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. 2020 Jun 3;15(6):e0234118. doi: 10.1371/journal.pone.0234118

Absolute and relative reliability of pain sensitivity and functional outcomes of the affected shoulder among women with pain after breast cancer treatment

G H F Rasmussen 1,*, M Kristiansen 1, M Arroyo-Morales 2, M Voigt 1, P Madeleine 1
Editor: César Calvo-Lobo3
PMCID: PMC7269234  PMID: 32492064

Abstract

Objective

Breast cancer survivors (BCS) are often characterized by decreased pressure pain thresholds (PPT), range of motion (ROM) and strength in and around the shoulder affected by the treatment. This intra-rater reliability study was to establish the relative and absolute reliability of PPT’s, active ROM and maximal isokinetic muscle strength (MIMS) of the affected shoulder in BCS with persistent pain after treatment.

Methods

Twenty-one BCS participated in the study. The PPTs of 17 locations and pain intensity were assessed using a pressure algometer and a numeric rating scale. The ROM was measured using a universal goniometer and MIMS was measured using an isokinetic dynamometer. Relative reliability was estimated using intra class correlation coefficient (ICC), and absolute reliability using standard error of measurement (SEM). Minimum detectable change (MDC) was calculated from SEM.

Results

The ICCs for PPTs ranged from 0.88–0.97, with SEM values ranging from 12.0 to 28.2 kPa and MDC ranging from 33.2 to 78.2 kPa. The ICCs for ROM ranged from 0.66–0.97, with SEM values ranging from 3.0 to 7.5° and MDC ranging from 8.4 to 20.8°. Finally, ICCs for MIMS ranged from 0.62–0.92, with SEM values ranging from 0.03 to 0.07 Nm/Kg FFM and MDC ranging from 0.09 to 0.19 Nm/kg FFM.

Conclusion

The results of this study indicate that PPTs, ROM and MIMS can be measured reliably on the affected shoulder in BCS with pain after treatment. This offer the possibility of using these measures to assess the effectiveness of interventions in this population.

Introduction

Breast cancer is the most common type of cancer among women. More than one million new cases were reported worldwide in 2018 [1]. Fortunately, due to new treatments and early detection, survival has improved over time [2] with a current 5-year survival rate of 90% [1]. However, breast cancer and its treatments result in both complications and common adverse effects, including severe pain and loss of shoulder function exemplified by limited shoulder range of motion (ROM) and decreased strength [3]. Pain in and around the surgical area affect 25–60% of the breast cancer survivors (BCS) [4], while 42–56% report difficulties in lifting the upper limb and 10–55% show restricted glenohumeral joint ROM [5]. These morbidities can be caused by scar tissue formation [6] and nerve damage [7] from the surgical incisions, and may be further exacerbated by soft tissue fibrosis secondary to radiation- and/or chemo therapy [8–10]. They may arise shortly after surgery and/or adjuvant treatment and can remain as a source of physical and psychological distress for several years [11]. Consequently, shoulder morbidity and pain after breast cancer treatment have received considerable attention in the literature with several recent reviews examining the extent of these issues [6], [12–14].

Importantly, pain after treatment for breast cancer can increase pain sensitivity [15] and reduce physical function [16]. Pain intensity is correlated with decreased muscle strength, ROM, job participation, and reduced use of the affected arm in leisure activities [17]. However, to the best of our knowledge, there are no studies linking shoulder pain sensitivity and physical function in BCS. Key methods for assessing pain sensitivity and shoulder function include pressure algometry, goniometry and isokinetic dynamometry. Pressure algometry can be used to assess mechanical pain sensitivity in different anatomical locations [18], and the assessment of multiple pressure pain threshold (PPT) locations enable the visualization and quantification of the spatial distribution of mechanical sensitivity to pain [19–21]. The spatial distribution of the mechanical pain sensitivity reveals the extent of hyperalgesia in BCS [22], [23], and localizing the most sensitive areas may be of interest to the design of specific rehabilitation programs [15]. Goniometric measurements can be performed with a universal goniometer, a low cost tool most commonly used for evaluating active and passive joint ROM in clinical settings [24]. Isokinetic dynamometry allows the measurement of maximum muscle strength with an accommodating resistance, at a constant angular velocity, thereby enabling maximum force production throughout a prescribed ROM [25].

The above mentioned methods have been used to assess mechanical pain sensitivity and shoulder function in BCS [15], [26], [27], and have been reported as reliable in both asymptomatic [25], [28], [29] and patient populations [30–32]. However, little is known about the relative and absolute reliability of these methods in BCS with pain after treatment. As previously established, ROM and muscle strength are affected by the presence of pain, and considering that substantial day-to-day fluctuations can be observed in perceived pain [33], measures of pressure algometry, goniometry and isokinetic dynamometry may vary considerably in BCS experiencing pain. In order to monitor the effectiveness of an intervention aimed at improving shoulder function and decreasing pain after breast cancer treatment, it is essential to have reliable tools for assessment of clinical outcomes [34]. Hence, the aim of the present study was to establish the spatial distribution of mechanical pain sensitivity, and the absolute and relative test-retest reliability of PPTs, active ROM and maximal isokinetic muscle strength (MIMS) in BCS with pain in body regions affected by the treatment, i.e. the ventral and dorsal regions of the shoulder.

