Description of the condition
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy globally. Worldwide, nearly 650,000 new cases and 350,000 deaths are reported annually (Jemal 2010). Upper aerodigestive tract malignancies form a major part of HNSCC and sites include the nasal cavity, paranasal sinus, middle ear cleft, oral cavity, nasopharynx, oropharynx, hypopharynx and larynx (Skarsgard 2000). Various risk factors are associated with the development of upper aerodigestive tract squamous cell carcinoma. Of these, tobacco use (smoking and smokeless tobacco), alcohol consumption and human papilloma virus infection are the most important and common associated risk factors (Barnes 2005). However, for nasopharynx, nasal cavity, paranasal sinus and middle ear cleft squamous cell carcinoma the risk factors, response to treatment and prognosis differ both from each other and from the other upper aerodigestive tract sites. Hence, when we use the term upper aerodigestive tract squamous cell carcinoma further this implies pathology arising from the oral cavity, oropharynx, hypopharynx and larynx. These sub-sites of the upper aerodigestive tract have similar risk factors, treatment outcomes and treatment impact on quality of life, and are the interest of this review.
Locally advanced HNSCC (stage III and IV) requires multimodality treatment to improve locoregional control and survival. Concurrent chemoradiotherapy forms part of this multimodality treatment, either as an adjuvant treatment or as a definitive treatment. A variety of chemotherapeutic agents have been used with radiotherapy, including cisplatin (Crissman 1987; Glickman 1994; Koch 1995; Marcial 1990), fluorouracil (Browman 1994; Byfield 1984), methotrexate (Gupta 1987), bleomycin (Cachin 1977) and mitomycin (Haffty 1997). However, concurrent chemoradiotherapy with cisplatin offers the best survival advantage, as shown in a recent meta-analysis (Pignon 2009). This meta-analysis showed an 8% improvement in overall survival with the concomitant use of platinum-based chemotherapy regimens. It also showed an overall 5% benefit at five years in non-metastatic, non-nasopharyngeal HNSCC.
Concurrent chemoradiotherapy with 100 mg/m² cisplatin has been accepted as the standard of care in patients receiving adjuvant treatment (Bernier 2004; Cooper 2004) and also in organ preservation treatment protocols for laryngeal and hypopharyngeal squamous cell carcinoma (Forastiere 2003). However, the associated severe grade III and IV toxicities are a limitation of this treatment protocol. Hence, a weekly cisplatin regimen with radiotherapy is seen as an effective alternative.
Description of the intervention
Theoretically, a high-dose chemotherapy schedule may help in preventing distant metastasis by neutralising occult micrometastasis (Hennequin 2002), especially in patients receiving induction and concomitant chemotherapy (Pignon 2009), but this has not been seen in patients receiving concurrent chemoradiotherapy in the adjuvant setting (Bernier 2004; Cooper 2004). On the contrary, low-dose weekly cisplatin acts as a radiosensitiser, by inhibiting potentially lethal and sub-lethal damage repair (Brizel 2006; Hennequin 2002). This will be an advantage in the concurrent chemoradiotherapy scenario. As mentioned, the disadvantage of using 100 mg/m² cisplatin is the side effects, such as mucositis and renal and haematological toxicity. This leads to frequent treatment breaks requiring hospitalisation and intensive supportive care, adding to the cost of treatment. Ultimately these frequent treatment breaks or inability to complete the scheduled treatment lead to poor outcomes in terms of survival and loco-regional control. Only about 60% of patients participating in a trial are able to complete the scheduled three cycles of cisplatin (Brizel 2006). In view of this, alternative low-dose regimens such as weekly (30 to 40 mg/m²) and daily (6 mg/m²) cisplatin have been tried (Marcu 2003). A weekly 30 to 40 mg/m² cisplatin concurrent chemoradiotherapy regimen has often been used outside trials. A few retrospective studies have reported a similar response rate to the three-weekly 100 mg/m² regimen (Gupta 2009; Homma 2011; Uygun 2009). Hence, the weekly regime could be of benefit to patients who are less likely to complete the standard three cycles of 100 mg/m² cisplatin.
