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Persistent pain after targeted intraoperative radiotherapy (TARGIT) or external breast radiotherapy for breast cancer: A randomized trial
The Breast 21 (2012) 46e49
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Persistent pain after targeted intraoperative radiotherapy (TARGIT) or external breast radiotherapy for breast cancer: A randomized trial Kenneth Geving Andersen a, b, *, Rune Gärtner c, Niels Kroman c, Henrik Flyger d, Henrik Kehlet a a
Section for Surgical Pathophysiology, Rigshospitalet, University of Copenhagen, Denmark Section of Acute Pain Management and Palliation, Rigshospitalet, University of Copenhagen, Denmark c Department of Breast Surgery, Rigshospitalet, University of Copenhagen, Denmark d Department of Breast Surgery, Herlev Hospital, University of Copenhagen, Denmark b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 April 2011 Received in revised form 8 July 2011 Accepted 22 July 2011
Persistent pain after breast cancer treatment (PPBCT) affects between 25 and 60% of patients depending on surgical and adjuvant treatment. External breast radiotherapy (EBRT) has been shown to be a riskfactor for PPBCT, raising the question whether intraoperative radiation therapy (IORT), with its smaller radiation field may reduce the development of PPBCT. Using data from the TARGIT-A trial, the aim of this study was to compare these two treatments with regard to development of PPBCT. A total of 281 patients enrolled in the TARGIT-A trial from the Copenhagen University Hospitals was screened for participation, and a total of 244 patients were included and received a detailed questionnaire. The response rate was 98%, leaving 238 patients for the final analysis. Pain prevalence were 33.9% in the EBRT group and 24.6% in the IORT group (p ¼ 0.11). Treatment with IORT may not alter the risk of PPBCT. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Radiation therapy Intraoperative radiotherapy TARGIT Persistent pain
Introduction Persistent pain following breast cancer treatment affects 25e60% of patients depending on treatment,1 reflecting a complex pathophysiology involving several pre-, intra- and postoperative risk factors.2 A recent review of the literature as well as a large nationwide study on persistent pain after breast cancer treatment (PPBCT) showed radiotherapy as a probable risk factor.1,3 Intraoperative radiation therapy (IORT) has been introduced in clinical trials due to the observation that local recurrence mostly occurs in the area adjacent to the primary tumor.4 The randomized trial TARGeted Intraoperative radioTherapy TARGIT-A,5 and a study on intraoperative radiotherapy with electrons (ELIOT)6 suggest intraoperative radiation therapy is similar to conventional external breast radiotherapy (EBRT) in terms of occurrence of local recurrence. IORT provides a potential for major reduction in patient effort as well as health care resource utilisation, however evaluation of toxicity in the TARGIT-A study5 did not allow conditions for assessment regarding PPBCT. Furthermore, IORT represents an interesting model to test the influence of radiotherapy on the development of PPBCT, as IORT limits the radiation field and thus * Corresponding author. Section for Surgical Pathophysiology, 4074, Rigshospitalet, Copenhagen University, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel.: þ45 35454236, þ45 26258003; fax: þ45 35457157. E-mail address: [email protected] (K. G. Andersen). 0960-9776/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2011.07.011
the exposure of radiation towards nerves. The purpose of this study was therefore to investigate in detail the development of PPBCT in patients from the Copenhagen University Hospitals, participating in the TARGIT-A study, randomized to treatment with IORT or EBRT. The primary aim of this study was to evaluate prevalence, intensity and frequency of PPBCT to enlighten this safety issue of the TARGIT treatment. Methods Trial design The study was a retrospective questionnaire study based on patients enrolled in the TARGIT-A trial from the Copenhagen University Hospitals. TARGIT-A was a non-inferiority randomized trial registered with clinicaltrials.gov, number NCT0098384. Further description is presented elsewhere.5 Patients Patients identified in the local TARGIT database from March 2007 to January 2010 were examined for eligibility. Inclusion criteria were: Postmenopausal women with primary unifocal and unilateral breast cancer age 50 years or older, T1, N0(N0(iþ) and N1(mi)), M0, estrogen receptor positive confirmed by cytological or
K.G. Andersen et al. / The Breast 21 (2012) 46e49
histological examination, suitable for breast conserving surgery, and available for regular follow-up for at least ten years. Exclusion criteria: bilateral breast cancer at the time of diagnosis, previous cancer in and/or irradiation to ipsilateral breast, patients known to have BRCA2 gene mutation, lobular cancer or extensive intraductal component (EIC¼>25% of the tumor is intraductal), patients undergoing primary medical treatments (hormones or chemotherapy). In addition patients with previous contralateral breast surgery, local recurrence, metastatic disease, other cancer or axillary lymph node dissection were excluded to rule out influence on pain measurement (see Fig. 1). Randomisation was made by the TARGIT trial centre in London, UK. Patients were not blinded to treatment. In the present study, data provided from the local TARGIT database, was blinded for the investigators. Data collection and analysis was made at Rigshospitalet, Copenhagen, Denmark. The study was performed in accordance with the Declaration of Helsinki and approved by the local ethics committee H-1-2010-029, the Danish Data Protection Agency.
