- Research article
- Open Access
- Open Peer Review
Survival, recurrence and toxicity of HNSCC in comparison of a radiotherapy combination with cisplatin versus cetuximab: a meta-analysis
- Received: 14 December 2015
- Accepted: 10 August 2016
- Published: 26 August 2016
Abstract
Background
Cisplatin-based treatment has been considered the standard treatment regimen of HNSCC. Cetuximab is an emerging target therapy that has potential therapeutic benefits over cisplatin. Nevertheless, curative effects of cisplatin-based chemoradiotherapy (CRT) versus cetuximab-based bioradiotherapy (BRT) are still controversial.
Methods
Potentially eligible studies were retrieved using PubMed, Embase and Medline. Basic characteristics of patients and statistical data were collected. A meta-analysis model was established to compare CRT and BRT.
Results
Thirty-one eligible studies and 4212 patients were found. The pooled HRs with 95 % confidence intervals (CIs) for OS and PFS were 0.32 [0.09, 0.55] and 0.51 [0.22, 0.80], respectively, and both were in favor of cisplatin. However, 3-year survival and recurrence analysis of the subgroups showed no differences between the two groups (p > 0.05). In subgroup analysis, oropharyngeal primary tumors exhibited improved results by cetuximab with a pooled HR of 1.56 [1.14, 2.13] for PFS. Additionally, the HPV+ status was a significant factor in positive outcomes with cetuximab with a pooled HR of 1.12 [0.46, 2.17] for OS.
Conclusion
Long-term use of BRT showed no significant difference compared with CRT, and both arms showed different aspects of toxicity. In subgroup analysis, taking the effects of treatment and adverse events into consideration, cetuximab plus radiation may show superior responses regarding OS and PFS in patients who have HPV+ or primary oropharyngeal HNSCC, respectively, but physicians should administer them with caution.
Keywords
- HNSCC
- Oropharynx
- HPV
- Cisplatin
- Cetuximab
- Radiotherapy
- Prognosis
- Recurrence
- Adverse event
Background
Squamous cell carcinoma of the head and neck (HNSCC) consists of cancers arising from the oral cavity, pharynx and larynx and comprises approximately 5 % of all cancers worldwide. The global incidence is increasing by half a million and causing more than 350,000 deaths every year [1, 2]. A limited number of patients with locally advanced disease are suitable for potentially curative surgery or definitive radiotherapy. Patients who are not candidates for surgery or definitive radiotherapy may receive chemotherapy plus radiation or systemic chemotherapy alone [3].
Cisplatin-based chemoradiotherapy is now considered to be the established standard, first-line chemotherapy to treat patients with locally advanced HNSCC [69]. Many large randomized studies and meta-analyses have demonstrated that cisplatin-based concurrent chemoradiotherapy regimens provide significantly higher response rates than radiotherapy alone [4, 5].
Epidermal growth factor receptor (EGFR) seems to be critical to cancer cell growth and proliferation, and the function of EGFR in these two settings appears to be different [6, 7]. Head and neck cancer cells exhibit this difference compared to normal cells without exception [8]. In addition, EGFR expression was markedly increased or over-expressed in HNSCC compared to normal tissue, which has been shown to be an independent prognostic factor for poor survival [9]. Thus, EGFR inhibitors have become a burgeoning strategy in anti-tumor treatment. To date, several monoclonal antibodies targeting EGFR have been successfully used in clinical practice with significant effects. Improved loco-regional control and prolonged survival time have already been achieved in lung and gastro-intestinal cancers [10–12].
Cetuximab, an EGFR-targeting monoclonal antibody, is the first targeted therapy to show therapeutic benefit in head and neck cancer [13] and received FDA approval for use in treating HNSCC in 2006 [14, 15]. The Bonner trial showed impressively increased survival outcomes and loco-regional control rates when comparing cetuximab plus radiation versus radiation alone [16]. The Merlano trial exhibited a promising treatment response from adding cetuximab to standard chemotherapy, with limited toxicity [17]. Clinical trials have shown that the addition of cetuximab to traditional treatment regimens (e.g., cisplatin plus radiation) could improve survival outcomes [18, 19]. However, this combination may lead to increased treatment-related toxicity and increased cost, and the administration of multiple drugs may worsen quality of life.
