A previous meta-analysis has investigated the role of chemotherapy in nasopharyngeal carcinoma (Baujat 2006; Baujat 2006a). That review compared chemotherapy plus radiotherapy to radiotherapy alone in locally advanced nasopharyngeal carcinoma, but the comparison of induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) versus concurrent chemoradiotherapy with or without adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma has not been reviewed.
Description of the condition
In 2008, there were approximately 84,000 cases of nasopharyngeal carcinoma which resulted in over 50,000 deaths. These figures represented nearly 0.7% of the global cancer burden. Nasopharyngeal carcinoma was, consequently, ranked as the 24th most frequently diagnosed cancer worldwide and 22nd in the developing world (Jemal 2011). It occurs more frequently in populations in Southern China, Southeast Asia, the Arctic and the Middle East/North Africa (Chang 2006; Wei 2005). Research shows that Chinese people living in the province of Guangdong are especially prone to the disease (Chang 2006; Jemal 2011; Wei 2005). The incidence of nasopharyngeal carcinoma among men and women in Hong Kong (adjacent to Guangdong province) is 20 to 30 per 100,000 and 15 to 20 per 100,000, respectively (Wei 2005). In particular, the incidence of nasopharyngeal carcinoma remains high among Chinese people who have emigrated to southeast Asia or North America, but it is lower among Chinese people born in North America than in those born in southern China (Buell 1974; Wei 2005). We can therefore conclude that genetic, ethnic, viral and environmental factors may play a vital role in the cause of nasopharyngeal carcinoma.
Most nasopharyngeal cancers are of epithelial origin. World Health Organization (WHO) type II (non-keratinising carcinoma) and WHO type III (undifferentiated carcinoma) are the more commonly diagnosed pathologies in Asia and account for almost 95% of all cases; however, around 25% of cases in North America have WHO type I histology (squamous cell carcinoma).
The anatomical position of the nasopharynx is hidden and the early symptoms of nasopharyngeal carcinoma are complex, therefore the disease is easily misdiagnosed. In addition, although the primary cancer is small or not obvious, the cervical lymph nodes and cranial nerve may be invaded. This is more frequently observed in nasopharyngeal carcinoma than in other head and neck cancers. Due to these characteristics, most nasopharyngeal carcinoma patients have a higher clinical stage at diagnosis (locally advanced or advanced) (Wei 2005).
Description of the intervention
Nasopharyngeal carcinoma is commonly treated by radiotherapy and chemotherapy rather than surgery due to its anatomic location (Al-Sarraf 1998; Baujat 2006; Baujat 2006a). As it tends to present with regional metastasis, and is sensitive to both chemotherapy and radiation therapy, multidisciplinary management is usually required for locally advanced nasopharyngeal carcinoma (Heilmann 2008).
Radiotherapy at a dose of 65 to 75 Gray (Gy) over six to seven weeks had been the standard treatment and successfully controlled T1 and T2 tumours in 75% to 90% of cases and T3 and T4 tumours in 50% to 75% of cases (Chua 2001; Wei 2005). Under this regime, overall survival at five years ranges from 32% to 52% in large series of patients with locally advanced disease treated with radiotherapy alone (Al-Sarraf 1998; Baujat 2006; Baujat 2006a; Wei 2005). In the past two decades, several studies have confirmed the efficacy and safety of the use of chemotherapy in combination with radiotherapy for the treatment of locally advanced nasopharyngeal carcinoma (Al-Sarraf 1998; Baujat 2006; Baujat 2006a; Wee 2005; Wei 2005). Therefore, more recently, concurrent chemoradiotherapy (CCRT) with or without adjuvant chemotherapy has become the standard therapy for locally advanced nasopharyngeal carcinoma (Al-Sarraf 1998; Baujat 2006; Baujat 2006a).
Historically, induction chemotherapy with cisplatin and fluorouracil (PF) has shown benefit in locally advanced head and neck cancer by reducing tumour size and micrometastases before definitive radiotherapy (Domenge 2000; Pignon 2000; Pignon 2009). Induction chemotherapy with docetaxel, cisplatin and fluorouracil (TPF) provides long-term survival benefit compared with PF in locally advanced head and neck cancer (Haddad 2013; Lorch 2011; Pointreau 2009; Posner 2007; Vermorken 2007).
How the intervention might work
Induction chemotherapy has two potential benefits: eradication of subclinical distant metastases and reduction of local tumour volume, which may potentially improve the efficacy of radiation therapy. Nasopharyngeal carcinoma is associated with high recurrence rates and is chemosensitive, therefore induction chemotherapy is an attractive option for the treatment of this disease (James 2010; Oh 2003).
