Title: Concomitant chemo-radiotherapy (CT-RT) versus altered fractionation

radiotherapy (AF-RT) in the radiotherapeutic management of loco-regionally

advanced head & neck squamous cell carcinoma (HNSCC): an adjusted indirect

comparison meta-analysis

Authors

Dr Tejpal Gupta1,2*, MD, Associate Professor

Ms Sadhana Kannan2, MSc, Biostatistician & Data Manager

Dr Sarbani Ghosh-Laskar1, MD, Associate Professor

Dr Jai Prakash Agarwal1, MD, Professor

1Department of Radiation Oncology, ACTREC/TMH, and

2Epidemiology &

Clinical Trials Unit, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai,

INDIA

*Corresponding author

Dr Tejpal Gupta, MD, DNB

Associate Professor, Radiation Oncology, Advanced Centre for Treatment Research

& Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi

Mumbai: 410210, INDIA

Tele: 91-22-27405057 and Fax: 91-22-27405061

E-mail: tejpalgupta@rediffmal.com

Running head: Indirect comparison meta-analysis of CT-RT with AF-RT

Number of pages: Twenty five pages

Head & Neck

This article has been accepted for publication and undergone full peer review but has not beenthrough the copyediting, typesetting, pagination and proofreading process which may lead todifferences between this version and the Version of Record. Please cite this article as an‘Accepted Article’, doi: 10.1002/hed.23661

2

Number of tables: Two

Number of figures: Three

Number of online supplementary files: Four online supplementary figures and two

web-appendices (web references & abbreviations list)

Word count: Abstract (150 words) and text (3209 words excluding references)

Conflict of interest: None of the authors have any conflict of interest to declare

Funding: No source of funding was involved in the preparation of the manuscript

Acknowledgements: None

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Concomitant chemo-radiotherapy (CT-RT) versus altered fractionation

radiotherapy (AF-RT) in the radiotherapeutic management of loco-regionally

advanced head & neck squamous cell carcinoma (HNSCC): an adjusted indirect

comparison meta-analysis

Abstract

Background:

Treatment intensification by using chemo-radiotherapy (CT-RT) or altered fractionation

radiotherapy (AF-RT) improves outcomes in loco-regionally advanced head and neck

squamous cell carcinoma (HNSCC).

Methods:

Two comprehensive meta-analyses with similar control arms (conventionally fractionated

radiotherapy) were compared indirectly.

Results:

The hazard ratio (HR) of death with 95% confidence interval (CI) for the overall

comparison of AF-RT with concomitant CT-RT was 1.13 (95%CI: 0.97-1.29, p=0.07)

suggesting no significant difference between both approaches. Compared to concomitant

CT-RT, the HR for death was 1.01 (95%CI: 0.89-1.15, p=0.82); 1.22 (95%CI: 0.94-1.59,

p=0.13); and 1.22 (95%CI: 1.07-1.39, p=0.002) for hyperfractionated radiotherapy (HF-

RT); accelerated radiotherapy (AX-RT) without total dose reduction; and AX-RT with

total dose reduction respectively.

Conclusion:

Concomitant CT-RT and HF-RT are comparable to one another on indirect comparison in

the radiotherapeutic management of loco-regionally advanced HNSCC. Any form of

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acceleration (with or without total dose reduction) may not compensate fully for lack of

chemotherapy.

Keywords: altered fractionation; concomitant chemo-radiotherapy; hyperfractionation;

indirect comparison; meta-analysis

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Background:

Head and neck squamous cell carcinoma (HNSCC) is the sixth common cause of cancer

with an estimated worldwide incidence of over 600,000 new cases annually.1, 2

Although

distant metastases are increasing being documented,3, 4

loco-regional recurrence remains

the predominant pattern of failure making definitive loco-regional therapy (either surgery

or radiotherapy or both) the cornerstone of treatment for HNSCC. Recent emphasis on

preservation of organ anatomy and function5, 6

has prompted more widespread the use of

definitive non-surgical approaches, particularly for cancers of the larynx and pharynx.

Traditionally, the most common non-surgical approach has been radical radiotherapy

(RT) using conventional fractionation typically defined as once daily radiotherapy with a

dose of 1.8-2Gy per fraction, given 5 days in a week for the prescribed total dose

(generally 60-70Gy in HNSCC) over 6-7 weeks.7, 8

There is now consistent and robust

high-quality evidence that intensification of treatment either by using chemo-

radiotherapy (CT-RT) or altered fractionation radiotherapy (AF-RT) improves outcomes

in the radiotherapeutic management of loco-regionally advanced HNSCC.9 The Meta-

Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) clearly established

the benefit of adding chemotherapy10 to loco-regional treatment which was later

reconfirmed in more recent and larger update.11. Although the addition of any

chemotherapy was beneficial, the maximum benefit in overall survival (6.5% at 5-years)

was seen with concomitant CT-RT approach. In parallel, the Meta-Analysis of

Radiotherapy in Carcinomas of the Head and neck (MARCH) also firmly established the

superiority of altered fractionation over conventional fractionation.12, 13

Altered

fractionation schedules were designed to increase dose-intensity by delivering higher

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total dose in the same overall treatment time (hyperfractionation); same total dose in

lesser (5-6 weeks) time, (acceleration without total dose reduction); or smaller total dose

in even shorter (3-4 weeks) time (acceleration with total dose reduction). Any alteration

of fractionation was associated with an overall survival benefit of 3.4%, with maximal

benefit (8.2% at 5-years) from hyperfractionation compared to conventional

fractionation.12, 13

However, despite impressive outcomes, AF-RT has not found much

favor within the head-neck oncology fraternity that has readily embraced concomitant

CT-RT using conventional fractionation as the contemporary standard of care in the

radiotherapeutic management of loco-regionally advanced HNSCC.14, 15

A relative lack

of randomized trials comparing concomitant CT-RT with AF-RT precludes a robust

direct comparison of these two approaches of treatment intensification with the choice

being currently dictated by personal and/or institutional biases.

