. 2024 Sep 11:386:e079089.

doi: 10.1136/bmj-2023-079089.

Randomised controlled trials on radiation dose fractionation in breast cancer: systematic review and meta-analysis with emphasis on side effects and cosmesis

Shing Fung Lee^{1

2}, Samantha K F Kennedy³, Saverio Caini⁴, Henry C Y Wong⁵, Pui Lam Yip^{6

2

7}, Philip M Poortmans^{8

9}, Icro Meattini^{10

11}, Orit Kaidar-Person^{12

13

14}, Abram Recht¹⁵, Tarek Hijal¹⁶, Mylin A Torres¹⁷, Jeffrey Q Cao¹⁸, Kimberly S Corbin¹⁹, J Isabelle Choi²⁰, Wee Yao Koh^{6

2}, Jennifer Y Y Kwan^{21

22}, Irene Karam^{22

3}, Adrian W Chan^{22

3}, Edward Chow^{22

3}, Gustavo N Marta^{23

24

25}

Affiliations

¹ Department of Radiation Oncology, National University Cancer Institute, National University Hospital, Singapore leesf@nuhs.edu.sg.
² Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³ Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
⁴ Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPO), Florence, Italy.
⁵ Department of Oncology, Princess Margaret Hospital, Hospital Authority, Hong Kong.
⁶ Department of Radiation Oncology, National University Cancer Institute, National University Hospital, Singapore.
⁷ Department of Clinical Oncology, Tuen Mun Hospital, New Territories West Cluster, Hospital Authority, Hong Kong.
⁸ Department of Radiation Oncology, Iridium Netwerk, Wilrijk-Antwerp, Belgium.
⁹ Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk-Antwerp, Belgium.
¹⁰ Department of Experimental and Clinical Biomedical Sciences "M Serio", University of Florence, Florence, Italy.
¹¹ Radiation Oncology Unit, Oncology Department, Azienda Ospedaliero Universitaria Careggi, Florence, Italy.
¹² Breast Cancer Radiation Therapy Unit, Sheba Medical Center, Ramat Gan, Israel.
¹³ School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
¹⁴ GROW-School for Oncology and Reproductive (Maastro), Maastricht University, Maastricht, Netherlands.
¹⁵ Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹⁶ Division of Radiation Oncology, McGill University Health Centre, Montreal, QC, Canada.
¹⁷ Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
¹⁸ Section of Radiation Oncology, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
¹⁹ Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
²⁰ Department of Radiation Oncology, New York Proton Center and Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²¹ Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
²² Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.
²³ Department of Radiation Oncology, Hospital Sírio-Libanês, São Paulo, Brazil.
²⁴ Latin America Cooperative Oncology Group, Porto Alegre, Brazil.
²⁵ Postgraduate Program, Department of Radiology and Oncology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

PMID: 39260879
PMCID: PMC11388113
DOI: 10.1136/bmj-2023-079089

Randomised controlled trials on radiation dose fractionation in breast cancer: systematic review and meta-analysis with emphasis on side effects and cosmesis

Shing Fung Lee et al. BMJ. 2024.

. 2024 Sep 11:386:e079089.

doi: 10.1136/bmj-2023-079089.

Authors

Affiliations

¹ Department of Radiation Oncology, National University Cancer Institute, National University Hospital, Singapore leesf@nuhs.edu.sg.
² Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³ Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
⁴ Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPO), Florence, Italy.
⁵ Department of Oncology, Princess Margaret Hospital, Hospital Authority, Hong Kong.
⁶ Department of Radiation Oncology, National University Cancer Institute, National University Hospital, Singapore.
⁷ Department of Clinical Oncology, Tuen Mun Hospital, New Territories West Cluster, Hospital Authority, Hong Kong.
⁸ Department of Radiation Oncology, Iridium Netwerk, Wilrijk-Antwerp, Belgium.
⁹ Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk-Antwerp, Belgium.
¹⁰ Department of Experimental and Clinical Biomedical Sciences "M Serio", University of Florence, Florence, Italy.
¹¹ Radiation Oncology Unit, Oncology Department, Azienda Ospedaliero Universitaria Careggi, Florence, Italy.
¹² Breast Cancer Radiation Therapy Unit, Sheba Medical Center, Ramat Gan, Israel.
¹³ School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
¹⁴ GROW-School for Oncology and Reproductive (Maastro), Maastricht University, Maastricht, Netherlands.
¹⁵ Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹⁶ Division of Radiation Oncology, McGill University Health Centre, Montreal, QC, Canada.
¹⁷ Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
¹⁸ Section of Radiation Oncology, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
¹⁹ Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
²⁰ Department of Radiation Oncology, New York Proton Center and Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²¹ Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
²² Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.
²³ Department of Radiation Oncology, Hospital Sírio-Libanês, São Paulo, Brazil.
²⁴ Latin America Cooperative Oncology Group, Porto Alegre, Brazil.
²⁵ Postgraduate Program, Department of Radiology and Oncology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

