Tumour bed boost radiotherapy for women after breast‐conserving surgery

Isabelle Kindts; Annouschka Laenen; Tom Depuydt; Caroline Weltens

doi:10.1002/14651858.CD011987.pub2

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Appendices

Appendix 1. CENTRAL

MeSH descriptor: [Breast Neoplasms] explode all trees
breast near cancer*
breast near neoplasm*
breast near carcinoma*
breast near tumour*
breast near tumor*
#1 or #2 or #3 or #4 or #5 or #6
MeSH descriptor: [Radiotherapy, Adjuvant] explode all trees
MeSH descriptor: [Radiotherapy, Conformal] explode all trees
MeSH descriptor: [Radiotherapy, Intensity‐Modulated] explode all trees
MeSH descriptor: [Brachytherapy] explode all trees
radiation therapy
external beam and (radiation or irradiation or radiotherapy)
three dimension* and (radiation or irradiation or radiotherapy)
3 d and (radiation or irradiation or radiotherapy)
3‐d and (radiation or irradiation or radiotherapy)
3 d conformal and (radiation or irradiation or radiotherapy)
3‐d conformal and (radiation or irradiation or radiotherapy)
cobalt‐60 and (radiation or irradiation or radiotherapy)
bed boost and (radiation or irradiation or radiotherapy)
whole breast and (radiation or irradiation or radiotherapy)
interstitial and (radiation or irradiation or radiotherapy)
electron and (radiation or irradiation or radiotherapy)
photon and (radiation or irradiation or radiotherapy)
#8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24
MeSH descriptor: [Mastectomy, Segmental] explode all trees
lumpectomy
quadrantectomy
breast conserving surgery
breast conserving therapy
surgery near breast*
wide excision
wide local excision
WLE
#26 or #27 or #28 or #29 or #31 or #32 or #33 or #34
#7 and #25 and #35

Appendix 2. MEDLINE

1	randomized controlled trial.pt.
2	controlled clinical trial.pt.
3	randomized.ab.
4	placebo.ab.
5	Clinical Trials as Topic/
6	randomly.ab.
7	trial.ti.
8	(crossover or cross‐over).tw.
9	Pragmatic Clinical Trials as Topic/
10	pragmatic clinical trial.pt.
11	or/1‐10
12	exp Breast Neoplasms/
13	(breast adj6 cancer$).tw.
14	(breast adj6 neoplasm$).tw.
15	(breast adj6 carcinoma$).tw.
16	(breast adj6 tumo?r$).tw.
17	or/12‐16
18	exp Radiotherapy, Adjuvant/
19	(external beam and (radiation or radiotherapy or irradiation)).tw.
20	(three dimensional and (radiation or radiotherapy or irradiation)).tw.
21	(3D and (radiation or radiotherapy or irradiation)).tw.
22	(3‐D and (radiation or radiotherapy or irradiation)).tw.
23	(3D conformal and (radiation or radiotherapy or irradiation)).tw.
24	(3‐D conformal and (radiation or radiotherapy or irradiation)).tw.
25	(three dimensional conformal and (radiation or radiotherapy or irradiation)).tw.
26	(cobalt‐60 and (radiation or radiotherapy or irradiation)).tw.
27	(whole breast and (radiation or radiotherapy or irradiation)).tw.
28	exp Radiotherapy, Conformal/
29	Radiotherapy, Intensity‐Modulated/
30	exp brachytherapy/
31	exp radiotherapy, computer‐assisted/
32	exp radiotherapy, high‐energy/
33	exp radiotherapy, image‐guided/
34	bed boost.tw.
35	(interstitial and (radiation or radiotherapy or irradiation)).tw.
36	(electron and (radiation or radiotherapy or irradiation)).tw.
37	(photon and (radiation or radiotherapy or irradiation)).tw.
38	18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37
39	exp Mastectomy, Segmental/
40	lumpectomy.tw.
41	quadrantectomy.tw.
42	breast conserving surgery.tw.
43	breast conserving therapy.tw.
44	(surgery adj5 breast$).tw.
45	wide excision.tw.
46	wide local excision.tw.
47	WLE.tw.
48	39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47
49	11 and 17 and 38 and 48
50	Animals/ not Humans/
51	49 not 50