Recently adjusted indirect comparisons16-19

are being widely used to estimate relative

treatment effects for health-care interventions20 including cancer therapy.

21 Briefly, it

means that one compares two treatments based on their relative efficacies versus a

common comparator. Thus if two treatments B and C have not been compared directly,

but each one has been separately compared directly with treatment A, one can estimate

the relative efficacy of B versus C using indirect comparison methods based on their

relative efficacies comparatively to treatment A.18, 20

Such methods mostly estimate

differences in the logarithms of hazard ratios (HR) for survival data and are being

increasing used either alone or in combination with direct comparisons22, if available.

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Aims:

The primary aim of this analysis was to compare the efficacy of concomitant CT-RT with

different schedules of AF-RT in terms of overall survival using data from previously

published meta-analyses.

Methods:

Data for this adjusted indirect comparison were extracted from two large, comprehensive,

and individual patient data meta-analyses viz. the MACH-NC10, 11

and MARCH12, 13

meta-analyses that have helped establish the current treatment paradigm in loco-

regionally advanced HNSCC. Figure 1 is a flowchart depicting the selection of studies

and patients’ allocations from both these meta-analyses for inclusion in the indirect

comparison meta-analysis. The MACH-NC and its updated analysis investigated the

benefit of adding any chemotherapy (induction, concomitant, or adjuvant) to loco-

regional treatment, while the MARCH meta-analysis investigated the role of altered

fractionation using different schedules such as hyperfractionated radiotherapy (HF-RT),

accelerated radiotherapy (AX-RT) without total dose reduction, or AX-RT with total dose

reduction. From the updated MACH-NC dataset, trials comparing RT alone with

concomitant CT-RT were identified. Subsequently, trials comparing altered fractionation

chemo-radiotherapy with altered fractionation radiotherapy alone were excluded, thereby

including only those trials that directly compared conventionally fractionated RT

(treatment A) with concomitant CT-RT using conventional fractionation (treatment B).

The entire dataset of MARCH meta-analysis was included. One trial23 in MARCH that

used nimorazole but no cytotoxic chemotherapy as a radiation sensitizer in both arms,

was included in the comparison of conventionally fractionated RT (treatment A) with

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AF-RT (treatment C). Studies testing the benefit of concomitant chemotherapy (MACH-

NC) or altered fractionation radiotherapy (MARCH) in the post-operative adjuvant

setting were also included provided the control arm was conventionally fractionated

radiotherapy alone. Multi-arm trials were counted more than once yielding more number

of comparisons and patients than actually included in the trials. The HR with respective

95% confidence interval (CI) of all included studies (concomitant CT-RT and AF-RT)

was recalculated individually using the random-effects model. Since the control arm for

both these extracted datasets from MACH-NC and MARCH meta-analyses was

conventionally fractionated RT (treatment A), an indirect comparison meta-analysis was

performed between concomitant CT-RT (treatment B) and different schedules of AF-RT

(treatment C). A detailed description of methodology of adjusted indirect comparison is

beyond the scope of this article and can be accessed from previous publications.18, 20

Briefly, the HR for the indirect comparison is estimated as the difference in the logarithm

(log) of hazard ratios from both the meta-analyses. The standard error of the indirect

comparison is estimated from the square-root of the sum of the squared standard errors.

Such analyses produce inverse-variance estimates that can be computed using either the

fixed-effects model or DerSimonian and Laird random-effects model or both. All indirect

comparison meta-analyses was done using Stata version 11.0 (StataCorp LP 2009,

College Station, TX, USA) and is reported as the point estimate of the HR with

corresponding 95%CI.

Results:

The updated MACH-NC analyses11 included 50 concomitant CT-RT trials (63

comparisons) involving 9615 patients (6560 deaths) with a median follow-up of 6.5 years

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that demonstrated an absolute survival benefit of 6.5% at 5-years for concomitant CT-RT

compared to RT alone. Ten of these trials (10 comparisons involving 1019 deaths in 1496

patients) compared altered fractionation radiotherapy with altered fractionation

concomitant chemo-radiotherapy and were excluded from the present indirect

comparison meta-analysis. Thus, the dataset of concomitant CT-RT used in the indirect

comparison finally included 4058 patients (2676 deaths) in 53 comparisons from 40 trials

(see online supplementary figure S1 and web-appendix 1). The overall pooled HR of

death in the included trials using the random-effects model was 0.76 (95%CI: 0.68-0.83,

p<0.001; I-squared=64.1%) favoring conventionally fractionated concomitant CT-RT

over conventionally fractionated RT alone. The MARCH12 analyses included 15 AF-RT

trials involving 6515 patients (4146 deaths) with a median follow-up of 6 years that

demonstrated an absolute survival benefit of 3·4% at 5-years for AF-RT over

conventionally fractionated RT alone. Although all schedules of altered fractionation

were better, the survival benefit at 5-years was highest with HF-RT (8.2%), followed by

AX-RT without total dose reduction (2%) and AX-RT with total dose reduction (1.7%).

The dataset of AF-RT used in the indirect comparison included 3650 patients (2313

deaths) in 17 comparisons from the 15 trials (see online supplementary figure S2 and

web-appendix 2). The overall pooled estimate using random-effects model favored AF-

RT (HR=0.86, 95%CI: 0.74-0.98, p<0.001; I-squared=79.0%) over conventionally

fractionated RT. Although two 3-arm trials the ORO 93-0124 and Vienna 2000

25 were

common to both meta-analyses, there was no overlap as only the appropriate arm was

included in each individual comparison. The control arm i.e conventionally fractionated

RT (treatment A) was similar in all the included trials allowing an indirect comparison of

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concomitant CT-RT using conventional fractionation (treatment B) with the three

prevalent schedules of AF-RT (treatment C).