Hence, we conducted a meta-analysis with the aims of gathering outcomes from clinical trials and obtaining a larger sample size to compare the curative effects between the administration of cisplatin-based chemoradiotherapy (CRT) or cetuximab-based bioradiotherapy (BRT) with regards to survival results, loco-regional control or distant metastasis (failure), and treatment-related adverse effects in patients with HNSCC.
Methods
Search strategy
PubMed, Embase and Medline were searched on Mar 13, 2016. The following keywords were used to retrieve articles and abstracts: head and neck squamous cell carcinoma (HNSCC), cancers of larynx, cancers of oral tongue, cancers of oropharynx, cancers of laryngopharynx, cetuximab, cisplatin and radiotherapy.
Study selection and inclusion/exclusion criteria
Titles and abstracts were reviewed in all of the searched studies, and full texts were reviewed in potentially eligible studies according to our inclusion criteria. To avoid duplicated data, when more than one trial was completed with crossed data in a single center, only the largest most updated trials were included.
In our meta-analysis, we used the following inclusion criteria: (1) studies containing patients with locally advanced HNSCC, including the following: cancers of the larynx, cancers of the oral tongue, cancers of the oropharynx, or cancers of the laryngopharynx; (2) studies comparing the administration of cisplatin-based chemotherapy versus cetuximab-based biotherapy; and (3) studies with available data regarding survival outcomes of patients included in the clinical trials. On the other hand, studies were excluded based on the following criteria: (1) articles that consisted of in vitro studies or were review articles; (2) studies with duplicated data, meaning that one analysis that had several articles reporting updated outcomes; and (3) studies containing metastatic and/or recurrent disease.
Data extraction
The following two investigators reviewed all of the articles independently: Huang JW and Shi CL. Any discrepancy was discussed until reaching a consensus. The data were independently extracted from eligible studies by two investigators (Huang JW and Shi CL), and then, the obtained data were integrated. The primary data consisted of HRs with a 95 % confidence interval (CI) or event/total patient numbers regarding survival outcomes, including OS and/or PFS and the recurrence rates, such as loco-regional and/or distant recurrence of disease in patients from cetuximab cohorts and cisplatin cohorts.
The additional data obtained from the studies included the first author, publication year, patient source (region), median age, percentage of each sex, TNM stage at diagnosis, treatment regimens, tumor site (%), survival outcomes, recurrence rates, type of study, toxicity N (G3 ~ 4) in CRT vs. BRT groups, and attitude of the original studies. The statistical data for acquiring logHR and SE were also obtained, including HR with a 95 % CI, Kaplan–Meier survival curves with p values, and response rates of the over-expression cohort compared to the normal/lower expression cohort [20].
Statistical methods
logHR and SE were required in our analysis. Some of the original papers provided logHR and SE directly, whereas other studies did not. As mentioned above, we utilized other data to calculate these values using methods developed by Parmar et al. (1998) [21], Williamson et al. (2002) [22], and Tierney et al. (2007) [23]. The logHRs and SEs were calculated with the methods described earlier when 1) there was a HR with 95 % CI or 2) there was a p value for the log-rank test with the Kaplan–Meier survival curve.
Hazard ratio (HR) was used as the measure index to describe the survival outcomes and disease control rates between the BRT arm and CRT arm (we considered the cisplatin regimen as the standard regimen). As a result of the analysis of survival in patients, a significant outcome was defined by a p value < 0.05, while a p value > 0.05 indicated no significant difference between the two comparison arms. Pooled HRs > 1 combined with p < 0.05 indicate a narrow difference between the two groups, and the cetuximab arm showed higher event incidences. In contrast, pooled HRs < 1 indicated a lower incidence of events in the cetuximab cohort. Furthermore, pooled HRs > 2 or <0.5 denote a significant result. We use the term “positive” to indicate a better outcome related to cetuximab treatment and “negative” to indicate an absence of correlation between the two comparison arms or better outcomes in the cisplatin arm.
In terms of heterogeneity, values of p < 0.10 or I2 > 50 % represent heterogeneity existing in the pooled HRs (Higgins et al., 2003) [24]. When homogeneity was minimal (p ≥ 0.10, I2 ≤ 50 %), a fixed-effects model was applied for secondary analysis; otherwise, a random-effects model was used. All of the earlier calculations and publication bias were measured using the Begg’s funnel plot, which was performed by STATA 11.0 (STATA Corporation, College Station, TX). This calculation for the current meta-analysis was performed using REVIEW MANAGER (version 5.0 for Windows; the Cochrane collaboration, Oxford, UK).
