04 - MARCH Cochrane 2010

Hyperfractionated or accelerated radiotherapy for head and
neck cancer (Review)
Baujat B, Bourhis J, Blanchard P, Overgaard J, Ang KK, Saunders M, Le Maître A, Bernier J,

Horiot JC, Maillard E, Pajak TF, Poulsen MG, Bourredjem A, O’Sullivan B, Dobrowsky W,
Andrzej H, Skladowski K, Hay JH, Pinto LHJ, Fu KK, Fallai C, Sylvester R, Pignon JP,
MARCH Collaborative Group
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2010, Issue 12
http://www.thecochranelibrary.com
Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure 11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Analysis 1.1. Comparison 1 Altered fractionated radiotherapy versus conventional radiotherapy, Outcome 1 Hazard ratio
of death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
of head and neck cancer death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
of locoregional control. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
of local control. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 57
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) i

[Intervention Review]
Hyperfractionated or accelerated radiotherapy for head and

neck cancer
Bertrand Baujat2 , Jean Bourhis3 , Pierre Blanchard1 , Jens Overgaard4 , Kian K Ang5 , Michelle Saunders6 , Aurélie Le Maître1 , Jacques
Bernier7 , Jean Claude Horiot8 , Emilie Maillard1, Thomas F Pajak9 , Michael G Poulsen10 , Abderrahmane Bourredjem1 , Brian O’Sullivan
11
, Werner Dobrowsky12 , Hliniak Andrzej13 , Krzystof Skladowski14 , John H Hay15 , Luiz HJ Pinto16 , Karen K Fu17 , Carlo Fallai18 ,
Richard Sylvester19 , Jean Pierre Pignon1 , MARCH Collaborative Group20
1 Biostatisticsand Epidemiology Department, Institut Gustave Roussy, Villejuif Cedex, France. 2 Head and Neck Surgery, Hôpital Foch,
Suresnes, France. 3 Département de Radiothérapie, Institut Gustave Roussy, Villejuif Cedex, France. 4 Department of Experimental
Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark. 5 Radiation Oncology Department, MD Anderson Cancer Center,
Houston, Texas, USA. 6 Radiation Oncology Department, Marie Curie Research Wing for Oncology, Northwood, UK. 7 Service de
Radio-Oncologie, Clinique de Genolia, Genolier, Switzerland. 8 Service de Radio-Oncologie, Clinique de Genolia, Genolia, Switzerland.
9 Statistical Headquarters, RTOG, Philadelphia, PA, USA. 10 Mater Queensland Radium Institute, Brisbane, Australia. 11 Radiation
Oncology Department, Princess Margaret Hospital, Toronto, Canada. 12 Newcastle General Hospital, Northern Centre for Cancer
Treatment, Newcastle upon Tyne, UK. 13 Center for Oncology - M.SKL Curie, Warsaw, Poland. 14 Radiotherapy Clinic, Centrum
Onkologii-Inst. M. Curie, Gliwice, Poland. 15 Department of Radiation Oncology, Vancouver Cancer Center, Vancouver, Canada.
16
Departamento de Radioterapia, Instituto Nacional de Cancer, Rio de Janeiro, Brazil. 17 University of California San Francisco,
San Mateo, CA, USA. 18 Dipartimento di Radiotherapia, Instituto Nazionale dei Tumori, Milano, Italy. 19 Data Center, European
Organisation for Research and Treatment of Cancer, Brussels, Belgium. 20 Villejuif Cedex, France
Contact address: Jean Pierre Pignon, Biostatistics and Epidemiology Department, Institut Gustave Roussy, 39, rue Camille Desmoulins,
Villejuif Cedex, 94805, France. jppignon@igr.fr.
Editorial group: Cochrane Ear, Nose and Throat Disorders Group.

Publication status and date: New, published in Issue 12, 2010.
Review content assessed as up-to-date: 7 August 2010.
Citation: Baujat B, Bourhis J, Blanchard P, Overgaard J, Ang KK, Saunders M, Le Maître A, Bernier J, Horiot JC, Maillard E, Pajak TF,
Poulsen MG, Bourredjem A, O’Sullivan B, Dobrowsky W, Andrzej H, Skladowski K, Hay JH, Pinto LHJ, Fu KK, Fallai C, Sylvester R,
Pignon JP, MARCH Collaborative Group. Hyperfractionated or accelerated radiotherapy for head and neck cancer. Cochrane Database
of Systematic Reviews 2010, Issue 12. Art. No.: CD002026. DOI: 10.1002/14651858.CD002026.pub2.
ABSTRACT
Background
Several trials have studied the role of altered fractionation radiotherapy in head and neck squamous cell carcinoma, but the effect of
such treatment on survival is not clear.
Objectives
The aim of this individual patient data (IPD) meta-analysis was to assess whether this type of radiotherapy could improve survival.
Search strategy
We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; CENTRAL (2010, Issue 3); PubMed; EMBASE;
CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ISRCTN and additional sources for published and
unpublished trials. The date of the most recent search was 8 August 2010.
Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 1
Selection criteria
We identified randomised trials comparing conventional radiotherapy with hyperfractionated or accelerated radiotherapy, or both, in
patients with non-metastatic head and neck squamous cell carcinomas and grouped trials into three pre-specified treatment categories:
hyperfractionated, accelerated and accelerated with total dose reduction. Trials were eligible if they began recruitment after 1969 and
ended before 1998.
Data collection and analysis
We obtained updated individual patient data. Overall survival was the main outcome measure. The secondary outcome measures were
local or regional control rates (or both), distant control rates and cause-specific mortality.
Main results
We included 15 trials with 6515 patients. The median follow up was six years. Tumour sites were mostly oropharynx and larynx; 5221
(74%) patients had stage III-IV disease (UICC 2002). There was a significant survival benefit with altered fractionation radiotherapy,
corresponding to an absolute benefit of 3.4% at five years (hazard ratio (HR) 0.92, 95% CI 0.86 to 0.97; P = 0.003). The benefit was
significantly higher with hyperfractionated radiotherapy (8% at five years) than with accelerated radiotherapy (2% with accelerated
fractionation without total dose reduction and 1.7% with total dose reduction at five years, P = 0.02). There was a benefit in locoregional
control in favour of altered fractionation versus conventional radiotherapy (6.4% at five years; P < 0.0001), which was particularly
efficient in reducing local failure, whereas the benefit on nodal control was less pronounced. The benefit was significantly higher in the
youngest patients (under 50 year old) (HR 0.78, 95% CI 0.65 to 0.94), 0.95 (95% CI 0.83 to 1.09) for 51 to 60 year olds, 0.92 (95%
CI 0.81 to 1.06) for 61 to 70 year olds, and 1.08 (95% CI 0.89 to 1.30) for those over 70 years old; test for trends P = 0.007).
Authors’ conclusions
Altered fractionation radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the
different types of altered radiotherapy suggests that hyperfractionation provides the greatest benefit. An update of this IPD meta-
analysis (MARCH 2), which will increase the power of this analysis and allow for other comparisons, is currently in progress.
PLAIN LANGUAGE SUMMARY

Hyperfractionated or accelerated radiotherapy for head and neck cancer
Radiotherapy is often used to treat head and neck cancers. The dosage of radiation is measured in Gray (Gy). When radiotherapy
is given alone, the most commonly used schedule is 2 Gy in a single fraction per day, five days a week, for seven weeks. However,
alternative radiotherapy regimens to reduce the total treatment time for head and neck cancers have been assessed. ’Acceleration’ of the
treatment (delivering the same total dose in a shorter time) should reduce the regrowth of the tumour between sessions, resulting in
improved local control of the disease. In ’hyperfractionated’ regimens, two to three fractions are delivered each day, with a reduced dose
per fraction equal to 1.1 to 1.2 Gy. The reduction of the dose per fraction may reduce the risk of late toxicity, despite an increased total
dose. Acceleration and hyperfractionation can be combined, in particular for regimens in which overall treatment time is reduced.
This Cochrane Review is an individual patient data based meta-analysis and the aim was to assess whether this type of radiotherapy
could improve survival. We identified randomised trials comparing conventional radiotherapy with hyperfractionated or accelerated
radiotherapy, or both, in patients with non-metastatic head and neck cancers and grouped trials into three pre-specified categories:
hyperfractionated, accelerated without total dose reduction and accelerated with total dose reduction. The results of this meta-analysis
suggest that altered fractionation radiotherapy improves survival in patients with head and neck cancer. Comparison of the different
types of altered fractionation radiotherapy suggests that hyperfractionation provides the greatest benefit.
Individual patient data meta-analysis is a long process and this review included all eligible trials which had completed recruiting patients
by 1998. A major update of the analysis, including data from more recent trials, is currently underway.

