Chow 2019

Radiotherapy and Oncology xxx (xxxx) xxx
Contents lists available at ScienceDirect
Radiotherapy and Oncology

journal homepage: www.thegreenjournal.com
Original Article
Single vs multiple fraction palliative radiation therapy for bone

metastases: Cumulative meta-analysis
Ronald Chow a,b,⇑, Peter Hoskin c,d, Steven E. Schild e, Srinivas Raman f, James Im a, Daniel Zhang a,
Stephanie Chan b, Nicholas Chiu b, Leonard Chiu b, Henry Lam b, Edward Chow b, Michael Lock a
a
London Regional Cancer Program, London Health Sciences Centre, University of Western Ontario, London; b Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of
Toronto, Canada; c Mount Vernon Hospital, London; d University of Manchester, United Kingdom; e Mayo Clinic, Scottsdale, USA; and f British Columbia Cancer Agency Vancouver
Centre, Canada
a r t i c l e i n f o a b s t r a c t
Article history: Introduction: There has been a long-standing debate regarding the efficacy of single fraction radiotherapy
Received 13 April 2019 (SFRT) compared to multiple fraction radiotherapy (MFRT); many systematic reviews and meta-analyses
Received in revised form 25 June 2019 have been conducted to resolve the debate and suggested SFRT is equally as effective as MFRT. Given the
Accepted 27 June 2019
adequate amalgamated sample size that exists, it is difficult to appreciate the need for further RCTs. The
Available online xxxx
aim of this paper was to conduct a cumulative meta-analysis to determine whether further trials will be
of value to the meta-conclusion. This paper also assessed publication quality.
Keywords:
Methods: A total of 29 studies were used in our meta-analysis. Comprehensive Meta-Analysis (Version 3)
Bone metastases
Palliative radiation
by Biostat was used to conduct a cumulative meta-analysis. The Cochrane Risk of Bias assessment tool
Randomized trials was employed to assess study quality of the included RCTs. Funnel plots were generated using Review
Meta-analysis Manager (RevMan 5.3) by Cochrane IMS, to visually assess for publication bias.
Systematic review Results: All but one endpoint, overall response rates in assessable patients, maintained the same meta-
conclusion over publication time; published studies did not change the amalgamated scientific conclu-
sion of existing literature. Additional studies have simply confirmed pre-existing conclusions and refined
the point estimate of the efficacy estimate. The majority of included studies have low risk of bias.
Conclusion: In conclusion, the meta-conclusion has remained consistent over time – SFRT is equally as
efficacious as MFRT. Recent studies have had little impact on the overall conclusion, and given the vast
amount of resources to execute a randomized trial, future resources should not be used to repeat these
studies, and can be better allocated to test other hypotheses.
Ó 2019 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2019) xxx–xxx
Pain originating from uncomplicated bone metastases, defined lished reviews [3,4] and is reflected in the guidelines published by
as those which have not resulted in and are not at imminent risk Choosing Wisely Canada and United States, and the American Soci-
for pathological fracture or spinal cord compression, is effectively ety for Therapeutic Radiology and Oncology [8–10]. Since the
palliated by conventional external beam radiation therapy (RT) reviews dating back to 2007 and the publication of guidelines,
[1,2]. There has been a long-standing debate regarding the efficacy new randomized controlled trials (RCTs) have still been conceived
of single fraction (SFRT) compared to multiple fraction RT (MFRT); and published [11–15]. Given the adequate amalgamated sample
many systematic reviews and meta-analyses have been conducted size that exists (34 RCTs by Rich et al. [5]), it is difficult to appreci-
to date to try to resolve the debate [3–5]. More recent reviews by ate the need for further RCTs. One may postulate that these more
Chow et al. have even explored the optimal RT dose in both the recent RCTs are conducted to try to further convince the global
SFRT and MFRT settings [6,7]. community about the equivalent efficacy of SFRT, as SFRT is not
The most recent of these reviews, published by Rich et al. in widely practiced, globally, and MFRT continues to be frequently
2018, reported that SFRT has similar outcomes to MFRT in pain implemented [16]. Some have argued that data are insufficient
control and toxicities [5]. This conclusion reaffirms previously pub- for major concerns, such as risk of cord compression and fracture
risk, as a reason to use MFRT. Concerns over bias of prior papers
may also be valid, as the earlier systematic reviews [3–5] did not
⇑ Corresponding author at: c/o Dr Michael Lock, London Health Sciences Centre, assess publication quality of papers. There hence exists a need
University of Western Ontario, 800 Commissioners Road East, London, ON N6A for a cumulative meta-analysis and risk of bias assessment, to
5W9, Canada.
definitively determine whether further trials in this field are
E-mail address: [email protected] (R. Chow).
https://doi.org/10.1016/j.radonc.2019.06.037
0167-8140/Ó 2019 Elsevier B.V. All rights reserved.
Please cite this article as: R. Chow, P. Hoskin, S. E. Schild et al., Single vs multiple fraction palliative radiation therapy for bone metastases: Cumulative
meta-analysis, Radiotherapy and Oncology, https://doi.org/10.1016/j.radonc.2019.06.037
2 Single vs multiple fraction palliative radioatherapy
Fig. 1. Overall response rates for single versus multiple fractions for patients in the intention-to-treat analysis.
needed and also whether past trials are sufficient or appropriate to were computed. Analyses were carried out, by intention-to-treat
serve as a solid foundation of knowledge. and assessable patients’ analyses.
The aim of this paper was to conduct a cumulative meta-
analysis to determine whether further trials will be of value to
Assessment of publication quality
the meta-conclusion. Additionally, this paper attempted to assess
publication quality. The Cochrane Risk of Bias assessment tool [40] was employed to
assess study quality of the included RCTs. Funnel plots were gener-
Methods ated using Review Manager (RevMan 5.3) by Cochrane IMS, to
visually assess for publication bias.
Included studies
Results
Papers included for this meta-analysis are the same as those
included by Rich et al. in 2018 [5], who conducted a literature
Intention-to-treat analysis
search, and conducted title & abstract and full-text screening to
assess eligibility for inclusion as per PRISMA guidelines. A total Over publication time, the meta-conclusion has remained
of 29 studies [11–39] were used in our meta-analysis, with the unchanged that SFRT and MFRT are equivalent in efficacy for over-
same endpoints as those previously reported used here – rates of all response rates, complete response rates, pathological fracture
complete and overall response (as reported and defined by trials), rates, spinal cord compression rates, and spinal cord compression
re-treatment, pathological fracture, acute toxicity and spinal cord rates for patients with spinal metastases. With respect to re-
compression. treatment rates, the conclusion is also unchanged over publication
time; MFRT is superior to SFRT (Figs. 1–6).
Statistical analysis
Assessable patients
Comprehensive Meta-Analysis (Version 3) by Biostat was used
to conduct a cumulative meta-analysis. The Mantel–Haenszel In 2007, the meta-conclusion shifted from not favouring either
model was applied, with a random effects analysis model. Risk fractionation to favouring MFRT over SFRT in the setting of overall
ratios (RR) and their accompanying 95% confidence intervals (CIs) response rates. SFRT and MFRT are equivalent in terms of complete
R. Chow et al. / Radiotherapy and Oncology xxx (xxxx) xxx 3
Fig. 2. Complete response rates for single versus multiple fractions for patients in the intention-to-treat analysis.
Study name Cumulative statistics Cumulative mh risk ratio (95% CI)