47
analgesics, sensory disturbances and pain elsewhere. A detailed study questionnaire developed for a previous nationwide study of persistent pain and sensory disturbances was used.1 Questions addressing prevalence for pain was dichotomous yes or no questions. Patients were then asked systematically to specify pain according to location (breast, side of chest wall, axilla or arm), and the intensity on a 0-10 numeric rating scale (0 ¼ no pain, 10 ¼ worst imaginable pain). Frequency of pain was assessed by a 3 point verbal categorial scale: 1) every day or almost every day, 2) one to three days a week or 3) more rarely. Treatment data was provided from the Danish Breast Cancer Cooperative Group (DBCG) and the TARGIT database. Sample size A power analysis was performed on basis of a prevalence of pain of 40% in the treatment group found in the nationwide questionnaire study,1 corresponding to the same treatment group as this study. We calculated a decrease in prevalence of 15%. Thus, with 80% power and a ¼ 0,05 a sample size of 120 in both groups were required.
Interventions Statistics Detailed description is presented elsewhere.5 Outcomes The primary outcome was pain present in the area of the operated breast, side of chest, axilla or arm. Secondary outcomes were: intensity and frequency of pain, pain in more than one area, use of
Statistical analysis was performed using PASW SPSS 18.0 for Windows (IBM SPSS, Chicago, IL). Normal distributed data was analyzed using the independent t-test, binary data using c2 or Fischer Exact test, NRS values were analyzed using WhitneyeMann U-test. All values were expressed as number of patients, percentages, means SD, medians (IQR), OR (95% CI). A p-value of 0,05 were considered statistically significant. Results Eligible patients were screened from the local TARGIT database and patients ineligible were discarded according to exclusion criteria on basis of registrations in the DBCG database (Fig. 1). Questionnaires were sent out the 16th of April 2010 to eligible 244 patients. Patients not responding one month after received a reminder. The response rate was 98% (N ¼ 240). Two questionnaires were discarded due to incompleteness (see Fig. 1). There were no statistically significant differences in age, follow-up, disease characteristics or endocrine therapy (see Table 1). All patients were treated with BCS and sentinel lymph node biopsy. No patients received axilliary lymph node dissection or chemotherapy. Pain The prevalence of pain was 33.9% in the EBRT group and 24.6% in the IORT group (p ¼ 0.11). Pain localization was similar in the two groups. Pain intensity was for most patients low and not different between the two groups, 71% of the pain patients the EBRT group and 77% in the IORT group scoring 3 or lower on the numerical rating scale. 86.8% of patients reporting pain in the EBRT group reported to have pain on a weekly basis or more often, versus 64.5% of the IORT patients (p ¼ 0.044). The prevalence of pain elsewhere (outside the treatment area) were found to be larger in the IORT group than in the EBRT group (40.7% vs. 26.4%) (p ¼ 0.027). Prevalence of sensory disturbances was similar (see Table 2). Discussion
Fig. 1. Flowchart presenting inclusion in the treatment groups.