BACKGROUND
could affect survival. This meta-analysis was undertaken by the
Head and neck squamous cell carcinomas are frequent tumours,
MARCH (Meta-Analysis of Radiotherapy in Carcinomas of Head
with more than 550,000 new cases of oral cavity, oropharynx, hy-
and neck) Collaborative Group. A major update of this analysis
popharynx and larynx cancer worldwide every year (Ferlay 2004).
(MARCH 2) is in progress.
About 40% of patients have locally advanced disease at diagnosis.
Surgery, radiation therapy, or both, have been used for decades to
achieve locoregional control. The most commonly used schedule, OBJECTIVES
when radiotherapy is given alone, is 2 Gray (Gy) in a single frac-
tion per day, five days a week, for seven weeks. Despite these treat- To study the effect of altered fractionation radiotherapy versus con-
ments, the prognosis of patients with head and neck squamous ventional radiotherapy on overall survival rates. We also planned
cell carcinomas with locally advanced disease remains poor, with a comparison between the effects of the three types of altered frac-
five-year survival rates of 30% to 35% (Pignon 2000a). tionation radiotherapy.
In the past decade, new radiotherapy regimens for the treatment

of head and neck squamous cell carcinomas have been assessed. METHODS
These regimens were designed to increase the dose-intensity by
delivering a higher total dose in the same time (EORTC 22791
1992; PMHToronto 2007; RIO 1991; RTOG 9003HF 2000),
Criteria for considering studies for this review
the same total dose in five to six weeks instead of seven weeks
(BCCA 9113 1997; CAIR 2000; DAHANCA 2003; EORTC
22851 1997; KBN PO 79 2002; Oro 9301 2003; RTOG 9003HF
Types of studies
2000; RTOG 9003B 2000; RTOG 9003S 2000) or a smaller
total dose given in three to four weeks (CHART 1997; GORTEC Trials had to be randomised in a way that ensured that investigators
9402 2006; RTOG 7913 1987; TROG 9101 2001; Vienna 2000). decided whether the patient was eligible without foreknowledge
Reducing the total treatment time, i.e. accelerating the treatment, of the assigned treatment. Trials were eligible if recruitment began
should reduce the repopulation of tumour cells between sessions, after 1969 and ended before 1998.
resulting in improved locoregional control. In hyperfractionated
regimens, two to three fractions are delivered each day, with a Types of participants
reduced dose per fraction equal to 1.1 to 1.2 Gy. The reduction of Trials including previously untreated patients (those who had not
the dose per fraction might reduce the risk of late toxicity, despite received prior radiotherapy or prior chemotherapy), with non-
an increased total dose. metastatic head and neck squamous cell carcinomas of the oral
Acceleration and hyperfractionation can be combined, in par- cavity, oropharynx, hypopharynx or larynx, were eligible. We ex-
ticular for regimens in which overall treatment time is reduced. cluded randomised trials including mainly or exclusively nasopha-
In some randomised trials, altered fractionation radiotherapy has ryngeal carcinomas as their epidemiology and response to radio-
proved to be of benefit in locoregional control (CAIR 2000; and chemotherapy is different from that of other head and neck
DAHANCA 2003; EORTC 22791 1992; GORTEC 9402 2006; cancers.
PMHToronto 2007; RIO 1991; RTOG 9003HF 2000) although
no benefit in survival was generally detected. The use of altered Types of interventions
fractionation radiotherapy is associated with some increase in tox-
Trials that compared conventional radiotherapy with accelerated
icity, mostly due to mucositis (BCCA 9113 1997; DAHANCA
or hyperfractionated radiotherapy, or both, in previously untreated
2003; EORTC 22851 1997; GORTEC 9402 2006; RTOG
patients with non-metastatic head and neck squamous cell carci-
9003HF 2000; RTOG 9003B 2000; RTOG 9003S 2000) and
nomas were eligible. Trials had to be unconfounded: they should
can add some practical constraints in radiotherapy departments,
differ only on radiotherapy modalities. Definition of conventional
for example treatment two to three times a day or at a weekend,
dose was based on expert opinion and chosen during the investiga-
that need to be balanced by substantial benefit (BCCA 9113 1997;
tor meeting before having seen the results: trials that used doses per
CAIR 2000; CHART 1997; DAHANCA 2003; EORTC 22791
fraction higher than 2.5 Gy were not eligible. Radiotherapy had to
1992; EORTC 22851 1997; GORTEC 9402 2006; KBN PO
be with curative intent. We excluded trials without a conventional
79 2002; PMHToronto 2007; RIO 1991; RTOG 9003HF 2000;
radiotherapy arm. We defined conventional curative radiotherapy
RTOG 9003B 2000; RTOG 9003S 2000; RTOG 7913 1987;
as radiotherapy equivalent to 66 to 70 Gy, in 2 Gy fractions, for
TROG 9101 2001; Vienna 2000).
five days a week. We also excluded trials of postoperative radio-
A meta-analysis of updated individual patient data is the most therapy from this meta-analysis because of their small number and
reliable way to assess whether altered fractionation radiotherapy their different total dose.

The Collaborative Group’s Steering Committee prespecified three Searching other resources
groups of trials with different modifications of fractionation that We scanned the reference lists of identified publications for addi-
correspond to three distinct biological questions. The first group tional trials and contacted trial authors where necessary. In addi-
(hyperfractionation) examined the effect of a higher total dose in tion, we searched PubMed, TRIPdatabase, NHS Evidence - ENT
the same overall time than in the reference arm (EORTC 22791 & Audiology and Google to retrieve existing systematic reviews
1992; PMHToronto 2007; RIO 1991; RTOG 9003HF 2000). relevant to this systematic review, so that we could scan their refer-
The second group (accelerated group) represented a pure test of ence lists for additional trials. We searched for conference abstracts
the effect of accelerating radiotherapy, while keeping the total dose using the Cochrane Ear, Nose and Throat Disorders Group Trials
the same (BCCA 9113 1997; CAIR 2000; DAHANCA 2003; Register and the websites for ASCO, ESMO, ASTRO, ECCO,
EORTC 22851 1997; KBN PO 79 2002; Oro 9301 2003; RTOG ESTRO and PDQ. We also asked experts and trialists who took
9003B 2000; RTOG 9003S 2000). Finally, the third group (ac- part in the meta-analysis to identify trials.
celerated with reduced dose group) tested the effect of acceler-
ating radiotherapy, but with reduced total dose (CHART 1997;
GORTEC 9402 2006; RTOG 7913 1987; TROG 9101 2001; Data collection and analysis
Vienna 2000).
Both the Institute Gustave Roussy and the European Organisa-
tion for Research and Treatment of Cancer (EORTC) meta-anal-
ysis unit performed data extraction. The data requested for all
Types of outcome measures patients were age, sex, tumour site, T and N classification, stage,
Overall survival was the main outcome measure and was defined histology, performance status, allocated treatment and date of ran-
as the time from randomisation to the last follow up or death, domisation. The date and types of the first tumour failure (local,
whatever the cause. regional or distant) and the date of second primary cancer were
The secondary outcome measures were local or regional control also recorded. We requested updated survival status and date of
rates (or both), distant control rates and cause-specific mortality. last follow up from the trialists. We obtained data for patients ex-
cluded from the analysis after randomisation whenever possible.
We did not gather data for morbidity and toxicity because this
information was not available in a common format.
We used standard checks to identify missing data and assess data
Search methods for identification of studies validity and consistency. We verified the amount of missing data
We conducted systematic searches for randomised controlled tri- and checked the order of dates. To assess randomisation integrity
als. There were no language, publication year or publication status we checked patterns of treatment allocation and balance of baseline
restrictions. The date of the last search was 8 August 2010. characteristics by treatment group. We checked follow up of sur-
viving patients to ensure that it was balanced by treatment group
and was up to date. We compared all data with the trial’s proto-
col and published reports. We resolved any queries and each trial
Electronic searches
investigator or statistician verified the final database. We verified
We searched the following databases from their inception for pub- ranges and extremes with the trialists.
lished, unpublished and ongoing trials: the Cochrane Ear, Nose We also assessed study quality using the Cochrane ’Risk of bias’ ap-
and Throat Disorders Group Trials Register; the Cochrane Cen- proach, which involved assessment of six domains: sequence gen-
tral Register of Controlled Trials (CENTRAL) (The Cochrane Li- eration; allocation concealment; blinding; incomplete outcome
brary 2010, Issue 3); PubMed; EMBASE; CINAHL; LILACS; data; selective outcome reporting and other sources of bias. Assess-
KoreaMed; IndMed; PakMediNet; CAB Abstracts; Web of Sci- ment involved describing each of these domains as reported in the
ence; BIOSIS Previews; CNKI; ISRCTN; ClinicalTrials.gov; IC- trial and then assigning a judgement about the adequacy of each
TRP and Google. entry. This meant answering a pre-specified question whereby a
We modelled subject strategies for databases on the search strat- judgement of ’Yes’ indicated low risk of bias, ’No’ indicated high
egy designed for CENTRAL. Where appropriate, we combined risk of bias, and ’Unclear’ indicated unclear or unknown risk of
subject strategies with adaptations of the highly sensitive search bias.
strategy designed by the Cochrane Collaboration for identifying We analysed each trial individually and sent the survival analyses
randomised controlled trials and controlled clinical trials (as de- to the trialists for validation. We computed median follow up by
scribed in The Cochrane Handbook for Systematic Reviews of In- the reverse Kaplan-Meier method (Schemper 1996). We stratified
terventions Version 5.0.2, Box 6.4.b. (Handbook 2009)). Search survival analyses by trials and used the log-rank observed minus
strategies for major databases including CENTRAL are provided expected numbers of deaths (O-E) and their variances to calcu-
in Appendix 1. late individual hazard ratios (HR) and overall HR with a fixed-

