Chest wall pain as a late effect following radiotherapy for breast cancer: A systematic review of prevalence and risk factors

Abstract

Background

Breast cancer is the most commonly diagnosed cancer in women with approximately 60% receiving adjuvant radiotherapy. Despite advances minimising radiation dose to normal tissues, many women report post treatment pain affecting quality of life. Limited evidence on pain location, severity and risk factors for occurrence impacts clinical management. This systematic review identified studies reporting the prevalence of chest wall pain after breast cancer radiotherapy and explored associated risk factors.

Methods

Searches of PubMed, Embase, CINAHL and Cochrane identified studies published between 2005 and 2025. Terms focused on breast cancer radiotherapy and chest wall pain, graded using either a clinician reported or patient reported outcome measure, more than three months post treatment. Abstracts and full texts were screened, appraised and a PRISMA diagram produced.

Results

Eight studies met inclusion criteria: six observational cohort studies and two randomised trials, totalling 5509 patients. Pooled prevalence for chest wall pain was 34.0%. Mild pain was most commonly reported at 26.1%, while 5.7% reported moderate to severe pain. Temporal patterns could not be determined. Younger age, tumour bed boost and treated volume > 107% dose were identified as potentially associated factors, although findings were inconsistent. Seven studies used clinician reported outcomes; one study using patient reported measures reported higher chest wall pain prevalence. Meta-analysis was not performed due to significant heterogeneity in populations, radiotherapy techniques, and assessments.

Discussion and conclusion

Chest wall pain is under recognised and poorly captured in breast radiotherapy research. It warrants evaluation as a distinct late effect. Further research is required to clarify prevalence, severity, trajectory, and risk factors.

Highlights

• •Chest wall pain is a poorly captured late adverse effect after breast cancer radiotherapy.
• •Few trials assess chest wall pain or distinguish causes after breast radiotherapy.
• •Risk factors for chest wall pain vary; tumour bed boost and younger age may raise risk.

Introduction

Breast cancer is the most frequently diagnosed malignancy in women with an estimated 374,000 new cases reported in Europe in 2022 [1]. Approximately half of these diagnoses occur in women aged between 45 and 69 years [1]. Advances in screening programmes, systemic treatments, surgical techniques, and radiotherapy have substantially improved outcomes, and in many European countries 5 year net survival now exceeds 90% [1]. Radiotherapy remains a fundamental component of breast cancer treatment, used in around 60% of women with breast cancer [2], [3]. Evidence from trials demonstrate that radiotherapy after breast cancer surgery significantly reduces the risk of local recurrence and breast cancer related mortality [4], [5]. Despite major technological improvements in radiotherapy delivery, women with breast cancer continue to report long term adverse effects that have an impact on their health related quality of life [6], [7], [8].

Chronic pain is consistently identified as a leading concern and an unmet need in adult cancer survivors [9], [10]. Pain following breast cancer treatment is common, with prevalence estimates from 29 to 60% [11], [12], [13]. In women with breast cancer, pain can manifest as a complex simultaneous presentation of different types of pain in multiple anatomical areas in and around the breast [14], [15]. This reflects the multifactorial causes of pain such as nerve injury resulting from surgery or musculoskeletal complications including rib fractures [16], [17].

A variety of clinical and treatment related factors have been proposed as predictors of long term pain in women with breast cancer, such as younger age, presence of pre-operative pain, increased body mass index (BMI), smoking, the extent of breast and nodal surgery, systemic anti-cancer therapies and radiotherapy [13], [17], [18]. However, the evidence regarding these associations remains inconsistent across studies [15], [19], [20], [21].

Radiotherapy induces a range of molecular and cellular alterations leading to changes in normal tissue structure and function. Resulting in acute and late side effects, the changes are driven by many factors including total dose, dose per fraction, volume treated and the intrinsic radiosensitivity of different tissue types [22].

Acute effects are driven by inflammation and the loss of rapidly dividing cells. In breast radiotherapy, acute effects typically present as erythema, desquamation, and localised swelling. These arise during treatment usually resolving within three months although some, such as epilation, may persist longer [23]. Late effects are symptoms that develop following a latent period from three months to many decades after completion of treatment [24]. They are associated with chronic inflammation, progressive fibrosis, depletion of stem cell populations, and vascular injury leading to tissue ischaemia [22]. In the context of breast radiotherapy, late effects can include lymphoedema, fibrosis, breast firmness or shrinkage and telangiectasia [25].

The chest wall differs structurally and biologically from breast tissue, comprising bone, muscle, and fascial connective tissues rather than glandular and fatty tissue. These components vary in their sensitivity to radiation, which will result in a distinct profile of late effects [26]. Potential radiation induced late effects to the chest wall include muscular fibrosis, costal fractures, and neuropathic injury, any of which may contribute to persistent or chronic chest wall pain (CWP). Despite the chest wall being irradiated during whole breast irradiation (WBI), partial breast irradiation (PBI) and chest wall irradiation (CWI), chest wall related pain remains poorly characterized. It has not featured in guidance or been a metric in any of major trials that have underpinned current breast radiotherapy practices [27]. A clearer understanding of this issue will support future assessment and identification of CWP and may inform treatment options intended to reduce long term pain. This review therefore aimed to examine CWP as a late adverse event following breast cancer radiotherapy.

Rationale and review questions

We sought to address: (i) the prevalence and severity of CWP after breast cancer radiotherapy, (ii) where in the cancer trajectory is it reported and if CWP changes over time, (iii) the assessments being used to identify CWP after radiotherapy and (iv) the clinical and treatment associated risk factors for developing CWP after radiotherapy.

Methods

This systematic review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines PRISMA [28]. A comprehensive search of PubMed, Embase, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Cochrane Central Register of Controlled Trials was conducted to identify relevant prospective and retrospective studies. The search terms (Appendix A) were informed by clinical encounters of the first author (LD), review team, an academic librarian and with a woman with lived experience of CWP. Google Scholar and articles referred to in publications were also searched. Final data searches were performed on 29 November 2025. Titles and abstracts were screened by the first author (LD) and full papers reviewed and discussed with senior author (SF). Full text articles were available for all authors; any disparities were resolved by discussion.