The results of this randomized study suggest that treatment with IORT does not modify the risk of development of PPBCT compared to EBRT. In the EBRT group 33.9% of the patients reported persistent pain in the breast area, side of chest, axilla or arm, whereas in the IORT group, 24.6% reported pain in these areas (P ¼ 0.11). The OR for
48
K.G. Andersen et al. / The Breast 21 (2012) 46e49
Table 1 Treatment characteristics.
N (%) Non-responders Age, years (mean) Follow-up, months (mean) Endocrine therapy, N (%) No ET AI TAM Unknown Tumor size, mm (mean) Lymph nodes (mean) WHO, N (%) Invasive ductal Invasive lobular Mucinous Medullary Papillary Tubular Others Unknown
EBRT
IORT
112 (47.1) 4 65.74 (SD 6.17) 17.06 (SD 10.39)
126 (52.9) 0 64.76 (SD 6.45) 17.36 (10.64)
P (95% CI)
95 (84.8) 17 (15.2) 0 0 10.75 (SD 3.59) 2.32 (SD 1.44)
99 (79.4) 26 (20.6) 0 0 10.65 (SD 4.14) 2.24 (SD 1.33)
94 (83.9) 1 (0.9) 5 (4.5) 0 1 (0.9) 5 (4.5) 3 (2.7) 3 (2.7)
106 (84.1) 0 6 (4.8) 0 3 (2.4) 8 (6.3) 2 (1.6) 1 (0.8)
0.23 (0.64e2.60) 0.87 0.28
0.85 (0.91e1.12) 0.67
Total 238 4 65.22 (SD 6.33) 17.22 (SD 10.50) 194 (81.9) 43 (18.1) 0 0 10.70 (SD 3.89) 2.28 (SD 1.38) 200 (84.0) 1 (0.4) 11 (4.6) 0 4 (1.7) 13 (5.4) 5 (2.1) 4 (1.7)
Abbreviations: EBRT: external breast radiotherapy, IORT: intraoperative radiation therapy, ET: endocrine therapy, AI: aromatase inhibitor, TAM: tamoxifen.
experiencing persistent pain was 1.57 (95% CI 0.90e2.77) in the EBRT group compared to IORT group, indicating that we with reasonable certainty can regard the treatment with IORT as safe as EBRT in terms of PPBCT. The trend towards a positive effect of IORT with regard to prevalence of PPBCT and frequency of pain, will require a larger population to evaluate. The prevalence of pain elsewhere was Table 2 Persistent pain after breast cancer treatment.
Reporting pain, N (%) cont. OR (95% CI) Localization, N (%) Breast Side of chest Axilla Arm Pain in more than 1 area, N (%) NRS (median, IQR) Worst (overall)a Breast Side of chest Axilla Arm Worst pain, N (%)b Light pain Moderate pain Severe pain Frequency of worst pain, N (%) Daily 1e3 d/week Less Use analgesics, N (%) Consulting doctor, N (%) Sensory disturbances, N (%)c Pain other locations, N (%)d
EBRT
IORT
P
Total
38 (33.9) 1.57 (0.90e2.77)
31 (24.6) 1
0.11
69 (29.0)
31 (81.6) 12 (31.6) 19 (50.0) 5 (13.2) 21 (55.3)
26 (83.9) 6 (19.4) 12 (38.7) 7 (22.6) 15 (48.4)
0,80 0.25 0.35 0.30 0.57
57 18 31 12 36
3 (2) 2 (1) 2,5 (3) 2 (2) 5 (6)
3 3 2 2 4
0.87 0.98 1.00 0.69 0.68 0.59
27 (71.0) 10 (26.3) 1 (2.6)
24 (77.4) 7 (22.6) 0
(1) (1) (2) (2) (4)
(82.6) (26.1) (44.9) (17.4) (52.2)
51 (73.9) 17 (24.6) 1 (1.4) 0.090
19 (50.0) 14 (36.8) 5 (13.2) 6 (15.8)
11 (35.5) 9 (29.0) 11 (35.5) 5 (16.1)
0.97
30 23 16 11
(43.5) (33.3) (23.2) (15.9)
5 (13.2)
3 (9.7)
0.65
8 (11.6)
27 (23.2)
26 (20.6)
0.75
53 (21.8)
28 (26.4)
48 (40.7)
0.02
76 (33.9)
Abbreviations: NRS: numerical rating scale. a Worst pain rating across all measured localizations. b Worst pain across all measured localizations, light pain: NRS 1e3, moderate pain: NRS 4e7, severe pain: NRS 8e10. c missing data on 3 patients, 1 in the EBRT group, 2 in the IORT group. d missing data on 14 patients, 6 in the EBRT group, 8 in the IORT group.