effect model. The weight of each trial in the pooled analysis was Description of studies
proportional to the variance of O-E, which is roughly equal to a
See: Characteristics of included studies; Characteristics of excluded
quarter of the number of deaths (Yusuf 1985). To eliminate the
studies; Characteristics of ongoing studies.
potential bias of an incorrect determination of the cause of death
Of 26 potentially eligible randomised trials we excluded nine: three
after recurrence, the log-rank analysis of deaths from non-head
were postoperative trials (Ang 2001; Awwad 1992; Awwad 2002),
and neck cancer cause covered only the period before recurrence
one had biased randomisation (Tandon 1999), two used un-
(i.e. data were censored at the first recurrence), as Peto and col-
conventional radiotherapy in the reference group (Sanchiz 1990;
leagues proposed (EBCT-CG 1995). We obtained an unbiased,
Van den Bogaert 1986) and three used hypofractionated radio-
although potentially diluted, log-rank analysis of head and neck
therapy in the experimental group (Overgaard 1989; Weissberg
cancer mortality indirectly by subtracting the log-rank statistic for
1982; Wiernik 1991). The ’ongoing’ trials list (see the table
non-head and neck cancer mortality from the log-rank statistic
Characteristics of ongoing studies) includes both trials that ended
for mortality from all causes (i.e. the two observed values are sub-
accrual of patients after the period of inclusion for trials defined
tracted from each other, the two expected values are subtracted
in the protocol (1998) and trials still ongoing.
from each other, and the two variances are subtracted from each
Data from one eligible trial (212 patients) were lost (Datta 1989).
other).
Fifteen trials fulfilled all the inclusion criteria and data were avail-
We used Chi² tests to study heterogeneity between trials and be-
able for 6515 patients (BCCA 9113 1997; CAIR 2000; CHART
tween trial groups (NSCLC-CG 1995). We used the I² statistic
1997; DAHANCA 2003; EORTC 22791 1992; EORTC 22851
to estimate the proportion of variability of the results related to
1997; GORTEC 9402 2006; KBN PO 79 2002; Oro 9301
heterogeneity rather than to sampling error (Higgins 2002). To
2003; PMHToronto 2007; RIO 1991; RTOG 7913 1987; RTOG
study the interaction between treatment and covariates, we car-
9003HF 2000; RTOG 9003B 2000; RTOG 9003S 2000; TROG
ried out an analysis stratified on trials for each covariate value, and
9101 2001; Vienna 2000). The length of follow up varied from
compared the HR for the different values of the covariate with
four to 10 years, with a median of six years. One trial, RTOG 9003,
a heterogeneity test. We computed stratified survival curves for
was a four-arm trial, with a reference arm and three experimental
control and experimental groups with annual death rates and HR,
arms. The reference arm of this trial was counted three times so that
and then used these to calculate absolute benefit at two years and
the three altered fraction modalities of the trial could be analysed
five years (EBCT-CG 1992). All P values are two-sided.
separately (RTOG 9003B 2000; RTOG 9003HF 2000; RTOG
9003S 2000). Overall, 17 comparisons were made for 7073 pa-
tients.
Trial and patient characteristics are presented in Figure 1 and
RESULTS Figure 2.

Figure 1. Description of trials comparing altered fractionated with conventional radiotherapy: patients
characteristicsBCCA = British Columbia Cancer Agency; CAIR = Continuous Accelerated Irradiation; CHART
= Continuous Hyperfractionated Accelerated Radiation Therapy; DAHANCA = Danish Head and Neck
Cancer Study Group; EORTC = European Organisation for Research and Treatment of Cancer; GORTEC =
Groupe d’Oncologie Radiothérapie Tête et Cou; KBN = Komiet Badan Naukowych (Committee for Scientific
Research); PMH-Toronto = Princess Margaret Hospital, Toronto; RTOG = Radiation Therapy Oncology Group;
TROG = Trans-Tansman Radiation Oncology GroupFigure from Bourhis J, Overgaard J, Audry H, Ang KK,
Saunders M, Bernier J et al on behalf of MARCH collaborative group. Hyperfractionated or accelerated
radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006;368:843-54 reproduced with permission
from Elsevier Ltd.

Figure 2. Description of patients included in trials comparing altered fractionated radiotherapy with
conventional radiotherapy by arm (n = 7073).Figure from Bourhis J, Overgaard J, Audry H, Ang KK, Saunders
M, Bernier J et al on behalf of MARCH collaborative group. Hyperfractionated or accelerated radiotherapy in
head and neck cancer: a meta-analysis. Lancet 2006;368:843-54 reproduced with permission from Elsevier Ltd.

Risk of bias in included studies analysis but we were able to gather data for 154 of the 163 ran-
All the included trials fulfilled the strict methodological criteria of domised patients who had been excluded from the published anal-
this individual patient data meta-analysis. One study was excluded yses. Lastly the length of follow up was good.
because of biased randomisation (Tandon 1999). For each trial, We also assessed study quality using the Cochrane ’Risk of bias’
the balance of covariates and the cumulative number of patients approach. The results of our assessments are shown in the ’Risk of
accrued over time were checked to identify possible problems with bias’ tables (Characteristics of included studies). A ’Risk of bias’
randomisation. Moreover, we compared the length of follow up graph (review authors’ judgements about each risk of bias item
by arm. Following these investigations, we identified no problems presented as percentages across all included studies) and summary
among the eligible trials. All trials scored ’A’ for randomisation (review authors’ judgements about each risk of bias item for each
concealment. Some trials did not perform an intention-to-treat included study) are shown in Figure 3 and Figure 4.
Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies. None of the studies of altered fractionation used a sham procedure for
radiotherapy blinding, but overall survival is a robust endpoint that should not be sensitive to this absence of
blinding.

Figure 4. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study. None of the studies of altered fractionation used a sham procedure for radiotherapy blinding, but overall
survival is a robust endpoint that should not be sensitive to this absence of blinding.

Effects of interventions
There was a good balance between the trial arms for site, stage,
sex, histology, age and performance status. The main tumour sites
were oropharynx (3079 patients, 44%) and larynx (2377, 34%).
In total, 1812 (26%) patients had stage I and II and 5221 (74%)
had stage III-IV tumours (UICC 2002).
There was a significant benefit for overall survival with altered frac-
tionation radiotherapy compared with conventional radiotherapy
(Analysis 1.1; Figure 5). This benefit corresponded to an 8% (95%
CI 3 to 14) reduction in the risk of dying and an absolute benefit
of 3.3% (0.9 to 5.7) and 3.4% (1.0 to 5.8) at two and five years,
respectively.

Figure 5. Survival curves by treatment arm for all trials and for the three groups of trials according to the
type of altered fractionated radiotherapy. The slopes of the broken lines from year 6 to year >= 7 are based on
the overall death rates in the seventh and subsequent years.RT = radiotherapyFigure from Bourhis J,
Overgaard J, Audry H, Ang KK, Saunders M, Bernier J et al on behalf of MARCH collaborative group.
Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006;368:843-54
reproduced with permission from Elsevier Ltd.

Heterogeneity was significant between trials (P = 0.001; I² = 58%).
Altered fractionation radiotherapy had no effect on death not re-
lated to cancer (HR 1.06, 95% CI 0.93 to 1.22) and the overall
benefit was due to the effect on death related to cancer (HR 0.88,
95% CI 0.83 to 0.94) (Analysis 1.2; Figure 6). The magnitude
of the survival benefit was significantly higher in the hyperfrac-
tionation group than in the two other groups (test for interaction,
P = 0.02; Analysis 1.1; Figure 5). This comparison should be in-
terpreted with caution because the populations included in the
three groups were dissimilar (Figure 7), for example more patients
with early stage or larynx tumour were included in the group with
accelerated fractionation and the same total dose.

Figure 6. Non-cancer death and cancer death survival curves for all trials and for the three groups of trials
according to the altered fractionated radiotherapy. The slopes of the broken lines from year 6 to year >= 7 are
based on the overall death rates in the seventh and subsequent years.RT = radiotherapyFigure from Bourhis J,

Figure 7. Description of patients included in trials comparing conventional radiotherapy with altered
fractionated radiotherapy by group of altered fractionated radiotherapy (n = 7073).Figure from Bourhis J,

Data about local and regional failures were available for only 14
of 17 trials (6410 patients; Figure 8). Local recurrence was the
main cause of first failure (2527 patients (39%), isolated in 1544
patients (24%) and associated with only a regional neck lymph
node failure in 909 (14%)), whereas regional failure was reported
in 1407 (22%) patients (isolated in 419 (7%)). Finally, distant
metastases were reported in 533 (8%) patients (isolated in 360
(5%)).
Figure 8. Distribution of type of first failure by arm.Figure from Bourhis J, Overgaard J, Audry H, Ang KK,
Saunders M, Bernier J et al on behalf of MARCH collaborative group. Hyperfractionated or accelerated
radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006;368:843-54 reproduced with permission
from Elsevier Ltd.
There was a significant benefit on locoregional control for al-

tered fractionation compared with conventional radiotherapy (P
< 0.0001; Analysis 1.3 and Figure 9). This benefit was seen in all
three groups, but was slightly more pronounced in the two groups
that did not decrease the total dose, compared with the reference
arm (Analysis 1.3; Figure 9; Figure 10).