How the intervention might work
The available data show that a cumulative dose between 200 and 250 mg/m² is needed to attain the desired therapeutic benefits in terms of survival and locoregional control (Brizel 2006). This can be achieved with a once-weekly 30 to 40 mg/m² cisplatin regimen. The weekly cisplatin regimen is associated with reduced toxicity in comparison to the three-weekly regimen, helping the patient achieve the desired cumulative dose of > 200 mg/m² (Gupta 2009; Homma 2011; Uygun 2009). This regimen can be administered on an outpatient basis (Gupta 2009; Homma 2011), which may in turn reduce the cost of treatment in terms of reduced hospital stay and supportive care. It will also eventually help the patient to attain better disease control by helping them complete the scheduled treatment.
Why it is important to do this review
It is important to carry out this systematic review to assess whether the once-weekly cisplatin regimen is at least as effective as the three-weekly regimen.
To assess the efficacy of a weekly cisplatin regimen compared to a three-weekly regimen, given with curative intent to treat locally advanced HNSCC, in terms of overall survival (at five years).
To assess the distant metastasis-free survival (at two years), disease-free survival (at two years) and the toxicity profile of the two regimens.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials comparing interventions for locally advanced HNSCC.
Types of participants
Patients with locally advanced, stage III/IV HNSCC. Nasopharyngeal, middle ear cleft, nasal cavity and paranasal sinus carcinoma will be excluded.
Types of interventions
Concurrent chemoradiotherapy with low-dose weekly cisplatin versus three-weekly cisplatin.
Types of outcome measures
- Overall survival
- Distant metastasis-free survival
- Disease-free survival
- Local/regional control rates or both
- Quality of life
- Treatment-related morbidity/toxicity
- Direct and indirect costs associated with treatment (to patients and health services)
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); Ovid MEDLINE; Ovid MEDLINE In-Process and Other Non-Indexed Citations; PubMed (as a top up to searches in Ovid MEDLINE); EMBASE; CINAHL; 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 (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.
Data collection and analysis
Selection of studies
Three review authors (ST, SN, TG) will independently scan the titles and abstracts of all reports identified through the electronic searches. Two review authors (ST, SN) will independently assess the full reports obtained to establish whether the studies meet the inclusion criteria or not. We will exclude those studies which clearly do not meet the inclusion criteria, and obtain copies of the full text of potentially relevant references or those for which there are insufficient data in the title and abstract to make a clear decision. Two review authors (ST, SN) will assess the eligibility of the retrieved papers independently. We will resolve disagreements if possible between ST and SN and, if necessary, involve a third review author (TG or SK). We will document the reasons for exclusion.
Data extraction and management
Two review authors (ST, SN) will extract data independently onto a data extraction spreadsheet specially designed for the review. We will resolve differences between review authors by discussion or by appeal to a third review author (TG) if necessary. We will extract the following data for each trial:
- first author, year of publication and journal (including language);
- demographic details of the participants (age, gender, habits, etc.);
- clinical details of the participants (disease site, associated co-morbid conditions, human papilloma virus status, number of nodes, presence or absence of extra-capsular spread);
- details of the intervention (cumulative dose, weekly or three-weekly, and type of chemotherapy);
- details of radiotherapy dose, fractionation, overall treatment time, treatment breaks, technique of radiotherapy (RT) delivery (intensity-modulated, 3D-RT, 2D-RT), compliance to protocol;
- details of survival outcome (number dead/alive at five years);
- details of disease recurrence (local, regional or distant metastasis) at two years;
- details of treatment-related morbidity, categorised as acute (< 90 days after treatment) or late (> 90 days) and classified according to the Common Terminology Criteria for Adverse Events (v4.2) (CTCAE 2009).
Assessment of risk of bias in included studies
All four authors will carry out the 'Risk of bias' assessment of the included trials, as guided by the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011) (summarised in Table 1 and Table 2).
We will use the Cochrane 'Risk of bias' tool in RevMan 5.2 (RevMan 2012), which involves describing each of these domains as reported in the trial and then assigning a judgement about the adequacy of each entry. This involves making a judgement of low risk of bias, high risk of bias or unclear (or unknown) risk of bias. Subsequently, we will describe the overall quality of the evidence and confidence in the result in a 'Summary of findings' table using the software GRADEprofiler.
For dichotomous outcomes, we will express the estimates of the effect of an intervention as risk ratios together with 95% confidence intervals. We will analyse the proportion surviving at two years for disease-free survival and distant metastasis-free survival and at five years for overall survival.