significantly higher in patients treated with TARGIT, but there is no pathophysiological explanation that IORT should give more pain in general, since pain elsewhere was described as headache, neckshoulder pain and low-back pain. Such unspecific pain complaints in the joints and muscles are a common side effect of aromatase inhibitors,7 but the use of aromatase inhibitors in the two groups was similar. However, general pain complaints have previously been shown to be associated with a higher risk of PPBCT1,3 and may therefore support that IORT may not increase the risk of PPBCT. Only 20% of the patients received adjuvant endocrine therapy due to inclusion of only patients with a low risk diagnose, and the relatively conservative treatment guidelines in Denmark in the study period. The nature of the TARGIT treatment precluded a blinding of patients, and may have introduced bias in the IORT population. However, the higher prevalence of pain elsewhere argues against this. The intensity of treatment related pain between the two treatment groups was similar, with most patients having light pain. The frequency of pain was high, with most patients experiencing pain on a weekly basis. Patients treated with EBRT experienced pain more frequently (P ¼ 0.044), suggesting a favorable effect of TARGIT. The pathophysiological background for the increased risk of PPBCT with radiation therapy is yet to be described, but it is reasonable to assume the impact on nerves is larger with a more extensive radiation field. Thus, with TARGIT, the smaller radiation field may reduce harm on nerves damage, as radiation is focused on breast tissue. However, sensory disturbances in the two groups were similar (about 22%), and somewhat lower than in the comparable population in the study by Gärtner et al, which found a prevalence of sensory disturbances of 31%.1 The explanations for this may be that the present cohort has an older population and with a shorter follow-up time, 17 months versus 26 months. The late effects of radiotherapy is reported to be accumulating with time.8 The strengths of our study are that it is a homogenous population in terms of treatment and disease status, and that the patients were randomized to IORT or EBRT, and a very high participation rate. The primary limitation of this study is that it is a retrospective questionnaire study, without pretreated baseline pain evaluation. Furthermore, it is a limitation that blinding of the patients was not possible, which is a potential source of bias. Since the patients were homogenous in terms of ethnicity, and are treated in a health care system with universal coverage for all, the results may not be generalized to other population with other ethnic composition or other health care systems.
K.G. Andersen et al. / The Breast 21 (2012) 46e49
49
Conclusion
References
This study is the first to compare IORT and EBRT in terms of the risk developing PPBCT in a randomized study, and show that IORT does not increase risk of developing PPBCT compared with EBRT, but with a tendency towards a positive effect of TARGIT with regard to prevalence and frequency of PPBCT.
1. Gartner R, Jensen MB, Nielsen J, Ewertz M, Kroman N, Kehlet, H. Prevalence of and factors associated with persistent pain following breast cancer surgery. JAMA 2009;302(18):1985e92. 2. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet 2006;367(9522):1618e25. 3. Andersen KG, Kehlet H. Persistent pain after breast cancer treatment: a critical review of risk factors and strategies for prevention. J Pain 2011;12(7):725e46. 4. Vaidya JS, Tobias JS, Baum M, Keshtgar M, Wenz F, Hough, J, et al. Intraoperative radiotherapy for breast cancer. Lancet Oncol 2004;5(3):165e73. 5. Vaidya JS, Joseph DJ, Tobias JS, Bulsara M, Wenz F, Saunders C, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. Lancet 2010;376(9735):91e102. 6. Veronesi U, Orecchia R, Luini A, Galimberti V, Zurrida S, Intra M, et al. Intraoperative radiotherapy during breast conserving surgery: a study on 1,822 cases treated with electrons. Breast Cancer Res Treat 2010;124(1):141e51. 7. Coleman RE, Bolten WW, Lansdown M, Dale S, Jackisch C, Merkel D, et al. Aromatase inhibitor-induced arthralgia: clinical experience and treatment recommendations. Cancer Treat Rev 2008;34(3):275e82. 8. Bajrovic A, Rades D, Fehlauer F, Tribius S, Hoeller U, Rudat V, et al. Is there a lifelong risk of brachial plexopathy after radiotherapy of supraclavicular lymph nodes in breast cancer patients? Radiother Oncol 2004;71(3):297e301.