On adjusted indirect comparison using DerSimonian and Laird random-effects model, the

HR of death for the overall comparison of concomitant AF-RT with CT-RT was 1.13

(95%CI: 0.97-1.29, p=0.07; I-squared=53.8%) suggesting no statistically significant

difference in efficacy between the two broad approaches of treatment intensification

(Figure 2). Using the random-effects model, the corresponding HRs of death for the three

prevalent schedules of AF-RT were 1.01 (95%CI: 0.89-1.15, p=0.82); 1.22 (95%CI:

0.94-1.59, p=0.13); and 1.22 (95%CI: 1.07-1.39, p=0.002) for HF-RT; AX-RT without

total dose reduction; and AX-RT with total dose reduction, respectively, compared to

concomitant CT-RT (Table 1). Similar comparison using the fixed-effects model (Table

1) yielded an HR of 1.10 (95%CI: 0.98-1.22, p=0.09) for HF-RT confirming no

significant difference in efficacy between concomitant CT-RT and HF-RT. However, the

fixed-effects model yielded an HR of 1.18 (95%CI: 1.08-1.28, p<0.001) for AXRT

without total dose reduction and 1.32 (95%CI: 1.18-1.47, p<0.001) for AX-RT with total

dose reduction compared to concomitant CT-RT, suggesting that acceleration alone (with

or without total dose reduction) may be inferior and unable to compensate fully for the

lack of chemotherapy. The difference between the random-effects and fixed-effects

model was further investigated with a sensitivity analysis and meta-regression approach.

Using fixed-effects model, studies are weighted proportionately in a meta-analysis based

on size alone without any consideration for study quality, consistency, or heterogeneity,

while the random-effects model weighs the studies relatively more equally thereby

generally providing a more conservative estimate of effect. It is important to note that

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formal statistical comparison of fixed- and random-effects estimates of intervention is not

feasible. Sensitivity analysis was performed by sequentially dropping one study at a time

from the primary meta-analyses (MACH-NC and MARCH) to ascertain its impact on the

overall effect. Despite the presence of significant heterogeneity, this could not identify

any single study that influenced the overall results in the primary comparisons of

concomitant CT-RT versus RT alone (see online supplementary figure S3) or AF-RT

versus RT (see online supplementary figure S4). Meta-regression analysis using different

schedules of AF-RT (HF-RT, AX-RT without total dose reduction, and AX-RT with total

dose reduction) as covariates also failed to demonstrate any significant impact (p=0.07)

of altered fractionation schedule on the overall results.

Discussion:

In the last few decades, a large body of evidence has consistently and convincingly

demonstrated that intensification of treatment improves outcomes in HNSCC. Although

both the approaches to treatment intensification viz addition of chemotherapy to

radiotherapy10, 11

and altering the fractionation12, 13

improve outcomes, AF-RT has not

found much favour with the head-neck oncology community that has readily embraced

conventionally fractionated concomitant CT-RT14 as the contemporary standard of care in

the radiotherapeutic management of HNSCC. The MACH-NC meta-analysis did not

demonstrate any significant benefit with either induction chemotherapy followed by

definitive loco-regional therapy or definitive loco-regional therapy followed by adjuvant

chemotherapy compared to definitive loco-regional therapy alone, but a recent meta-

analysis suggests that taxane-based induction chemotherapy regimens26 followed by

definitive (chemo)radiotherapy may also be a reasonable strategy for organ preservation

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and improvement of survival. Radiotherapy infrastructure (both equipment and skilled

human resource) is grossly inadequate in large parts of the underdeveloped and

developing countries where head and neck cancers are more prevalent resulting in

suboptimal access to radiotherapy services as well as long waiting times for initiation of

radiotherapy. Apart from logistic issues of scheduling more than one fraction daily

throughout the course of radiotherapy (as in HF-RT) or in the latter half of radiotherapy

(as in concomitant boost regimen), or treating over the weekend as mandated by most

schedules of AF-RT, another important reason for the indifference towards AF-RT could

be lack of direct randomized comparison between these forms of treatment

intensification.

While there are over 55 trials comparing conventionally fractionated RT alone with

concomitant CT-RT or AF-RT, only three randomized trials have directly compared

conventionally fractionated concomitant CT-RT with AF-RT (Table 2). The first of these,

ORO 93-01 (included in both MACH-NC and MARCH meta-analyses) was a three-arm

trial24 that randomized 192 patients with advanced oropharyngeal cancer to either

conventionally fractionated RT alone; split-course accelerated-hyperfractionated

schedule; or concomitant CT-RT using conventional fractionation. At a median follow-up

of 8.3 years, the 5-year overall survival was numerically superior though not statistically

significant between split-course AF-RT and concomitant CT-RT (21% vs 40%, p=0.39).

One criticism of ORO 93-01 was the use of an unconventional AF-RT schedule (split-

course) which was likely to be less efficacious due to potential of accelerated

repopulation inherent to a planned break in radiotherapy. This was also evidenced by the

fact that the 5-year overall survival of the split-course schedule was similar to

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conventionally radiotherapy alone (20%). The second trial27 involving 150 patients

compared conventional radiotherapy (5 fractions per week) with concomitant CT-RT and

AX-RT (6 fractions per week). At a median follow-up of 17 months, 2-year overall

survival of 44%, 58%, and 44% was reported in the three arms respectively with no

statistically significant differences (p=0.35). A more recent trial pioneered by Groupe

d’Oncologie Radiotherapie Tete Et Cou (GORTEC) involving over 840 patients was also

a three-arm direct comparison of conventionally fractionated concomitant CT-RT with

accelerated CT-RT and very AX-RT alone.28 At a median follow-up of 5.2 years, there

was a significant difference in loco-regional control (p=0.045), progression-free survival

(p=0.041), and overall survival (p=0.040) favouring conventionally fractionated

concomitant CT-RT compared to very AX-RT alone.