Inclusion exclusion criteria

Articles published in English between January 2005 to January 2025 were included. Criteria were studies that reported pain as a late adverse event in patients who had received radiotherapy for breast cancer; specifically reported CWP, included data on the incidence of reported CWP, and graded pain using a clearly defined clinician reported or patient reported assessment tool. Studies were excluded if they did not have a clear distinction between breast pain and CWP, reported only acute side effects within 3 months of completing radiotherapy or involved techniques other than fractionated external beam photon radiotherapy such as brachytherapy, proton therapy or single fraction techniques. Systematic reviews, commentaries and conference abstracts were also excluded to ensure primary data was evaluated. The study protocol was defined prior to data extraction and analysis but not published or registered in an open access database.

Data extraction

Titles and abstracts were screened for inclusion; full texts were retrieved where it was not possible to determine eligibility from the abstract alone as detailed in a PRISMA flow chart (Fig. 1). Included articles were assessed by LD using checklists to evaluate study design and ensure completeness of data [29] (Appendix B). Study information recorded sample size and dates of treatment, with clinical and treatment related factors that could influence the development of CWP. Pain related information including assessment tools, clinician or patient reported outcomes and follow up time between radiotherapy and pain assessment were also derived. Only outcomes directly pertaining to CWP were evaluated, wider determinants such as cosmetic appearance were not extracted.

Fig. 1.

PRISMA flow chart showing selection of studies.

Comparison of radiotherapy adverse event assessment tools for chest wall pain

To enable comparison across studies that used different assessment tools, pain grades and descriptors were harmonised, by the review team, into four categories of none, mild, moderate, and severe, following the approach described by Wang et al. [17] (Table 1). In all cases the outcome of the assessment was specifically documented as relating to CWP, rather than breast or more generalised pain.

Table 1.

Method for harmonisation of chest wall pain grades and descriptors across assessment tools.

Assessment tool, date of publication	CWP grading descriptor
	None	Mild	Moderate	Severe
CTCAE v3 2003 [30]	Grade 0: None	Grade 1: Mild pain not interfering with function	Grade 2: Moderate pain; pain or analgesics interfering with function, but not ADL	Grade 3: Severe pain; pain or analgesics severely interfering with ADL	Grade 4: Disabling
CTCAE v4 2009 [31] CTCAE v5 2017 [32]	Grade 0: None	Grade 1: Mild pain	Grade 2: Moderate pain limiting instrumental ADL	Grade 3: Severe pain: limiting self-care ADL	–
LENT/SOMA 1995 [33]	–	Occasional and minimal	Intermittent and tolerable	Persistent and intense	Refractory and excruciating
EORTC PROMs QLQ-C30 1993 [34] QLQ- BR23 1996 [35]QLQ- BR45 2020 [36]	Not at all	A little	Quite a bit	Very much	–

Abbreviations: CWP, chest wall pain; CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; LENT/SOMA, Late Effects Normal Tissue Task Force- Subjective, Objective, Management, Analytic; EORTC PROM, European Organisation for Research Treatment of Cancer patients reported outcome measure; QLQ-C30 quality of life module; QLQ-BR23 and QLQ-BR45 breast cancer specific PROMs; ADL, activities of daily living.

A data availability table was constructed to assess the completeness of reporting for each pain grade and to identify any pooling of categories or missing data (Table 2). Where data were not explicitly reported in the text but could be reliably extracted from published figures and validated against other reported values, these data were extracted and clearly labelled to ensure transparency. Supplementary materials were reviewed where available, and earlier publications from the same trial cohorts were examined to maximise data completeness.

Table 2.

Study characteristics, radiotherapy details, chest wall pain prevalence and potential risk factors.