Conflict of interests The authors declare no conflict of interests. Acknowledgements This study is a part of the Europain project, funded by the Innovative Medicines Initiative Joint Undertaking (IMI JU) Grant no 115007 (www.imi.europa.eu), and was also supported by a grant from the Lundbeck Foundation and The Danish Cancer Society.
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Persistent pain after targeted intraoperative radiotherapy (TARGIT) or external breast radiotherapy for breast cancer: A randomized trial Kenneth Geving Andersen a, b, *, Rune Gärtner c, Niels Kroman c, Henrik Flyger d, Henrik Kehlet a a
Section for Surgical Pathophysiology, Rigshospitalet, University of Copenhagen, Denmark Section of Acute Pain Management and Palliation, Rigshospitalet, University of Copenhagen, Denmark c Department of Breast Surgery, Rigshospitalet, University of Copenhagen, Denmark d Department of Breast Surgery, Herlev Hospital, University of Copenhagen, Denmark b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 April 2011 Received in revised form 8 July 2011 Accepted 22 July 2011
Persistent pain after breast cancer treatment (PPBCT) affects between 25 and 60% of patients depending on surgical and adjuvant treatment. External breast radiotherapy (EBRT) has been shown to be a riskfactor for PPBCT, raising the question whether intraoperative radiation therapy (IORT), with its smaller radiation field may reduce the development of PPBCT. Using data from the TARGIT-A trial, the aim of this study was to compare these two treatments with regard to development of PPBCT. A total of 281 patients enrolled in the TARGIT-A trial from the Copenhagen University Hospitals was screened for participation, and a total of 244 patients were included and received a detailed questionnaire. The response rate was 98%, leaving 238 patients for the final analysis. Pain prevalence were 33.9% in the EBRT group and 24.6% in the IORT group (p ¼ 0.11). Treatment with IORT may not alter the risk of PPBCT. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Radiation therapy Intraoperative radiotherapy TARGIT Persistent pain
Introduction Persistent pain following breast cancer treatment affects 25e60% of patients depending on treatment,1 reflecting a complex pathophysiology involving several pre-, intra- and postoperative risk factors.2 A recent review of the literature as well as a large nationwide study on persistent pain after breast cancer treatment (PPBCT) showed radiotherapy as a probable risk factor.1,3 Intraoperative radiation therapy (IORT) has been introduced in clinical trials due to the observation that local recurrence mostly occurs in the area adjacent to the primary tumor.4 The randomized trial TARGeted Intraoperative radioTherapy TARGIT-A,5 and a study on intraoperative radiotherapy with electrons (ELIOT)6 suggest intraoperative radiation therapy is similar to conventional external breast radiotherapy (EBRT) in terms of occurrence of local recurrence. IORT provides a potential for major reduction in patient effort as well as health care resource utilisation, however evaluation of toxicity in the TARGIT-A study5 did not allow conditions for assessment regarding PPBCT. Furthermore, IORT represents an interesting model to test the influence of radiotherapy on the development of PPBCT, as IORT limits the radiation field and thus * Corresponding author. Section for Surgical Pathophysiology, 4074, Rigshospitalet, Copenhagen University, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel.: þ45 35454236, þ45 26258003; fax: þ45 35457157. E-mail address: [email protected] (K. G. Andersen). 0960-9776/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2011.07.011
the exposure of radiation towards nerves. The purpose of this study was therefore to investigate in detail the development of PPBCT in patients from the Copenhagen University Hospitals, participating in the TARGIT-A study, randomized to treatment with IORT or EBRT. The primary aim of this study was to evaluate prevalence, intensity and frequency of PPBCT to enlighten this safety issue of the TARGIT treatment. Methods Trial design The study was a retrospective questionnaire study based on patients enrolled in the TARGIT-A trial from the Copenhagen University Hospitals. TARGIT-A was a non-inferiority randomized trial registered with clinicaltrials.gov, number NCT0098384. Further description is presented elsewhere.5 Patients Patients identified in the local TARGIT database from March 2007 to January 2010 were examined for eligibility. Inclusion criteria were: Postmenopausal women with primary unifocal and unilateral breast cancer age 50 years or older, T1, N0(N0(iþ) and N1(mi)), M0, estrogen receptor positive confirmed by cytological or