A weighted pooled analysis (Figure 3) of all three trials directly comparing

conventionally fractionated concomitant CT-RT with AF-RT clearly shows the

superiority of the concomitant approach over acceleration, reinforcing the belief that the

lack of chemotherapy may not be compensated by any form of acceleration. Whether

hyperfractionation can compensate for the lack of chemotherapy could have been

answered by results from the 4-arm European Organization for Research and Treatment

of Cancer (EORTC) trial 2296229 that compared conventional radiotherapy versus HF-RT

with or without chemotherapy including a direct comparison of HF-RT with

conventionally fractionated concomitant CT-RT. Unfortunately, the trial had to be closed

prematurely (after enrolling only 57 patients) due to slow accrual, thereby precluding a

robust direct comparison of HF-RT with conventionally fractionated concomitant CT-RT.

Since both forms of treatment intensification improve outcomes, combining concomitant

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CT-RT with altered fractionation presents an attractive option to further improve the

efficacy of therapy. This has been recently been endorsed by the mixed treatment

comparison or network meta-analysis30 of the MACH-NC and MARCH dataset

combining direct and indirect comparisons that allows simultaneous inference from pair-

wise comparison of all possible modes of combining chemotherapy with radiotherapy or

altering fractionation. From this pooled analysis of 24,000 patients in 102 trials, altered

fractionation concomitant chemo-radiotherapy emerged as the best treatment option with

an overall probability of 94.5% using the random-effects model. Altered fractionation

concomitant chemo-radiotherapy was associated with the highest survival in non-

metastatic HNSCC (HR=0.70, 95%CI: 0.61-0.80) followed by conventionally

fractionated concomitant CT-RT (HR=0.82, 95%CI: 0.78-0.86). However, more may not

always be better, as two large randomized trials, GORTEC 99-0228 and Radiation

Therapy Oncology Group (RTOG) 012931 showed no significant benefit of altered

fractionation concomitant chemo-radiotherapy over standard fractionation CT-RT.

Strengths and limitations: Some core assumptions of indirect comparison methodology

include similarity of treatment effects, homogeneity, and consistency.17 If the similarity

assumption is violated, the validity of indirect comparison becomes questionable.

Homogeneity refers to similarity in the head-to-head trials of A versus B and A vs C.

Consistency refers to the similarity of direct and indirect evidence for the same treatment

comparison. The present analysis excluded trials where the control arm was dissimilar,

thereby making the indirect comparisons valid and robust. The present indirect

comparison was limited to the MACH-NC and MARCH datasets both of which are

rigorously and uniformly performed individual patient data meta-analyses with mature

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follow-up. Although both analyses reported some clinical heterogeneity, the included

trials were similar in trial designs and methodological quality thereby providing good

internal validity. Overall survival, considered as the gold standard and hardest outcome

measure was chosen as the primary endpoint of interest in this indirect comparison,

making the results and interpretation relevant to modern oncologic practice. However,

certain pitfalls and caveats still remain. It is common knowledge that both forms of

treatment intensification (CT-RT and AF-RT) are associated with increased acute and

late toxicity compared to conventionally fractionated RT alone with potential negative

impact upon quality of life. However, reliable toxicity or quality of life data was not

available from a large majority of trials precluding any comparison of late toxicity or

quality of life between the two approaches. Neither the MACH-NC nor the MARCH

meta-analyses involved any kind of formal or informal analyses of cost-effectiveness of

treatment intensification. In absence of such data from the index meta-analyses, it is not

possible to comment on the most cost-effective form of treatment intensification.

Several, randomized trials have since been updated and new trials reported in the indexed

medical literature that were not considered in the present analysis. Some of these have

used newer and more potent chemotherapeutic agents32 or targeted therapy

33 concurrently

with radiation that may further enhance the efficacy of the concomitant regimen. In

parallel, some recent reports of AF-RT34, 35

have also demonstrated much larger survival

benefit than was demonstrated by the MARCH meta-analysis and are being included in

an updated meta-analysis of altered fractionation (MARCH 2). Indirect comparison of

AF-RT (from updated MARCH 2 meta-analysis) with concomitant CT-RT from updated

MACH-NC data is planned and shall form the basis of a later updated report. It is

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important to note that neither MACH-NC nor MARCH pertain to the era of advanced

radiotherapy technology36 such as intensity-modulated radiation therapy (IMRT) which is

now considered the radiotherapy technique of choice in HNSCC.37 Although there is

widespread variability in dose-fractionation38 schedules employed in IMRT across the

globe, the most popular schedules use the simultaneous integrated boost approach that are

both modestly hypofractionated (2.1-2.4Gy per fraction) as well as accelerated (overall

treatment time of 5-6 weeks) and hence cannot be considered as conventional

fractionation. A subset analysis by primary site could have yielded interesting results,

particularly with accumulating evidence that the epidemiology of head and neck cancer

may be changing with human papilloma virus (HPV) associated oropharyngeal cancer

emerging as a disease with distinct epidemiological, molecular, and clinical features.39

The benefit of adding concurrent chemotherapy has been demonstrated to be consistent

for all tumor locations regardless of the primary site, but such data has not yet been

published for altered fractionation radiotherapy, precluding an indirect comparison by

primary site. Published data suggests that the benefit of AX-RT40 is likely to be more

pronounced in HPV-positive than HPV-negative tumors. It is also being increasingly

realized that HPV-associated head and neck tumors may have increased intrinsic radio-

sensitivity that may be potentially allow treatment de-intensification by reducing or even

eliminating chemotherapy. Neither the MACH-NC or MARCH meta-analysis, nor the

present analysis has taken the HPV-status into consideration that has now emerged as a

strong and independent prognostic factor.41 Finally, caution is warranted in interpreting

data based on indirect comparisons. Ideally, direct comparisons should inform evidence-

based practice. However, when direct comparisons are either unavailable or rather

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limited, adjusted indirect comparison may be used to assess the magnitude of treatment

effect across studies recognizing the limited strength of inference.