Figure 9. Locoregional failure by treatment arm according to the type of radiotherapy. The slopes of the
broken lines from year 6 to year >= 7 are based on the overall death rates in the seventh and subsequent
years.RT = radiotherapyFigure from Bourhis J, Overgaard J, Audry H, Ang KK, Saunders M, Bernier J et al on
behalf of MARCH collaborative group. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a
meta-analysis. Lancet 2006;368:843-54 reproduced with permission from Elsevier Ltd.

Figure 10. Hazard ratio (95% CI) of altered fractionated radiotherapy versus conventional radiotherapy on
overall population and type of radiotherapy for locoregional, local, regional, and metastatic control (n =
7073).Figure from Bourhis J, Overgaard J, Audry H, Ang KK, Saunders M, Bernier J et al on behalf of MARCH
collaborative group. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis.
Lancet 2006;368:843-54 reproduced with permission from Elsevier Ltd.
Altered fractionated radiotherapy was especially effective in the

reduction of local failure in all three groups (Analysis 1.4), with ation without total dose reduction), and counted only once the
a 23% reduction in the risk and an absolute benefit of 8.5% (5.7 control group of the RTOG 9003 trial (data not shown). These
to 11.3) at five years. The benefit of this treatment on regional analyses led to very similar overall results and often to a decrease in
control was also significant, with a 13% reduction in the risk and the heterogeneity and its disappearance for all analyses excluding
an absolute benefit of 1.9% (-0.7 to 4.5) at five years, although the CAIR trial.
much less pronounced than for local control (Figure 10). No effect There was no significant interaction between sex, performance
of altered fractionation radiotherapy could be detected on distant status, tumour stage, nodal stage, overall stage, tumour site and
metastases. The fact that the hyperfractionation group and the the treatment effect on overall survival, but an interaction with
group with accelerated fractionation without total dose reduction age was recorded (Figure 11). Indeed, a test for trend revealed a
shared the same benefit for local control (Analysis 1.4), but had significant interaction between age and treatment effect for over-
a different effect on survival (Analysis 1.1; Figure 5), could be all survival (P = 0.007), and death related to cancer (P = 0.008),
attributable to an excess of non-cancer related deaths in the group local control (P = 0.002) and locoregional control (P = 0.002). A
with accelerated fractionation without total dose reduction (Figure significant interaction was also noted between performance status
6). At five years, for example, 2.4% more patients in the group and treatment effect, but only for tumour control (test for trend,
with accelerated fractionation without total dose reduction had P < 0.0001 for locoregional control, P = 0.0001 for local control,
non-cancer related deaths. P = 0.004 for regional control). The effect of altered fractionation
We performed several sensitivity analyses on overall survival, can- radiotherapy on tumour control was higher in patients with good
cer mortality and locoregional control endpoints. These analyses performance status. The effect of altered fractionation radiother-
excluded stage I and II tumours, the CAIR trial (a trial with outly- apy on tumour control did not differ significantly according to
ing results), the Oro 9301 2003 and RTOG 9003HF 2000 trials tumour stage and tumour site. Treatment effect on locoregional
(that did not fit perfectly in the group with accelerated fraction- failure was better for N0 and N1 than for N2 or N3 nodal stage
(test for trend P = 0.02).

Figure 11. Hazard ratio of death with altered fractionated radiotherapy versus conventional radiotherapy
by age, sex, performance status, stage and site of tumour. Test for trend was significant for age (P =
0.007).Figure from Bourhis J, Overgaard J, Audry H, Ang KK, Saunders M, Bernier J et al on behalf of MARCH
collaborative group. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis.
Lancet 2006;368:843-54 reproduced with permission from Elsevier Ltd.

showed an increased risk with accelerated fractionation without
total dose reduction and two (CHART 1997; TROG 9101 2001)
showed a decreased risk with accelerated fractionation with total
DISCUSSION
dose reduction.
Individual patient data meta-analysis is a long process, as the au-
thors need to obtain all the updated data from the trialists before The effect of altered fractionation was significantly more pro-
starting the analyses. MARCH (Meta-Analysis of Radiotherapy in nounced on the primary tumour than on nodal disease. The in-
Carcinomas of Head and neck) started in 2000 and was first pub- terpretation of this observation is not easy, since we studied only
lished in 2006 (Bourhis 2006). This is the reason why recent trials the first site of failure and simultaneous failures in the primary
were not included in this meta-analysis. MARCH 2, which will in- site and in the nodes were frequent. Altered fractionation radio-
clude more recent studies, is currently underway (see Implications therapy could be appropriate for patients with N0 and N1 dis-
for research). ease, whereas combinations of chemotherapy and radiotherapy
could be more appropriate for patients with more advanced nodal
Meta-analysis of individual patient data shows that different types disease. Altered fractionation had no effect on distant metastases
of altered fractionation radiotherapy could be more effective in (Figure 10). However, this result should be viewed with caution
treating head and neck squamous cell carcinomas, compared with as the low observed rate of distant metastases could be related to
conventional radiotherapy, with a small but significant benefit in poor recording, thus resulting in low power for this analysis. In
survival and a more pronounced benefit in locoregional and local the patients randomly assigned to the conventional radiotherapy
control. Our findings provide strong evidence that altered frac- group, the overall survival of the larynx subgroup was significantly
tionation radiotherapy can improve survival in this disease. The better than that for the other sites (data not shown). However, the
survival benefit was mainly seen in the group with increased total effect of altered fractionation radiotherapy did not differ for the
dose (i.e. hyperfractionated radiotherapy) and corresponded to an larynx compared with the other sites. A stratification of data on
absolute benefit of 8% at five years in this group. This benefit is the larynx site did not change the results (data not shown).
of the same size as the effect due to the use of chemotherapy con-
comitantly with radiotherapy in this type of cancer (i.e. 8% at five The strong suggestion of a decreasing effect of altered fractiona-
years with the method used in a meta-analysis of chemotherapy tion radiotherapy with increasing age and with poor performance
(Pignon 2000a; Stewart 1993) and 6.5% with the same method status might be partly explained by an excess of non-cancer re-
used here). lated deaths in patients aged 71 years and over (Pignon 2007), but
also by lower compliance and tolerance in these patients and in
Analyses of the different types of altered fractionation radiother-
patients with poor general health status (Khalil 2003). However,
apy suggest that the hyperfractionation group showed the greatest
tolerance was difficult to assess from our database, since recording
benefit (P = 0.02). However, this difference was noted only for
and scoring acute and late radiation effects could vary between
survival, whereas for locoregional control a non-significant trend
trials. The decreasing effect of more intense treatment in older
only was recorded in favour of hyperfractionation and of accel-
patients has also been reported in patients with head and neck
erated fractionation without total dose reduction. These findings
squamous cell carcinomas treated with concomitant chemother-
suggest that substantial acceleration could only partly compensate
apy and radiotherapy (Bourhis 2004; Pignon 2000a).
for decreasing the total dose (Analysis 1.3; Analysis 1.4; Figure 9).
Increasing the total dose in hyperfractionated radiotherapy could
be an attractive option, since this is the only group in which a
benefit was seen both on survival and local control. However, the AUTHORS’ CONCLUSIONS
benefit in locoregional control was much the same in the group Implications for practice
of trials with moderate acceleration and in which the total dose
We have shown that altered fractionation radiotherapy confers
was kept the same as in the reference arm. It is necessary to define
greater benefit than conventional radiotherapy in tumour control
which characteristics of the patients and tumours could be used
and survival. The effect was greater for the primary tumour than
in order to select the optimum altered fractionation radiotherapy
for nodal disease. The effect was also more pronounced in younger
for individual patients.
patients and in those with good performance status. Hyperfrac-
The modest 3.4% survival benefit of altered fractionation radio- tionation seemed to yield a more consistent advantage for survival
therapy at five years could be offset by an increased risk in late than accelerated radiotherapy. However, there was more diversity
toxicities. Among the four trials reporting significant differences in accelerated fractionation regimens than in hyperfractionated
in late toxicity, two (BCCA 9113 1997; EORTC 22851 1997) regimens, and some of these regimens might be associated with

higher non-cancer related death, off-setting their benefit in im- tial for electronic literature searches and Gemma Sandberg for up-
proving tumour control. dating the bibliography.
Implications for research

An update of MARCH is scheduled (MARCH 2). This study MARCH Collaborative Group
should increase the power of this analyses and allow for other
comparisons: current trials investigate whether the benefit of hy- Secretariat
perfractionated radiotherapy versus standard radiotherapy persists H Audry, J Bourhis, M Bolla, L Duchateau, C Hill, A Le Maître,
when combined with concomitant chemotherapy or when applied J-P Pignon, R Sylvester, N Syz
in a postoperative setting. MARCH 2 may allow us to provide a Steering Committee
global estimator of the treatment effect. Strategies with intensity- KK Ang, J Bernier, S Dische, F Eschwege, KK Fu, J-C Horiot, J
modulated radiotherapy or targeted therapy will also have to be Overgaard, MKB Parmar
assessed. Investigators
KK Ang, HK Awwad, B Baerg, E Benhamou, J Bernier, J Bourhis,
L Collette, BJ Cummings, S Dische, W Dobrowsky, JW Denham,
C Fallai, KK Fu, C Grau, H Sand Hansen, JH Hay, A Hliniak, J-
C Horiot, SM Jacskon, E Kraszewska, M Lotayef, B Maciejewski,
ACKNOWLEDGEMENTS
P Olmi, B O’Sullivan, J Overgaard, TF Pajak, MKB Parmar, M
We thank the trialists who agreed to share and update their data. Pintilie, LHJ Pinto, MG Poulsen, M Saunders, K Skladowski, N
We thank Denise Avenell for secretarial assistance, Francine Cour- Tandon, V Torri, J Widder, B Baujat, P Blanchard, A Bourredjem
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Den Bogaert W, et al.Compliance to the prescribed dose and overall ∗
Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
BCCA 9113 1997
Methods Inclusion period: 1991 to 1995