Why it is important to do this review
It is still unknown whether induction chemotherapy followed by CCRT has more benefits for nasopharyngeal carcinoma patients. Several clinical trials (Fountzilas 2012; Hui 2009; Kong 2010; Ruste 2011) have been completed and a multicentre randomised controlled trial (NCT01245959) is being conducted, but no systematic review has yet been carried out. Hui and colleagues (Hui 2009) reported that neoadjuvant docetaxel-cisplatin followed by CCRT was well tolerated with a manageable toxicity profile that allowed subsequent delivery of full-dose CCRT. Preliminary results suggested a positive impact on survival. Similar results were found in the report of the Shanghai Cancer Centre (Kong 2010). However, Fountzilas et al (Fountzilas 2012) reported that induction chemotherapy with three cycles of cisplatin, epirubicin and paclitaxel (CEP) when followed by CCRT did not significantly improve response rates and/or survival compared with CCRT alone. In addition, a recent clinical trial carried out in the Philippine General Hospital (Ruste 2011), where 30 nasopharyngeal carcinoma patients were randomised to receive induction chemotherapy followed by CCRT or CCRT with adjuvant chemotherapy, found no significant difference between the two groups in terms of three-year overall survival (hazard ratio = 0.92, P = 0.889). Given the above conflicting findings, it is necessary to conduct this systematic review to investigate the efficacy and toxicity of induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy with or without adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma.
To evaluate the efficacy and toxicity of induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy with or without adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs).
Types of participants
Patients with histologically or cytologically confirmed locally advanced nasopharyngeal carcinoma, but without distant metastases. Patients with serious cardiopulmonary diseases and other severe basic diseases, for example unstable cardiac disease requiring treatment, renal disease, chronic hepatitis, diabetes with poor control and emotional disturbance, will be excluded.
Types of interventions
Induction chemotherapy followed by concurrent chemoradiotherapy (the treatment group) versus concurrent chemoradiotherapy with or without adjuvant chemotherapy (the control group). We will accept any induction chemotherapy regimen: PF, TPF or other. All patients should receive curative radiotherapy; studies with adjuvant or palliative radiotherapy will be excluded.
Types of outcome measures
Overall survival is defined as the duration from the date of random assignment to the date of death resulting from any cause or censored at the date of last follow-up. Progression-free survival is defined as the duration from the date of random assignment to the date of disease progression or censored at the date of last follow-up. Locoregional failure-free survival is defined as the latency (i.e. time from randomisation) to the first locoregional failure. Distant failure-free survival is defined as the latency (i.e. time from randomisation) to the first remote failure.
- Progression-free survival
- Overall survival
- Adverse effects
- Locoregional failure-free survival
- Distant failure-free survival
- Quality of life
Search methods for identification of studies
We will conduct systematic searches for randomised controlled trials. There will be no language, publication year or publication status restrictions. We may contact original authors for clarification and further data if trial reports are unclear and we will arrange translations of papers where necessary.
We will identify published, unpublished and ongoing studies by searching the following databases from their inception: the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, current issue); PubMed; EMBASE; CINAHL; CNKI; CBM; VIP; LILACS; KoreaMed; IndMed; PakMediNet; CAB Abstracts; Web of Science; ISRCTN; ClinicalTrials.gov; ICTRP; Google Scholar and Google.
We will model subject strategies for databases on the search strategy designed for CENTRAL (see Appendix 1). Where appropriate, we will combine subject strategies with adaptations of the highly sensitive search strategy designed by The Cochrane Collaboration for identifying randomised controlled trials and controlled clinical trials (as described in theCochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b. (Handbook 2011)).
Searching other resources
We will scan the reference lists of identified publications for additional trials and contact trial authors if necessary. In addition, we will search PubMed, TRIPdatabase, The Cochrane Library and Google to retrieve existing systematic reviews relevant to this systematic review, so that we can scan their reference lists for additional trials. We will search for conference abstracts using the Cochrane Ear, Nose and Throat Disorders Group Trials Register and EMBASE. Furthermore, we will check abstracts that are published in major academic conferences (e.g. American Society of Clinical Oncology, European Society for Medical Oncology and American Society for Therapeutic Radiology and Oncology).
Data collection and analysis
Selection of studies
Two review authors (ZRZ and ZYZ) will perform the selection of studies, data extraction and management, and assessment of risk of bias in the included studies. ZRZ will conduct the initial screening and ZYZ will double check. Disagreements will be resolved by discussion between the two review authors; if no agreement can be reached, a third author will be consulted.
Data extraction and management
Two review authors will independently extract data from the included studies using a specially designed data extraction form. An example of this form is available in Appendix 2. Should any disagreement arise, we will discuss and document our decisions. When necessary, we will contact the authors of the included studies for further or missing information to resolve the disagreement. If all the above avenues are exhausted, but consensus still cannot be reached, we will add the trial to the 'awaiting assessment' section.
Assessment of risk of bias in included studies
ZRZ and ZYZ will undertake assessment of risk of bias of included trials independently. The assessment will be carried out in accordance with guidelines of theCochrane Handbook for Systematic Reviews of Interventions (Handbook 2011), where the following items will be evaluated for each included study:
- sequence generation;
- allocation concealment;
- incomplete outcome data;
- selective outcome reporting;
- other sources of bias.
We will use the Cochrane 'Risk of bias' tool in RevMan 5 (RevMan 2012), which involves describing each of the above domains as reported in included trials and assigning a judgement as to whether they have 'low', 'high' or 'unclear' risk of bias.