Subgroup analysis and investigation of heterogeneity
We will attempt subgroup analysis for the following whenever possible to reduce the heterogeneity in the outcomes: chemotherapy type (definitive versus adjuvant), cumulative dose of cisplatin (< 200 mg/m
We will consider two types of analysis model. We will adopt a random-effects model if the I
We will carry out sensitivity analyses as follows:
- by performing a separate analysis excluding unpublished studies, when present;
- by performing a separate analysis excluding studies found to have the highest risk of bias; and
- by performing a separate analysis excluding one or more large studies, when present, to investigate how much they dominate the results.
Appendix 1. CENTRAL search strategy
#1 MeSH descriptor: [Head and Neck Neoplasms] explode all trees
#2 MeSH descriptor: [Otorhinolaryngologic Neoplasms] explode all trees
#3 MeSH descriptor: [Neoplasms] explode all trees
#4 cancer* or carcinoma* or neoplasm* or tumor* or tumour* or metastas* or SCC*
#5 #3 or #4
#6 head near neck
#7 face or facial or oesophageal or esophageal or oesophagus or esophageal or esophagus or thyroid or salivary or paranasal or "aero digestive" or aerodigestive or aero-digestive or UADT or "middle ear cleft" or "nasal cavity" or larynx or laryngeal or glottis or glottic or "oral cavity" or nasopharynx or nasopharyngeal or hypopharynx or hypopharyngeal or pharynx or pharyngeal or parapharyngeal or mouth
#8 MeSH descriptor: [Larynx] explode all trees
#9 MeSH descriptor: [Pharynx] explode all trees
#10 MeSH descriptor: [Mouth] explode all trees
#11 MeSH descriptor: [Nose] explode all trees
#12 #6 or #7 or #8 or #9 or #10 or #11
#13 #5 and #12
#14 "HNSCC" or "SCCHN" or "LACHN"
#15 #1 or #2 or #13 or #14
#16 MeSH descriptor: [Chemoradiotherapy] explode all trees
#17 chemoradiotherap* or chemo-radiotherap* or "chemo radiotherap*" or Radiochemtherap* or CCRT or CRT or "CT/RT" or chemoratiat*
#18 (radiotherap* or radiation or irradiat*) near (concurrent or concomitant or adjuvant or combin* or neoadjuvant or conjunction) near (chemo* or cisplatin or "antineoplastic agent*" or "cis platin" or cis-platin or cis-Platinum or "cis Platinum")
#19 MeSH descriptor: [Radiotherapy] explode all trees
#20 MeSH descriptor: [Antineoplastic Agents] explode all trees
#21 #19 and #20
#22 #16 or #17 or #18 or #21
#23 #15 and #22
#24 MeSH descriptor: [Head and Neck Neoplasms] explode all trees and with qualifiers: [Drug therapy - DT]
#25 MeSH descriptor: [Head and Neck Neoplasms] explode all trees and with qualifiers: [Radiotherapy - RT]
#26 #24 and #25
#27 MeSH descriptor: [Carcinoma, Squamous Cell] explode all trees and with qualifiers: [Drug therapy - DT]
#28 MeSH descriptor: [Carcinoma, Squamous Cell] explode all trees and with qualifiers: [Radiotherapy - RT]
#29 #27 and #2
#30 #23 or #26 or #29
#31 MeSH descriptor: [Cisplatin] explode all trees
#32 cis-Diamminedichloroplatinum or (Platinum and Diamminodichloride) or cis-Platinum or "cis Platinum" or Dichlorodiammineplatinum "cis Diamminedichloroplatinum" or Platinol or Platidiam or Platino or NSC-119875 or Biocisplatinum or cisplatin or "cis platin" or cis-platin or CDDP or CIS or CP
#33 #31 or #32
#34 #30 and #33
Contributions of authors
Shivakumar Thiagarajan (ST): conception and registration of title, drafting of protocol and review, 'Risk of bias' assessment, data extraction, data analysis and writing of review.
Sudhir Nair (SN): 'Risk of bias' assessment, data extraction, writing of review, editorial input and advice.
Tejpal Gupta (TG): 'Risk of bias' assessment, data extraction, editorial input and advice.
Sadhana Kannan (SK): protocol development, 'Risk of bias' assessment, data extraction and data analysis.
Declarations of interest
Sources of support
- None, Not specified.
- None, Not specified.