PMID: 39260879
PMCID: PMC11388113
DOI: 10.1136/bmj-2023-079089

Abstract

Objective: To provide a comprehensive assessment of various fractionation schemes in radiation therapy for breast cancer, with a focus on side effects, cosmesis, quality of life, risks of recurrence, and survival outcomes.

Design: Systematic review and meta-analysis.

Data sources: Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (from inception to 23 October 2023).

Study selection: Included studies were randomised controlled trials focusing on conventional fractionation (CF; daily fractions of 1.8-2 Gy, reaching a total dose of 50-50.4 Gy over 5-6 weeks), moderate hypofractionation (MHF; fraction sizes of 2.65-3.3 Gy for 13-16 fractions over 3-5 weeks), and/or ultra-hypofractionation (UHF; schedule of only 5 fractions).

Data extraction: Two independent investigators screened studies and extracted data. Risk of bias and quality of evidence were assessed using the Cochrane Collaboration's tool and the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach, respectively.

Data synthesis: Pooled risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random effects model. Heterogeneity was analysed using Cochran's Q test and I² statistic. Network meta-analysis was used to integrate all available evidence.

Main outcome measures: The pre-specified primary outcome was grade ≥2 acute radiation dermatitis and late radiation therapy related side effects; secondary outcomes included cosmesis, quality of life, recurrence, and survival metrics.

Results: From 1754 studies, 59 articles representing 35 trials (20 237 patients) were assessed; 21.6% of outcomes showed low risk of bias, whereas 78.4% had some concerns or high risk, particularly in outcome measurement (47.4%). The RR for grade ≥2 acute radiation dermatitis for MHF compared with CF was 0.54 (95% CI 0.49 to 0.61; P<0.001) and 0.68 (0.49 to 0.93; P=0.02) following breast conserving therapy and mastectomy, respectively. Hyperpigmentation and grade ≥2 breast shrinkage were less frequent after MHF than after CF, with RRs of 0.77 (0.62 to 0.95; P=0.02) and 0.92 (0.85 to 0.99; P=0.03), respectively, in the combined breast conserving therapy and mastectomy population. However, in the breast conserving therapy only trials, these differences in hyperpigmentation (RR 0.79, 0.60 to 1.03; P=0.08) and breast shrinkage (0.94, 0.83 to 1.07; P=0.35) were not statistically significant. The RR for grade ≥2 acute radiation dermatitis for UHF compared with MHF was 0.85 (0.47 to 1.55; P=0.60) for breast conserving therapy and mastectomy patients combined. MHF was associated with improved cosmesis and quality of life compared with CF, whereas data on UHF were less conclusive. Survival and recurrence outcomes were similar between UHF, MHF, and CF.

Conclusions: MHF shows improved safety profile, cosmesis, and quality of life compared with CF while maintaining equivalent oncological outcomes. Fewer randomised controlled trials have compared UHF with other fractionation schedules, but its safety and oncological effectiveness seem to be similar with short term follow-up. Given the advantages of reduced treatment time, enhanced convenience for patients, and potential cost effectiveness, MHF and UHF should be considered as preferred options over CF in appropriate clinical settings, with further research needed to solidify these findings.

Systematic review registration: PROSPERO CRD42023460249.

PubMed Disclaimer

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; IC has received consulting fees from Pfizer, Novartis, Eli Lilly, Seagen, Gilead, Astra Zeneca, Daiichi Sankyo, and Menarini StemLine and is a clinical board member of the European Society for Radiotherapy and Oncology (unpaid); JQC has received funding from the Canadian Institutes of Health Research and honorariums from Roche, Pfizer, Novartis, AstraZeneca, Well Doc Alberta, Merck, La Roche-Posay, Knight, Seagen, Oncology Education, and Gilead; no other relationships or activities that could appear to have influenced the submitted work.