Author and study design; Primary aim of study	CWP assessment tool; CRO or PROM	Participant numbers, BC stage; age	Timing of radiotherapy treatment and follow up timepoints	Radiotherapy technique and boost; % patients receiving boost	WBI, CWI, APBI dose (Gy) and fractionation (#); Gy per #. Boost dose (Gy) and fractionation (#); Gy per #	Total number of patients assessed for CWP	No CWP (N=)	Mild CWP (N=)	Moderate CWP (N=)	Severe CWP (N=)	Statistical analysis and CWP risk factors
Nozaki et al. 2012 (Japan) [37]; Prospective multicentre cohort study; Cosmetic outcomes and late adverse effects from conventionally fractionated radiotherapy	NCI CTCAE v3; CRO	N = 703 women, all stages of BC (stages I-IV with 98% stages I-II) treated with breast conserving surgery; Median age 55 (range 27–82)	Radiotherapy prior to 03/2005; Median follow up 48 months (range 36–108 months), CWP data reported at a single time point between 03/2008–05/2008	Conventionally fractionated WBI + sequential boost; 36% boost	WBI 50Gy 25#; 2Gy/#. Boost 10Gy 5#; 2Gy/#	703	633	67	3	0	Categorical analysis with Chi squared of CWP Grade ≥ 2 against treatment parameters found no significant difference in boost and non-boost patients
Bantema-Joppe et al. 2012 (Netherlands) [38]; Prospective single centre cohort study; Cosmetic outcomes, late toxicities and risk factors for toxicity from conventional radiotherapy with simultaneous integrated boost	NCI CTCAE v3; CRO	N = 940 women early BC (stages I-III) with breast conserving surgery; Mean age 59 years (SD 10.2)	Radiotherapy from 01/ 2005 to 06/2010; Median follow up 30 months (range 6–54 months), CWP data reported at annual timepoints, between 04/2008–12/2010	Conventionally fractionated WBI + simultaneous integrated boost either high or low dose; 100% boost (75% high boost and 25% low boost)	WBI 50.4Gy 28#; 1.8 Gy/#. High boost dose 67.2Gy 28#; 2.4Gy/#. Low boost dose 64.4Gy 28#; 2.3Gy/#	562 at 12 months	494*	55*	13*	0	Multivariate regression analysis of CWP at 12 months using forward selection and extended bootstrapping. CWP was significantly associated with younger age < 50 2.4-fold higher risk than >50 (OR 0.41, 95% CI 0.2–0.7). High boost dose 2.1-fold increase in CWP compared to low boost dose (OR 2.06, 95% CI 1.2–3.7) (*values from graph)
Koukourakis et al. 2013 (Greece) [39]; Prospective single centre cohort study; Tolerance, efficacy and toxicities of radiotherapy with and without Amifostine cytoprotectant	LENT/SOMA; CRO	N = 112 women, high-risk breast cancer (stages I-IV positive nodes) treated with mastectomy; Median age 63 (range 28–84)	Radiotherapy between 03/2003 to 03/2010; Median follow up 44 months (range 24–90 months), dates of follow up not specified, patients seen Year 1 = 3 monthly, Year 2 = 4 monthly, Year 3+ = 6 monthly. Highest grade CWP reported at any time during follow up	Moderately hypo fractionated CWI + sequential boost; 100% boost	CWI 35Gy 10#; 3.5Gy/#. Boost 8Gy 4#; 2Gy/#	112	99	11	2	0	No statistical analysis. No risk factors for CWP
Dewan et al. 2018 (India) [40]; Prospective single centre feasibility study; Clinicopathological and dosimetric factors on toxicity and cosmetic outcomes of conventional radiotherapy and simultaneous integrated boost	NCI CTCAE v5; CRO	N = 233 women, early-stage BC (stages I-II) after breast conserving surgery; Mean age 48 (range 24–73)	Radiotherapy between 01/2014 to 06/2017; Median follow up 18 months (range 12–48 months), dates of follow up not specified, patients seen at 3, 6 and 12 months. CWP data only reported at 12 months	Conventionally fractionated WBI + simultaneous integrated boost; 100% boost	WBI 46Gy 28#; 1.64Gy/#. Boost 59.9Gy 28#; 2.14Gy/#	233	202 (Grades none & mild combined)		31 (Grades moderate and severe combined)		Univariate analysis found GTV V107% significantly induced chest wall pain. No risk factors for CWP identified with multivariate logistic regression analysis using ENTER method. Younger age, locoregional radiotherapy and boost increased late effects but not specifically CWP
Poppe et al. 2020 (USA) [41]; Prospective phase 2 multicentre study; 5-year follow up data of toxicity and recurrence from a novel hypofractionation regime	NCI CTCAE v4; CRO	N = 67 women, locally advanced BC (stages II-IIIa) treated with mastectomy (59% had immediate reconstruction); Median age 54 (range from ≤40 to >70)	Radiotherapy between 2010 and 2014; Median follow up 54 months (no further data provided). Highest grade CWP reported at any time during follow up after 6 months	Moderately hypo fractionated CWI + sequential boost; 97% boost	CWI 36.63Gy 11#; 3.33Gy/#. Boost 13.32Gy 4#; 3.33Gy/#	67	53	9	5	0	No statistical analysis. No risk factors for CWP discussed
Batenburg et al. 2023 (Netherlands) [42]; Prospective single centre cohort survey; Self-reported symptoms of late toxicity & quality of life	EORTC QLQ-C30, EORTC QLQ-BR23; PROM. Plus 4 additional questions on breast and chest wall pain, firmness & cosmesis from CTCAE V4, EORTC QLQ-C30 RTOG	N = 1613 patients, (99.6% women & men 0.4%), all stages of breast cancer (stages I-IV) with breast conserving surgery or mastectomy; Median age 58 years (IQR 24–84 range)	Radiotherapy between 2013 and 2020; Median follow up at 38 months (IQR 21–55, maximum 90 months). CWP data reported at a single time point between 10/2019 to 12/2020	Moderately hypo fractionated WBI or CWI + simultaneous integrated boost; 45% boost	WBI 40Gy 15#; 2.67Gy/#. High boost dose 58.6Gy 22# or 61.2Gy 23#; 2.67Gy/#. Low boost dose 53.4Gy 20# or 55.9Gy 21#; 2.67Gy/#	1613	710*	678*	225 (Grades moderate and severe combined)		Descriptive analysis showing both locoregional radiotherapy and boost increased CWP. In general, younger age, locoregional radiotherapy, and boost increased late toxicities. (* values from graph)
Whelan et al. 2019 (Canada) [43]; RCT single centre trial; Feasibility, safety, tolerance and toxicities of APBI versus WBI	NCI CTCAE v3; CRO	N = 2135 women, APBI (n = 1070), WBI (n = 1065), early-stage BC (stage I) treated with breast conserving surgery; Median age 61 (IQR 54–68)	Radiotherapy between 2006 and 2013; Median FU 103 months (IQR 88–119). Highest grade CWP reported at any time during follow up after 3 months	Accelerated, hypo fractionated APBI bi-daily fractions 6–8 h apart (n = 1070) or Moderately Hypo fractionated (n = 873) or conventionally (n = 192) fractionated WBI +/− sequential boost; 100% boost	APBI 38.5Gy 10#; 3.85Gy/#, Bi-daily. WBI 42.5Gy 16#; 2.66Gy/# or 50Gy 25#; 2Gy/#. Boost 10Gy 5#; 2Gy/#	APBI 1070 WBI 1065	Not reported	Not reported	APBI 26 WBI 3	APBI 4 WBI 0	Descriptive analysis. No risk factors for CWP discussed
Burkon et al. 2024 (Czech Republic) [44]; RCT single centre trial; Feasibility, safety, tolerance and toxicities of APBI versus WBI	CTCAE (version not stated); CRO. EORTC QLQ-C30 and EORTC QLQ-BR45; PROM	N = 84 women, APBI (n = 42), WBI (n = 42), early-stage BC (stage 1) treated with breast conserving surgery; Median age 65 (range 51–81)	Radiotherapy between 2019 and 2021; Median FU 37 months (range 21–45 months). Highest grade CWP reported at any time during follow up after 3 months	Ultra-hypo fractionated APBI (n = 42) or Moderately hypo fractionated WBI + sequential boost (n = 42); 100% boost	APBI 30Gy 5#; 6Gy/# or WBI 40Gy 15#; 2.67Gy/#. Boost 10Gy 5# 2Gy/#	APBI 42 WBI 42	APBI 42 WBI 41	APBI 0 WBI 1	APBI 0 WBI 0	APBI 0 WBI 0	No statistical difference between ABPI and WBI for chest wall pain