The sensitive analysis, which aims to test for the heterogeneity of all of the included studies and to determine if heterogeneity arose from any single study, was performed by STATA 11.0 (STATA Corporation, College Station, TX). In the analytic figure, an absence of heterogeneity is indicated by the containment of the studies within the constricted interval (defined between lower CI limit and Upper CI limit), while the existence of a single study far outside the confidence interval indicates that the heterogeneity is due to that individual study.
Results
Eligible studies
Selection of Studies
Basic characteristics of included studies
Author | Type of study | Region | Age | Stage | Female (%) | Therapy regimens | HPV statue (+) | Survival | |||
|---|---|---|---|---|---|---|---|---|---|---|---|
Cisplatin | Cetuximab | Cisplatin | Cetuximab | Cisplatin | Cetuximab | ||||||
Vermorken JB | RS | America | CRT: 57.8 | BRT: 57 | Stage III/IV | NR | RT-CIS VS. RT-CET | NR | 2-yrOS 1-yr PFS | ||
Caudell JJ | RS | America | CRT: 55 | BRT: 54 | Stage III/V | BRT: 20.7 % | CRT: 22.3 % | CCRT VS. Concurrent RT+CET | NR | 1-yr OS 2-yr OS | |
L.D. Koutcher | RS | America | NR | RT-CIS VS. RT-CET | 16 (42 %) | 8 (35 %) | 30-mon PFS 30-mon OS | ||||
Jensen AD | RS | Germany | CRT: 38 | BRT: 38 | Stage III/IV | NR | RT-CIS VS. RT-CET | NR | 2-yr OS 2-yr PFS 2-yr L-PFS 2-yr D-PFS | ||
Koutcher L | RS | America | CRT: 56 | BRT: 66 | Stage III/IV | CRT:17 (13.6 %) | BRT:11 (22.5 %) | RT-CIS VS. RT-CET | NR | 2-yr FFS 2-yr OS 2-yr LRC | |
Beijer, Y.J. | RS | Netherland | Primary: 56 | Primary: 64 | Stage II-IV | CRT Primary: 37 | CET Primary: 43 | RT-CIS VS. RT-CET | NR | 1-yr OS 1-yr DFS 2-year OS 2-yr DFS LRR | |
Adjuvant: 59 | Adjuvant: 56 | CRT Adjuvant: 36 | CET Adjuvant: 36 | ||||||||
Ley J | RS | America | CRT: 55 | BRT: 62 | Stage III/IV | CRT: 16.7 | BRT: 34.5 | RT-CIS VS. RT-CET | NR | 3-yr DSS 3-yr LRR | |
Ye AY | RS | Canada | CRT: 57 | BRT: 62 | Stage III/IV | CRT: 17 | BRT: 14 | RT-CIS VS. RT-CET | NR | 3-yr OS 3-yr DFS 3-yr LRC | |
Pajares B | RS | Spain | p16 Negative: 59 | p16 positive: 57 | Stage III/IV | p16 Negative:7 | p16 Positive: 6 | RT-CIS VS. RT-CET | 10 (18 %) | 8 (15 %) | 2-yr OS 2-yr DFS 2-yr LRR |
Lefebvre JL | Phase II RCT | France | CRT: 57.5 | BRT: 57.8 | Stage II-IV | CRT: 13.3 | BRT: 1.7 | RT-CIS VS. RT-CET | NR | 18-mon OS 18-mon LRR 36-mon OS | |
M. Ghi | RCT | Italy | 60 | Stage III/IV | 80.5 | CCRT VS. Cet+RT | NR | 3-yr OS 3-yr PFS | |||
N. Riaz | RCT | America | NR | NR | NR | CCRT VS. Cet+RT | 24 (56%) | 11 (75%) | NR | ||
Hu MH | RCT | Taiwan | CRT: 55 | BRT: 78 | Stage III/IV | CRT: 3.4 | BRT: 3.7 | CCRT VS. Cet+RT | LRR 3-yr RFS 3-yr OS DM | ||
Levy A | RCT | Germany | CRT: 58 | BRT: 60 | Stage III/IV | CRT: 20 | BRT: 23 | CCRT VS. BRT | NR | 2-yr OS 2-yr LRC 2-yr DM | |
Tang C | RCT | America | CRT: 58 | BRT: 73 | Stage I-IV | CRT: 10 | BRT: 1 | CCRT VS. Concurrent Cet+RT | NR | 2-yr LRC 2-yr EFS 2-yr OS | |