Conclusion:

Concomitant CT-RT and HF-RT are significantly better than conventionally fractionated

radiotherapy alone, but are comparable to one another for overall survival on indirect

comparison in the radiotherapeutic management of loco-regionally advanced HNSCC.

Any form of acceleration (with or without total dose reduction) may not be able to

compensate fully for the lack of chemotherapy. Caution is warranted in interpreting data

based on indirect comparisons recognizing the limited strength of inference.

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24. Fallai C, Bolner A, Signor M, et al. Long-term results of conventional radiotherapy

versus accelerated hyperfractionated radiotherapy versus concomitant radiotherapy and

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chemotherapy in locoregionally advanced carcinoma of the oropharynx. Tumori.

2006;92: 41-54.

25. Dobrowsky W, Naude J. Continuous hyperfractionated accelerated radiotherapy

with/without mitomycin C in head and neck cancers. Radiother Oncol. 2000;57: 119-124.

26. Blanchard P BJ, Lacas B, et al. Taxane-Cisplatin-Flourouracil as induction

chemotherapy in locally advanced head and neck cancers: an individual patient data

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Clin Oncol. 2013;31: 2854-2860.

27. Ghosh S, Agarwal JP, Bhutani R, et al. Randomized trial of Conventional

Fractionated RT (CFRT) versus Concomitant Chemo-radiotherapy (CTRT) and

Accelerated Radiotherapy (ACRT) in Patients with Advenced, Non-Nasopharyngeal

Squamous Cell Cancers of the Head and Neck region. Int J Radiat Oncol Biol Phys.

2006;66: S191.

28. Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration

of radiotherapy with or without concomitant chemotherapy in locally advanced head and

neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol.

2012;13: 145-153.

29. Horiot JC. EORTC 22962: Phase III comparison study of conventional vs

hyperfractioned radiotherapy in head and neck squamous cell carcinoma with or without

concomitant chemotherapy. PDQ data base 2007.

30. Blanchard P, Hill C, Guihenneuc-Jouyaux C, Baey C, Bourhis J, Pignon JP. Mixed

treatment comparison meta-analysis of altered fractionated radiotherapy and

chemotherapy in head and neck cancer. J Clin Epidemiol. 2011;64: 985-992.

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31. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients

with oropharyngeal cancer. N Engl J Med. 2010;363: 24-35.

32. Halim AA, Wahba HA, El-Hadaad HA, Abo-Elyazeed A. Concomitant

chemoradiotherapy using low-dose weekly gemcitabine versus low-dose weekly

paclitaxel in locally advanced head and neck squamous cell carcinoma: a phase III study.

Med Oncol. 2012;29: 279-284.

33. Bernier J, Schneider D. Cetuximab combined with radiotherapy: an alternative to

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head and neck? Eur J Cancer. 2007;43: 35-45.

34. Ghoshal S, Goda JS, Mallick I, Kehwar TS, Sharma SC. Concomitant boost

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Radiol). 2008;20: 212-220.

35. Overgaard J, Mohanti BK, Begum N, et al. Five versus six fractions of radiotherapy

per week for squamous-cell carcinoma of the head and neck (IAEA-ACC study): a

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39. Gillison ML. Human papillomavirus-associated head and neck cancer is a distinct

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Figure legends:

Figure 1: Flowchart of study selection and patient allocation from MACH-NC and

MARCH meta-analyses for inclusion in indirect comparison meta-analysis

Figure 2: Forest plot of concomitant chemo-radiotherapy (CT-RT) versus altered

fractionation radiotherapy (AF-RT). Note the point estimates of the hazard

ratio (HR) of death with 95% confidence intervals (CI) for all three

subgroups of AF-RT viz. hyperfractionated radiotherapy (HF-RT);

accelerated radiotherapy (AX-RT) without total dose reduction; and AX-RT

with total dose reduction separately as well as the overall indirect

comparison of concomitant CT-RT with AF-RT using the random-effects

model

Figure 3: Weighted-pooled analysis of all three trials directly comparing

concomitant chemo-radiotherapy (CT-RT) with altered fractionation

radiotherapy (AF-RT). Note that the point estimate of the hazard ratio (HR)

of death with 95% confidence intervals (CI) clearly favors concomitant CT-

RT over AF-RT

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Online supplementary file figure legends:

Figure S1: Forest plot of 53 individual direct comparisons of conventionally

fractionated radiotherapy (RT) alone (treatment A) with concomitant

chemo-radiotherapy (CT-RT) using conventional fractionation (treatment B)

derived from the updated MACH-NC dataset using random-effects model.