Appendix 3. Embase

random* OR factorial* OR crossover* OR cross NEXT/1 over* OR placebo* OR (doubl* AND blind*) OR (singl* AND blind*) OR assign*OR allocat* OR volunteer* OR 'crossover procedure'/exp OR 'crossover procedure' OR 'double blind procedure'/exp OR 'double blind procedure' OR 'randomized controlled trial'/exp OR 'randomized controlled trial' OR 'single blind procedure'/exp OR 'single blind procedure'
'breast'/exp OR 'breast disease'/exp AND 'neoplasm'/exp OR 'breast tumor'/exp OR (breast* NEAR/5 neoplas*):ab,ti OR (breast*NEAR/5 cancer*):ab,ti OR (breast* NEAR/5 carcin*):ab,ti OR (breast* NEAR/5 tumo*):ab,ti OR (breast* NEAR/5 metasta*):ab,ti OR (breast* NEAR/5 malig*):ab,ti
'breast cancer'/exp OR 'breast cancer' OR 'breast neoplasm' OR 'breast carcinoma'/exp OR 'breast carcinoma' OR 'breast tumour' OR'breast tumor'/exp OR 'breast tumor'
#2 OR #3
'radiotherapy adjuvant'/exp
'external beam' AND (radiation OR radiotherapy OR irradiation)
'three dimensional' AND (radiation OR radiotherapy OR irradiation)
3d AND (radiation OR radiotherapy OR irradiation)
'3 d' AND (radiation OR radiotherapy OR irradiation)
'3 d' AND conformal AND (radiation OR radiotherapy OR irradiation)
'three dimensional conformal radiation therapy'
'cobalt 60' AND (radiation OR radiotherapy OR irradiation)
'cobalt therapy'/exp
'external beam radiotherapy'/exp
'intensity modulated radiation therapy'/exp
'whole breast' AND (radiation OR radiotherapy OR irradiation)
'interstitial radiation'/exp
'brachytherapy'/exp OR brachytherapy
'computer assisted radiotherapy'/exp
'megavoltage radiotherapy'/exp
'image guided radiotherapy'/exp
'bed boost' AND (radiation OR radiotherapy OR irradiation)
'electron' AND (radiation OR radiotherapy OR irradiation)
'photon' AND (radiation OR radiotherapy OR irradiation)
#5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR#23 OR #24
'segmental mastectomy'/exp
'partial mastectomy'/exp OR lumpectomy
quadrantectomy
'breast conserving surgery'
'breast conserving therapy'
surgery NEAR/5 breast*
'wide local excision' OR 'wide excision' OR WLE
#26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32
#1 AND #4 AND #25 AND #33
#34 AND [humans]/lim AND [embase]/lim