Fayette J | RS | France | 56 | Stage III/IV | 10 | CCRT VS. Concurrent Cet+RT | NR | 5-yr OS 5-yr DFS | |||
Huang J | RS | Japan | CRT: 55 | BRT: 77 | Stage III/IV | IMRT/ cisplatin: 13 | IMRT/ cetuxima:19 | IMRT/CIS VS. IMRT/CET | NR | LRC DM OS CSS | |
Shapiro LQ | RS | America | NR | stage II-IV | CRT:13.1 | BRT: 22.4 | IMRT/CIS VS. IMRT/CET | NR | 4-yr OS 4-yr LRF | ||
M.R. Kanakamedala | RS | America | 53 | NR | NR | RT-CIS VS. RT-CET | NR | LRC 3-yr OS 2-yr PFS | |||
Riaz N | RS | America | NR | NR | NR | RT-CIS VS. RT-CET | NR | NR | |||
Riaz N | RS | America | NR | Stage III/IV | CRT: 21 | BRT: 22 | RT-CIS VS. RT-CET | 31 (86 %) | 17 (74 %) | NR | |
Peddi P | RS | America | CRT: 55 | BRT: 61 | Stage III/IV | CRT: 26.7 | BRT: 29.7 | CCRT VS. Concurrent RT-CET | NR | 2-yr OS 2-yr PFS | |
S.L.Galper | RS | America | CRT: 58 | BRT: 71 | NR | NR | RT-CIS VS. RT-CET | NR | NR | ||
D.Borchiellini | RS | France | CRT: 56 | BRT: 57 | NR | CRT 16 % | BRT 8 % | RT-CIS VS. RT-CET | NR | NR | |
Lorraine Walsh | RS | Ireland | CRT: 57.5 | BRT: 63 | Stage III/IV | CRT : 9 % | BRT : 11.8 % | RT-CIS VS. RT-CET | NR | NR | |
Stefano Maria Magrini | RCT | America | CRT: 67.5 | BRT: 61 | Stage III/IV | CRT: 31 % | BRT:26 % | RT-CIS VS. RT-CET | NR | 2-yr OS | |
Tobin J. Strom | RS | America | CRT: 58 | BRT: 62 | Stage III/IV | CRT: 16.2 | BRT: 5.3 | RT-CIS VS. RT-CET | 43.4 % | 41.2 % | 2-yrOS |
Nadeem Riaz | NR | America | CRT: 118 < 71 7 >71 | BRT: 38 < 71 11>71 | NR | CRT : 21 % | BRT: 22 % | RT-CIS VS. RT-CET | 86 | 74 | 3-yr LRC 3-yr OS 3-yr PFS |
Comparison between cisplatin-based and cetuximab regarding overall survival
Pooled HRs (95 % Cl) comparing survival outcomes and recurrence between BRT & CRT
Comparison | Survival outcome | Study N. | Model | HR (95 % Cl) | P value | Heterogeneity (p ,I2) | Conclusion |
|---|---|---|---|---|---|---|---|
BRT vs. CRT | OS | 23 | Random | 0.32 [0.09, 0.55] | 0.006 | P < 0.00001; I² = 84.6 % | Positive |
BRT vs. CRT | OS for 2-yr | 11 | Random | 0.44 [0.13, 0.76] | 0.006 | P < 0.0001; I² = 76.9 % | Positive |
BRT vs. CRT | OS for 3-yr | 12 | Random | 0.21 [-0.14, 0.55] | 0.241 | P < 0.00001; I² = 88.8 % | Negative |
BRT vs. CRT | PFS | 21 | Random | 0.51 [0.22, 0.80] | 0.001 | P < 0.00001; I² = 90.1 % | Positive |
BRT vs. CRT | PFS for 2-yr | 10 | Random | 0.56 [0.20, 0.92] | 0.002 | P < 0.00001; I² = 88.2 % | Positive |
BRT vs. CRT | PFS for 3-yr | 11 | Random | 0.45 [-0.05, 0.95] | 0.076 | P < 0.00001; I² = 91.8 % | Negative |
BRT vs. CRT | Locoregional control | 19 | Random | 0.49 [0.14, 0.85] | 0.007 | P < 0.00001; I² = 91 % | Positive |
BRT vs. CRT | Locoregional control for 2-yr | 9 | Random | 0.63 [0.09, 1.17] | 0.023 | P < 0.00001; I² = 83 % | Positive |
BRT vs. CRT | Locoregional control for 3-yr | 10 | Random | 0.06 [-0.40, 0.52] | 0.808 | P < 0.00001; I² = 93.3 % | Negative |
BRT vs. CRT | Distant control | 5 | Random | 0.25 [0-0.06, 0.56] | 0.118 | P < 0.00001; I² = 88.3 % | Negative |
BRT vs. CRT | OS for oropharynx | 7 | Random | 0.13 [-0.03, 0.89] | 0.743 | P < 0.00001; I² = 84.8 % | Negative |
