, indicating that induction chemotherapy could cause different effect to the subsequent concomitant strategy.[47] After 3 cycles of intensive TPF induction chemotherapy, the patients could tolerate concurrent cetuximab more easily than concurrent high-dose cisplatin-based chemotherapy. Therefore, concurrent cetuximab could achieve a better survival by avoiding the severe toxicity caused by concurrent chemotherapy. But the interaction test did not reach the statistical significance (P = .088). Similarly, in the subgroup analyses stratified by study types, the combined HR for OS was 0.50 (95%CI, 0.39–0.65, P < .001) in the 19 retrospective studies, and 0.53 (95%CI, 0.30–0.93, P < .001) in the 5 prospective studies. The results of the subgroup and pooled analysis were similar, demonstrating that patients treated with CRT had a better outcome in locally advanced HNSCC.

HPV (+) and HPV (−) HNSCC are different groups with different treatment strategies. HPV (+) HNSCC has higher chemosensitivity and radiosensitivity with a better prognosis, in which de-intensification is being investigated widely. Previous studies reported that HPV infection and EGFR status were inversely associated.[59] Therefore, EGFR inhibition may be inferior to chemotherapy in HPV (+) HNSCC; however, the studies had inconsistent conclusions regarding this. Some studies reported better outcomes with cetuximab than with cisplatin in HPV (+) HNSCC.[45,60] Recently, 2 randomized studies demonstrated that cetuximab was inferior to cisplatin for patients in terms of OS. Furthermore, cetuximab also caused severe toxicity similar to cisplatin. Similarly, our meta-analysis, also showed that cisplatin had better survival in HPV (+) HNSCC.[11,12] Hence, cisplatin should remain the standard of care for HPV (+) HNSCC patients. As is known to all, HPV (+) OPC is genetically different from HPV (−) HNSCC. Activating mutations in downstream genes of the EGFR pathway might cause anti-EGFR resistance in HPV (+) OPC. Amplification, overexpression of EGFR, and downstream signal transduction are more frequent in HPV (−) HNSCC.[61] Retrospective study suggested that EGFR inhibition might be more effective in HPV (−) disease than in HPV (+) disease.[13,14] Considering the effect of cetuximab in two different groups might be different, it is not appropriate to ratiocinate the results of this meta-analysis to HPV(−) HNSCC. Additionally, we conducted subgroup analyses to explore the potential areas of bias. A reduced heterogeneity was found when we included prospective studies suggesting that the differences in study types could be a source of heterogeneity. Moreover, heterogeneity might partly result from different administration and doses of cisplatin. Cisplatin was given at 40 mg/m2 weekly in some studies,[25,28,35,41,42] while 100 mg/m2 was administered every 3 weeks in others studies. The heterogeneity may be reduced after the standardization of the issues in the future. In terms of publication bias, Egger test demonstrated that there was no publication bias. Moreover, there is no need to worry about the publication bias in this meta-analysis. Also, it is clinically meaningful and highly publishable no matter CRT or BRT is better.

However, this meta-analysis has some limitations. Firstly, the data were extracted from prospective or retrospective studies with different inclusion criteria, which might bring bias. Furthermore, the choice of CRT or BRT might be on account of the patients’ characteristics and clinical condition in the retrospective studies. Also, this meta-analysis lacks individual data. Furthermore, we excluded studies that had no adequate data to calculate HR. Finally, the sample size of each study varied widely.

5. Conclusion

In this meta-analysis, we observed that CRT had better OS, PFS, LRC, and DMFS in locally advanced HNSCC than BRT. Thus, concurrent cisplatin should remain the standard of treatment for patients in this setting. Concurrent cetuximab may still be administered to patients who cannot tolerate cisplatin.

Author contributions

Data curation: Wen-Hua Tang.

Formal analysis: Wei Sun, Wen-Hua Tang.

Investigation: Guo-Xian Long.

Methodology: Wei Sun, Wen-Hua Tang.

Supervision: Guo-Xian Long.

Validation: Wei Sun.

Writing – original draft: Wen-Hua Tang.

Writing – review & editing: Guo-Xian Long.

Supplementary Digital Content.

Supplementary Material

Supplemental Digital Content
medi-99-e21785-s001.docx (22.9KB, docx)

Footnotes

Abbreviations: – = negative, + = positive, BRT = concurrent cetuximab with radiotherapy, CIs = confidence intervals, CRT = concurrent cisplatin with radiotherapy, DMFS = distant metastasis-free survival, EGFR = epidermal growth factor receptor, HNC = head and neck cancer, HNSCC = head and neck squamous cell carcinomas, HPV = human papillomavirus, HR = hazard ratio, LRC = locoregional control, NCCN = National Comprehensive Cancer Network, OS = overall survival, PFS = progression-free survival, RT = radiotherapy.