Embase search 01/03/2017 via OvidSP

1	Randomized controlled trial/
2	Controlled clinical study/
3	Random$.ti,ab.
4	randomization/
5	intermethod comparison/
6	placebo.ti,ab.
7	(compare or compared or comparison).ti.
8	(open adj label).ti,ab.
9	((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab.
10	double blind procedure/
11	parallel group$1.ti,ab.
12	(crossover or cross over).ti,ab.
13	((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or patient$1 or subject$1 or participant$1)).ti,ab.
14	(assigned or allocated).ti,ab.
15	(controlled adj7 (study or design or trial)).ti,ab.
16	(volunteer or volunteers).ti,ab.
17	trial.ti.
18	or/1‐17
19	exp breast/
20	exp breast disease/
21	(19 or 20) and exp neoplasm/
22	exp breast tumor/
23	exp breast cancer/
24	exp breast carcinoma/
25	(breast$ adj5 (neoplas$ or cancer$ or carcin$ or tumo$ or metasta$ or malig$)).ti,ab.
26	or/21‐25
27	exp adjuvant radiotherapy/
28	(external beam and (radiation or radiotherapy or irradiation)).tw.
29	(three dimensional and (radiation or radiotherapy or irradiation)).tw.
30	(3D and (radiation or radiotherapy or irradiation)).tw.
31	(3D conformal and (radiation or radiotherapy or irradiation)).tw.
32	(3‐D conformal and (radiation or radiotherapy or irradiation)).tw.
33	(three dimensional conformal and (radiation or radiotherapy or irradiation)).tw.
34	(cobalt‐60 and (radiation or radiotherapy or irradiation)).tw.
35	exp cobalt therapy/
36	exp external beam radiotherapy/
37	exp intensity modulated radiation therapy/
38	(whole breast and (radiation or radiotherapy or irradiation)).tw.
39	exp radioisotope therapy/
40	exp brachytherapy/
41	brachytherapy.tw.
42	exp computer assisted radiotherapy/
43	exp megavoltage radiotherapy/
44	exp image guided radiotherapy/
45	(bed boost and (radiation or radiotherapy or irradiation)).tw.
46	(electron and (radiation or radiotherapy or irradiation)).tw.
47	(photon and (radiation or radiotherapy or irradiation)).tw.
48	or/27‐47
49	exp segmental mastectomy/
50	exp partial mastectomy/
51	lumpectomy.tw.
52	quadrantectomy.tw.
53	breast conserving surgery.tw.
54	breast conserving therapy.tw.
55	(surgery adj5 breast$).tw.
56	wide excision.tw.
57	wide local excision.tw.
58	WLE.tw.
59	or/49‐58
60	18 and 26 and 48 and 59
61	limit 60 to (human and embase)
62	limit 61 to yr="2015 ‐Current"

Appendix 4. WHO ICTRP

Basic Searches:

1. breast cancer AND tumour bed boost

2. breast cancer AND radiotherapy AND breast conserving surgery

3. breast cancer AND radiotherapy AND partial mastectomy

Advanced Searches:

1.

Title: Tumour bed boost radiotherapy for women with breast cancer

Recruitment Status: ALL

2.

Condition: breast cancer OR breast neoplasm

Intervention: (radiation OR irradiation OR radiotherapy) AND (breast conserving surgery OR breast conserving therapy OR partial mastectomy OR lumpectomy)

Recruitment Status: ALL

3.

Condition: breast cancer OR breast neoplasm

Intervention: bed boost AND (breast conserving surgery OR breast conserving therapy OR partial mastectomy OR lumpectomy)

Recruitment Status: ALL

4.

Condition: breast cancer OR breast neoplasm

Intervention: (cobalt‐60 OR brachytherapy OR interstitial therapy) AND (breast conserving surgery OR breast conserving therapy OR partial mastectomy OR lumpectomy)

Recruitment Status: ALL

Appendix 5. ClinicalTrials.gov

Basic Searches:

1. breast cancer AND tumour bed boost

2. breast cancer AND radiotherapy AND breast conserving surgery

3. breast cancer AND radiotherapy AND partial mastectomy

Advanced Searches:

1.

Title: Tumour bed boost radiotherapy for women with breast cancer

Recruitment: All Studies

Study Results: All Studies

Study Type: All Studies

Gender: All Studies

2.

Condition: breast cancer OR breast neoplasm

Intervention: (breast irradiation OR tumour bed boost OR tumour bed boost) AND (breast conserving surgery OR breast conserving therapy OR segmental mastectomy OR partial mastectomy OR lumpectomy)

Recruitment: All Studies

Study Results: All Studies

Study Type: All Studies

Gender: All Studies

3.

Condition: breast cancer OR breast neoplasm

Intervention: (external beam irradiation OR conformal irradiation OR cobalt‐60 OR intensity‐modulated irradiation) AND (breast conserving surgery OR breast conserving therapy OR segmental mastectomy OR partial mastectomy OR lumpectomy)

Recruitment: All Studies

Study Results: All Studies

Study Type: All Studies

Gender: All Studies

4.