BRT vs. CRT | PFS for oropharynx | 3 | Random | 1.56 [1.14, 2.13] | 0.006 | P < 0.00001; I² = 96 % | Positive |
BRT vs. CRT | Locoregional control for oropharynx | 6 | Random | 1.75 [0.6, 5.26] | 0.31 | P < 0.00001; I² = 89.1 % | Negative |
BRT vs. CRT | OS for HPV+ | 5 | Fixed | 1.12 [0.46, 2.17] | 0.015 | P = 0.22; I² = 38 % | Positive |
BRT vs. CRT | PFS for HPV+ | 5 | Random | 0.80 [0.38, 1.67] | 0.55 | P < 0.00001; I² = 92 % | Negative |
BRT vs. CRT | Locoregional control for HPV+ | 5 | Random | 1.17 [0.69, 2.00] | 0.56 | P = 0.01; I² = 71.1 % | Negative |
Meta-analysis estimated OS comparing cisplatin-based chemoradiotherapy versus cetuximab-based bioradiotherapy. (a) subgroup of estimation of 2-yr OS; (b) subgroup of estimation of 3-yr OS. OS, overall survival
Subgroup analysis
As survival outcomes were largely influenced by time of observation, we categorized OS outcomes by year of estimation: 2-years, 3-years, or 5-years and beyond. The pooled HR for 2-year estimation was 0.44 [0.13, 0.76], p = 0.006, which supports better survival achieved with cisplatin-based therapy, while the 3-year or 5-year and beyond time assessments showed no significant difference between the two groups, with pooled HRs of 0.21 [-0.14, 0.55], p = 0.241and 0.95 [0.51, 1.74], p = 0.86, respectively (Table 2; Fig. 2).
Meta-analysis compared cisplatin-based chemoradiotherapy versus cetuximab-based bioradiotherapy in estimating patients in HPV+ subgroup regarding to OS, PFS, and LRC. OS, overall survival; PFS, progression-free survival; LRC, locoregional control
Meta-analysis compared cisplatin-based chemoradiotherapy versus cetuximab-based bioradiotherapy in estimating patients with oropharyngeal primary tumor regarding to OS, PFS and LRC. OS, overall survival; PFS, progression-free survival; LRC, locoregional control
Comparison between cisplatin-based and cetuximab therapies regarding progression-free survival
Meta-analysis estimated PFS comparing cisplatin-based chemoradiotherapy versus cetuximab-based bioradiotherapy. (a) subgroup of estimation of 2-yr PFS; (b) subgroup of estimation of 3-yr PFS. PFS, progression-free survival
Subgroup analysis
As assessed in the OS data, we categorized PFS outcomes by time intervals of estimation: 2-years, or 3-years and beyond. The pooled HRs were 0.56 [0.20, 0.92], p = 0.002, and 0.45 [-0.05, 0.95], p = 0.076 for the 2-year and 3-years and beyond time assessments, respectively, which indicate that better survival was achieved with cisplatin-based therapy (Table 2; Fig. 5).
For the HPV+ group, cetuximab-based therapy again showed outcomes superior to those of cisplatin-based therapy, and the pooled HR was 0.80 [0.38, 1.67], p = 0.55 (Table 2; Fig. 3).
We also analyzed PFS separately in patients with oropharynx tumors, and those patients who received cetuximab-based regimens showed prolonged PFS compared with administration of cisplatin-based therapy; the pooled HR was 1.56 [1.14, 2.13], p = 0.006 (Table 2; Fig. 4).