Lower Upper
Point limit limit Z-Value p-Value
Price et al (1986) 3.964 1.123 13.993 2.140 0.032
Cole (1989) 4.377 1.376 13.923 2.500 0.012
Nielson et al (1998) 2.453 1.212 4.967 2.493 0.013
Bone Party Trial Working Party (1999) 2.402 1.432 4.029 3.321 0.001
Altundag et al (2002) 2.436 1.463 4.056 3.423 0.001
Altundag et al (2002) (2) 2.498 1.512 4.129 3.572 0.000
van der Linden at al (2004) 2.888 1.905 4.378 4.995 0.000
Hartsell et al (2005) 2.724 1.891 3.924 5.381 0.000
Roos at al (2005) 2.337 1.681 3.249 5.052 0.000
Kaasa et al (2006) 2.421 1.772 3.307 5.555 0.000
EI-Shenshawy et al (2006) 2.406 1.779 3.253 5.705 0.000
EI-Shenshawy et al (2006) (2) 2.475 1.841 3.329 5.995 0.000
Hamouda et al (2007) 2.518 1.877 3.377 6.164 0.000
Safwat et al (2007) 2.431 1.829 3.232 6.115 0.000
Safwat et al (2007) (2) 2.427 1.837 3.208 6.234 0.000
Foro Amid et al (2008) 2.548 1.936 3.352 6.679 0.000
El Hawwari et al (2012) 2.465 1.885 3.224 6.590 0.000
El Hawwari et al (2012) (2) 2.449 1.880 3.188 6.649 0.000
Malik at al (2012) 2.455 1.889 3.191 6.715 0.000
Malik at al (2012) (2) 2.462 1.898 3.194 6.781 0.000
Gutierrez Bayard et al (2014) 2.420 1.874 3.125 6.770 0.000
2.420 1.874 3.125 6.770 0.000
0.1 0.2 0.5 1 2 5 10
Single Fraction Multiple Fraction
Fig. 3. Re-treatment rates for single versus multiple fractions for patients in the intention-to-treat analysis.
response rates, pathological fracture rates, spinal cord compres- publication time. Higher re-treatment rates have always been
sion rates, and spinal cord compression rates in patients with observed for SFRT over publication time (Supplementary
spinal metastases; this conclusion has remained consistent over Material 1–6).