Methods

Participants

According to the guidelines of Bujang & Baharum [35], assuming two observations per participant, an alpha level of 0.05, a beta level of 80% and an expected ICC of 0.60, the minimum sample size required for this study was 15 participants. To account for potential dropout it was decided to enrol 21 BCS. Participants were recruited by means of a database letter through the national database managed by the Danish Breast Cancer corporate Group. The inclusion and exclusion criteria were similar to those used by Caro-Morán & colleagues [15]. Accordingly, the inclusion criteria were: I) primary diagnosis of breast cancer (grades I-IIIA); II) adult women at least 18 years of age; III) having received breast cancer treatment (i.e. surgery and possible adjuvant chemo and/or radiotherapy) at least 18 months before the start of the study; IV) self reported pain in the areas of the breast, shoulder, axilla, arm and/or side of body with an intensity of ≥ 3 on a numeric rating scale (0 = no pain, 10 = worst pain imaginable); V) no signs of cancer recurrence; VI) reading, writing and speaking Danish. The exclusion criteria were: I) breast surgery for cosmetic reasons or prophylactic mastectomy; II) bilateral breast cancer; III) lymphedema; IV) other chronic pain conditions (e.g., rheumatoid arthritis) or V) previous diagnosis of fibromyalgia syndrome. All the participants were instructed to maintain their normal everyday lifestyle, but avoid physical activity and consumption of alcohol, caffeine, nicotine, or painkillers in the last 24 hours prior to the experimental sessions. This was confirmed verbally upon arrival at the laboratory. The study protocol was approved by the local Ethics Committee (N-20180090) and conducted according to the Declaration of Helsinki. Following a detailed written and verbal explanation of the experimental risks of the study, the participants gave their written informed consent prior to participating in the study.

Study design

This intra-rater reliability study was conducted in accordance with the GRRAS guidelines [36]. In line with the GRRAS guidelines, we report information on sample selection, study design, and statistical analysis (S1 Appendix). Each participant completed a familiarization session (FS), followed by two experimental sessions (ES1 & ES2), see Fig 1. In agreement with previous studies on PPT and MIMS in chronic pain populations [32], [37], familiarization and the two experimental sessions were separated by a time period of seven days. Baseline characteristics and profile on physical, health, surgical, medical and pain status were collected during the FS. The PPT, active range of motion (ROM) and MIMS were measured unilaterally on the operated side in all sessions by the same experimenter (GHFR) (Fig 1).

Fig 1. Experimental overview.

Fig 1

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Overview of the experimental protocol at test-retest. Abbreviations: Bioelectrical Impedance Analysis: BIA, Anthropometrics: Anth, Questionnaire: Quest, Pressure pain threshold: PPT, Active range of motion: ROM, Maximal isokinetic muscle strength: MIMS.

Outcomes

Pain intensity and mechanical sensitivity measures

Pain intensity (PI) during everyday living was rated for the chest, shoulder, axilla, arm and side of body at the beginning of FS using a 0–10 numeric pain rating scale [38]. The cut-off scores used as reference were: 0 = no pain; 1–3 = mild; 4–6 = moderate; 7–10 = severe pain [39]. The highest pain intensity rated across locations was reported as peak pain.

Pressure pain thresholds were measured unilaterally over 6 points on the dorsal and 11 points on the ventral part of the chest, shoulder, and neck regions for a total of 17 points. A single measurement was collected from the ipsilateral tibialis anterior muscle as a distant reference point [7]. For the measurements performed on the dorsal region, participants were seated with their chest supported and elbows resting on the knees with the humerus perpendicular to the floor. For measurements performed on the ventral region, participants were lying supine on an examination table with both arms resting along the body. All PPT measurements were made using a pressure algometer (Somedic AB, Farsta, Sweden) with a 1 cm2 probe and a constant pressure rate of 30 kPa/s. The participants were instructed to press a handheld button as soon as the pressure sensation changed to pain sensation. The assessments were performed twice over two rounds in systematic order and a third time if the point assessed had a coefficient of variance over 20% [40]. There were approx. 6-minutes between measurements made over the same point to avoid temporal summation of pain.

Pressure pain threshold mapping of the dorsal region using the average PPT values of the six points was performed by measuring the distance d between C7 and acromion for each participant to compute the inter-distance between the six points covering the dorsal muscles (Fig 2). Similarly, PPT mapping of the ventral region was generated using the average PPT values of the 11 points and the distance e between acromion and the sternoclavicular joint for positioning of measuring points (Fig 3). Adjacent points were separated by varying distances according to their anatomical location relative to the reference points (Figs 2 and 3). We applied an inverse distance weighted interpolation to obtain a map of the spatial pressure pain distribution of the dorsal and ventral region [19]. For more details about the mathematical aspects, see Alburquerque-Sendin et al. [18]

Fig 2. Dorsal grid.

Fig 2

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Schematic representation of the dorsal grid for pressure pain threshold (PPT) assessments. The PPTs were measured over 6 points located on the trapezius muscle (P1-P2), infraspinatus (P3), posterior deltoid (P4), latissimus dorsi (P5) and lateral deltoid (P6). d = distance between the seventh cervical vertebra (C7) and acromion (ACR) on the x-axis.

Fig 3. Ventral grid.

Fig 3

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Schematic representation of the ventral grid for pressure pain threshold (PPT) assessments. The PPTs were measured over 11 points located on the anterior deltoid (P7-P10) and pectoralis major (P11-P17). e = distance between the sternoclavicular joint (SCJ) and acromion (ACR) on the x-axis. C = the summed distance between P11 and P12, P12 and P14, and P14, and P16 on the x-axis.

Physical measures

Body mass index (kg/m2) was calculated from height and weight measured at baseline. The fat free mass (FFM) was computed using bioelectrical impedance analysis (InBody 370, Biospace, Seoul, Korea) in agreement with the manufacturer’s recommendations.

Active ROM was measured for supine shoulder flexion, supine horizontal shoulder flexion/extension, supine internal/external shoulder rotation, and seated upright shoulder abduction (Fig 4A–4F). Similar levels of reliability have been reported for supine and upright measures of active ROM [28] and hence, positions were chosen to match the MIMS protocol. In agreement with Norkin & White [41], supine measurements were performed with the knees flexed to flatten the lumbar spine. For the seated upright measurement participants were positioned seated firmly against the back of the chair to ensure trunk stabilization, and instructed to maintain a neutral head position in agreement with Dougherty et al. [42].