Comparison between cisplatin-based and cetuximab therapies regarding loco-regional containment
Meta-analysis estimated LRC comparing cisplatin-based chemoradiotherapy versus cetuximab-based bioradiotherapy. (a) subgroup of estimation of 2-yr LRC; (b) subgroup of estimation of 3-yr LRC. LRC, locoregional control
Subgroup analysis
Loco-regional control, like other recurrence rates and survival outcomes, directly correlated to the estimated time interval, and thus, we categorized the loco-regional control rates by the year of estimation: 2-years, 3-years, or 5-years and beyond. The pooled HR for the 2-year estimation was 0.63 [0.09, 1.17], p = 0.023, which supports better survival achieved with cisplatin-based therapy, while the 3-years or 5-years and beyond time assessments showed no significant difference between the two groups, and the pooled HRs were 0.34 [-0.12, 0.79], p = 0.15 and 2.67 [0.47, 8.73], p = 0.27, respectively (Table 2; Fig. 6).
Patients with HPV+ infection states showed a non-significantly better prognosis and prolonged survival in the cetuximab single agent group, and the pooled HR was 0.06 [-0.40, 0.52], p = 0.808 (Table 2; Fig. 3).
Analysis of patients with primary tumors in the oropharynx showed no significant difference between the cisplatin and cetuximab groups with a pooled HR of -0.05 [-1.34, 0.35], p = 0.248 (Table 2; Fig. 4).
Comparison between cisplatin-based and cetuximab therapies regarding distant metastasis
Meta-analysis estimated DM comparing cisplatin-based chemoradiotherapy versus cetuximab-based bioradiotherapy. DM, distant metastasis
Assessment of adverse events
Meta-analysis compared cisplatin-based chemoradiotherapy versus cetuximab-based bioradiotherapy in estimating toxicities including acute and late toxicities
Subgroup analysis
Meta-analysis compared cisplatin-based chemoradiotherapy versus cetuximab-based bioradiotherapy in estimating patients with oropharyngeal primary tumor and with single toxicity separately
Pooled HRs 95 % Cl for toxicity between CRT & BRT
Comparison | Adverse event/ Toxicity | Study N. | Model | HR 95 % [Cl] | P value | Heterogeneity (p ,I2) | Conclusion |
|---|---|---|---|---|---|---|---|
CRT vs. BRT | Mucositis | 7 | Fixed | 0.05 [-0.09, 0.19] | p=0.493 | P = 0.45; I² = 36.9 % | Negative |
CRT vs. BRT | Dysphagia | 5 | Fixed | -0.07 [-0.35, 0.21], | p=0.63 | P = 0.89; I² = 0 % | Negative |
CRT vs. BRT | Xerostomia | 2 | Fixed | 0.51 [0.09, 2.95], | p=0.46 | P = 0.17; I² = 46 % | Negative |
CRT vs. BRT | Laryngeal edema | 2 | Fixed | 0.91 [0.71, 1.18] | p=0.49 | P = 0.89; I² = 0 % | Negative |
CRT vs. BRT | Acute kidney injury | 5 | Fixed | -1.30 [-2.11, -0.49] | p=0.002 | P = 0.32; I² = 0 % | Positive |
CRT vs. BRT | Nausea or vomiting | 4 | Random | -1.30 [-2.66, 0.06], | p=0.061 | P = 0.03; I² = 57.2 % | Negative |
CRT vs. BRT | Radiation dermatitis | 4 | Random | 0.31 [-0.45, 1.08] | p=0.419 | P = 0.001; I² = 87.6 % | Negative |
CRT vs. BRT | Acneiform rash | 5 | Random | 3.49 [1.23, 5.74] | P=0.002 | P = 0.87; I² = 81 % | Positive |
CRT vs. BRT | Neutropenia | 3 | Fixed | -0.88 [-1.42, -0.33] | p=0.002 | P < 0.00001; I² = 0.0 % | Positive |
CRT vs. BRT | Ototoxicity | 3 | Fixed | 0.16 [0.04, 0.69] | p=0.10 | P = 0.60; I² = 0 % | Negative |
CRT vs. BRT | Infectious | 2 | Fixed | 3.31 [0.55, 19.87] | p=0.19 | P = 0.59; I² = 0 % | Negative |
CRT vs. BRT | Neuropathy | 2 | Fixed | 0.80 [0.46, 1.41] | p=0.44 | P = 0.37; I² = 0 % | Negative |
CRT vs. BRT | Pain | 2 | Fixed | 0.92 [0.80, 1.06] | p=0.24 | P = 0.74; I² = 0 % | Negative |
CRT vs. BRT | Leukopenia | 4 | Fixed | -0.76 [-1.16, -0.36] | P=0.001 | P = 0.19; I² = 44.2 % | Positive |
CRT vs. BRT | Late toxicity | 4 | Fixed | 1.11 [0.83, 1.47], | p=0.48 | P = 0.53; I² = 0 % | Negative |
CRT vs. BRT | Total toxicity | 21 | Random | -0.34 [-0.72, 0.04] | P=0.079 | P < 0.00001; I² = 91.7 % | Negative |
Results from sensitive tests
Sensitive analysis evaluated heterogeneity of OS cohort, PFS cohort and related subgroups. (a) Evaluation in OS group: total, 2-yr and 3-yr. (b) Evaluation in PFS group: total, 2-yr, and 3-yr. OS, overall survival; PFS, progression-free survival
Assessment of publication bias