Median follow up: 7.8 years
Participants 82 patients
Interventions Altered fractionated arm: 66 Gy, 2 daily fractions, 3.5 weeks

Conventional arm: 66 Gy, 1 daily fraction, 6.5 weeks
Outcomes Overall survival, locoregional control, local control, regional control, distant control,
cause-specific mortality
Notes BCCA = British Columbia Cancer Agency

Patients’ written consent: yes / ethical board: unspecified
Risk of bias
Item Authors’ judgement Description
Adequate sequence generation? Yes
Allocation concealment? Yes A - Adequate
Blinding? Unclear None of the studies of altered fractiona-

All outcomes tion used a sham procedure for radiother-
apy blinding, but overall survival is a ro-
bust endpoint that should not be sensitive
to this absence of blinding
Incomplete outcome data addressed? Yes

All outcomes
Free of selective reporting? Yes
Free of other bias? Yes
CAIR 2000


CAIR 2000 (Continued)
Interventions Altered fractionated arm: 64 to 74 Gy, 1 daily fraction, 4.5 to 5 weeks

Conventional arm: 64 to 74 Gy, 1 daily fraction, 6.5 to 8 weeks
Notes Because of the high incidence of toxicity in the accelerated arm, the schedules were
modified for the next patients. The dose per fraction was reduced from 2.0 to 1.8 Gy
and a second fraction was given twice a week in both arms. In the non-accelerated arm,
there was a 3-day break each weekend
CAIR = Continuous Accelerated Irradiation
Patients’ written consent/ethical board: yes
Risk of bias


All outcomes
CHART 1997



CHART 1997 (Continued)
Notes CHART = Continuous Hyperfractionated Accelerated Radiation Therapy

Risk of bias


All outcomes
DAHANCA 2003

Interventions Altered fractionated arm: 66 to 68 Gy, 1 daily fraction, 6 weeks

Conventional arm: 66 to 68 Gy, 1 daily fraction, 7 weeks
Notes 5.5% of patients included in 1999. Radiosensitiser nimorazole in both arms for DA-
HANCA 7 (791 patients)
DAHANCA = Danish Head and Neck Cancer Study Group
Risk of bias

DAHANCA 2003 (Continued)


All outcomes
EORTC 22791 1992

Interventions Altered fractionated arm: 80.5 Gy, 2 daily fractions, 7 weeks

Conventional arm: 70 Gy, 1 daily fraction, 7 weeks
Notes EORTC = European Organisation for Research and Treatment of Cancer

Patients’ written consent/ethical board: unspecified
Risk of bias


All outcomes

EORTC 22791 1992 (Continued)
EORTC 22851 1997

Interventions Altered fractionated arm: 72 Gy, 3 daily fractions, 5 weeks sc‡

Notes ‡ Firstcourse: 28.8 Gy, in 18 fractions for 8 days, 12 to 14 days split, 43.2 Gy in 27
fractions for 17 days
EORTC = European Organisation for Research and Treatment of Cancer
Patients’ written consent/ethical board: unspecified
Risk of bias


All outcomes

GORTEC 9402 2006

Interventions Altered fractionated arm: 62 to 64 Gy, 2 daily fractions, 3 weeks

Notes GORTEC = Groupe d’Oncologie Radiothérapie Tête et Cou

Patients’ written consent: yes/ethical board: unspecified
Risk of bias


All outcomes
KBN PO 79 2002

Interventions Altered fractionated arm: 66 Gy, 1 daily fraction, 5.5 weeks b


KBN PO 79 2002 (Continued)
Notes KBN = Komiet Badan Naukowych (Committee for Scientific Research)

Risk of bias


All outcomes
Oro 9301 2003

Interventions Altered fractionated arm: 64 to 67 Gy, 2 daily fractions, 6.5 weeks sc*
Conventional arm: 66 to 70 Gy, 1 daily fraction, 7 weeks
Notes Third arm with radio-chemotherapy

*First course: 38.4 Gy in 24 fractions for 2.5 weeks, 2 weeks split, 25.6 to 28.8 Gy in
16 to 18 fractions for 2.5 to 3 weeks
Risk of bias

Oro 9301 2003 (Continued)


All outcomes
PMHToronto 2007

Interventions Altered fractionated arm: 58 Gy, 2 daily fractions of 1.45 Gy, 4 weeks
Conventional arm: 51 Gy, 1 daily fraction 2.5 Gy, 4 weeks**
Notes ** 51 Gy translates to 50 Gy prescribed at the 90% isodose

It was considered by the investigators that 20 fraction of 2.5 Gy over 28 days was
equivalent to 66 to 70 Gy using 2 Gy daily fractions over 6.5 to 7 weeks
PMH-Toronto = Princess Margaret Hospital, Toronto
Risk of bias


PMHToronto 2007 (Continued)

All outcomes
RIO 1991

Interventions Altered fractionated arm: 70.4 Gy, 2 daily fractions, 6.5 weeks
Outcomes Overall survival, locoregional control, distant control, cause-specific mortality
Notes Patients’ written consent/ethical board: yes
Risk of bias


All outcomes

RTOG 7913 1987

Interventions Altered fractionated arm: 60 Gy, 2 daily fractions, 6 weeks

Notes RTOG = Radiation Therapy Oncology Group

Risk of bias


All outcomes
RTOG 9003B 2000

Interventions Altered fractionated arm: 72 Gy, 2 daily fractions, 6 weeks b


RTOG 9003B 2000 (Continued)
Notes Four-arm trials, each experimental arm was compared with the control arm
RTOG = Radiation Therapy Oncology Group
’RTOG 9003 B’ for boost
Risk of bias


All outcomes
RTOG 9003HF 2000

Interventions Altered fractionated arm: 81.6 Gy, 2 daily fractions, 7 weeks

’RTOG 9003 HF’ for hyperfractionated
Risk of bias

RTOG 9003HF 2000 (Continued)


All outcomes
RTOG 9003S 2000

Interventions Altered fractionated arm: 67.6 Gy, 2 daily fractions, 6 weeks sc

’RTOG 9003 S’ for split course
Risk of bias


RTOG 9003S 2000 (Continued)

All outcomes
TROG 9101 2001

Interventions Altered fractionated arm: 59.4 Gy, 2 daily fractions, 3.5 weeks
Notes TROG = Trans-Tansman Radiation Oncology Group

Risk of bias


All outcomes

Vienna 2000


Notes Third arm with accelerated radiotherapy plus mitomycin C

Risk of bias


All outcomes
b = boost; Gy = Gray; sc = split course
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Awwad 2002 radical RT ALLOCATION: biased randomisation, incomplete data
Datta 1989 Data were lost

(Continued)
Overgaard 1989 ALLOCATION: randomised trial

PARTICIPANTS: 626 patients with pharynx and larynx carcinoma
INTERVENTIONS: hypofractionated radiotherapy in the experimental group
Sanchiz 1990 ALLOCATION: randomised trial

PARTICIPANTS: 859 patients with T3-T4, NO-3, MO head and neck cancer
INTERVENTIONS: unconventional radiotherapy in the reference group
Skladowski 2007 ALLOCATION: randomised trial

INTERVENTIONS: no standard arm (CAIR versus concomitant boost)
Tandon 1999 ALLOCATION: biased randomisation
Van den Bogaert 1986 ALLOCATION: randomised trial

PARTICIPANTS: 523 patients with advanced head and neck cancer
INTERVENTIONS: unconventional radiotherapy in the reference group
Weissberg 1982 ALLOCATION: randomised trial

PARTICIPANTS: 64 patients with non-resectable head and neck cancer
Wiernik 1991 ALLOCATION: randomised trial

PARTICIPANTS: 611 patients with locally advanced head and neck cancer
CAIR = Continuous Accelerated Irradiation
Characteristics of ongoing studies [ordered by study ID]
Ang 2001
Trial name or title Randomized trial addressing risk feature and times factors of surgery plus radiotherapy in advanced head and
neck cancer
Methods Randomised trial
Interventions Conventional postoperative RT versus accelerated postoperative RT
Outcomes Survival, LRC
Starting date Inclusion period:

1991 to 1997
Contact information See reference

Ang 2001 (Continued)
Notes None
Ang 2010
Trial name or title RTOG H0129
Interventions Conventional RT + cisplatin versus accelerated fractionation by concomitant boost + cisplatin
Outcomes Survival, LRC, DFS

NA
Contact information NA
Notes None
ARTSCAN II
Trial name or title ARTSCAN II
Participants 260 patients planned (resectable cancer of the oral cavity)
Interventions Preoperative accelerated versus postoperative conventional radiotherapy in patients with resectable cancer of
the oral cavity
Outcomes Primary: local and regional tumour control

Secondary: OS, DFS, quality of life
Starting date 2008
Contact information Johan Wennerberg (Dept of ORL/Head & Neck Surgery University Hospital Lund, SE-22185, Lund, Sweden)
Notes Potentially confounded trial which studies both a fractionation modification and a difference in treatment
strategy (preoperative versus postoperative RT)