Abbreviations: BC, breast cancer; WBI, whole breast irradiation; CWI, chest wall irradiation; APBI, accelerated partial breast irradiation; CRO, clinician reported outcome; PROM, patient reported outcome measure; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; RTOG, Radiation Therapy Oncology Group; LENT-SOMA, Late Effects Normal Tissue Task Force- Subjective, Objective, Management, Analytic; EORTC QLQ-C30, European Organisation for Research Treatment of Cancer; EORTC QLQ-BR23 and EORTC QLQ-BR45, EORTC breast cancer PROM; Gy, Gray; #, Radiotherapy fraction; OR, Odds ratio; CI, confidence interval; IQR, interquartile range; FU, follow-up.

Data across studies were pooled for overall CWP prevalence figures and individual CWP gradings. Descriptive values and statistical analyses were collated to identify potential risk factors for CWP. A meta-analysis of CWP prevalence was not possible, and a descriptive synthesis was undertaken. Study characteristics and outcomes are summarised in Table 2, including assessment time points, use of clinician reported outcomes (CRO) or patient reported outcome measure (PROM) assessment tools, and patient characteristics. Radiotherapy treatment details, such as dose and fractionation schedules and use of tumour bed boost, were also reported, alongside the incidence and grading of CWP and associated risk factors.

Results

The literature search identified a total of 2510 articles, as illustrated in the PRISMA flow diagram (Fig. 1). After removal of duplicates, 1960 titles and abstracts were screened. Of the 335 full text articles assessed for eligibility, 327 were excluded for failing to meet the inclusion criteria. Among these, 107 studies reported late adverse effects but did not include pain as an outcome; 94 reported pain but did not distinguish CWP from other pain categories; 4 reported CWP without providing incidence data, and 1 reported CWP incidence but did not use an assessment with a pain grading tool [45]. Eight studies met the predefined inclusion criteria. These were published between 2012 and 2024 and comprised six prospective cohort studies [[37], [38], [39], [40], [41], [42]] and two randomised controlled trials (RCTs) comparing different radiotherapy regimens [[43], [44]].

Formal grading of the evidence was not undertaken, as CWP was inconsistently and incompletely reported across the included studies. Consequently, the available data were limited and insufficiently robust to support meaningful evidence grading or to add value to the review.

The eight studies included a total of 5887 participants, of whom 5509 were evaluable for CWP (Table 2). Attrition due to death or loss to follow up meant that not all participants from the original radiotherapy cohorts were available for long term assessment. Although studies were not limited to those including women, male patients only represented 0.4% of the study population in a single study [42]. Several studies combined adjacent pain categories, such as none/mild [40], or moderate/severe [[40], [42]], which reduced the number of patients contributing to specific CWP severity estimates. Mild, moderate, and severe pain were reported in all studies except Whelan et al. [43] which recorded only CTCAE grade ≥ 2 events (moderate/severe pain), and did not provide data for patients reporting mild pain. No studies reported CTCAE grade 4 disabling pain or LENT/SOMA refractory/excruciating pain.

Prevalence and severity of chest wall pain

The overall prevalence of CWP could be calculated from six studies [[37], [38], [39], [41], [42], [44]] and estimated to be 34.0% (1069 of 3141 patients reported CWP). Two studies had pooled data or missing data and could not be used in the overall prevalence calculation [[40], [43]].

Six studies could be used to estimate the prevalence of mild CWP [[37], [38], [39], [41], [42], [44]], with an overall rate of 26.1% (821 of 3141 patients reported CWP).

Pooled prevalence of moderate/severe CWP could be evaluated from all eight studies [[37], [38], [39], [40], [41], [42], [43], [44]] at 5.7% (312 of 5509 patients reported CWP).

There was substantial variation in the reported prevalence and gradings of CWP across all studies. Prevalence ranged from 2.4% (1 out of 42 patients reported CWP) in the WBI arm of the Burkon et al. RCT [44] to 56.0% (903 out of 1613 patients reported CWP) in the WBI cohort study by Batenburg et al. [42]. No cases of CWP were reported in the accelerated partial breast irradiation (APBI) arm of the Burkon et al. RCT [44]. This heterogeneity is likely attributable to several factors discussed below; pain assessment methods, variations in participant clinical characteristics, radiotherapy related factors of dose and fractionation, and volume of tissue irradiated.

Changes in CWP over time

The trajectory of CWP over time could not be reliably determined because of differences in the types and timings of assessments (Table 2). Follow up ranged from 3 to 119 months [[43], [44]], with a weighted mean of 44 months accounting for sample sizes. Four studies reported only crude incidence, defined as the highest pain grade observed at any point during follow up [[39], [41], [43], [44]]. Poppe et al. [41] reported highest pain grade after 6 months and noted that CWP appeared transient but did not report specific timings. Two studies used a single time point method, Batenburg et al. [42] at a median of 38 months and Nozaki et al. [37] at a median of 48 months. Dewan et al. [40] collected late toxicity data between 12 and 48 months but only reported 12 month CWP outcomes. Only the study from Bantema-Joppe et al. [38] reported sequential annual follow up, showing a decline in CWP from 12.1% at 12 months (68 of 562 patients reporting CWP) to 7.0% at 24 months (36 of 515 patients), 6.7% at 36 months (29 of 436 patients), and 7.5% at 48 months (15 of 200 patients).