K.G. Andersen et al. / The Breast 21 (2012) 46e49
histological examination, suitable for breast conserving surgery, and available for regular follow-up for at least ten years. Exclusion criteria: bilateral breast cancer at the time of diagnosis, previous cancer in and/or irradiation to ipsilateral breast, patients known to have BRCA2 gene mutation, lobular cancer or extensive intraductal component (EIC¼>25% of the tumor is intraductal), patients undergoing primary medical treatments (hormones or chemotherapy). In addition patients with previous contralateral breast surgery, local recurrence, metastatic disease, other cancer or axillary lymph node dissection were excluded to rule out influence on pain measurement (see Fig. 1). Randomisation was made by the TARGIT trial centre in London, UK. Patients were not blinded to treatment. In the present study, data provided from the local TARGIT database, was blinded for the investigators. Data collection and analysis was made at Rigshospitalet, Copenhagen, Denmark. The study was performed in accordance with the Declaration of Helsinki and approved by the local ethics committee H-1-2010-029, the Danish Data Protection Agency.
47
analgesics, sensory disturbances and pain elsewhere. A detailed study questionnaire developed for a previous nationwide study of persistent pain and sensory disturbances was used.1 Questions addressing prevalence for pain was dichotomous yes or no questions. Patients were then asked systematically to specify pain according to location (breast, side of chest wall, axilla or arm), and the intensity on a 0-10 numeric rating scale (0 ¼ no pain, 10 ¼ worst imaginable pain). Frequency of pain was assessed by a 3 point verbal categorial scale: 1) every day or almost every day, 2) one to three days a week or 3) more rarely. Treatment data was provided from the Danish Breast Cancer Cooperative Group (DBCG) and the TARGIT database. Sample size A power analysis was performed on basis of a prevalence of pain of 40% in the treatment group found in the nationwide questionnaire study,1 corresponding to the same treatment group as this study. We calculated a decrease in prevalence of 15%. Thus, with 80% power and a ¼ 0,05 a sample size of 120 in both groups were required.
Interventions Statistics Detailed description is presented elsewhere.5 Outcomes The primary outcome was pain present in the area of the operated breast, side of chest, axilla or arm. Secondary outcomes were: intensity and frequency of pain, pain in more than one area, use of
Statistical analysis was performed using PASW SPSS 18.0 for Windows (IBM SPSS, Chicago, IL). Normal distributed data was analyzed using the independent t-test, binary data using c2 or Fischer Exact test, NRS values were analyzed using WhitneyeMann U-test. All values were expressed as number of patients, percentages, means SD, medians (IQR), OR (95% CI). A p-value of 0,05 were considered statistically significant. Results Eligible patients were screened from the local TARGIT database and patients ineligible were discarded according to exclusion criteria on basis of registrations in the DBCG database (Fig. 1). Questionnaires were sent out the 16th of April 2010 to eligible 244 patients. Patients not responding one month after received a reminder. The response rate was 98% (N ¼ 240). Two questionnaires were discarded due to incompleteness (see Fig. 1). There were no statistically significant differences in age, follow-up, disease characteristics or endocrine therapy (see Table 1). All patients were treated with BCS and sentinel lymph node biopsy. No patients received axilliary lymph node dissection or chemotherapy. Pain The prevalence of pain was 33.9% in the EBRT group and 24.6% in the IORT group (p ¼ 0.11). Pain localization was similar in the two groups. Pain intensity was for most patients low and not different between the two groups, 71% of the pain patients the EBRT group and 77% in the IORT group scoring 3 or lower on the numerical rating scale. 86.8% of patients reporting pain in the EBRT group reported to have pain on a weekly basis or more often, versus 64.5% of the IORT patients (p ¼ 0.044). The prevalence of pain elsewhere (outside the treatment area) were found to be larger in the IORT group than in the EBRT group (40.7% vs. 26.4%) (p ¼ 0.027). Prevalence of sensory disturbances was similar (see Table 2). Discussion
Fig. 1. Flowchart presenting inclusion in the treatment groups.