Fig 4. Active range of motion positions.

Fig 4

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Schematic movement directions measured for active range of motion (ROM) on the affected side; shoulder flexion (A), horizontal shoulder flexion/extension (B and C), seated shoulder abduction (D) and internal/external shoulder rotation (F, 1 (internal) and 2 (external)) performed with 90° shoulder abduction and elbow flexion. Starting positions are marked in bold with arrows referencing movement direction (large) and axis of rotation (small) of the arm and shoulder.

Shoulder flexion ROM was measured as maximal shoulder flexion starting with the arm in 0°-shoulder flexion, 0°- abduction/adduction and rotation, 0° -elbow flexion and 0° -forearm supination/pronation (Fig 4A). Horizontal flexion/extension ROM was measured as maximal horizontal shoulder flexion/extension starting with the arm in 90° -shoulder flexion, 0° -shoulder abduction/adduction and rotation, 0° -elbow flexion and 0° -forearm supination/pronation (Fig 4B and 4C). Shoulder abduction ROM was measured as maximal shoulder abduction starting with the arm in 0° -shoulder flexion, abduction/adduction, 45° -shoulder rotation, 0° -elbow flexion and 90° -forearm supination (Fig 4D). Internal/external shoulder rotation ROM was measured as maximal internal/external rotation starting with the arm in 90° -shoulder abduction, 90° -elbow flexion, and the forearm perpendicular to the supporting surface in 0° of supination/pronation for supine internal/external rotation (Fig 4E and 4F).

Goniometric measurements were obtained with a goniometer by aligning the goniometer arms between bony landmarks (e.g. olecranon process and ulnar styloid of the forearm, and medial epicondyle of the humerus) and positioning the fulcrum of the goniometer above the approximate projection of the given joint center on the movement plane [28]. The assessments were performed twice over two rounds in systematic order and a third time if the measurements had a coefficient of variance ≥ 20%. The mean ROM values were calculated for each movement direction.

Maximal isokinetic muscle strength (MIMS) was measured in the shoulder flexors/extensors, horizontal extensors/flexors, abductors/adductors and internal/external rotators using an isokinetic dynamometer (Humac Norm, model 770, Computer Sports Medicine Inc., Stoughton, USA). Participants were positioned for each assessment according to the manual with stabilizing straps positioned over the hips and chest. The anatomical axis of rotation of the shoulder joint was carefully aligned with the fulcrum of the dynamometer. Each participant was familiarized with the protocol during FS, and a brief general warm up (approx. 10-minutes) of various stretching exercises for the prime movers was conducted prior to testing. Isokinetic strength testing was performed at a speed of 60°/s through the active ROM previously measured for each movement direction in line with Brown & Weir [43].

A series of 10 consecutive contractions with submaximal progressive effort followed by a series of five consecutive contractions at maximal effort was performed for each muscle group with a 2-minute rest period between series. Rest between strength measures for different movement patterns consisted of the time required for readjustment of the dynamometer (approximately 5 minutes). In agreement with Brown & Weir [43] the first repetition of each maximal trial was discarded and mean peak torque at a fixed position was calculated for the remaining four. Peak torque was normalized to FFM and is expressed as Nm/kg FFM [44]. The fixed joint position for each movement pattern was determined by identifying the participant that demonstrated the lowest ROM in each pattern and calculating the joint angle corresponding to midrange. Gravity correction was performed for each participant prior to the series of assessments.

Statistical analysis

Intra-class correlation coefficient (ICC2,1 for absolute agreement) was computed for all measures to assess the relative variability and interpreted according to Landis and Koch in which an ICC between 0.00 and 0.20 is considered “poor”, 0.21–0.40 is “fair”, 0.41–0.60 is “moderate”, 0.61–0.80 is “substantial”, and 0.81–1.00 is “almost perfect” [45]. Furthermore, Bland-Altman plots were constructed to evaluate heteroscedasticity of the measurements and detect any systematic bias in the mean difference between sessions for PPT, ROM and MIMS. Bias exists when the second set of measurements yield a different mean and heteroscedasticity occurs when the mean difference between measurements changes as their average changes [46]. Absolute reliability of each measure was estimated by computing the standard error of measurement (SEM). Using the standard deviation of the measurements from participants in both sessions (SD), SEM was calculated with the following formula:

SEM=SD1-ICC

SEM was further utilized to calculate minimal detectable chance (MDC), which represents the minimal value for which a difference can be considered as real. The formula for MDC is the following:

MDC=SEMx1.96x2

A 2-way repeated measures analysis of variance (ANOVA) was performed to investigate potential differences between sessions. PPT was used as dependent factor with anatomical location (P1-17) and experimental session (ES1 & ES2) as independent factors. Similarly, active ROM and MIMS were used as dependent factors with movement direction (1–6 & 1–8) and experimental session (ES1 & ES2) as independent factors. All post hoc analyses were performed with Bonferroni correction for multiple comparisons. The Shapiro-Wilks test of normality was applied to test the assumption of normal distribution and Mauchly’s test of sphericity was used to test for equality of variance in the differences between levels. If the assumption of sphericity was violated a Greenhouse-Geisser correction was applied. A P value less than 0.05 was considered statistically significant. Differences are expressed as mean (confidence interval (CI) 95%).

Results

Participants

Pain intensity, severity and painful locations of the 21 participants are reported in Table 1. Participants (mean (CI 95%); age: 57.4 (54;60.8) years, height 167.9 (165.5;170.2) cm, body mass index: 27.6 (25.3;29.8) kg/m2) had experienced pain for a mean (95% CI) period of 58.9 (42.9;75) months prior to participating in the study. See supplemental information for detailed cohort description (S2 Appendix).

Table 1. Perceived pain characteristics of the 21 women participating in this study.