Condition: breast cancer OR breast neoplasm

Intervention: (brachytherapy OR interstitial therapy OR electron radiotherapy OR photon radiotherapy OR adjuvant radiotherapy) AND (breast conserving surgery OR breast conserving therapy OR segmental mastectomy OR partial mastectomy OR lumpectomy)

Recruitment: All Studies

Study Results: All Studies

Study Type: All Studies

Gender: All Studies

Illustration of the breast retraction assessment (BRA) measurements as reported by EORTC. BRA = √((a1 ‐ b1)² + (a2 ‐ b2)²); reference length = √(b1² + b2²); percentage breast retraction assessment = (BRA/reference length) x 100.

Figure 1

Illustration of the breast retraction assessment (BRA) measurements as reported by EORTC. BRA = √((a₁ ‐ b₁)² + (a₂ ‐ b₂)²); reference length = √(b₁² + b₂²); percentage breast retraction assessment = (BRA/reference length) x 100.

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Figure 2

Study flow diagram.

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Figure 3

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Forest plot of comparison: 1 Tumour bed boost radiotherapy versus no boost, outcome: 1.1 Local control.

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Figure 5

Forest plot of comparison: 1 Tumour bed boost radiotherapy versus no boost, outcome: 1.5 Overall survival.

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Figure 6

Forest plot of comparison: 1 Tumour bed boost radiotherapy versus no boost, outcome: 1.8 Cosmesis, Panel.

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Analysis 1.1

Comparison 1 Tumour bed boost radiotherapy versus no boost, Outcome 1 Local control.

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Analysis 1.2

Comparison 1 Tumour bed boost radiotherapy versus no boost, Outcome 2 Local control ‐ sensitivity analysis.

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Analysis 1.3

Comparison 1 Tumour bed boost radiotherapy versus no boost, Outcome 3 Local control ‐ subgroup +40 years.

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Analysis 1.4

Comparison 1 Tumour bed boost radiotherapy versus no boost, Outcome 4 Local control ‐ subgroup low boost dose.

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Analysis 1.5

Comparison 1 Tumour bed boost radiotherapy versus no boost, Outcome 5 Overall survival.

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Analysis 1.6

Comparison 1 Tumour bed boost radiotherapy versus no boost, Outcome 6 Disease‐free survival.

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Analysis 1.7

Comparison 1 Tumour bed boost radiotherapy versus no boost, Outcome 7 Late toxicity, pBRA.

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Analysis 1.8

Comparison 1 Tumour bed boost radiotherapy versus no boost, Outcome 8 Cosmesis, Panel.

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Analysis 1.9

Comparison 1 Tumour bed boost radiotherapy versus no boost, Outcome 9 Cosmesis, Physician.

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Summary of findings for the main comparison. Boost compared to no boost in breast cancer radiotherapy

Boost compared to no boost in breast cancer radiotherapy
Patient or population: breast‐conserving radiotherapy for breast cancer Setting: radiotherapy centres Intervention: boost Comparison: no boost
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk without boost	Risk with boost
Local control: recurrence at 5 years	Study population		HR 0.64 (0.55 to 0.75)	8315 (5 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	Nice did not report 5‐year local control.
	70 per 1000	45 per 1000 (39 to 53)
Overall survival: mortality at 5 years	Study population		HR 1.04 (0.94 to 1.14)	6342 (2 RCTs)	⊕⊕⊕⊝ MODERATE ³
	91 per 1000	94 per 1000 (86 to 103)
Disease‐free survival: disease progression/mortality at 5 years	Study population		HR 0.94 (0.87 to 1.02)	6549 (3 RCTs)	⊕⊕⊝⊝ LOW ^{4 5}	EORTC did not report 5‐year disease‐free survival.
	221 per 1000	209 per 1000 (195 to 224)
Late toxicity, pBRA	Mean pBRA 8.17, range 7.55 to 10	Mean pBRA 8.55, range 8.26 to 9.4	MD 0.38 higher (0.18 lower to 0.93 higher)	1526 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{2 5}
Cosmesis, panel scored: fair or poor	Study population		OR 1.41 (1.07 to 1.85)	1116 (2 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}
	202 per 1000	263 per 1000 (213 to 319)
Cosmesis, physician‐scored: fair or poor	Study population		OR 1.58 (0.93 to 2.69)	592 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 5 6}
	85 per 1000	128 per 1000 (80 to 200)
Sensitivity analysis: local control ‐ recurrence at 5 years	Study population		HR 0.62 (0.52 to 0.73)	6963 (3 RCTs)	⊕⊕⊕⊕ HIGH
	74 per 1000	47 per 1000 (39 to 55)
Subgroup analysis: local control ‐ > 40 years old, recurrence at 5 years	Study population		HR 0.65 (0.53 to 0.81)	5058 (2 RCTs)	⊕⊕⊕⊕ HIGH
	59 per 1000	39 per 1000 (32 to 48)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HR: hazard ratio; MD: mean difference; OR: odds ratio; pBRA: percentage breast retraction assessment; RCT: randomised controlled trial
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of the effect.
¹High risk of selective reporting in one study. ²There was considerable clinical heterogeneity with respect to radiotherapy dose and the use of quality assurance procedures. ³One of the two studies has a very wide confidence interval. ⁴There was considerable clinical heterogeneity on statistical testing, but not on visual inspection. ⁵Both studies have wide confidence intervals. ⁶High risk of bias for blinding of outcome assessment in one study.

