Concurrent chemoradiotherapy with weekly versus three-weekly cisplatin in locally advanced head and neck squamous cell carcinoma

  • Protocol
  • Intervention

Authors

  • Thiagarajan Shivakumar,

    Corresponding author
    1. Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Surgical Oncology (Head & Neck Services), Navi Mumbai, India
    • Thiagarajan Shivakumar, Surgical Oncology (Head & Neck Services), Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, 410210, India. drshiva78in@gmail.com.

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  • Sudhir Nair,

    1. Advanced Centre for Treatment Research & Education in Cancer (ACTREC), Tata Memorial Centre, Surgical Oncology, Navi Mumbai, India
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  • Tejpal Gupta,

    1. Advanced Centre for Treatment Research & Education in Cancer (ACTREC), Tata Memorial Centre, Radiation Oncology, Navi Mumbai, India
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  • Sadhana Kannan

    1. Advanced Centre for Treatment Research & Education in Cancer (ACTREC), Tata Memorial Centre, Clinical Research Secretariat/Epidemiology & Clinical Trial Unit, Navi Mumbai, India
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

Primary objective

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).

Secondary objective

To assess the distant metastasis-free survival (at two years), disease-free survival (at two years) and the toxicity profile of the two regimens.

Background

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.

Objectives

Primary objective

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).

Secondary objective

To assess the distant metastasis-free survival (at two years), disease-free survival (at two years) and the toxicity profile of the two regimens.

Methods

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

Primary outcomes
  • Overall survival

  • Distant metastasis-free survival

  • Disease-free survival

  • Local/regional control rates or both

Secondary outcomes
  • 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.

Electronic searches

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).

Table 1. Classification scheme for bias in intervention studies
  1. (Handbook 2011, Chapter 8.4a).

Type of bias Sources of bias Reason for bias
Selection bias

Sequence generation

Allocation concealment

Due to an inadequate process of randomised sequence generation or inadequate concealment of allocation before entering into the study
Performance biasBlinding of participants and personnelDue to knowledge of the allocated intervention by the participants or the personnel (or both) during the study
Detection biasBlinding of outcome assessmentDue to knowledge of the allocated intervention by the outcome assessor(s)
Attrition biasIncomplete outcome dataDue to the amount, nature or handling of incomplete outcome data
Reporting biasSelective reportingSelective reporting of outcome data
Other biasIssues not covered elsewhereAny bias not addressed elsewhere in the table
Table 2. 'Risk of bias' assessment criteria
Risk of bias Random sequence generation Allocation concealment Blinding of participants and personnel Blinding of outcome assessment Incomplete outcome data Selective reportingOther bias
Low risk of bias
  • Random number table

  • Computer-generated random numbers

  • Tossing of coin

  • Shuffling card

  • Throwing dice

  • Telephone-based method

  • Web-based method

  • Opaque sealed envelopes

  • Appropriate blinding of participants and personnel

  • Blinding not likely to affect outcome, irrespective of the method

Unlikely to influence outcome, irrespective of blinding
  • No missing outcome data

  • If present, the reasons are unlikely to alter outcome

  • Missing data balanced across intervention groups

  • Appropriate imputation method applied

  • For dichotomous data the proportion of missing data compared with the observed event risk is unlikely to influence outcome

  • Study protocol available with prespecified outcomes

  • Protocol not available but published report includes all expected outcomes

No other sources of bias
Unclear risk of biasWhen the process of random sequence generation is not mentioned, or the description is insufficient to allow a judgementWhen the process of allocation concealment is not mentioned, or the description is insufficient to allow a judgement
  • Incomplete information

  • Study did not address the issue

  • Incomplete information

  • Study did not address the issue

  • Insufficient reporting of attrition or exclusion to allow a judgement

  • Study did not address this issue

Insufficient information to allow a judgementInsufficient information, rationale or evidence to assess whether a risk of bias exists
High risk of bias
  • By date of birth

  • Hospital case number

  • Date/day of admission

  • By preference of patient or doctor

  • Using random numbers

  • Using unsealed or non-opaque envelopes

  • By date of birth

  • Hospital record number

  • Any other unconcealed method

  • Outcome likely to be affected by no or incomplete blinding

  • Blinding attempted, but likely to be have been broken, influencing the outcome

Blinding not done, or likely to have been broken, influencing the outcome
  • Reasons for missing data likely to influence the outcome

  • Inappropriate application of imputation

  • For dichotomous data, the proportion of missing data compared with the observed event risk is likely to influence the outcome

  • Not all prespecified primary outcomes reported

  • One or more primary outcomes were not prespecified, reported incompletely or reported using measurements or methods of analysis which were not prespecified

Bias related to study design or other bias

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.

Data synthesis

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/m2 versus > 200 mg/m2) and site (oropharyngeal versus non-oropharyngeal).

We will consider two types of analysis model. We will adopt a random-effects model if the I2 statistic is greater than 50% (P ≤ 0.10). If it is not, we will choose a fixed-effect model. For dichotomous data we will use the Mantel-Haenszel (M-H) method for meta-analysis. For the hypothesis test we will set statistical significance at P < 0.05.

Sensitivity analysis

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.

Acknowledgements

None.

Appendices

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

None known.

Sources of support

Internal sources

  • None, Not specified.

External sources

  • None, Not specified.

Ancillary