Characteristic: Cases (N = 21)
Peak pain intensity, mean (CI: 95%) 7.2 (6.6;7.9)
Pain severity, No. (%)
Light 0 (0)
Moderate 10 (48)
Severe 11 (52)
Location, No. (%)
Chest 17 (81)
Shoulder 8 (38)
Axilla 8 (38)
Arm 4 (19)
Side of body 8 (38)
More than 1 location 11 (52)
Time with pain, mean (CI: 95%), months 58.9 (42.9;75)
Use of pain relieving medicine, No. (%) 7 (33)
Pain considered biggest problem post treatment, No. (%) 10 (48)
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Abbreviations: 95% confidence interval, CI:95%.

Pressure pain threshold

Relative and absolute reliability of PPT is reported in Table 2. The ICCs of the 17 anatomical locations on the dorsal and ventral shoulder regions were “almost perfect” [45], with ICC values ranging from 0.88–0.97. SEM values ranged from 12.0 to 28.2 kPa, while MDC ranged from 33.2 to 78.2 kPa. The ICC of tibialis anterior was 0.91 with an SEM and MDC of 27.0 and 74.8 kPa respectively. The analysis of the Bland-Altman plot showed no apparent systematic bias in the data with zero included in the 95% confidence interval. Heteroscedasticity was absent indicating a lack of systematic errors during the PPT measurements. The upper-lower limits of agreement (LOA) ranged from 46.5 to 117.4 kPa and -119.9 to -45.3 kPa with a bias ranging from -13.2 to 19.7 kPa (Fig 5). See supplemental information for individual Bland-Altman plots (S3 Appendix).

Table 2. Test-retest reliability of each pressure pain threshold location in breast cancer survivors (N = 21).

PPT locations (kPa) Mean ES 1 (95% CI) Mean ES 2 (95% CI) ICC2,1 (95% CI) SEM1 MDC 2
Point 1 164.2 (130.0;198.3) 152.7 (123.5;181.8) 0.92 (0.81;0.97) 19.4 53.8
Point 2 178.1 (135.6;220.6) 176.7 (128.1;225.2) 0.94 (0.86;0.98) 24.0 66.6
Point 3 168.6 (135.4;201.8) 157.8 (122.8;192.7) 0.91 (0.79;0.96) 22.0 61.0
Point 4 194.7 (144.7;244.6) 182.7 (139.2;226.1) 0.92 (0.81;0.97) 28.2 78.2
Point 5 151.3 (117.6;185.1) 159.5 (120.9;198.1) 0.89 (0.73;0.96) 26.2 72.7
Point 6 159.3 (119.9;198.7) 146.1 (114.5;177.7) 0.90 (0.75;0.96) 25.0 69.2
Mean.Dors 169.4 (130.4;208.4) 162.6 (124.6;200.5) 0.95 (0.88;0.98) 18.9 52.4
Point 7 139.4 (115.4;163.5) 145.7 (116.3;175.1) 0.90 (0.74;0.96) 18.9 52.4
Point 8 126.7 (103.9;149.4) 125.9 (102.0;149.8) 0.94 (0.86;0.98) 12.0 33.2
Point 9 131.1 (106.5;155.7) 132.0 (106.8;157.2) 0.88 (0.71;0.95) 18.6 51.4
Point 10 131.9 (104.1;159.7) 134.5 (103.4;165.5) 0.89 (0.71;0.95) 22.3 61.8
Point 11 125.6 (92.1;159.0) 125.2 (90.2;160.1) 0.94 (0.85;0.98) 18.5 51.2
Point 12 114.5 (78.2;150.9) 108.7 (82.5;135.0) 0.89 (0.73;0.96) 22.7 63.0
Point 13 109.0 (70.6;147.3) 97.0 (65.2;128.9) 0.95 (0.89;0.98) 16.5 45.6
Point 14 110.6 (88.6;132.7) 116.2 (86.7;145.8) 0.89 (0.73;0.96) 18.9 52.3
Point 15 93.6 (73.8;113.3) 96.7 (71.9;121.6) 0.94 (0.84;0.97) 12.4 34.5
Point 16 112.2 (85.0;139.4) 115.3 (88.3;142.4) 0.93 (0.84;0.97) 15.1 41.9
Point 17 99.4 (74.5;124.3) 100.1 (74.3;125.9) 0.94 (0.86;0.98) 13.0 36.1
Mean.Vent 117.6 (89.5;145.7) 117.9 (89.3;146.6) 0.98 (0.94;0.99) 9.4 26.2
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Abbreviations: Pressure pain threshold: PPT; Experimental session: ES; Intra-class correlation coefficient: ICC; Confidence interval: CI; Standard error of measurement: SEM; Minimum detectable change: MDC; Mean dorsal shoulder: Mean.Dors; Mean ventral shoulder: Mean. Vent.

1 using pooled SD.

2 at the 95% confidence interval.

Fig 5. Bland-Altman summary.

Fig 5

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Summary of the Bland-Altman analysis plotted for the differences in pressures pain threshold (PPT), active range of motion (ROM) and maximal isokinetic muscle strength (MIMS) from the affected side between experimental session 1 and 2. The black boxes represent the bias and the grey error bars represents the upper-lower limits of agreement for each outcome. See supplemental information for full visualization of Bland-Altman plots (S3, S5 and S6 Appendices).

The PPT maps showed that the BCS were most sensitive at the inferior portion of the pectoralis major on the ventral region, and least sensitive at the posterior deltoid on the dorsal region (Fig 6). The 2-way RM ANOVA revealed no significant interaction effect between Location and Session, (F (2,16) = 0.889, p = 0.518). There was a significant main effect of location, (F (2,16) = 14.211, p < 0.01) but not of session (F (2,1) = 0.264, p = 0.613). See supplemental information for pairwise comparisons among anatomical locations (S4 Appendix).