Figures

**Fig 1**
PRISMA diagram of study selection

**Fig 2**
Risk of bias by outcome (percentage)

**Fig 3**
Forest plot showing risk ratios for grade ≥2 acute radiation dermatitis for moderate versus conventional fractionation in all trials. Cairo trial used RTOG toxicity criteria for acute radiation dermatitis. Beijing trial reported incidence of acute radiation dermatitis across grade 1–2 and 3; however, only grade 3 data have been included in this forest plot for analysis. Kolkata trial reported incidence of only grade ≥3 acute radiation dermatitis. CF=conventional fractionation; CI=confidence interval; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 4**
Forest plot showing risk ratios for grade ≥2 acute radiation dermatitis for moderate versus conventional fractionation in breast conserving treatment trials. Cairo trial used RTOG toxicity criteria for acute radiation dermatitis. CF=conventional fractionation; CI=confidence interval; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 5**
Forest plot showing risk ratios for grade ≥2 acute radiation dermatitis for moderate versus conventional fractionation in mastectomy trials. Beijing trial reported incidence of acute radiation dermatitis across grade 1–2 and 3; however, only grade 3 data have been included in this forest plot for analysis. Kolkata trial reported incidence of only grade ≥3 acute radiation dermatitis. CF=conventional fractionation; CI=confidence interval; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 6**
Forest plot showing risk ratios for grade ≥2 acute radiation dermatitis for ultra-hypofractionation versus moderate hypofractionation in all trials. CI=confidence interval; M-H=Mantel-Haenszel; MHF=moderate hypofractionation; UHF= ultra-hypofractionation

**Fig 7**
Forest plot showing risk ratios for grade ≥2 acute radiation dermatitis for ultra-hypofractionation versus moderate hypofractionation in breast conserving surgery trials. CI=confidence interval; M-H=Mantel-Haenszel; MHF=moderate hypofractionation; UHF= ultra-hypofractionation