Estimated Begg’s funnel plots of publication bias regarding OS, PFS, LRC, and DM cohort respectively. OS, overall survival; PFS, progression-free survival; LRC, locoregional control; DM, distant metastasis
Discussion
In this systemic review, we conducted a meta-analysis to compare the effect of cisplatin-based chemotherapy plus radiotherapy versus cetuximab plus radiotherapy in controlling the overall survival, progression-free survival, loco-regional recurrence and distant metastasis of locally advanced HNSCC. Meanwhile, different time periods of estimation, primary tumor sites in the oropharynx and HPV infection status were also taken into consideration. Our study demonstrated that in all settings of the estimated OS time duration, the outcomes were found to be better with cisplatin treatment; however, specifically observing the longer follow-up time intervals, patients between the two groups shared similar overall survival rates, as there was no statistical significance between the two groups with a follow-up time duration equal to or longer than 3 years. Progression-free survival and loco-regional control rates displayed similar tendencies as the OS rates. In subgroup analysis, tumors with a primary site in the oropharynx and tumors with HPV+ infection status showed non significantly better PFS and OS, respectively, with cetuximab single agent treatment plus radiotherapy, while no remarkable difference was observed between the remaining survival outcomes and loco-regional control in the two subgroups, indicating that equivalent effects of the two treatment regimens were achieved in these categories.
Concurrent cisplatin-based therapy has been regarded as the standard treatment regimen for patients with HNSCC [51]; however, cisplatin has been reported to cause immediate treatment-related adverse events and delayed toxicity. Cetuximab, an emerging monoclonal antibody therapeutic, targeting epidermal growth factor receptor (EGFR), seemed promising to provide patients with an effective alternative treatment [52]. Whether cetuximab could replace cisplatin in definitive chemoradiotherapy for HNSCC remains controversial because cetuximab has a reasonably good toxicity profile [53] but the tumor control effect and survival benefit present inconsistent results.
Therefore, to achieve better quality of life and avoid these aggressive treatment regimens, concurrent cetuximab plus radiation versus cisplatin plus radiation therapies have been compared. A recent meta-analysis including 15 studies comparing CCRT and concurrent cetuximab with radiotherapy, with various estimation time intervals, suggested that cisplatin usage improved OS and PFS [54], consistent with our results. Nevertheless, it seems that these drug responses and effects will benefit patients in certain circumstances. In our analysis, we showed that patients from selected subgroups of HNSCC might benefit from concurrent cetuximab plus radiotherapy.
In our analysis, we found that both the oropharyngeal primary tumor and HPV+ subgroups showed differences regarding survival outcomes, possibly supporting the utility of cetuximab to a large extent.
We focused on HPV+ patients, as the biological behavior of these tumors showed particularity. HPV is now considered to be an independent and important risk factor in HNSCC [55, 56]. Recently, Dayyani et al. published a meta-analysis, which showed that HPV infection has a critical impact on survival and response to therapy, and they also demonstrated that HPV+ status was not rare (HPV+ 22 %, with 86.7 % exhibiting HPV16+ genotype) [57]. However, some negative outcomes also exist, and no significant difference was shown between cisplatin and cetuximab with radiation in LAHNC [58]. One major obstacle in this work was the lack of information regarding the HPV/p16 status; thus, we suggest that patients should undergo HPV testing for this unique and separate biologic entity. In our analysis, patients in the HPV+ group achieved better OS due to the highly selective and biologic characteristics, which made the HPV+ group more suitable for the concurrent BRT treatment regimen than the whole HNSCC group.