Fig 6. Pressure pain threshold maps.

Fig 6

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Mean pressure pain threshold (PPT) maps from the eleven anatomical locations on the ventral shoulder region, and six locations on the dorsal shoulder region of the affected side at experimental session 1 (A and B) and 2 (C and D). There were no significant difference between sessions for all locations (p> 0.05).

Active range of motion

Relative and absolute reliability of active ROM is reported in Table 3. The ICCs of the six movement directions ranged from “substantial” to “almost perfect”, with ICC values ranging from 0.66–0.97. SEM values ranged from 3.0 to 7.5°, while MDC ranged from 8.4 to 20.8°. The analysis of the Bland-Altman plot showed no apparent systematic bias in the data with zero included in the 95% confidence interval. Heteroscedasticity was absent indicating a lack of systematic errors during the active ROM measurements. The upper-lower limits of agreement (LOA) ranged from 10.6 to 27.4° and -29.8 to -10.5° with a bias ranging from -1.2 to 0.7° (Fig 5). See supplemental information for individual Bland-Altman plots (S5 Appendix).

Table 3. Relative and absolute reliability of active shoulder range of motion in breast cancer survivors (N = 21).

Active shoulder range of motion (°) Mean ES 1 (95% CI) Mean ES 2 (95% CI) ICC2,1 (95% CI) SEM1 MDC2
Flexion 158.5 (151.3;165.7) 158.7 (150.9;166.5) 0.95 (0.87;0.98) 3.7 10.2
Hor. Flexion 21.5 (19.5;23.4) 21.5 (18.8;24.3) 0.66 (0.15;0.86) 3.0 8.4
Hor. Extension 97.5 (90.1;104.8) 98.2 (90.8;105.6) 0.91 (0.77;0.96) 4.9 13.6
Abduction 144.2 (134.8;153.6) 143.0 (133.0;153.0) 0.87 (0.69;0.95) 7.5 20.8
Internal rotation 43.2 (37.2;49.3) 42.0 (36.5;47.5) 0.93 (0.83;0.97) 3.3 9.2
External rotation 72.4 (65.8;79.1) 72.8 (65.4;80.2) 0.78 (0.44;0.91) 7.2 20.1
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Abbreviations: Range of Motion: ROM; Joint angle: °; Intra-class correlation coefficient: ICC; Confidence interval: CI; Standard error of measurement: SEM; Minimum detectable change: MDC.

1 using pooled SD.

2 at the 95% confidence interval.

The 2-way RM ANOVA revealed no significant interaction effect between Direction and Session, (F (2,5) = 0.168, p = 0.930). There was a significant main effect of Direction, (F (2,5) = 444.298, p < 0.01) but not of session (F (2,1) = 0.020, p = 0.888). See supplemental information for pairwise comparisons among movement directions (S4 Appendix).

Maximal isokinetic muscle strength

Relative and absolute reliability of MIMS is reported in Table 4. The ICCs of the eight movement directions ranged from “substantial” to “almost perfect”, with ICC values ranging from 0.62–0.92. SEM values ranged from 0.03 to 0.07 Nm/Kg FFM, while MDC ranged from 0.09 to 0.19 Nm/kg FFM. The analysis of the Bland-Altman plot showed no apparent systematic bias in the data with zero included in the 95% confidence interval. Heteroscedasticity was absent indicating a lack of systematic errors during the MIMS measurements. The upper-lower limits of agreement (LOA) ranged from 0.15 to 0.25 Nm/kg FFM and -0.27 to -0.15 Nm/kg FFM with a bias ranging from -0.02 to 0.01 Nm/kg FFM (Fig 5). See supplemental information for individual Bland-Altman plots (S6 Appendix).

Table 4. Relative and absolute reliability of maximum isokinetic muscle strength in breast cancer survivors (N = 21).

Maximal isokinetic muscle strength (Nm/kg FFM) Mean ES 1 (95% CI) Mean ES 2 (95% CI) ICC2,1 (95% CI) SEM1 MDC2
Extension (63°) 0.47 (0.44;0.50) 0.47 (0.42;0.52) 0.62 (0.02;0.85) 0.06 0.15
Flexion (63°) 0.53 (0.48;0.58) 0.53 (0.47;0.58) 0.78 (0.43;0.91) 0.05 0.14
Hor. extension (33°) 0.43 (0.37;0.49) 0.44 (0.37;0.51) 0.85 (0.62;0.94) 0.05 0.14
Hor. flexion (8°) 0.56 (0.48;0.63) 0.55 (0.47;0.63) 0.83 (0.58;0.93) 0.07 0.19
Abduction (58°) 0.55 (0.49;0.61) 0.53 (0.47;0.6) 0.79 (0.47;0.92) 0.06 0.16
Adduction (58°) 0.40 (0.36;0.45) 0.41 (0.37;0.46) 0.77 (0.42;0.91) 0.05 0.13
Int. rotation (11°) 0.25 (0.22;0.29) 0.26 (0.23;0.29) 0.79 (0.48;0.92) 0.03 0.09
Ext. rotation (23°) 0.25 (0.21;0.28) 0.26 (0.22;0.3) 0.83 (0.58;0.93) 0.03 0.09
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Abbreviations: Joint angle from anatomical zero: °; Newton meter: Nm; Fat Free Mass: FFM; Intra-class correlation coefficient: ICC; Confidence interval: CI; Standard error of measurement: SEM; Minimum detectable change: MDC.

1 using pooled SD.

2 at the 95% confidence interval.

The 2-way RM ANOVA revealed no significant interaction effect between Direction and Session, (F (2,7) = 0.290, p = 0.894). There was a significant main effect of Direction, (F (2,7) = 53.072, p < 0.01) but not of session (F (2,1) = 0.022, p = 0.882). See supplemental information for pairwise comparisons among movement directions (S4 Appendix).