Awwad 1992
Trial name or title Accelerated versus conventional fractionation in the postoperative irradiation of locally advanced head and
neck cancer: influence of tumour proliferation
Interventions Conventional RT versus accelerated hyperfractionated RT
Outcomes Survival, DFS
Starting date Inclusion period: 1987 to 1989
Notes None
Awwad 2002
Trial name or title Accelerated hyperfractionation (AHF) compared to conventional fractionation (CF) in the postoperative
radiotherapy of locally advanced head and neck cancer: influence of proliferation
Interventions Conventional RT versus accelerated hyperfractionation RT
Notes None
Bartelink 2002
Trial name or title Concomitant cisplatin and radiotherapy in a conventional and modified fractionation schedule in locally
advanced head and neck cancer: a randomised phase II EORTC trial
Interventions Conventional RT + concomitant cisplatin versus multiple fractions per day RT + concomitant cisplatin

Bartelink 2002 (Continued)

NA
Notes None
Bourhis 2010
Trial name or title GORTEC 99-02
Interventions Conventional RT + concomitant CT (5FU-carboplatin) versus accelerated RT + concomitant CT (5FU-

carboplatin) versus very accelerated RT
Starting date Inclusion period: 2000 to NA
Contact information NA
Notes Trial with 3 arms
Dische 2007
Trial name or title CHARTWEL
Interventions Conventional RT versus CHARTWEL (continuous hyperfractionated accelerated RT)
Notes None

Ezzat 2005
Trial name or title Randomized study of accelerated fractionation radiotherapy with and without mitomycin C in the treatment
of locally advanced head and neck cancer
Interventions Conventional fractionation RT versus accelerated fractionation RT

1998 to 2001
Notes Trial with 3 arms but only 2 arms are eligible
Ghosh 2006
Trial name or title Randomized trial of conventional fractionated RT (CFRT) vs concomitant chemo radiotherapy (CTRT) and
accelerated radiotherapy (ACRT) in patients with advanced, non nasopharyngeal, squamous cell cancers of
the head and neck region
Interventions Conventional RT + concomitant cisplatin versus hyperfractionated RT + concomitant cisplatin
Horiot 2007
Trial name or title EORTC 22962
Interventions Conventional RT versus hyperfractionated RT

Horiot 2007 (Continued)
Notes None
Johnson 1995
Trial name or title Standard once daily versus thrice-daily concomitant boost accelerated superfractionated irradiation for ad-
vanced squamous cell carcinoma of the head and neck: preliminary results of a prospective randomized trial
Interventions Conventional RT versus thrice-daily concomitant boost
Starting date Inclusion period: 1992 to NA
Notes None
Krstevska 2006
Trial name or title Altered and conventional fractionated radiotherapy in locoregional control and survival of patients with
squamous cell carcinoma of the larynx, oropharynx, and hypopharynx
Interventions Conventional RT versus hyperfractionation RT versus accelerated fractionation RT

Langendijk 2007a
Trial name or title POPART

Ongoing
Notes See reference
Langendijk 2007b
Trial name or title PARTIR

Ongoing
Notes See reference
Overgaard 2010
Trial name or title IEAE-ACC
Interventions Conventional RT versus 6 weekly fractions RT

Overgaard 2010 (Continued)
Notes None
Sanguineti 2005
Trial name or title Accelerated versus conventional fractionated postoperative radiotherapy for advanced head and neck cancer:
results of a multicenter phase III study
Interventions Conventional RT versus accelerated fractionated RT
Notes None
Sastri 2008
Trial name or title Concomitant boost: an effective regimen in locoregionally advanced head and neck cancers - a phase III
randomised trial from a single institute in India
Interventions Conventional RT versus concomitant boost RT

NA
Notes None

Slevin 2002
Trial name or title A randomised two arm trial of modestly accelerated radiotherapy with synchronous cisplatinum chemotherapy
versus conventional radiotherapy with synchronous cisplatinum chemotherapy in the treatment of head and
neck squamous cell carcinoma: a pilot study
Interventions Accelerated or conventional radiotherapy with concomitant cisplatinum (100 mg/m2 every 3 weeks)
Outcomes Tolerability, DFS, toxicity
Starting date 2002
Contact information NJ Slevin (Clinical Oncology Christie Hospital NHS Trust, Wilmslow Road, Withington, M20 4BX, Manch-
ester, United Kingdom)
Notes None
Suwinski 2008
Trial name or title p-CAIR
Interventions Conventional postoperative RT versus 7 days a week postoperative continuous RT
Notes None
Trotti 2006
Trial name or title RTOG 9512
Interventions Conventional RT versus hyperfractionated RT

Trotti 2006 (Continued)
Notes None
Zackrisson 2007
Trial name or title ARTSCAN
Interventions Conventional RT versus accelerated fractionation RT with a concomitant boost
Notes None
AHF = accelerated hyperfractionation

DFS = disease-free survival
EORTC = European Organisation for Research and Treatment of Cancer
LRC = locoregional control
NA = not available
OS = overall survival
RT = radiotherapy
This table presents the characteristics of studies that ended after the period of inclusion for trials defined in the protocol (1998) and
studies still ongoing.

DATA AND ANALYSES
Comparison 1. Altered fractionated radiotherapy versus conventional radiotherapy
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Hazard ratio of death 17 7073 Peto Odds Ratio (95% CI) 0.92 [0.86, 0.97]
1.1 Hyperfractionation 4 1350 Peto Odds Ratio (95% CI) 0.78 [0.69, 0.89]
1.2 Accelerated fractionation 8 3818 Peto Odds Ratio (95% CI) 0.97 [0.89, 1.05]
without total dose reduction
with total dose reduction
2 Hazard ratio of head and neck 17 7073 Peto Odds Ratio (95% CI) 0.88 [0.83, 0.94]
cancer death
3 Hazard ratio of locoregional 17 7073 Peto Odds Ratio (95% CI) 0.82 [0.77, 0.88]
control
4 Hazard ratio of local control 14 6410 Peto Odds Ratio (95% CI) 0.77 [0.71, 0.83]

Analysis 1.1. Comparison 1 Altered fractionated radiotherapy versus conventional radiotherapy, Outcome
1 Hazard ratio of death.
Review: Hyperfractionated or accelerated radiotherapy for head and neck cancer
Comparison: 1 Altered fractionated radiotherapy versus conventional radiotherapy
Outcome: 1 Hazard ratio of death
Study or subgroup Altered fraction. RT Conventional RT Peto Odds Ratio Weight Peto Odds Ratio
n/N n/N Exp[(O-E)/V],Fixed,95% CI Exp[(O-E)/V],Fixed,95% CI
1 Hyperfractionation
EORTC 22791 1992 126/180 135/176 5.7 % 0.76 [ 0.60, 0.98 ]
RIO 1991 41/52 47/51 1.8 % 0.57 [ 0.37, 0.88 ]
PMHToronto 2007 119/172 124/164 5.3 % 0.79 [ 0.62, 1.02 ]
RTOG 9003HF 2000 184/276 201/279 8.5 % 0.85 [ 0.69, 1.03 ]
Subtotal (95% CI) 680 670 21.4 % 0.78 [ 0.69, 0.89 ]

Heterogeneity: Chi2 = 2.67, df = 3 (P = 0.45); I2 =0.0%
Test for overall effect: Z = 3.77 (P = 0.00016)
2 Accelerated fractionation without total dose reduction
EORTC 22851 1997 171/257 164/255 7.4 % 0.98 [ 0.79, 1.22 ]
RTOG 9003S 2000 205/281 201/279 9.0 % 1.01 [ 0.83, 1.23 ]
RTOG 9003B 2000 190/277 201/279 8.7 % 0.91 [ 0.75, 1.11 ]
BCCA 9113 1997 30/41 23/41 1.2 % 1.44 [ 0.84, 2.48 ]
DAHANCA 2003 422/755 413/730 18.6 % 0.98 [ 0.85, 1.12 ]
Oro 9301 2003 51/65 48/63 2.2 % 1.22 [ 0.82, 1.81 ]
CAIR 2000 19/51 37/49 1.1 % 0.27 [ 0.16, 0.47 ]
KBN PO 79 2002 42/196 41/199 1.8 % 1.06 [ 0.69, 1.64 ]
Subtotal (95% CI) 1923 1895 50.0 % 0.97 [ 0.89, 1.05 ]

Heterogeneity: Chi2 = 24.69, df = 7 (P = 0.00086); I2 =72%
3 Accelerated fractionation with total dose reduction
RTOG 7913 1987 91/106 87/104 3.9 % 0.94 [ 0.70, 1.26 ]
CHART 1997 359/552 227/366 12.5 % 1.04 [ 0.88, 1.23 ]
Vienna 2000 62/78 66/81 2.8 % 0.91 [ 0.64, 1.28 ]
TROG 9101 2001 96/174 109/176 4.6 % 0.83 [ 0.63, 1.09 ]
GORTEC 9402 2006 105/137 111/131 4.8 % 0.82 [ 0.63, 1.07 ]
Subtotal (95% CI) 1047 858 28.6 % 0.94 [ 0.84, 1.05 ]

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control
(Continued . . . )