The overall hazard ratio (HR) and 95% confidence intervals (CI)

significantly favor concomitant CT-RT

Figure S2: Forest plot of 17 individual direct comparisons of conventionally

fractionated radiotherapy (RT) alone (treatment A) with altered

fractionation radiotherapy (AF-RT) of any form (treatment C) derived from

the MARCH dataset using random-effects model. The overall hazard ratio

(HR) and 95% confidence intervals (CI) are significantly in favor of AF-RT

Figure S3: Sensitivity analysis of MACH-NC dataset showing no significant

influence of any individual study on the overall treatment effect

Figure S4: Sensitivity analysis of MARCH dataset showing no significant influence

of any individual study on the overall treatment effect

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Table 1: Hazard ratio (HR) for death with 95% confidence intervals (CI) on adjusted indirect comparison meta-analysis of concomitant

chemo-radiotherapy (CT-RT) with all three schedules of altered fractionation radiotherapy

Concomitant CT-RT Hyperfractionated

radiation therapy (HF-RT)

Accelerated RT (AX-RT)

without total dose reduction

AX-RT with total dose

reduction

Comparison Method HR (95% CI) p-value HR (95%CI) p-value HR (95%CI) p-value

Inverse-variance (fixed-effects) 1.10 (0.98-1.22) 0.09 1.18 (1.08-1.28) <0.001 1.32 (1.18-1.47) <0.001

DerSimonian and Laird (random-effects) 1.01 (0.89-1.15) 0.82 1.22 (0.94-1.59) 0.13 1.22 (1.07-1.39) 0.002

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5051525354555657585960

Table 2: Randomized controlled trials directly comparing conventionally fractionated concomitant chemo-radiotherapy with altered

fractionation radiotherapy

Study ref

Concomitant Chemo-Radiotherapy (CT-RT)

Altered Fractionation Radiotherapy (AF-RT)

p-value

Pts

CT-RT regimen Survival Pts AF-RT schedule Survival

ORO 93-0124

64 pts Carboplatin @ 75mg/m2 x 4 days

5-FU @ 100mg/m2 x 4 days

4-weekly cycles (wk 1, 5, 9)

RT: 66-70Gy/33-35#/6.5-7 wks

40% at 5-yrs 65 pts Split-course accelerated hyper-

fractionated RT: 1.6Gy/#, twice daily,

4-6 hr inter# interval, 5 days/wk to a

dose of 64-67.2Gy with a planned 2-

wk break at 38.4Gy

21% at 5-yrs 0.39

TMH study27

50 pts Cisplatin @ 30mg/m2 weekly x 6-7

cycles throughout RT

RT: 66-70Gy/33-35#/6.5-7 wks

58% at 2-yrs 50 pts Accelerated normofractionated RT:

2Gy/#, 6#s/wk to a dose of 66-70Gy

in 33-35# over 5.5-6 wks

44% at 2-yrs 0.35

GORTEC 99-0228

279 pts Carboplatin @ 70mg/m2 x 4 days

5-FU @ 600mg/m2 x 4 days

3-weekly cycles (days 1, 22, 43)

RT: 70Gy/35#/7 wks

42.6% at 3-yrs 281 pts Very accelerated RT: 1.8Gy/#, twice

daily, 8-hr inter# interval, 5 days/wk

to a dose of 64.8Gy in 3.5 wks

36.5% at3-yrs 0.04

Pts=patients, #=fraction, yrs=years, wks=weeks, hr=hour

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5051525354555657585960

183x192mm (150 x 150 DPI)

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274x175mm (150 x 150 DPI)

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275x182mm (150 x 150 DPI)

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286x190mm (150 x 150 DPI)

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258x191mm (120 x 120 DPI)

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225x150mm (150 x 150 DPI)

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WEB-APPENDIX 1

Reference list of studies selected from MACH-NC meta-analysis for inclusion in indirect comparison

1. Shanta V, Krishnamurthi S. Combined bleomycin and radiotherapy in oral cancer. Clin Radiol

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2. Eschwege F, Sancgho-Garnier H, Gerard JP, et al. Ten-year results of a randomized trial comparing

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Monograph 1988;6:275–78.

3. Kapstad B, Bang G, Rennaes S, Dhaler A. Combined preoperative treatment with cobalt and

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Oncol Biol Phys 1978;4:85–89.

4. Parvinen LM, Parvinen M, Nordman E, Kortekangas AE. Combined bleomycin treatment and

radiation therapy in squamous cell carcinoma of the head and neck region. Acta Radiol Oncol

1985;24:487–89.

5. Morita K. Clinical significance of radiation therapy combined with chemotherapy.

Strahlentherapie 1980;156:228–33.

6. Vermund H, Kaalhus O, Winther F, Tausjø J, Thorud E, Harang R. Bleomycin and radiation therapy

in squamous cell carcinoma of the upper aero-digestive tract: a phase III clinical trial. Int J Radiat

Oncol Biol Phys 1985:11:1877–86.

7. Sanchiz F, Milla A, Torner J, et al. Single fraction per day versus two fractions per day versus

radiochemotherapy in the treatment of head and neck cancer. Int J Radiat Oncol Biol Phys

1990;19:1347–50.

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8. Gupta NK, Pointon RCS, Wilkinson PM. A randomised clinical trial to contrast radiotherapy with

radiotherapy and methotrexate given synchronously in head and neck cancer. Clin Radiol

1987;38:575–81.

9. Weissberg JB, Son YH, Papac RJ, et al. Randomized clinical trial of mitomycin C as an adjunct to

radiotherapy in head and neck cancer. Int J Radiat Oncol Biol Phys 1989;17:3–9.

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18.

11. Haselow RE, Warshaw MG, Oken MM, et al. Radiation alone versus radiation with weekly low

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ME, et al, eds. Head and Neck Cancer. Vol II. Philadelphia: BC Decker, 1990;279–81.

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13. Bachaud JM, Cohen-Jonathan E, Alzieu C, David JM, Serrano E, Daly-Schveitzer N. Combined

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14. SECOG II. Randomized trial comparing radiotherapy alone, synchronous chemoradiotherapy, and

sequential chemoradiotherapy in squamous cell carcinoma of the head and neck. Hougthon J,

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15. Weissler MC, Melin S, Sailer SL, Qaqish F, Rosenman JG, Pillsbury HC. Simultaneous

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16. Haffty BG, Son YH, Sasaki CT, et al. Mitomycin C as an adjunct to postoperative radiation therapy

in squamous cell carcinoma of the head and neck: results from two randomized clinical trials. Int J

Radiat Oncol Biol Phys 1993;27:241–50.