Discussion

The results of this study indicate that PPTs, active ROM and MIMS of the affected shoulder can be measured reliably across days in BCS with pain after treatment. The assessments of PPTs, active ROM and MIMS in the upper limb are of particular interest since both surgical and adjuvant treatment for breast cancer can affect these measures. These assessments provide important information of mechanical pain sensitivity and shoulder function in terms of movement and strength. Hence, the relative and absolute reliability of PPT, ROM and MIMS suggests that these measures can be used to evaluate the effects of an intervention on shoulder function and pain sensitivity in BCS.

The PPT values and distribution observed in this study are similar to those reported by Caro-Morán et al. for BCS with neck-shoulder pain approximately 20 months after treatment for breast cancer [15]. It should be noted that the participants of the present study reported pain in the chest, shoulder, axilla, arm and/or side of body approximately 70 months post treatment. This may indicate that sensitization of the group III and group IV afferents and thus, mechanical hyperalgesia is a long lasting characteristic of BCS with pain. Interestingly, we found spatial differences within and between ventral and dorsal region with the chest area of the ventral region being the most sensitive. This area is directly affected by surgery and adjuvant radiotherapy, and thus more susceptible to nerve damage which may explain the observed hyperalgesia [7], [10].

The active ROM and MIMS values performed by the BCS were generally lower compared with asymptomatic adults [47], [48]. More specifically, the limited ROM during shoulder abduction and external rotation highlight long lasting shoulder impairments from breast cancer treatment. Notably, we also observed lower ROM and MIMS than previously reported among BCS [26], [49–54]. These differences may be due to the methodology used to assess ROM and MIMS and to the time elapsed since cancer treatment among these studies. For example, several previous studies have only provided vague descriptions of their procedure for measuring ROM and do not specify if ROM was measured actively or passively [49–53]. Considering that passive ROM is subject to measurement errors due to the fact that the stretching of soft tissues at the limits of motion depends on the force applied to the limb [55], this could explain the higher ROM values. Furthermore, this study was performed approximately 70 months post treatment compared with approximately 1–2 months [26], [49], 15 months [50], [51], 24 months [53] and 32 months [52]. This is important, because pain and fear of complications are known sources of reduced exercise activity and use of the affected limb in BCS [56]. Disuse is a source of gradual reductions in muscular strength [57] and joint motion [58], which would likely be more pronounced over time. Collectively these aspects provide possible explanations for the lower ROM and MIMS observed in the current study.

According to the GRRAS guidelines [36], reliability studies should report both relative and absolute reliability of the outcome measures. Hence, we computed ICCs and SEMs as indices of relative and absolute reliability respectively, along with MDC that served as an indicator for sensitivity to change. The ICCs in this study showed high relative reliability and were in agreement with previous studies in other populations [25], [31], [47]. ICCs showed almost perfect reliability for the PPTs and substantial to almost perfect reliability for both ROM and MIMS. Similar ICCs have been reported for PPTs in both the upper- and lower extremities of both asymptomatic and patient populations [29], [37], [59–61].

Absolute reliability, reflected in the SEM and MDC values, is difficult to compare with previous studies, as these parameters are specific to the studied population and body region. The present study is the first study to report absolute reliability for PPT, ROM and MIMS in BCS. For example, SEM for PPTs in this study ranged from 9.4–18.9 kPa for respectively the ventral and dorsal shoulder region, compared with 31–74 kPa reported for the knee region in patients with knee osteoarthritis [31]. SEM for ROM ranged from 3°-7.5° which is similar to healthy individuals [47], whereas SEM for MIMS cannot be accurately compared with previous studies due to the absence of a normalization procedure in these investigations [25], [32], [48]. Body size is a known confounder of muscle strength testing and should be taken into account when evaluating muscular strength [44]. Finally, the MDCs found in this study may provide a frame of reference for evaluating the effects of an intervention on mechanical pain sensitivity and shoulder function, and hence should be reported in conjunction with significant findings [34]. However, some studies have recommended to use the percentage of participants meeting the MDC criterion instead of using the overall group change [62], [63].

The main limitation of this study is the included heterogeneous cohort. Specifically, the participant cohort included women with a broad range for age, time since treatment, and body composition. Further, participants had received varying treatment paradigms and reported pain of different intensities in different body areas. Consequently, the results are not representative of any specific group of BCS. However, BCS are arguably a heterogeneous population in general due to the highly individual nature of diagnosis, related treatment paradigm, long-term complications and adverse effects. Thus, the inclusion of a heterogeneous cohort provide the results with a higher level of validity and generalizability for this population.

In conclusion, the results of present study suggest that PPTs, active ROM and MIMS are reliable parameters assessing mechanical pain sensitivity and shoulder function in BCS with pain after treatment. Hence, these outcome measures can be used to evaluate the effects of e.g. training interventions in this population. In addition, significant differences anatomical locations was observed in the distribution of mechanical pain sensitivity, suggesting that the ventral shoulder region is affected more by the treatment and may benefit from exercises targeting the anterior deltoid and pectoralis major.

Supporting information

S1 Appendix. Guidelines for Reporting Reliability and Agreement Studies (GRRAS).

(DOCX)

Click here for additional data file. (16.9KB, docx)
S2 Appendix. Cohort description of the breast cancer survivors of the current study.

(DOCX)

Click here for additional data file. (22KB, docx)
S3 Appendix. Bland-Altman plots for pressure pain threshold.

(DOCX)

Click here for additional data file. (35.6MB, docx)
S4 Appendix. Pairwise comparisons for pressure pain threshold, active range of motion and maximal isokinetic muscle strength.

(DOCX)

Click here for additional data file. (26.3KB, docx)
S5 Appendix. Bland-Altman plots for active range of motion.