Lower Upper
Price et al (1986) 0.352 0.012 9.936 -0.612 0.540
Cole (1989) 0.310 0.030 3.211 -0.982 0.326
Nielson et al (1998) 0.704 0.202 2.451 -0.552 0.581
Steenland et al (1999) 1.569 0.712 3.455 1.118 0.263
Hartsell et al (2005) 1.467 0.752 2.861 1.125 0.261
Roos et al (2005) 1.417 0.769 2.612 1.117 0.264
Kaasa et al (2006) 1.107 0.639 1.919 0.362 0.717
El-Shenshawy et al (2006) 1.187 0.698 2.017 0.632 0.527
Hamouda et al (2007) 1.100 0.664 1.824 0.371 0.710
Malik et al (2012) 1.126 0.684 1.856 0.467 0.640
Malik et al (2012) (2) 1.122 0.686 1.836 0.460 0.645
Gutierrez Bayard et al (2014) 1.214 0.755 1.951 0.800 0.424
1.214 0.755 1.951 0.800 0.424
0.1 0.2 0.5 1 2 5 10
Fig. 4. Pathological fracture rates for single versus multiple fractions for patients in the intention-to-treat analysis.

Lower Upper
Price et al (1996) 2.114 0.194 23.058 0.614 0.539
Steenland et al (1999) 1.366 0.631 2.957 0.791 0.429
Altunciag et al (2002) 1.428 0.750 2.719 1.084 0.278
Roos et al (2005) 1.314 0.775 2.228 1.014 0.311
Kaasa et al (2006) 1.436 0.895 2.302 1.501 0.133
1.436 0.895 2.302 1.501 0.133
0.1 0.2 0.5 1 2 5 10
Fig. 5. Spinal cord compression rates for single versus multiple fractions for patients in the intention-to-treat analysis.
Lower Upper
Price et al (1986) 1.946 0.180 20.993 0.549 0.583

Steenland et al (1999) 1.390 0.653 2.959 0.855 0.393
1.401 0.735 2.671 1.024 0.306
0.1 0.2 0.5 1 2 5 10
Fig. 6. Spinal cord compression rates for single versus multiple fractions for patients with spinal metastases in the intention-to-treat analysis.
Assessment of bias Discussion

There exists some concern for publication bias for the endpoint
The purpose of this paper was to critically appraise the litera-
of re-treatment rates, in both the ITT and assessable-patients anal-
ture to see the impact of publications on the meta-conclusion
ysis. No other obvious publication biases exist in other endpoints
and determine whether further studies are warranted. All but
(Supplementary Material 7–18). Most of the studies had a low risk
one endpoint, overall response rates in assessable patients, has
of bias, according to the Cochrane Risk of Bias assessment tool
maintained the same meta-conclusion over publication time; pub-
(Supplementary Material 19).
R. Chow et al. / Radiotherapy and Oncology xxx (xxxx) xxx 5
lished studies did not change the amalgamated scientific conclu- [8] Lutz S, Berk L, Chang E, et al. Palliative radiotherapy for bone metastases: an
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Radiotherapy and Oncology xxx (xxxx) xxx

Contents lists available at ScienceDirect

Radiotherapy and Oncology

Single vs multiple fraction palliative radiation therapy for bone

Study name Cumulative statistics Cumulative mh risk ratio (95% CI)

Study name Cumulative statistics Cumulative mh risk ratio (95% CI)

Single Fraction Multiple Fraction

Study name Cumulative statistics Cumulative mh risk ratio (95% CI)

0.1 0.2 0.5 1 2 5 10

Single Fraction Multiple Fraction

Study name Cumulative statistics Cumulative mh risk ratio (95% CI)

Price et al (1986) 1.946 0.180 20.993 0.549 0.583

0.1 0.2 0.5 1 2 5 10

Single Fraction Multiple Fraction

Assessment of bias Discussion

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