(. . . Continued)
Total (95% CI) 100.0 % 0.92 [ 0.86, 0.97 ]
Test for subgroup differences: Chi2 = 7.55, df = 2 (P = 0.02), I2 =74%
0.1 0.2 0.5 1 2 5 10

2 Hazard ratio of head and neck cancer death.
Outcome: 2 Hazard ratio of head and neck cancer death
EORTC 22791 1992 104/180 115/176 5.9 % 0.75 [ 0.58, 0.99 ]
RIO 1991 37/52 44/51 2.1 % 0.55 [ 0.35, 0.87 ]
PMHToronto 2007 92/172 98/164 5.1 % 0.80 [ 0.60, 1.06 ]
RTOG 9003HF 2000 163/276 179/279 9.4 % 0.86 [ 0.69, 1.06 ]
Subtotal (95% CI) 680 670 22.5 % 0.78 [ 0.68, 0.90 ]

EORTC 22851 1997 127/257 143/255 7.4 % 0.87 [ 0.69, 1.11 ]
RTOG 9003S 2000 179/281 179/279 9.8 % 1.01 [ 0.82, 1.24 ]
RTOG 9003B 2000 170/277 179/279 9.6 % 0.93 [ 0.75, 1.15 ]
BCCA 9113 1997 23/41 18/41 1.1 % 1.40 [ 0.76, 2.58 ]
DAHANCA 2003 244/755 274/730 14.2 % 0.87 [ 0.73, 1.03 ]
Oro 9301 2003 45/65 44/63 2.4 % 1.18 [ 0.78, 1.79 ]
0.1 0.2 0.5 1 2 5 10

(Continued . . . )

(. . . Continued)
CAIR 2000 13/51 35/49 1.2 % 0.23 [ 0.13, 0.41 ]
KBN PO 79 2002 34/196 34/199 1.9 % 1.04 [ 0.65, 1.68 ]
Subtotal (95% CI) 1923 1895 47.7 % 0.91 [ 0.83, 1.00 ]

RTOG 7913 1987 86/106 77/104 4.4 % 1.00 [ 0.73, 1.36 ]
CHART 1997 279/552 181/366 12.1 % 1.02 [ 0.85, 1.23 ]
Vienna 2000 52/78 61/81 3.1 % 0.83 [ 0.57, 1.20 ]
TROG 9101 2001 85/174 92/176 4.9 % 0.88 [ 0.66, 1.19 ]
GORTEC 9402 2006 93/137 103/131 5.3 % 0.81 [ 0.61, 1.07 ]
Subtotal (95% CI) 1047 858 29.8 % 0.93 [ 0.83, 1.05 ]

Total (95% CI) 100.0 % 0.88 [ 0.83, 0.94 ]
0.1 0.2 0.5 1 2 5 10


3 Hazard ratio of locoregional control.
Outcome: 3 Hazard ratio of locoregional control
EORTC 22791 1992 78/180 99/176 5.3 % 0.68 [ 0.50, 0.91 ]
RIO 1991 18/52 16/51 1.0 % 0.84 [ 0.43, 1.67 ]
PMHToronto 2007 91/172 101/164 5.8 % 0.81 [ 0.61, 1.07 ]
RTOG 9003HF 2000 123/276 147/279 8.1 % 0.78 [ 0.62, 0.99 ]
Subtotal (95% CI) 680 670 20.2 % 0.76 [ 0.66, 0.89 ]

EORTC 22851 1997 97/257 122/255 6.6 % 0.75 [ 0.57, 0.97 ]
RTOG 9003S 2000 143/281 147/279 8.7 % 0.92 [ 0.73, 1.16 ]
RTOG 9003B 2000 121/277 147/279 8.1 % 0.78 [ 0.62, 0.99 ]
BCCA 9113 1997 25/41 21/41 1.4 % 1.21 [ 0.68, 2.16 ]
DAHANCA 2003 230/755 292/730 15.7 % 0.75 [ 0.63, 0.89 ]
Oro 9301 2003 47/65 47/63 2.8 % 1.08 [ 0.72, 1.63 ]
CAIR 2000 13/51 31/49 1.2 % 0.26 [ 0.14, 0.49 ]
KBN PO 79 2002 36/196 49/199 2.6 % 0.75 [ 0.49, 1.15 ]
Subtotal (95% CI) 1923 1895 47.1 % 0.79 [ 0.72, 0.87 ]

Test for overall effect: Z = 4.63 (P < 0.00001)
RTOG 7913 1987 77/106 74/104 4.5 % 0.98 [ 0.71, 1.35 ]
CHART 1997 295/552 196/366 14.2 % 0.98 [ 0.82, 1.18 ]
Vienna 2000 49/78 57/81 3.2 % 0.84 [ 0.57, 1.23 ]
TROG 9101 2001 87/174 94/176 5.5 % 0.93 [ 0.69, 1.24 ]
GORTEC 9402 2006 80/137 101/131 5.4 % 0.67 [ 0.50, 0.90 ]
Subtotal (95% CI) 1047 858 32.7 % 0.90 [ 0.80, 1.02 ]

0.1 0.2 0.5 1 2 5 10

(Continued . . . )

(. . . Continued)
Total (95% CI) 100.0 % 0.82 [ 0.77, 0.88 ]
0.1 0.2 0.5 1 2 5 10

4 Hazard ratio of local control.
Outcome: 4 Hazard ratio of local control
EORTC 22791 1992 74/180 95/176 6.7 % 0.67 [ 0.50, 0.91 ]
PMHToronto 2007 77/172 94/164 6.8 % 0.74 [ 0.55, 1.00 ]
RTOG 9003HF 2000 97/276 110/279 8.3 % 0.82 [ 0.63, 1.08 ]
Subtotal (95% CI) 628 619 21.8 % 0.75 [ 0.63, 0.89 ]

EORTC 22851 1997 82/257 108/255 7.6 % 0.72 [ 0.54, 0.96 ]
RTOG 9003S 2000 107/281 110/279 8.7 % 0.92 [ 0.70, 1.20 ]
RTOG 9003B 2000 89/277 110/279 8.0 % 0.77 [ 0.58, 1.01 ]
BCCA 9113 1997 18/41 18/41 1.4 % 1.00 [ 0.52, 1.92 ]
DAHANCA 2003 183/755 253/730 17.4 % 0.69 [ 0.57, 0.83 ]
Oro 9301 2003 36/65 38/63 2.9 % 1.02 [ 0.65, 1.61 ]
CAIR 2000 11/51 30/49 1.5 % 0.25 [ 0.13, 0.48 ]
0.1 0.2 0.5 1 2 5 10

(Continued . . . )

(. . . Continued)
KBN PO 79 2002 33/196 48/199 3.2 % 0.70 [ 0.45, 1.09 ]
Subtotal (95% CI) 1923 1895 50.8 % 0.74 [ 0.67, 0.83 ]

CHART 1997 251/552 183/366 16.6 % 0.90 [ 0.74, 1.09 ]
Vienna 2000 48/78 55/81 4.1 % 0.86 [ 0.58, 1.26 ]
GORTEC 9402 2006 74/137 95/131 6.7 % 0.67 [ 0.49, 0.91 ]
Subtotal (95% CI) 767 578 27.4 % 0.83 [ 0.71, 0.96 ]

Total (95% CI) 100.0 % 0.77 [ 0.71, 0.83 ]
Test for subgroup differences: Chi2 = 1.40, df = 2 (P = 0.50), I2 =0.0%
0.1 0.2 0.5 1 2 5 10

APPENDICES
Appendix 1. Search strategies
CENTRAL PubMed EMBASE (Ovid) CINAHL (EBSCO)
#1 MeSH descriptor Head and #1 “Head 1 exp *“head and neck tumor”/ S1 (MH “Otorhinolaryngo-
Neck Neoplasms, this term and Neck Neoplasms”[Mesh: 2 exp larynx tumor/ logic Neoplasms+”)
only NoExp] OR “Otorhinolaryn- 3 exp neoplasm/ S2 (MM “Head and Neck Neo-
#2 MeSH descriptor Otorhi- gologic Neoplasms”[Mesh] 4 (cancer* or carcinom* or tu- plasms”)
nolaryngologic Neoplasms ex- #2 “Neoplasms”[Mesh] OR mor* or tumour* or neoplas*) S3 TI cancer* or carcinom* or
plode all trees cancer* [ti] OR carcinom* [ti] .ti. tumor* or tumour* or neoplas*
#3 MeSH descriptor Neo- OR tumor* [ti] OR tumour* 5 3 or 4 S4 TI HNSCC or SCCHN or
plasms explode all trees [ti] OR neoplas* [ti] 6 exp mouth cavity/ (head and neck) or “oral cavity”
#4 (cancer* or carcinom* or tu- #3 “Lar- 7 exp pharynx/ or oropharyn* or hypopharyn*
mor* or tumour* or neoplas*): ynx” [Mesh] OR “Pharnyx” 8 exp larynx/ or laryn*
ti [Mesh] OR HNSCC [ti] OR 9 (HNSCC or SCCHN or S5 S3 and S4
#5 (#3 OR #4) SCCHN [ti] OR “head and (head and neck) or “oral cavity” S6 (MH “Radiotherapy+”)
#6 MeSH descriptor Larynx ex- neck” [ti] OR “head neck” [ti] or oropharyn* or hypopharyn* S7 TI Hyperfractionat* OR
plode all trees OR “head-neck” [ti] OR “head- or laryn*).ti.