How to cite this article: Tang WH, Sun W, Long GX. Concurrent cisplatin or cetuximab with radiotherapy in patients with locally advanced head and neck squamous cell carcinoma: a meta-analysis. Medicine. 2020;99:36(e21785).

The authors have no conflicts of interests to disclose.

The datasets generated during and/or analyzed during the current study are publicly available.

References

  • [1].Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359–86.. [DOI] [PubMed] [Google Scholar]
  • [2].Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7–30.. [DOI] [PubMed] [Google Scholar]
  • [3].Mehanna H, Paleri V, West CM, et al. Head and neck cancer--Part 1: epidemiology, presentation, and prevention. BMJ 2010;341:c4684. [DOI] [PubMed] [Google Scholar]
  • [4].Colevas AD, Yom SS, Pfister DG, et al. NCCN guidelines insights: head and neck cancers, version 1.2018. J Natl Compr Canc Netw 2018;16:479–90.. [DOI] [PubMed] [Google Scholar]
  • [5].Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937–44.. [DOI] [PubMed] [Google Scholar]
  • [6].Pignon JP, le Maitre A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4–14.. [DOI] [PubMed] [Google Scholar]
  • [7].Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92–8.. [DOI] [PubMed] [Google Scholar]
  • [8].Dent P, Reardon DB, Park JS, et al. Radiation-induced release of transforming growth factor alpha activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death. Mol Biol Cell 1999;10:2493–506.. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [9].Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11:21–8.. [DOI] [PubMed] [Google Scholar]
  • [10].Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567–78.. [DOI] [PubMed] [Google Scholar]
  • [11].Mehanna H, Robinson M, Hartley A, et al. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. Lancet 2019;393:51–60.. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet 2019;393:40–50.. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Vermorken JB, Stohlmacher-Williams J, Davidenko I, et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol 2013;14:697–710.. [DOI] [PubMed] [Google Scholar]
  • [14].Fayette J, Wirth L, Oprean C, et al. Randomized phase II study of duligotuzumab (MEHD7945A) vs. cetuximab in squamous cell carcinoma of the head and neck (MEHGAN Study). Front Oncol 2016;6:232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Plos Med 2009;6:e1000097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Tierney JF, Stewart LA, Ghersi D, et al. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007;8:16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [17].Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998;17:2815–34.. [DOI] [PubMed] [Google Scholar]
  • [18].Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603–5.. [DOI] [PubMed] [Google Scholar]
  • [19].Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [20].Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–60.. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [21].Egger M, Davey SG, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34.. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Bauml JM, Vinnakota R, Anna PY, et al. Cisplatin versus cetuximab with definitive concurrent radiotherapy for head and neck squamous cell carcinoma: an analysis of veterans health affairs data. Cancer-Am Cancer Soc 2019;125:406–15.. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Amini A, Eguchi M, Jones BL, et al. Outcomes between concurrent cisplatin versus cetuximab in locally advanced oropharyngeal carcinoma: a seer-Medicare analysis. Int J Radiat Oncol 2018;100:1335. [Google Scholar]
  • [24].Onita B, Lester DRT, Iman AA, et al. Comparison of high-dose Cisplatin-based chemoradiotherapy and Cetuximab-based bioradiotherapy for p16-positive oropharyngeal squamous cell carcinoma in the context of revised HPV-based staging. XXX 2018;23:451–7.. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [25].Rawat S, Ahlawat P, Kakria A, et al. Comparison between weekly cisplatin-enhanced radiotherapy and cetuximab-enhanced radiotherapy in locally advanced head and neck cancer: first retrospective study in Asian population. Asia-Pac J Clin Onco 2017;13:195–203.. [DOI] [PubMed] [Google Scholar]