Measures of treatment effect
The measures of treatment effect will differ according to the data type and outcome variables.
Where possible, we intend to calculate risk ratio (RR) and its 95% confidence interval (CI) for binary data, using a fixed-effect model. Compared to the odds ratio (OR), the RR is more intuitive and less likely to be misinterpreted in clinical settings (Deeks 2000).
We will analyse continuous data using the standardised mean difference (SMD) or mean difference (MD), with 95% CI.
Time-to-event data and count data
We will analyse time-to-event data using the hazard ratio (HR) (depending on the available data) and count data using the risk ratio (RR), with 95% CI.
Unit of analysis issues
It is unlikely that cross-over or cluster-randomised controlled trials could be designed to study radiotherapy or chemotherapy treatments for nasopharyngeal carcinoma. Nevertheless, should this issue become a concern, we will perform separate analyses based on different periods of follow-up. For example, one-year, two-year, three-year overall survival etc.
Dealing with missing data
According to the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011), we will use the following guidelines to deal with missing data.
- Whenever possible, we will contact the original investigators to request missing data.
- We will make explicit the assumptions of any methods used to cope with missing data.
- We will perform sensitivity analyses to assess how sensitive results are to reasonable changes in the assumptions that are made.
- We will address the potential impact of missing data on the findings of the review in the 'Discussion' section.
Assessment of heterogeneity
We will use the Chi
Assessment of reporting biases
We will investigate reporting biases (such as publication bias) using funnel plots when there are 10 or more studies eligible for meta-analysis. We will assess publication bias through visual inspection of a funnel plot.
We will perform all statistical analyses using the RevMan 5 software, as described in Measures of treatment effect.
Subgroup analysis and investigation of heterogeneity
We intend to explore the following potential sources of heterogeneity using subgroup analyses (depending on the available data):
- induction chemotherapy regimens: for example TPF versus non-TPF; with docetaxel versus without docetaxel;
- regimens of control group: with adjuvant chemotherapy versus without adjuvant chemotherapy.
We will perform sensitivity analysis for different items regarding study quality.
The authors thank the following academic partners for valuable discussions: Bo Li, Digestive System Department, Xiyuan Hospital, China Academy of Traditional Chinese Medicine; Xiantao Zeng, Department of Stomatology, Taihe Hospital, Hubei University of Medicine; Zhi Mao, Department of Orthopaedics, Chinese PLA General Hospital.
Appendix 1. CENTRAL search strategy
#1 MeSH descriptor: [Nasopharyngeal Neoplasms] explode all trees
#2 MeSH descriptor: [Nasopharyngeal Diseases] explode all trees
#3 MeSH descriptor: [Nasopharynx] explode all trees
#4 nasophar* or rhinophar* or naso-phar* or chonae
#5 MeSH descriptor: [Neoplasms] explode all trees
#6 carcinom* or cancer* or precancer* or pre-cancer* or neoplas* or tumor* or tumour* or malignan* or premalignan* or pre-malignan*
#7 (#2 or #3 or #4) and (#5 or #6)
#9 #1 or #7 or #8
#10 MeSH descriptor: [Induction Chemotherapy] explode all trees
#11 induction or neoadjuvant or IC
#12 #10 or #11
#13 #9 and #12
#14 MeSH descriptor: [Chemoradiotherapy] explode all trees
#15 chemorad* or radiochem* or CCRT or concomitant or concurrent* or synchronous or simultaneous* or sequential*
#16 MeSH descriptor: [Carcinoma] explode all trees and with qualifiers: [Drug therapy - DT]
#17 MeSH descriptor: [Carcinoma] explode all trees and with qualifiers: [Radiotherapy - RT]
#18 #16 and #17
#19 MeSH descriptor: [Nasopharyngeal Neoplasms] explode all trees and with qualifiers: [Drug therapy - DT]
#20 MeSH descriptor: [Nasopharyngeal Neoplasms] explode all trees and with qualifiers: [Radiotherapy - RT]
#21 #19 and #20
#22 MeSH descriptor: [Drug Therapy] explode all trees
#23 MeSH descriptor: [Radiotherapy] explode all trees
#24 #22 and #23
#25 #14 or #15 or #18 or #21 or #24
#26 #13 and #25
Appendix 2. Data extraction form
- Title of review
- Data extractor
- Date of completing form
- Study ID
- The source of information
- Year of publication of study
- Confirm eligibility for review
- Reason for exclusion
- Study design
- Sequence generation
- Allocation sequence concealment
- Incomplete outcome data
- Selective outcome reporting
- Other concerns about bias
- Total number
Contributions of authors
- Zhi Rui Zhou proposed the title, registered the review and participated in writing the protocol.
- Jun Xia and Zhang Yu Zou participated in the writing of the protocol.
- Jun Xia provided advice on the methodological perspective for the protocol, guided and revised the text.
- Song Qu provided valuable suggestions on the clinical setting for the protocol.
Declarations of interest
The authors declare that they have no conflict of interest.
Sources of support
- None, Not specified.
- None, Not specified.