None of the included studies reported baseline prevalence of CWP prior to radiotherapy, limiting the ability to determine the extent to which post treatment pain was attributable to radiotherapy rather than pre-existing symptoms. Three studies reported both acute and late CWP outcomes. Koukourakis et al. [39] found that CWP increased over time, with 6.3% of patients reporting acute CWP (7 of 112 patients) one month post radiotherapy compared with 11.6% reporting late CWP (13 of 112 patients). However, they assessed acute toxicity using CTCAE and late effects with LENT/SOMA limiting direct comparison. In contrast, Poppe et al. used CTCAE for both acute and late assessments and observed relatively stable rates of CWP, with 22.3% of patients reporting acute CWP (15 of 67 patients) and 20.9% reporting late CWP (14 of 67 patients). Similarly, Burkon et al. [44] used CTCAE throughout and reported a reduction in CWP following WBI from 7.1% acute CWP (3 of 42 patients) to 2.4% at late follow up (1 of 42 patients). In their APBI arm, CWP rates remained very low, decreasing from 2.4% acute CWP (1 of 42 patients) to no reported cases at late follow up.

Assessments used to identify chest wall pain

Seven studies used clinician reported outcomes (CROs), most commonly using the CTCAE (versions 3.0, 4.0, or 5.0) [[37], [38], [40], [41], [43], [44]]. Koukourakis et al. [39] instead used the LENT/SOMA scoring system, this can incorporate both clinician and patient reported outcomes although the study specified clinician review.

Patient reported outcome measures (PROMs) were only reported in one study [42]. Batenburg et al. [42] incorporated questions from the EORTC QLQ-C30 and QLQ-BR23, supplemented with targeted CWP questions derived from other assessment tools including CTCAE, Radiation Therapy Oncology Group (RTOG) criteria [46], and expert clinical opinion. Burkon et al. [44] used the breast specific EORTC QLQ-BR45 alongside CTCAE gradings, although the PROM data were not reported.

Clinically related risk factors for chest wall pain

Clinical related factors that may contribute to the development of CWP after radiotherapy were not consistently evaluated across the included studies. Age was collected universally (pooled median age 59 years), and Batenburg et al. [42] noted that women experiencing late adverse effects tended to be younger but did not offer any specifically analysis of age in relation to CWP.

Only two studies specifically examined the association between age and CWP, categorising patients as either younger than 50 years or 50 years and older. Bantema-Joppe et al. [38] analysed 562 patients at 12 months post treatment (mean age 59 years) and found that women younger than 50 years had a significantly higher risk of developing CWP than those aged 50 years or older (OR 0.4, 95% CI 0.2–0.7). In contrast, Dewan et al. [40], analysed 233 patients with a mean age of 48 years and reported no significant association between age and CWP. Although both studies employed multivariable regression analyses, differences in sample size, patient characteristics, statistical models, and outcome assessment methods may explain the inconsistent findings. Furthermore, Dewan et al. [40] excluded mild CWP from their analysis, which may have resulted in an underestimation of overall CWP prevalence and reduced the ability to detect age related differences.

Other potential risk factors, including smoking status, BMI and educational level, were either collected but not analysed [[38], [42], [44]], or not collected at all [[37], [39], [40], [41], [43]]. Further clinically related factors including surgical extent and adjuvant therapies were not analysed in relation to CWP.

Radiotherapy related risk factors for chest wall pain

Radiotherapy related factors were broadly categorised into dose and fractionation parameters, and the volume of tissue irradiated, both of which are well established determinants of the development of late radiation effects [22].

Dose and fractionation

Dose and fractionation were well documented for all eight studies. Radiotherapy fractionation schedules were categorised into four broad groups [27]: conventional fractionation delivering 1.64–2.14 Gray (Gy) per fraction over five to six weeks; moderate hypofractionation delivering 2.66–3.5 Gy per fraction over two to four weeks; accelerated hypofractionation delivering 3.4–3.85 Gy per fraction twice daily over one week; and ultra hypofractionation, defined as doses exceeding 5 Gy per fraction.

Fractionation schedules varied considerably across the included studies, with CWP reported following all regimens except ultra hypofractionation [44] (Table 2). Conventional fractionation was evaluated in three studies [[37], [38], [40]]. Nozaki et al. [37] delivered 50 Gy in 25 fractions WBI, plus a sequential 10 Gy boost in one-third of the patients and reported CWP in 10.0% of patients (70 of 703 patients). Bantema-Joppe et al. [38] reported a similar prevalence of 12.1% (68 of 562 patients) using 50.4Gy in 28 fractions WBI with a simultaneous integrated boost (SIB) to the tumour bed up to 64.4Gy or 67.2Gy. Rates of moderate/severe CWP were comparatively low in these studies, occurring in 0.4% (3 of 703 patients) and 2.3% (13 of 562) of patients, respectively [[37], [38]]. Although Dewan et al. [40] used a slightly lower dose of conventionally fractionated radiotherapy of 46Gy in 28 fractions WBI with a SIB of 59.9Gy, mild CWP was not reported separately limiting direct comparison, but the prevalence of moderate/severe CWP was higher at 13.3% (31 of 233 patients).

Greater variation was observed among five studies evaluating moderately hypofractionated regimens [[39], [41], [42], [43], [44]]. The prevalence of any grade CWP ranged from 2.4% (1 of 42 patients) for 40Gy in 15 fractions WBI with a 10Gy sequential boost to the whole breast in one arm of Burkon et al. [44] RCT, to 56.0% CWP (903 of 1613 patients) after a regimen of 40Gy in 15 fractions WBI with an SIB in 45% of patients of 53.4–55.9Gy for a low boost dose or 56.8–61.2Gy for a high boost dose [[42], [44]]. In these studies rates of moderate/severe CWP ranged from 0% (0 of 42 patients) to 13.9% (225 of 1612 of patients) [[42], [44]]. Evidence relating to accelerated hypofractionation and ultra hypofractionation was limited to single treatment arms from separate RCTs. The accelerated hypofractionated regimen of 38.5Gy in 10 fractions delivered bi-daily as PBI was associated with moderate/severe CWP in 2.8% of patients (30 in 1070 patients) [43], whereas no cases of CWP were reported among the 42 patients who received ultra hypofractionated APBI treatment of 30Gy in 5 fractions [44]. No clear relationship between fractionation schedule and CWP risk could be established.