17. Merlano M, Vitale R, et al. Treatment of advanced squamous cell carcinoma of the head and neck

with alternating chemotherapy and radiotherapy. N Engl J Med 1992;327:1115–21.

18. Browman GP, Cripps C, Hodson DI, Eapen L, Sathya J, Levine M. Placebo-controlled randomized

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19. Jeremic B, Shibamoto Y, Stanisavljevic B, Miliojevic L, Milicic B, Nikolic N. Radiation therapy alone

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20. Wendt TG, Grabenbauer GG, Rödel CM, et al. Simultaneous radiochemotherapy versus

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21. Adelstein DJ, Lavertu P, Saxton JP, Secic M, Wood BG, Wanamaker JR, et al. Mature results of a

phase III randomized trial comparing concurrent chemoradiotherapy with radiotherapy alone in

patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer 2000;88:876-

83.

22. Denis F, Garaud P, Bardet E, Alfonsi M, Sire C, Germain T, et al. Final results of 94-01 French Head

and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with

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23. Lefevbre JL and Horiot JC. EORTC 22954: Phase III study on larynx preservation comparing

radiotherapy versus concomitant chemo-radiotherapy in resectable larynx and hypopharynx

cancers. PDQ database 1999 (unpublished).

24. Olmi P, Crispino S, Fallai C, Torri V, Rossi F, Bolner A, et al. Locoregionally advanced carcinoma of

the oropharynx: conventional radiotherapy versus accelerated hyperfractionated radiotherapy

versus concomitant radiotherapy and chemotherapy - A multicenter randomized trial. Int J Rad

Oncol Biol Phys 2003;55:78¬92.

25. Adelstein DJ, Li Y, Adams GL, Wagner W Jr, Kish JA, Ensley JF, et al. A intergroup phase III

comparison of standard radiotherapy therapy and two schedules concurrent chemoradiotherapy

in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92-8.

26. Corvo R, Corvo R, Sanguineti G, Lionetto R, Bacigalupo A, Margarino G, et al. Alternating

chemoradiotherapy versus partly accelerated radiotherapy in locally advanced squamous cell

carcinoma of the head and neck: results of a phase III randomized trial. Cancer 2001;92:2856-67.

27. Grau C, Prakash Agarwal J, Jabeen K, Jabeen K, Abdul Rab Khan A, Abeyakoon S, et al.

Radiotherapy with or without mitomycin c in the treatment of locally advanced head and neck

cancer: results of the IAEA multicentre randomised trial. Radiother Oncol 2003;67:17-26.

28. Tobias JS, Monson KM, Glaholm J, MacDougall RH, Gupta NK, Peto J, et al. UKHAN-1: A

prospective multi-centre randomised trial investigating chemotherapy as part of initial

management in advanced head and neck cancer. Radiother Oncol 2001;58 (Suppl 1): S16.

29. Bernier J, Domenge C, Ozsahin M, Matuszewska K,Lefébvre JL, Greiner RH, et al. Postoperative

irradiation with or without concomitant chemotherapy for locally advanced head and neck

carcinomas. N Engl J Med 2004;350:1945-52.

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30. Grau C, Prakash Agarwal J, Jabeen K, Jabeen K, Abdul Rab Khan A, Abeyakoon S, et al.

Radiotherapy with or without mitomycin c in the treatment of locally advanced head and neck

cancer: results of the IAEA multicentre randomised trial. Radiother Oncol 2003;67:17-26.

31. Lartigau EF, Giralt J, Glassman P, Lawton A, von Roemeling R. A phase IIII double-blind

randomized placebo controlled study of porfiromycin and radiation therapy in patients with head

and neck cancer. Int J Rad Oncol Biol Phys 2003;54 (suppl):74.

32. Kumar S, Datta NR, Ahuja RC, Mali HR, Agarwal GN, Ayyagari S. Feasibility of non-cisplatin-based

induction chemotherapy and concurrent chemoradiotherapy in advanced head and neck cancer.

Acta Oncologica 1996;35:721-5.

33. Fountzilas G, Ciuleanu E, Dafni U, Plataniotis G, Kalogera-Fountzila A, Samantas E, et al.

Concomitant radio chemotherapy vs radiotherapy alone in patients with head and neck cancer: a

Hellenic Cooperative Oncology Group Phase III Study. Med Oncol 2004;21:95-107.

34. Zakotnik B, Budihna M, Smid L, Soba E, Strojan P, Fajdiga I, Zargi M, Oblak I, Lesnicar H. Patterns

of failure in patients with locally advanced head-and neck cancer treated postoperatively with

irradiation or concomitant irradiation with mitomycin C and bleomycin. Int J Radiat Oncol Biol

Phys 2007;67:685-90.

35. Forastiere A A, Goepfert H, Maor M, Pajak T F, Weber R, Morrison W, et al. Concurrent

chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J

Med 2003;349:2091-8.

36. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative

concurrent radio-chemotherapy in high-risk squamous-cell carcinoma of the head and neck. N

Engl J Med 2004;350:1937-44.

37. Hussey DH, Abrams JP. Combined therapy in advanced head and neck cancer: hydroxyurea and

radiotherapy. Prog Clin Cancer 1975;6:79–86.

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38. Bezwoda WR, de Moor NG, Derman DPI. Treatment of advanced head and neck cancer by means

of radiation plus chemotherapy: a randomised trial. Med Pediatr Oncol 1979;6:353–58.

39. Nissenbaum M, Browde S, Bezwoda W, de Moor NG, Derman DP. Treatment of advanced head

and neck cancer: multiple daily dose fractionated radiation therapy and sequential multimodal

treatment approach. Med Pediatr Oncol 1984;12:204–08.

40. Horiot JC. EORTC 22962: Phase III comparison study of conventional vs hyperfractioned

radiotherapy in head and neck squamous cell carcinoma with or without concomitant

chemotherapy. PDQ data base 2007 (unpublished).