(DOCX)

Click here for additional data file. (11.2MB, docx)
S6 Appendix. Bland-Altman plots for maximal isokinetic muscle strength.

(DOCX)

Click here for additional data file. (13.1MB, docx)

Acknowledgments

This study was conducted in collaboration with the The Society of Cancer Survivor and Late Effects Group and the Danish Cancer Society.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

GHFR, PM, MK and MV received a grant (grant nr. R204-A12469) from the Danish Cancer Society (URL: https://www.cancer.dk/). The grant covered salary and equipment expenses. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

César Calvo-Lobo

1 May 2020

PONE-D-20-08793

Absolute and relative reliability of pain sensitivity and functional outcomes of the affected shoulder among women with pain after breast cancer treatment

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Reviewer #2: Yes

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Reviewer #1: This is a well written manuscript but some minor issues could be imporved in order to achieve a better research paper.

Introduction section is deep enough with and adequate background.

Participants section is well described is so intresting to add some references in order to enforce the inclusion and exclusion criteria

Study design section in line 112 there is a mistake with a reference, please correct it. Also in line 140.

Statistical analysis is well conducten in order to handle the mail hypoythesis

Discussion section is well explained but sometimes is difficult to follow. Please rewrite the third paragraph in order to achieve a better understunding for readers.

Conclusions are supoorted by the shown data

Reviewer #2: I have enjoyed after reading the manuscript titled “Absolute and relative reliability of pain sensitivity and functional outcomes of the affected shoulder among women with pain after breast cancer treatment”. Authors concluded that PPTs, ROM and MIMS can be measured reliably on the affected shoulder in BCS with pain after treatment. In addition, authors offer the possibility of using these measures to assess the effectiveness of interventions in this specific population. Nice study. Please, consider the following considerations:

1. Abstract and introduction provide a clear state-of-the-art and summarize the main findings of this study.

2. The methods should include a subsection called study design, including the type of study and the followed guidelines. Please, consider to add the checklist and reference of the STARD1 criteria available at https://www.equator-network.org/reporting-guidelines/stard/

1 Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig L, LijmerJG Moher D, Rennie D, de Vet HCW, Kressel HY, Rifai N, Golub RM, Altman DG, Hooft L, Korevaar DA, Cohen JF, For the STARD Group. STARD 2015: An Updated List of Essential Items for Reporting Diagnostic Accuracy Studies. BMJ. 2015;351:h5527. PMID: 26511519

3. In participants’ section, the following sentence needs to be referenced in an correct way: “The PPT, active range of motion (ROM) and MIMS were measured unilaterally on the operated side in all sessions”. Please, correct it.

4. The same in the following sentence of pain sensitivity and mechanical sensitivity measures section: “Adjacent points were separated by varying distances according to their anatomical location relative to the reference points”.

5. Nice statistical analysis and results sections.

6. It would be adequate to add a brief commentary or discussion about supplemental information for individual Bland-Altman plots. It seems that heteroscedasticity was not shown and thus there were not systematic errors of measurement.

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2020 Jun 3;15(6):e0234118. doi: 10.1371/journal.pone.0234118.r002

Author response to Decision Letter 0

15 May 2020

PONE-D-20-08793

Absolute and relative reliability of pain sensitivity and functional outcomes of the affected shoulder among women with pain after breast cancer treatment

Reviewers' comments:

Reviewer #1:

This is a well written manuscript but some minor issues could be imporved in order to achieve a better research paper.

Response: Thank you for your positive feedback as well as constructive and useful comments that have contributed to improve the overall readability and quality of the manuscript. Changes made in the manuscript according to your comments are highlighted in yellow. Please find the specific actions and responses to you suggestions below.

Introduction section is deep enough with and adequate background.

Response: Thank you once again for your positive feedback.

Participants section is well described is so intresting to add some references in order to enforce the inclusion and exclusion criteria.

Response: The inclusion and exclusion criteria were the ones defined in our application to the ethics committee in line with e.g. studies by Caro-Morán and colleagues. These criteria were developed based on our experience with clinical studies and on the discussion we have had with Professor Niels Kroman, breast surgeon and leading physician at the Danish Cancer Society. We have added a reference that have utilized similar inclusion and exclusion criteria on page 5, line 91-92:

“The inclusion and exclusion criteria were similar to those used by Caro-Morán & colleagues (15).”

Study design section in line 112 there is a mistake with a reference, please correct it. Also in line 140.

Response and action: We corrected these mistakes. Please see highlighted changes on page 6, line 116 and page 7, line 144.

Statistical analysis is well conducten in order to handle the mail hypoythesis

Response: Thank you, we are grateful for your positive comments.

Discussion section is well explained but sometimes is difficult to follow. Please rewrite the third paragraph in order to achieve a better understunding for readers.

Response and action: The 3rd paragraph of the discussion was edited to facilitate its understanding. We have reordered our argumentation starting with ROM and MIMS values and continuing with the effects of the time elapsed since treatment. Se highlighted changes below:

The active ROM and MIMS values performed by the BCS were generally lower compared with asymptomatic adults (47,48). More specifically, the limited ROM during shoulder abduction and external rotation highlight long lasting shoulder impairments from breast cancer treatment. Notably, we also observed lower ROM and MIMS than previously reported among BCS (26,49–54). These differences may be due to the methodology used to assess ROM and MIMS and to the time elapsed since cancer treatment among these studies. For example, several previous studies have only provided vague descriptions of their procedure for measuring ROM and do not specify if ROM was measured actively or passively (49–53). Considering that passive ROM is subject to measurement errors due to the fact that the stretching of soft tissues at the limits of motion depends on the force applied to the limb (55), this could explain the higher ROM values. Furthermore, this study was performed approximately 70 months post treatment compared with approximately 1-2 months (26,49), 15 months (50,51), 24 months (53) and 32 months (52). This is important, because pain and fear of complications are known sources of reduced exercise activity and use of the affected limb in BCS (56). Disuse is a source of gradual reductions in muscular strength (57) and joint motion (58), which would likely be more pronounced over time. Collectively these aspects provide possible explanations for the lower ROM and MIMS observed in the current study.