Only one study reported chest wall dose–volume parameters, limiting assessment of the relationship between irradiated volume and CWP. Dewan et al. [40] used WBI with a SIB and reported that a higher GTV volume receiving more than 107% of the dose (V107%) was associated with increased CWP on univariate analysis, but this association was not significant on multivariate analysis, preventing firm conclusions regarding its contribution to CWP development.

Treatment volumes and radiotherapy technique

CWP was reported in patients with residual breast tissue who received WBI or PBI as well as in patients who underwent mastectomy followed by CWI. Several studies indicated that use of a tumour bed boost may increase the risk of CWP. Boost radiation was delivered sequentially after WBI or CWI using either electrons or photons [[37], [39], [41], [43], [44]] or as a SIB during WBI increasing the dose per fraction to the boost site [[38], [40], [42]]. Nozaki et al. [37] reported higher proportions of any grade CWP among patients receiving a sequential boost with 16.9% reporting CWP compared with 7.8% no boost, although statistical significance with Chi-squared tests was not reached. In the Bantema-Joppe et al. study [38], 12 months after breast irradiation, risk of CWP was doubled in patients treated with high boost dosage, with an absolute increase in CWP from 10.2% in the low boost group to 18.9% in the high boost dosage group (OR 2.06; CI 1.2–3.7). Batenburg et al. [42] also identified higher CWP among patients who had received a boost, regardless of whether they underwent local irradiation (50.8% reported CWP without a boost compared to 57.3% with a boost) or loco-regional treatment (55.4% reported CWP without a boost compared to 65.4% with a boost). Differences among studies did not allow for meaningful comparison between sequential and simultaneous boosts with respect to CWP risk.

Older studies used 3- dimensional conformal radiotherapy (3DCRT) to encompass the whole breast tissue. Nozaki et al. [37] reported 10.0% CWP (70 of 703 patients) with 0.4% moderate /severe CWP (3 of 703 patients), and Bantema-Joppe al. [38] 12.1% CWP (68 of 562 patients) and 2.3% moderate/severe CWP (13 of 562 patients). 3DCRT was also used for CWI after mastectomy. Koukourakis et al. [39] treated using a moderately hypofractionated regimen of 35Gy in 10 fractions with an 8Gy sequential boost and reported 11.6% patients any grade CWP (13 of 112 patients) and 1.8% moderate/severe CWP (2 of 112 patients). Poppe et al. [41] treated the chest wall to 36.6Gy in 11 fractions with a 13.3Gy sequential boost and found 19.4% reported CWP (13 of 67 patients) with 7.5% moderate/severe CWP (5 of 67 patients). The use of bolus in some of Poppe et al. patients likely altered chest wall dosimetry. Intensity modulated radiotherapy (IMRT) to the whole breast was used by Dewan et al. [40] reporting 13.3% moderate/severe CWP (31 of 233 patients). Batenburg et al. [42] used whole breast IMRT and reported similar rates of 13.9% moderate/severe CWP (225 of 1613 patients). However, Whelan et al. [43] also used whole breast IMRT but only reported 0.3% moderate/severe CWP (3 of 1065 patients). Volumetric modulated arc therapy (VMAT) treatment delivered to the whole breast by Burkon et al. [44] found no incidences of moderate/severe CWP (0 of 42 patients) and only 2.4% of mild CWP (1 of 42 patients). PBI techniques, which limit the volume of breast tissue treated, were associated with low reported rates of CWP. Whelan et al. [43] used 3.85Gy per fraction in 10 bi-daily treatments and reported 2.8% moderate/severe CWP (30 of 1070 patients). Burkon et al. [44] treated partial breast volumes in 6Gy fractions and reported no CWP (0 of 42 patients).

All eight studies treated patients in a supine position, no prone radiotherapy studies reported incidences of CWP to be included in this review.

Discussion

The findings of this review suggest that CWP may be a common late effect following breast cancer radiotherapy, affecting up to one third of patients (34.0%). Approximately one quarter of patients (26.1%) reported mild pain, and 5.7% had moderate/severe pain that persisted beyond treatment. The development and resolution of CWP is not clear due to a paucity of both baseline and longitudinal data. Most studies used CROs to report CWP, whereas the only study using a targeted PROM identified substantially higher rates of CWP. Younger age and a tumour bed boost may increase the risk of CWP, but due to heterogeneity in study design no definitive risk factors could be identified.

Prevalence and severity of chest wall pain

There was marked variation in the reported prevalence of CWP across the included studies. Establishing an accurate estimate was challenging because studies differed substantially in all aspects. For example, Batenburg et al. [42] reported the highest prevalence of CWP, with 56.0% of patients affected, whereas no cases of CWP were reported in the ultra hypofractionated arm of the RCT by Burkon et al. [44]. These studies differed considerably in several aspects relevant to CWP including radiotherapy dose and fractionation (40 Gy in 15 fractions vs 30 Gy in 5 fractions) and treatment volumes (WBI vs PBI, respectively). The use of pooled categories of data and missing data in some studies [[40], [43]] meant different studies contributed to different prevalence estimates, further complicating comparisons.

Trajectory of chest wall pain

Most studies used cross sectional or infrequent post treatment clinical assessments, limiting insight into the trajectory of CWP. In contrast, longitudinal outcome assessment is well established for breast cancer survivorship research [47], [48]. Enabling patients to report symptoms as they arise through patient reported ongoing monitoring, rather than at predefined screening time points, may reduce the likelihood of transient or evolving symptoms being missed [49]. Such an approach could provide a more accurate understanding of the onset, persistence, and resolution of CWP over time without increasing the burden of routine clinic visits.

Interpretation of the available evidence was further limited by the absence of pre-treatment baseline assessments, therefore we were unable to determine whether CWP was present before radiotherapy and to quantify its specific contribution. Studies that attempted to evaluate the relationship between acute and late radiotherapy toxicities within the same patient populations produced inconclusive findings, largely due to methodological limitations.