Trial group abbreviations (online supplementary figure S1: MACH-NC meta-analysis)

AC Camargo = Hospital AC Camargo (Brazil), Aro = Academic Radiation Oncologists, CH = Chapel Hill

(USA), ECOG = Eastern Cooperative Oncology Group (USA), EORTC = European Organisation for Research

and Treatment of Cancer, GORTEC = Groupe d’Oncologie Radiothérapie Tête et Cou, HeCOG = Hellenic

Cooperative Oncology Group, IAEA = International Atomic Energy Agency, INRC-HN= Instituto Nazionale

per la Ricerca sul Cancro-Head and Neck (Italy), INT= US INTer group trial, LOHNG = Ljubljana Oncology

Head and Neck Group (Slovenia), MDA= MD Anderson (USA), NCI = National Cancer Institute, NRH =

Norwegian Radium Hospital (Norway), Ontario = McMaster University and Cancer Care Ontario -

Hamilton and Ottawa regional Cancer Centres (Canada), PMHCG = Princess Margaret Hospital

Cooperative Group Study (Canada), RPC= Radiological Physics Center, RTOG = Radiation Therapy

Oncology Group (USA), SAKK = Swiss Group for Clinical Cancer Research, SECOG = South-East

Cooperative Oncology Group (England), Turku = Turku University (Finland), UKHAN = United Kingdom

Head And Neck, UW = University of Washington Radiation Oncology; WIA-OC = Cancer Institute (WIA)

Oral Cavity (India)

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WEB-APPENDIX 2

Reference list of studies selected from MARCH meta-analysis for inclusion in indirect comparison

1. Horiot JC, LeFur R, N’Guyen T, et al. Hyperfractionation versus conventional fractionation in

oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of

radiotherapy. Radiother Oncol 1992;25: 231–41.

2. Pinto LH, Canary PC, Araujo CM, Bacelar SC, Souhami L. Prospective randomized trial comparing

hyperfractionated versus conventional radiotherapy in stage III and IV oropharyngeal carcinoma.

Int J Radiat Oncol Biol Phys 1991;21: 557–62.

3. Cummings B, O’Sullivan B, Keane T, et al. 5-year results of 4 week/twice daily radiation

schedule—the Toronto trial. Radiother Oncol 2000;56 (suppl 1):S8.

4. Fu KK, Pajak TF, Trotti A, et al. A radiation therapy oncology group (RTOG) phase III randomized

study to compare hyperfractionation and two variants of accelerated fractionation to standard

fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG

9003. Int J Radiat Oncol Biol Phys2000;48: 7–16.

5. Horiot JC, Bontemps P, Van Den Bogaert W, et al. Accelerated fractionation compared to

conventional fractionation improves locoregional control in the radiotherapy of advanced head

and neck cancer: results of the EORTC 22851 randomized trial. Radiother Oncol 1997;44:39–46.

6. Jackson SM, Weir LM, Hay JH, Tsang VH, Durham JS. A randomized trial of accelerated versus

conventional radiotherapy in head and neck cancer. Radiother Oncol 1997;43:39–46.

7. Overgaard J, Hansen HS, Specht L, et al. Five compared with six fractions per week of

conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6&7

randomised controlled trial. Lancet 2003;362:933–40.

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8. Olmi P, Crispino S, Fallai C, et al. Locoregionally advanced carcinoma of the oropharynx:

conventional radiotherapy versus accelerated hyperfractionated radiotherapy versus

concomitant radiotherapy and chemotherapy—a multicenter randomized trial. Int J Radiat

Oncol Biol Phys 2003;55:78–92.

9. Skladowski K, Maciejewski B, Golen M, Pilecki, B, Przeorek W, Tarnawski R. Randomized clinical

trial on 7-days-continuous accelerated irradiation (CAIR) of head and neck cancer–report on 3-

year tumor control and normal tissue toxicity. Radiother Oncol 2000; 55:101–10.

10. Hliniak A, Gwiazdowska B, Szutkowski Z, et al. A multicenter randomized/controlled trial of a

conventional versus modestly accelerated radiotherapy in the laryngeal cancer: influence of a 1

week shortening overall time. Radiother Oncol 2002; 62:1–10.

11. Marcial VA, Pajak TF, Chang C, Tupchong L, Stetz J. Hyperfractionated photon radiation therapy

in the treatment of advanced squamous cell carcinoma of the oral cavity, pharynx, larynx, and

sinuses, using radiation therapy as the only planned modality: (preliminary report) by the

Radiation Therapy Oncology Group (RTOG).Int J Radiat Oncol Biol Phys 1987; 13:41–47.

12. Dische S, Saunders M, Barrett A, Harvey A, Gibson D, Parmar M. A randomized multicentre trial

of CHART vs conventional radiotherapy in head and neck cancer. Radiother Oncol 1997; 44:123–

36.

13. Dobrowsky W, Naudé J. Continuous hyperfractionated accelerated radiotherapy with/without

mitomycin C in head and neck cancer. Radiother Oncol 2000; 57:119–24.

14. Poulsen MG, Denham JW, Peters LJ, et al. A randomised trial of accelerated and conventional

radiotherapy for stage III and IV squamous carcinoma of the head and neck: a Trans-Tasman

Radiation Oncology Group Study. Radiother Oncol 2001; 60:113–22.

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15. Bourhis J, Lapeyre M, Tortochaux J, et al. Phase III randomized trialof very accelerated radiation

therapy compared with conventional radiation therapy in squamous cell head and neck cancer:

a GORTEC trial. J Clin Oncol 2006;24:2873–78.

Trial group abbreviations (online supplementary figure S2: MARCH meta-analysis)

BCCA = 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-Tasman Radiation Oncology Group

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