**Fig 8**
Forest plot showing risk ratios for late skin and soft tissue side effects for moderate versus conventional fractionation trials: grade ≥2 telangiectasia in all trials. Iran trial, Tehran trial, and DBCG HYPO trial reported incidence of any grade of telangiectasia. CI=confidence interval; CF=conventional fractionation; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 9**
Forest plot showing risk ratios for late skin and soft tissue side effects for moderate versus conventional fractionation trials: any hyperpigmentation in all trials. CI=confidence interval; CF=conventional fractionation; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 10**
Forest plot showing risk ratios for late skin and soft tissue side effects for moderate versus conventional fractionation trials: grade ≥2 breast or chest wall induration or fibrosis in all trials. Iran trial reported the incidence of grade ≥2 breast induration or fibrosis. Tehran trial, DBCG HYPO trial, Chinese trial, Italy trial, and Belgium trial reported incidence of any grade of breast induration or fibrosis. CI=confidence interval; CF=conventional fractionation; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 11**
Forest plot showing risk ratios for late skin and soft tissue side effects for moderate versus conventional fractionation trials: grade ≥2 breast shrinkage in all trials. Iran trial reported incidence of any grade of breast shrinkage. CI=confidence interval; CF=conventional fractionation; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 12**
Forest plot showing risk ratios for late skin and soft tissue side effects for moderate versus conventional fractionation trials: grade ≥2 breast oedema in all trials. Iran trial and DBCG HYPO trial reported incidence of any grade of breast oedema. CI=confidence interval; CF=conventional fractionation; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 13**
Forest plot showing risk ratios for late skin and soft tissue side effects for moderate versus conventional fractionation trials: grade ≥2 telangiectasia in and breast conserving treatment trials. Iran trial, Tehran trial, and DBCG HYPO trial reported incidence of any grade of telangiectasia. CF=conventional fractionation; CI=confidence interval; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 14**
Forest plot showing risk ratios for late skin and soft tissue side effects for moderate versus conventional fractionation trials: any hyperpigmentation in breast conserving treatment trials. CF=conventional fractionation; CI=confidence interval; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 15**
Forest plot showing risk ratios for late skin and soft tissue side effects for moderate versus conventional fractionation trials: grade ≥2 breast or chest wall induration or fibrosis in breast conserving treatment trials. Tehran trial, DBCG HYPO trial, Chinese trial, and Italy trial reported incidence of any grade of breast induration or fibrosis. CF=conventional fractionation; CI=confidence interval; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 16**
Forest plot showing risk ratios for late skin and soft tissue side effects for moderate versus conventional fractionation trials: grade ≥2 breast shrinkage in breast conserving treatment trials. Iran trial reported incidence of any grade of breast shrinkage. CF=conventional fractionation; CI=confidence interval; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 17**
Forest plot showing risk ratios for late skin and soft tissue side effects for moderate versus conventional fractionation trials: grade ≥2 breast oedema in breast conserving treatment trials. Iran trial and DBCG HYPO trial reported incidence of any grade of breast oedema. CF=conventional fractionation; CI=confidence interval; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 18**
Forest plot showing risk ratios for late skin and soft tissue side effects for moderate versus conventional fractionation trials: grade ≥2 breast pain in breast conserving treatment trials. CF=conventional fractionation; CI=confidence interval; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 19**
Forest plot showing risk ratios for late non-skin side effects for moderate versus conventional fractionation: grade ≥2 lymphoedema. Beijing trial reported incidence of lymphoedema across grades 1-2 and grade 3; however, only grade 3 data have been included in this forest plot for analysis. Chinese trial reported only incidence of grade 2 lymphoedema. Kolkata trial reported incidence of only grade ≥3 lymphoedema. CF=conventional fractionation; CI=confidence interval; IHD=ischaemic heart disease; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 20**
Forest plot showing risk ratios for late non-skin side effects for moderate versus conventional fractionation: grade ≥2 pneumonitis or symptomatic lung fibrosis. Beijing trial reported incidence of lung fibrosis across grades 1-2 and grade 3; however, only grade 3 data have been included in this forest plot for analysis. Chinese trial reported only incidence of grade 2 lung fibrosis. Kolkata trial reported incidence of only grade ≥3 lung side effects. CF=conventional fractionation; CI=confidence interval; IHD=ischaemic heart disease; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 21**
Forest plot showing risk ratios for late non-skin side effects for moderate versus conventional fractionation: ischaemic heart disease. CF=conventional fractionation; CI=confidence interval; IHD=ischaemic heart disease; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 22**
Forest plot showing risk ratios for late non-skin side effects for moderate versus conventional fractionation: grade ≥2 shoulder stiffness or dysfunction. Beijing trial reported incidences of shoulder dysfunction across grades 1-2 and grade 3; however, only grade 3 data have been included in this forest plot for analysis. Chinese trial reported only incidence of grade 2 shoulder stiffness. CF=conventional fractionation; CI=confidence interval; IHD=ischaemic heart disease; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

**Fig 23**
Forest plot showing risk ratios for late non-skin side effects for moderate versus conventional fractionation: symptomatic rib fracture. CF=conventional fractionation; CI=confidence interval; IHD=ischaemic heart disease; M-H=Mantel-Haenszel; MHF=moderate hypofractionation

See this image and copyright information in PMC

References

1. Sung H, Ferlay J, Siegel RL, et al. . Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49. 10.3322/caac.21660 - DOI - PubMed
1. Cardoso F, Kyriakides S, Ohno S, et al. ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org . Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol 2019;30:1194-220. 10.1093/annonc/mdz173 - DOI - PubMed
1. Smith BD, Bellon JR, Blitzblau R, et al. . Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline. Pract Radiat Oncol 2018;8:145-52. 10.1016/j.prro.2018.01.012 - DOI - PubMed
1. McGale P, Taylor C, Correa C, et al. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group) . Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 2014;383:2127-35. 10.1016/S0140-6736(14)60488-8 - DOI - PMC - PubMed
1. Bentzen SM, Agrawal RK, Aird EG, et al. START Trialists’ Group . The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet 2008;371:1098-107. 10.1016/S0140-6736(08)60348-7 - DOI - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Randomised controlled trials on radiation dose fractionation in breast cancer: systematic review and meta-analysis with emphasis on side effects and cosmesis

Affiliations

Randomised controlled trials on radiation dose fractionation in breast cancer: systematic review and meta-analysis with emphasis on side effects and cosmesis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources

Medical