Longitudinal follow up of the same patient cohort would provide insight into the temporal trajectory of CWP and enable evaluation of its development following radiotherapy. Bantema Joppe et al. [38] employed annual assessment and reported a decline in CWP prevalence during follow up. Interpretation of these findings is limited by substantial attrition, with the study population decreasing from 562 to 200 patients. Consequently, it remains unclear whether CWP resolved among affected individuals, persisted in a subset of patients, or developed later following treatment completion.

Assessment of chest wall pain

Inconsistent reporting of CWP is compounded by the absence of a standardised definition and the frequent reliance on generic or indirect measures of pain. Although the CTCAE has included a specific descriptor for CWP since version 4 in 2010 [31], defining it as a musculoskeletal and connective tissue disorder “characterized by a sensation of marked discomfort in the chest wall”, other commonly used assessment tools do not provide a specific definition. For example, LENT/SOMA scales and the EORTC PROMs assess broader pain related symptoms without specifically identifying CWP. Consequently, studies using different assessment instruments may capture different pain experiences, limiting comparability between findings.

This lack of standardisation also affected study eligibility for the present review. For example, a bi-daily APBI study by Gatti et al. [45] reported that 19% of patients experienced transient CWP during follow up. However, the study assessed toxicity using the Radiation Therapy Oncology Group (RTOG) late effects grading schema [46], which does not include a specific category for pain. As a result, the reported outcomes could not be reliably mapped to the harmonised CWP grading system used in this review and the study was therefore excluded. This highlights the challenges associated with synthesising evidence across studies that employ different toxicity assessment frameworks and reinforces the need for a standardised definition and reporting approach for CWP in breast radiotherapy research.

Pain symptoms are frequently captured through proxies such as analgesic use or functional limitation, which may underestimate both prevalence and impact [50]. CROs have repeatedly been shown to under report treatment related symptoms compared with patient self-report [51], [52], [53]. In contrast, PROMs could provide a more meaningful reflection of day-to-day health status and symptom burden [54].

The importance of targeted assessment for PROMs is illustrated by Batenburg et al. [42], who incorporated a direct question on CWP and reported a substantially higher prevalence than studies using less specific assessment tools. The key question, “Did you have any pain in your chest wall? For example, (muscle) pain in your ribs?”, was both explicit and concise. The instrument further distinguished CWP from breast pain by defining pain in the affected breast as pain “other than muscle pain or rib pain” and instructing patients who had undergone mastectomy without reconstruction not to complete that item. This level of specificity likely contributed to the higher prevalence of CWP reported compared with other studies included in this review.

The use of a PROM to evaluate CWP was limited to a single study [42], preventing corroboration of these findings across independent cohorts. Nevertheless, the study's rigorous design and large sample size strengthen confidence in the validity of its findings and support the value of targeted PROMs for identifying CWP. These results suggest that less specific assessment tools may underestimate the true prevalence of CWP.

The use of a more targeted assessment also ensures that CWP is recognised as a distinct clinical entity rather than being conflated with breast pain. This could be further exploited to aid understanding of the underlying aetiology of CWP. Such differentiation is particularly important given the heterogeneous anatomy of the chest wall, comprising bone, muscle, connective tissue, and neurovascular structures, all of which may be affected by radiotherapy. Although rib fractures have been associated with CWP, most radiation induced rib fractures are asymptomatic, suggesting that osseous injury alone does not fully explain the pathophysiology of CWP [55]. Radiation can induce structural and functional changes within the pectoral musculature, including fibrosis, stiffness, atrophy, and persistent inflammatory changes, which could contribute to the development of pain [56], [57].

Electronic PROMs (ePROMs) provide a practical and scalable mechanism to deliver targeted assessment longitudinally [58], [59]. Traditional follow up pathways prioritise oncological surveillance and often provide limited opportunities for patients to report late adverse effects, particularly once discharged to remote follow up models. ePROMs enable patients to report symptoms as they arise, support continuous monitoring from baseline through long term survivorship and have demonstrated greater sensitivity than CROs in detecting acute treatment related toxicity [60]. Broader implementation of targeted ePROM systems could therefore improve detection and characterisation of CWP, facilitate earlier screening and more personalised intervention, and reduce reliance on routine outpatient follow up.

Clinical factors for chest wall pain

The development of CWP is likely multifactorial, reflecting complex interactions between patient, treatment, and biological related factors. The marked variation in late effects observed among patients receiving similar treatments suggests that additional determinants, such as body composition or radiation dose distribution also contribute to risk of late effects [21], [26].

Defining an association between age and CWP is complicated by potential confounding from treatment related factors. Younger patients are more likely to receive intensive multimodality treatment, including systemic therapies and tumour bed boosts, both of which may increase the risk of developing CWP. Consequently, it remains unclear whether younger age is an independent risk factor for CWP or whether the observed association reflects differences in treatment exposure. Based on the evidence identified in this review, the independent contribution of age to CWP development cannot be reliably determined.

Nevertheless, as breast cancer survival continues to improve, younger patients may live for many decades following treatment and therefore have a longer period during which late treatment related effects can emerge and persist. Understanding the long term burden of CWP in this population is therefore increasingly important for optimising survivorship care.

Radiotherapy factors for chest wall pain

The reviewed studies spanned more than two decades, from the early 2000s [[37], [39]] to 2021 [44], reflecting substantial evolution in radiotherapy planning and delivery techniques. Earlier studies provided limited technical detail and typically employed tangential fields with electron boosts [37], while later studies incorporated more advanced techniques including image guidance, personalised immobilisation, deep inspiration breath hold (DIBH), and volumetric modulated arc therapy (VMAT) [44]. Consequently, it was not possible to disentangle the individual contributions of fractionation schedule, total radiation dose, dose per fraction, boost delivery, or boost timing (sequential versus SIB) to the development of CWP.

The chest wall receives some dose in all breast radiotherapy treatment types; WBI, CWI and PBI. Patient positioning may influence the extent of chest wall irradiation. In the supine position, breast tissue spreads across the chest wall, increasing the volume of underlying chest wall structures exposed to radiation. Data regarding chest wall volumes are not widely available, probably because the chest wall is not considered a structure in breast radiotherapy or contoured for planning purposes. Rudat et al. reported that the average volume of irradiated chest wall tissue exceeded 612 cm³ in post mastectomy patients treated in the supine position [61]. In contrast, prone positioning allows the breast tissue to fall away from the chest wall, potentially reducing the volume of chest wall structures receiving high doses.