  • [26].Stokes WA, Sumner WA, Breggren KL, et al. A comparison of concurrent cisplatin versus cetuximab with radiotherapy in locally-advanced head and neck cancer: a bi-institutional analysis. Rep Pract Oncol Radiother 2017;22:389–95.. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Riaz N, Sherman E, Koutcher L, et al. Concurrent chemoradiotherapy with cisplatin versus cetuximab for squamous cell carcinoma of the head and neck. Am J Clin Oncol 2016;39:27–31.. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Law KS, Wong RKY, Yu E, et al. Treatment outcome of cetuximab compared with cisplatin during radical radiotherapy for locally advanced head and neck cancer. Hong Kong J Radiol 2016;19:96–102.. [Google Scholar]
  • [29].Ou D, Levy A, Blanchard P, et al. Concurrent chemoradiotherapy with cisplatin or cetuximab for locally advanced head and neck squamous cell carcinomas: does human papilloma virus play a role? Oral Oncol 2016;59:50–7.. [DOI] [PubMed] [Google Scholar]
  • [30].Bhattasali O, Iganej S. Cetuximab-based bioradiation therapy versus cisplatin-based chemoradiation therapy in the definitive treatment of locally advanced oropharyngeal squamous cell carcinoma. Int J Radiat Oncol 2016;96: 2 Supplement 1: S82–3.. [Google Scholar]
  • [31].Weller MA, Ward MC, Berriochoa CA, et al. Cetuximab-based bioradiation therapy is associated with higher rates of distant metastases than platinum-based chemoradiation therapy in human papillomavirusepositive oropharyngeal cancer. Int J Radiat Oncol 2015;93: 3 SUPPL 1: S76–7.. [Google Scholar]
  • [32].Strom TJ, Trotti AM, Kish J, et al. Comparison of every 3 week cisplatin or weekly cetuximab with concurrent radiotherapy for locally advanced head and neck cancer. Oral Oncol 2015;51:704–8.. [DOI] [PubMed] [Google Scholar]
  • [33].Sakashita T, Homma A, Hatakeyama H, et al. Comparison of acute toxicities associated with cetuximab-based bioradiotherapy and platinum-based chemoradiotherapy for head and neck squamous cell carcinomas: a single-institution retrospective study in Japan. Acta Otolaryngol 2015;135:853–8.. [DOI] [PubMed] [Google Scholar]
  • [34].Peddi P, Shi R, Nair B, et al. Cisplatin, cetuximab, and radiation in locally advanced head and neck squamous cell cancer: a retrospective review. Clin Med Insights Oncol 2015;9:1–7.. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [35].Kanakamedala MR, Giri SP, Abraham RS, et al. Comparison of cisplatin versus cetuximab with intensity modulated radiation therapy in locally advanced squamous cell carcinomas of head and neck: toxicity, patterns of failure, and survival analysis. Int J Radiat Oncol 2014;901:S565. [Google Scholar]
  • [36].Ley J, Mehan P, Wildes TM, et al. Cisplatin versus cetuximab given concurrently with definitive radiation therapy for locally advanced head and neck squamous cell carcinoma. Oncology 2013;85:290–6.. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [37].Ye AY, Hay JH, Laskin JJ, et al. Toxicity and outcomes in combined modality treatment of head and neck squamous cell carcinoma: cisplatin versus cetuximab. J Cancer Res Ther 2013;9:607–12.. [DOI] [PubMed] [Google Scholar]
  • [38].Chew A, Hay J, Laskin JJ, et al. Toxicity in combined modality treatment of HNSCC: cisplatin versus cetuximab. J Clin Oncol 2011;29: 15_Suppl: 5526. [Google Scholar]
  • [39].Walsh L, Gillham C, Dunne M, et al. Toxicity of cetuximab versus cisplatin concurrent with radiotherapy in locally advanced head and neck squamous cell cancer (LAHNSCC). Radiother Oncol 2011;98:38–41.. [DOI] [PubMed] [Google Scholar]
  • [40].Galper SL, Deshpande H, Rose MG, et al. Cetuximab versus cisplatin concurrent with IMRT in locally advanced head and neck cancer (LAHNC). J Clin Oncol 2009;27: 15_suppl: e17030. [Google Scholar]
  • [41].Caroline B, Sundus Y, Dawn D, et al. Cost analysis of cetuximab (Erbitux) plus radiotherapy (ERT) versus concomitant cisplatin plus radiotherapy (CRT) within an NHS oncology unit (single institution): a pilot study. Br J Radiol 2016;89:20160105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Magrini SM, Buglione M, Corvo R, et al. Cetuximab and radiotherapy versus cisplatin and radiotherapy for locally advanced head and neck cancer: a randomized phase II trial. J Clin Oncol 2016;34:427–35.. [DOI] [PubMed] [Google Scholar]
  • [43].Lefebvre JL, Pointreau Y, Rolland F, et al. Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: The TREMPLIN randomized phase II study. Dysphagia 2014;29:287–8.. [DOI] [PubMed] [Google Scholar]
  • [44].Petrelli F, Coinu A, Riboldi V, et al. Concomitant platinum-based chemotherapy or cetuximab with radiotherapy for locally advanced head and neck cancer: a systematic review and meta-analysis of published studies. Oral Oncol 2014;50:1041–8.. [DOI] [PubMed] [Google Scholar]