(Continued)
#7 MeSH descriptor Pharynx and-neck” [ti] OR “oral cavity” 10 6 or 7 or 8 or 9 Fraction* OR Radiotherap*

explode all trees [ti] OR oropharyn* [ti] OR hy- 11 5 and 10 OR Radiat* OR Irradiat* OR
#8 MeSH descriptor Mouth ex- popharyn* [ti] OR laryn* [ti] 12 1 or 2 or 11 CFRT OR CTRT OR ACRT
plode all trees #4 #2 AND #3 13 exp radiotherapy/ OR AHF
#9 (HNSCC or SCCHN or #5 #1 OR #4 14 (Hyperfractionat* or Frac- S8 S6 or S7
head NEAR neck or oral NEXT #6 “Radiotherapy”[Mesh] OR tion* or Radiotherap* or Ra- S9 S1 or S2 or S5
cavity or oropharyn* or hy- “Radiother- diat* or Irradiat* or CFRT or S10 S8 and S9
popharyn* or laryn*):ti apy”[subheading] OR Hyper- CTRT or ACRT or AHF or CF S11 TX conventional* or cfrt or
#10 (#6 OR #7 OR #8 OR # fractionat* [ti] OR Fraction* or standard or classic*
9) [ti] OR Radiotherap* [ti] OR ARTSCAN or CHARTWELL S12 S10 and S11
#11 (#5 AND #10) Radiat* [ti] OR Irradiat* [ti] or DAHANCA or EORTC
#12 (#1 OR #2 OR #11) OR CFRT [ti] OR CTRT [ti] or GORTEC or POPART or
#13 MeSH descriptor Radio- OR ACRT [ti] OR AHF [ti] PARTIR or RTOG).ti.
therapy explode all trees OR CF [ti] OR ARTSCAN[ti] 15 13 or 14
#14 (Hyperfractionat* or Frac- OR CHARTWELL [ti] OR 16 12 and 15
tion* or Radiotherap* or Ra- DAHANCA [ti] OR EORTC 17 (conventional* or cfrt or cf
diat* or Irradiat* or CFRT or [ti] OR GORTEC [ti] OR or ((standard or classic*) and
CTRT or ACRT or AHF or CF POPART [ti] OR PARTIR [ti] (fraction* or hyperfraction* or
or OR RTOG [ti] superfraction* or radio*))).tw.
ARTSCAN or CHARTWELL #7 #5 AND #6 18 16 AND 17
or DAHANCA or EORTC #8 conventional* [tiab] OR
or GORTEC or POPART or cfrt [tiab] OR cf [tiab] OR
PARTIR or RTOG):ti ((standard [tiab] OR classic*
#15 (#13 OR #14) [tiab]) AND (fraction* [tiab]
#16 (#12 AND #15) OR hyperfraction* [tiab] OR
#17 (conventional* or cfrt or superfraction* [tiab] OR radio*
cf or ((standard or classic*) and [tiab]))
(fraction* or hyperfraction* or #9 #7 AND #8
superfraction* or radio*)))
#18 (#16 AND #17)
Web of Science BIOSIS Previews (Web of CAB Abstracts (Ovid) ISRCTN

Knowledge)
#1 TI=((cancer* OR carcinom* #1 TI=((cancer* OR carcinom* 1 HNSCC OR SCCHN (conventional OR classic OR

OR neoplas* OR tumor* OR OR neoplas* OR tumor* OR 2 (cancer* or carcinom* or tu- standard OR CF OR CFRT)
tumour*) AND (Radiotherap* tumour*) AND (Radiotherap* mor* or tumour* or neoplas*) AND radiotherapy (conven-
OR Radiat* OR Irradiat* OR OR Radiat* OR Irradiat* OR .ti. tional OR classic OR standard
Hyperfractionat* OR Fraction* Hyperfractionat* OR Fraction* 3 ((head and neck) or “oral OR CF OR CFRT) AND radi-
OR OR cavity” or oropharyn* or hy- ation AND therapy
superfraction* OR ACRT OR superfraction* OR ACRT OR popharyn* or laryn*).ti.
AHF OR CF OR ARTSCAN AHF OR CF OR ARTSCAN 4 2 AND 3
OR CHARTWELL OR DA- OR CHARTWELL OR DA- 5 1 OR 4
HANCA OR EORTC OR HANCA OR EORTC OR 6
GORTEC OR POPART OR GORTEC OR POPART OR (Hyperfractionat* or Fraction*
PARTIR OR RTOG)) PARTIR OR RTOG)) or Radiotherap* or Radiat* or
#2 TI=(HNSCC or SCCHN or #2 TI=(HNSCC or SCCHN or Irradiat* or CFRT or CTRT
(head and neck) or “oral cavity” (head and neck) or “oral cavity” or ACRT or AHF or CF or
or oropharyn* or hypopharyn* or oropharyn* or hypopharyn* ARTSCAN or CHARTWELL

(Continued)
or laryn*) or laryn*) or DAHANCA or EORTC

#3 TS=(conventional* OR cfrt #3 TS=(conventional* OR cfrt or GORTEC or POPART or
OR cf OR ((standard* OR clas- OR cf OR ((standard* OR clas- PARTIR or RTOG).ti.
sic*) AND (fraction* OR hy- sic*) AND (fraction* OR hy- 7 (conventional* or cfrt or cf or
perfraction* OR superfraction* perfraction* OR superfraction* ((standard or classic*) and (frac-
OR radio*))) OR radio*))) tion* or hyperfraction* or su-
#4 #3 AND #2 AND #1 #4 #3 AND #2 AND #1 perfraction* or radio*))).tw.
8 5 AND 6 AND 7
HISTORY
Protocol first published: Issue 2, 2000
Review first published: Issue 12, 2010
Date Event Description
26 September 2008 Amended Converted to new review format.
CONTRIBUTIONS OF AUTHORS
B Baujat, J Bourhis, J-P Pignon, L Duchateau, R Sylvester and M Bolla, with the help of the members of the steering committee,
contributed to the conception of the study. J-P Pignon, N Syz, A Le Maître, L Duchateau and R Sylvester collected and checked the
data with the help of the investigators who validated the re-analysis of their trials. J-P Pignon, B Baujat, A Le Maître and E Maillard
did the statistical analysis. The manuscript was drafted by B Baujat, J Bourhis, J Overgaard, K Ang, A Le Maître, P Blanchard, E
Maillard and J-P Pignon and submitted for comments to the members of the secretariat and the steering committee. The investigators
contributed to the interpretation of the results during the investigator meeting and revision of the manuscript. All authors have seen
and approved the final version.
DECLARATIONS OF INTEREST
We declare that we have no conflict of interest.

SOURCES OF SUPPORT
Internal sources
• Institut Gustave-Roussy, France.
External sources
• Association pour la Recherche sur le Cancer n°5137, France.
• Programme Hospitalier de Recherche Clinique n°IDF98083, France.
• Ligue Nationale Contre le Cancer, France.
• Sanofi Aventis unrestricted grant, France.
• US National Cancer Institute 2U10CA11488-36, USA.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

We have adopted and used the Cochrane ’Risk of bias’ method for the assessment of study quality.
NOTES
The financial sponsors of this study had no role in the study design, data collection, data analysis, data interpretation or the writing of
the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit
for publication.


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Hyperfractionated or accelerated radiotherapy for head and

neck cancer (Review)

Baujat B, Bourhis J, Blanchard P, Overgaard J, Ang KK, Saunders M, Le Maître A, Bernier J,

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review)

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) i

Hyperfractionated or accelerated radiotherapy for head and

Editorial group: Cochrane Ear, Nose and Throat Disorders Group.

PLAIN LANGUAGE SUMMARY

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 2

In the past decade, new radiotherapy regimens for the treatment

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 3

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 4

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 5

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 6

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 7

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 8

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 9

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 10

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 11

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 12

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 13

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 14

There was a significant benefit on locoregional control for al-

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 15

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 16

Altered fractionated radiotherapy was especially effective in the

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 17

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 18

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 19

Implications for research

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 22

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 23

Characteristics of included studies [ordered by study ID]

BCCA 9113 1997

Methods Inclusion period: 1991 to 1995

Interventions Altered fractionated arm: 66 Gy, 2 daily fractions, 3.5 weeks

Notes BCCA = British Columbia Cancer Agency

Item Authors’ judgement Description

Adequate sequence generation? Yes

Allocation concealment? Yes A - Adequate

Blinding? Unclear None of the studies of altered fractiona-

Incomplete outcome data addressed? Yes

Free of selective reporting? Yes

Free of other bias? Yes

Methods Inclusion period: 1994 to 1996

Participants 100 patients

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 24

Interventions Altered fractionated arm: 64 to 74 Gy, 1 daily fraction, 4.5 to 5 weeks

Item Authors’ judgement Description

Adequate sequence generation? Yes

Allocation concealment? Yes A - Adequate

Blinding? Unclear None of the studies of altered fractiona-

Incomplete outcome data addressed? Yes

Free of selective reporting? Yes

Free of other bias? Yes

Methods Inclusion period: 1990 to 1995

Participants 918 patients

Interventions Altered fractionated arm: 54 Gy, 3 daily fractions, 1.7 weeks

Hyperfractionated or accelerated radiotherapy for head and neck cancer (Review) 25

Notes CHART = Continuous Hyperfractionated Accelerated Radiation Therapy