Conclusions are supoorted by the shown data.

Response: Thank you for the positive evaluation of our manuscript.

 

Reviewer #2:

I have enjoyed after reading the manuscript titled “Absolute and relative reliability of pain sensitivity and functional outcomes of the affected shoulder among women with pain after breast cancer treatment”. Authors concluded that PPTs, ROM and MIMS can be measured reliably on the affected shoulder in BCS with pain after treatment. In addition, authors offer the possibility of using these measures to assess the effectiveness of interventions in this specific population. Nice study. Please, consider the following considerations:

Response: Thank you for your positive feedback as well as constructive and useful comments that have contributed to improve the overall readability and quality of the manuscript. Changes made in the manuscript according to your comments are highlighted in green. Please find the specific actions and responses to you suggestions below.

1. Abstract and introduction provide a clear state-of-the-art and summarize the main findings of this study.

Response: Thank you, these positive comments are most appreciated.

2. The methods should include a subsection called study design, including the type of study and the followed guidelines. Please, consider to add the checklist and reference of the STARD1 criteria available at https://www.equator-network.org/reporting-guidelines/stard/

Response and action: We added a subsection entitled “Study design”, including the type of study and the followed guidelines. It is our understanding that the STARD guidelines refer more to accuracy studies than reliability studies like this one. Thus, we did not include the suggested STARD criteria. Rather, we clearly emphasized that this study was conducted in accordance with the Guidelines for Reporting Reliability and Agreement Studies (GRRAS) by adding the following sentence on page 6, lines 108-110. See also S1 appendix.

“This intra-rater reliability study was conducted in accordance with the GRRAS guidelines (37). In line with the GRRAS guidelines, we report information on sample selection, study design, and statistical analysis (S1 appendix).”

3. In participants’ section, the following sentence needs to be referenced in an correct way: “The PPT, active range of motion (ROM) and MIMS were measured unilaterally on the operated side in all sessions”. Please, correct it.

Response and action: We corrected that sentence accordingly adding that the sentence refers to figure 1. Please note that the correction is highlighted in yellow on page 6, line 116

4. The same in the following sentence of pain sensitivity and mechanical sensitivity measures section: “Adjacent points were separated by varying distances according to their anatomical location relative to the reference points”.

Response and action: We also corrected that sentence accordingly adding that the sentence refers to figure 2 and 3. Please note that the correction is highlighted in yellow on page 7, line 144.

5. Nice statistical analysis and results sections.

Response: Thank you, we appreciate your positive feedback.

6. It would be adequate to add a brief commentary or discussion about supplemental information for individual Bland-Altman plots. It seems that heteroscedasticity was not shown and thus there were not systematic errors of measurement.

Response and action: We added comments in the methods and results section related to the Bland-Altman plots (heteroscedasticity and lack of systematic errors) in order to further elaborate this part of the analysis. See highlighted changes below.

Page 10, line 215-219:

“Bland-Altman plots were constructed to evaluate heteroscedasticity of the measurements and detect any systematic bias in the mean difference between sessions for PPT, ROM and MIMS. Bias exists when the second set of measurements yield a different mean and heteroscedasticity occurs when the mean difference between measurements changes as their average changes (46).”

Page 13, line 256-257:

“Heteroscedasticity was absent indicating a lack of systematic errors during the PPT measurements.”

Page 16, line 288-289:

“Heteroscedasticity was absent indicating a lack of systematic errors during the active ROM measurements.”

Page 17, line 307-308:

“Heteroscedasticity was absent indicating a lack of systematic errors during the MIMS measurements.”

Attachment

Submitted filename: Response to Reviewers PONE-D-20-08793R1.docx

Click here for additional data file. (40.2KB, docx)

Decision Letter 1

César Calvo-Lobo

20 May 2020

Absolute and relative reliability of pain sensitivity and functional outcomes of the affected shoulder among women with pain after breast cancer treatment

PONE-D-20-08793R1

Dear Dr. Fogh Rasmussen,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

César Calvo-Lobo, PhD, MSc, PT

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thanks for addressing all reviewers' suggestions in a correct way. 

Reviewers' comments:

Acceptance letter

César Calvo-Lobo

22 May 2020

PONE-D-20-08793R1

Absolute and relative reliability of pain sensitivity and functional outcomes of the affected shoulder among women with pain after breast cancer treatment

Dear Dr. F. Rasmussen:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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With kind regards,

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on behalf of

Dr. César Calvo-Lobo

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Appendix. Guidelines for Reporting Reliability and Agreement Studies (GRRAS).

    (DOCX)

    Click here for additional data file. (16.9KB, docx)
    S2 Appendix. Cohort description of the breast cancer survivors of the current study.

    (DOCX)

    Click here for additional data file. (22KB, docx)
    S3 Appendix. Bland-Altman plots for pressure pain threshold.

    (DOCX)

    Click here for additional data file. (35.6MB, docx)
    S4 Appendix. Pairwise comparisons for pressure pain threshold, active range of motion and maximal isokinetic muscle strength.

    (DOCX)

    Click here for additional data file. (26.3KB, docx)
    S5 Appendix. Bland-Altman plots for active range of motion.

    (DOCX)

    Click here for additional data file. (11.2MB, docx)
    S6 Appendix. Bland-Altman plots for maximal isokinetic muscle strength.

    (DOCX)

    Click here for additional data file. (13.1MB, docx)
    Attachment

    Submitted filename: Response to Reviewers PONE-D-20-08793R1.docx

    Click here for additional data file. (40.2KB, docx)

    Data Availability Statement

    All relevant data are within the paper and its Supporting Information files.

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