Kirby et al. [62] compared prone and supine radiotherapy plans generated for the same patients for both WBI and PBI. They demonstrated a reduction in the volume of chest wall receiving the full prescription dose (V100%) from 26 cm³ supine to 1 cm³ prone for WBI, and from 14 cm³ supine to 0 cm³ prone for PBI. These findings suggest that prone positioning may reduce chest wall dose although further literature has suggested this may only be advantageous for patients with tumours located away from the chest wall [63]. Despite its potential advantages, prone positioning has not been widely implemented in routine clinical practice [64] and its impact on the development of CWP remains unexplored.

IMRT, VMAT and PBI techniques have the potential to reduce exposure of chest wall structures by limiting the volume of tissue irradiated. In this review, studies employing IMRT [[40], [42], [43], [44]] still reported CWP. VMAT and PBI reported relatively low rates of CWP [[43], [44]] however, the available evidence was limited to two RCTs and differences in study design, patient selection, and outcome assessment preclude firm conclusions regarding the impact on CWP.

In this review, the overall quality and granularity of the radiotherapy data were limited. The volume of chest wall tissue irradiated, together with the dose delivered, may contribute to the development of CWP. This is supported by the data from Dewan et al. [40] demonstrating a relationship between high dose regions (e.g. V107%) and increased rates of CWP. Similar associations between irradiated chest wall volume and pain have been well documented in lung cancer radiotherapy studies where the occurrence of CWP has driven the development of chest wall dose constraints [65], [66]. However, in breast cancer radiotherapy planning, the chest wall is not routinely considered an organ at risk [26], [67], [68].

Detailed information regarding chest wall doses and irradiated volumes was largely unavailable, restricting exploration of potential dose–volume effects. This was especially pertinent for tumour bed boost irradiation, which showed some evidence of an association with CWP, although the relationship was not consistently demonstrated across studies. Tumour bed boost irradiation may increase the dose received by adjacent chest wall structures, including the ribs, connective tissues, and musculature. As the chest wall is composed predominantly of connective tissues, these structures may be particularly susceptible to radiation induced fibrosis, a recognised late effect of radiotherapy that may contribute to the development of CWP [69], [70]. This raises the possibility that any observed association between boost irradiation and CWP may, in part, reflect a dose–response relationship involving chest wall tissues. However, the available studies provided insufficient dosimetric data to adequately evaluate this hypothesis. These findings highlight the need for future studies to incorporate detailed chest wall dosimetry, including dose–volume parameters for relevant normal tissues, alongside standardised pain assessment measures to better understand treatment related risk factors for CWP.

Larger, harmonised datasets would enable robust multivariable analyses to define risk profiles and explore symptom clustering. Particularly the co-occurrence of CWP with tumour bed boosts and other late effects such as fibrosis and musculoskeletal dysfunction. The REQUITE study demonstrated the feasibility of integrating genomics, radiotherapy planning data, and PROMs, including the EORTC QLQ-C30 [34] and QLQ-BR23 [71] to reduce adverse effects. However, as highlighted by this review, these instruments lack specificity for CWP, capturing overall breast pain but not specifically CWP. This underscores both the limitations of existing datasets and the potential for future inclusion of more targeted outcome measures to better assess risk factors for late radiotherapy effects after breast cancer treatment.

Batenburg et al. [42] reported that patients experiencing late effects following breast cancer radiotherapy were two to eight times more likely to require additional supportive care interventions, including analgesic medication, physiotherapy, and lymphoedema management, than patients without late effects. This increased healthcare utilisation suggests that late radiotherapy effects may have a substantial impact on quality of life and healthcare costs. However, the specific impact of CWP remains poorly understood, as few studies have examined its functional, psychological, or economic consequences in isolation. Further research is therefore needed to determine the broader burden of CWP and to inform strategies for identifying patients at risk, preventing its development, and optimising long term management.

This systematic review has several limitations. Only a small number of eligible studies reported CWP, and most were observational cohort studies. Although RCTs were included, CWP was not a primary endpoint, limiting causal inference. In addition, pooled pain outcomes and missing data for specific pain grades meant that different studies contributed to different prevalence estimates, reducing comparability across studies. The absence of baseline pain assessments further limits interpretation, as it is unclear whether post radiotherapy pain was treatment related or pre-existing. Consequently, the specific contribution of radiotherapy to CWP remains uncertain.

Conclusion

Chest wall pain (CWP) following breast cancer radiotherapy is a potentially common, clinically significant, and insufficiently recognised late effect. Wide variability in the reported CWP data resulted from differences in study design, assessment methods and the limited reporting of clinical and treatment related factors. Improved longitudinal assessment from baseline, the use of standardised and targeted pain measures, and wider adoption of electronic PROMs are needed to accurately characterise its prevalence, trajectory, and impact. Larger prospective datasets will be essential to identify risk factors, explore symptom clustering, and better understand the burden of CWP. Greater consideration of the chest wall during radiotherapy planning may help reduce the risk of CWP and improve long term quality of life for breast cancer survivors. As breast cancer diagnosis and treatment continue to advance and survivorship improves, further research into CWP as a late effect of breast cancer radiotherapy is warranted.

CRediT authorship contribution statement

Lisa Durrant: Writing – review & editing, Writing – original draft, Methodology, Funding acquisition, Formal analysis, Data curation, Conceptualization. Rachel Harris: Writing – review & editing, Writing – original draft, Methodology, Conceptualization. Charlotte Atkinson: Writing – review & editing, Writing – original draft, Methodology, Conceptualization. Sara Faithfull: Writing – review & editing, Writing – original draft, Supervision, Methodology, Formal analysis, Conceptualization.

Funding

LD received funding from NIHR University of Exeter BRC. This study/research is funded by the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Lisa Durrant reports financial support was provided by NIHR Exeter Biomedical Research Centre. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

Supplementary material 1

Supplementary material 2