  • [45].Huang J, Zhang J, Shi C, et al. Survival, recurrence and toxicity of HNSCC in comparison of a radiotherapy combination with cisplatin versus cetuximab: a meta-analysis. BMC Cancer 2016;16:689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [46].Ghi M, Paccagnella A, Orecchia R, et al. A Phase 2–3 study comparing concomitant chemoradiation therapy (CRT) versus cetuximab/RT (CET/RT) with or without induction docetaxel/cisplatin/5-fluorouracil (TPF) in locally-advanced head and neck squamous cell carcinoma (LASCCHN) - efficacy results of the GSTTC Italian study (NCT01086826). Int J Radiat Oncol 2013;87S:S2. [Google Scholar]
  • [47].Ghi MG, Paccagnella A, Ferrari D, et al. Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial. Ann Oncol 2017;28:2206–12.. [DOI] [PubMed] [Google Scholar]
  • [48].Caudell JJ, Sawrie SM, Spencer SA, et al. Locoregionally advanced head and neck cancer treated with primary radiotherapy: a comparison of the addition of cetuximab or chemotherapy and the impact of protocol treatment. Int J Radiat Oncol Biol Phys 2008;71:676–81.. [DOI] [PubMed] [Google Scholar]
  • [49].Tang C, Chan C, Jiang W, et al. Concurrent cetuximab versus platinum-based chemoradiation for the definitive treatment of locoregionally advanced head and neck cancer. Head Neck 2015;37:386–92.. [DOI] [PubMed] [Google Scholar]
  • [50].Hu MH, Wang LW, Lu HJ, et al. Cisplatin-based chemotherapy versus cetuximab in concurrent chemoradiotherapy for locally advanced head and neck cancer treatment. Biomed Res Int 2014;2014:904341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [51].Koutcher L, Sherman E, Fury M, et al. Concurrent cisplatin and radiation versus cetuximab and radiation for locally advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2011;81:915–22.. [DOI] [PubMed] [Google Scholar]
  • [52].Riaz N, Baschnagel A, Adkins D, et al. Multi-institution analysis of concurrent chemoradiation therapy with cisplatin (CDDP) versus cetuximab (C225) in locally advanced squamous cell carcinoma of the head and neck (LAHNSCC): can HPV help decide which agent? Int J Radiat Oncol 2014;88:472. [Google Scholar]
  • [53].Shapiro LQ, Sherman EJ, Riaz N, et al. Efficacy of concurrent cetuximab vs. 5-fluorouracil/carboplatin or high-dose cisplatin with intensity-modulated radiation therapy (IMRT) for locally-advanced head and neck cancer (LAHNSCC). Oral Oncol 2014;50:947–55.. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [54].Levy A, Blanchard P, Bellefqih S, et al. Concurrent use of cisplatin or cetuximab with definitive radiotherapy for locally advanced head and neck squamous cell carcinomas. Strahlenther Onkol 2014;190:823–31.. [DOI] [PubMed] [Google Scholar]
  • [55].Ou D, Adam J, Garberis I, et al. Clinical relevance of tumor infiltrating lymphocytes, PD-L1 expression and correlation with HPV/p16 in head and neck cancer treated with bio- or chemo-radiotherapy. Oncoimmunology 2017;6:e1341030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [56].Ou D, Garberis I, Adam J, et al. Prognostic value of tissue necrosis, hypoxia-related markers and correlation with HPV status in head and neck cancer patients treated with bio- or chemo-radiotherapy. Radiother Oncol 2018;126:116–24.. [DOI] [PubMed] [Google Scholar]
  • [57].Amini A, Eguchi M, Jones BL, et al. Comparing outcomes of concurrent chemotherapy regimens in patients 65 years or older with locally advanced oropharyngeal carcinoma. Cancer-Am Cancer Soc 2018;124:4322–31.. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [58].Peddi P, Shi R, Panu L, et al. Cisplatin (CDDP) and radiation versus cetuximab (Cx) and radiation in locally advanced head and neck squamous cell cancer (SCHNC): a retrospective review. J Clin Oncol 2012;30: 15 SUPPL 1: e16009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [59].Reimers N, Kasper HU, Weissenborn SJ, et al. Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer. Int J Cancer 2007;120:1731–8.. [DOI] [PubMed] [Google Scholar]
  • [60].Pajares B, Trigo JM, Toledo MD, et al. Differential outcome of concurrent radiotherapy plus epidermal growth factor receptor inhibitors versus radiotherapy plus cisplatin in patients with human papillomavirus-related head and neck cancer. Bmc Cancer 2013;13:26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [61].Hayes DN, Van Waes C, Seiwert TY. Genetic landscape of human papillomavirus-associated head and neck cancer and comparison to tobacco-related tumors. J Clin Oncol 2015;33:3227–34.. [DOI] [PMC free article] [PubMed] [Google Scholar]

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