We also observed unique responses in patients who had primary lesions in the oropharynx. One comprehensive study estimated chemotherapy effects via tumor sites, and the results showed increased benefits only for oropharyngeal and laryngeal tumors [59, 60]. There are well-established patient risk factors associated with HPV infection in oropharyngeal cancer, and a higher incidence of HPV infection was found in cancers of the oropharynx [61, 62]. In our analysis, better PFS was observed in the oropharyngeal group rather than all cases of HNSCC, which could support the administration of cetuximab as a single agent plus radiation in this specific subgroup.
Adverse effects are important additional parameters to be taken into consideration when comparing treatment regimens. In our analysis, we found that there were no significant differences between the two groups for all toxicity data. The cisplatin regimen resulted in adverse events, including high-grade neutropenia, leukopenia and acute kidney injury, while adverse events due to BRT included grade 3-4 acne-like rash and oral mucositis. We found that the incidence of adverse events was elevated in advanced cases. One recent study published by Lawrence D. Koutcher et al, showed serious grade radiation dermatitis with spontaneous bleeding in patients undergoing the BRT regimen [63], which could further decrease quality of life [64] and have a negative impact on cosmetic outcomes [65]. As the total incidence of adverse events did not show significance between cisplatin and cetuximab and the two regimens cause different adverse events in different aspects, doctors need to take toxicity into consideration and choose regimens according to each patient’s condition.
To further confirm the quantity of evidence of the analyzed the data, heterogeneity and sensitive analysis were examined, and no obvious heterogeneity was detected; as shown in every group estimation, I2 was <50 %, with no exception. In addition, the further sensitive analysis assessed heterogeneity in detail and revealed only limited heterogeneity. In addition, as this is a meta-analysis, some limitations still exist. Primarily, only published data from prospective or retrospective studies were included in our meta-analysis, without individual data. Therefore, we could only use these integrated data, which may lead to patient selection bias as patient selection and reporting processes could not be controlled by us. In addition, we combined both retrospective and randomized trials in our meta-analysis, which could also contribute to the bias of this meta-analysis as the inclusion criteria of these two types of studies may not be the same and result in mixed data bias. Additionally, in pooled-data calculation processes, we chose multivariate data, if they were available. Otherwise, our calculated data consisted of univariate data without adjusting for some other influencing factors, such as age, sex, and histologic grade. This would represent a source of bias because multivariate studies examine the prognostic value independently, while univariate studies consider single factor.
Conclusion
In spite of all of the limitations and biases of our meta-analysis, we conclude that long-term use of cetuximab plus radiation showed no significant difference compared with cisplatin plus radiation for all of the survival and toxicity data examined. In subgroup analysis, cetuximab plus radiation may show superior responses regarding OS and PFS in patients who have HPV+ or primary oropharyngeal HNSCC, respectively, but physicians should administer them with caution.
This analysis is a combination of current data. Previously, it was thought that cetuximab could cause fewer side effects and may be preferable to cisplatin, as they showed similar survival outcomes. However, we showed that the two regimens caused toxicity without significant differences, while cisplatin treatments exhibited better survival outcomes. Thus, with all of the limitations, we recommend further RCTs to determine the utility of cetuximab in HNSCC, especially in the oropharyngeal and/or HPV+ specific subgroups.
Declarations
Acknowledgments
The authors thank the study participants in each of the individual studies for their involvement.
Funding
This study was supported by the National Natural Science Foundation of China, Beijing, China (Grant No. 81101991) and Research Award Fund for New Young Teachers in Higher Education Institutions, China (Grant No. 20120181120024). The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the article.
Availability of data and materials
All relevant data are within the paper and its Supporting Information files.
Authors’ contribution
This study was designed by LL and WYQ, and the manuscript was written by HJW. Data were collected by HJW and SCL. Statistical process was done by SCL and ZJ. Figures and tables were made by HJW and SCL. All authors have read and approved the manuscript, and ensure that this is the case.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Not applicable.
Ethics approval and consent to participate
Not applicable.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Authors’ Affiliations
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