Summary of findings for the main comparison. Boost compared to no boost in breast cancer radiotherapy

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Table 1. RTOG/EORTC late radiation morbidity scoring scheme

Organ tissue	0	Grade 1	Grade 2	Grade 3	Grade 4
Skin	None	Slight atrophy; pigmentation change; some hair loss	Patchy atrophy; moderate telangiectasia; total hair loss	Marked atrophy; gross telangiectasia	Ulceration
Subcutaneous tissue	None	Slight induration (fibrosis) and loss of subcutaneous fat	Moderate fibrosis but asymptomatic; slight field contracture; < 10% linear reduction	Severe induration and loss of subcutaneous tissue; field contracture > 10% linear measurement	Necrosis
RTOG/EORTC: Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer

Table 1. RTOG/EORTC late radiation morbidity scoring scheme

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Table 2. Harvard cosmetic score

Cosmetic score

Excellent

Good

Fair

Poor

Table 2. Harvard cosmetic score

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Comparison 1. Tumour bed boost radiotherapy versus no boost

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Local control Show forest plot	5	8315	Hazard Ratio (Fixed, 95% CI)	0.64 [0.55, 0.75]

2 Local control ‐ sensitivity analysis Show forest plot	3	6963	Hazard Ratio (Fixed, 95% CI)	0.62 [0.52, 0.73]

3 Local control ‐ subgroup +40 years Show forest plot	2	5058	Hazard Ratio (Fixed, 95% CI)	0.65 [0.53, 0.81]

4 Local control ‐ subgroup low boost dose Show forest plot	2	1352	Hazard Ratio (Fixed, 95% CI)	0.95 [0.55, 1.62]

5 Overall survival Show forest plot	2	6342	Hazard Ratio (Fixed, 95% CI)	1.04 [0.94, 1.14]

6 Disease‐free survival Show forest plot	3	6549	Hazard Ratio (Fixed, 95% CI)	0.94 [0.87, 1.02]

7 Late toxicity, pBRA Show forest plot	2	1526	Mean Difference (IV, Fixed, 95% CI)	0.38 [‐0.18, 0.93]

8 Cosmesis, Panel Show forest plot	2	1116	Odds Ratio (M‐H, Fixed, 95% CI)	1.41 [1.07, 1.86]

9 Cosmesis, Physician Show forest plot	2	592	Odds Ratio (M‐H, Fixed, 95% CI)	1.58 [0.93, 2.69]

Comparison 1. Tumour bed boost radiotherapy versus no boost

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Radioterapi bidang tumor untuk wanita selepas pembedahan pemuliharaan payudara

Appendices

Appendix 1. CENTRAL

Appendix 2. MEDLINE

Appendix 3. Embase

Appendix 4. WHO ICTRP

Appendix 5. ClinicalTrials.gov

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Appendices

Appendix 1. CENTRAL

Appendix 2. MEDLINE

Appendix 3. Embase

Appendix 4. WHO ICTRP

Appendix 5. ClinicalTrials.gov

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