The results of this randomized study suggest that treatment with IORT does not modify the risk of development of PPBCT compared to EBRT. In the EBRT group 33.9% of the patients reported persistent pain in the breast area, side of chest, axilla or arm, whereas in the IORT group, 24.6% reported pain in these areas (P ¼ 0.11). The OR for
48
K.G. Andersen et al. / The Breast 21 (2012) 46e49
Table 1 Treatment characteristics.
N (%) Non-responders Age, years (mean) Follow-up, months (mean) Endocrine therapy, N (%) No ET AI TAM Unknown Tumor size, mm (mean) Lymph nodes (mean) WHO, N (%) Invasive ductal Invasive lobular Mucinous Medullary Papillary Tubular Others Unknown
EBRT
IORT
112 (47.1) 4 65.74 (SD 6.17) 17.06 (SD 10.39)
126 (52.9) 0 64.76 (SD 6.45) 17.36 (10.64)
P (95% CI)
95 (84.8) 17 (15.2) 0 0 10.75 (SD 3.59) 2.32 (SD 1.44)
99 (79.4) 26 (20.6) 0 0 10.65 (SD 4.14) 2.24 (SD 1.33)
94 (83.9) 1 (0.9) 5 (4.5) 0 1 (0.9) 5 (4.5) 3 (2.7) 3 (2.7)
106 (84.1) 0 6 (4.8) 0 3 (2.4) 8 (6.3) 2 (1.6) 1 (0.8)
0.23 (0.64e2.60) 0.87 0.28
0.85 (0.91e1.12) 0.67
Total 238 4 65.22 (SD 6.33) 17.22 (SD 10.50) 194 (81.9) 43 (18.1) 0 0 10.70 (SD 3.89) 2.28 (SD 1.38) 200 (84.0) 1 (0.4) 11 (4.6) 0 4 (1.7) 13 (5.4) 5 (2.1) 4 (1.7)
Abbreviations: EBRT: external breast radiotherapy, IORT: intraoperative radiation therapy, ET: endocrine therapy, AI: aromatase inhibitor, TAM: tamoxifen.
experiencing persistent pain was 1.57 (95% CI 0.90e2.77) in the EBRT group compared to IORT group, indicating that we with reasonable certainty can regard the treatment with IORT as safe as EBRT in terms of PPBCT. The trend towards a positive effect of IORT with regard to prevalence of PPBCT and frequency of pain, will require a larger population to evaluate. The prevalence of pain elsewhere was Table 2 Persistent pain after breast cancer treatment.
Reporting pain, N (%) cont. OR (95% CI) Localization, N (%) Breast Side of chest Axilla Arm Pain in more than 1 area, N (%) NRS (median, IQR) Worst (overall)a Breast Side of chest Axilla Arm Worst pain, N (%)b Light pain Moderate pain Severe pain Frequency of worst pain, N (%) Daily 1e3 d/week Less Use analgesics, N (%) Consulting doctor, N (%) Sensory disturbances, N (%)c Pain other locations, N (%)d
EBRT
IORT
P
Total
38 (33.9) 1.57 (0.90e2.77)
31 (24.6) 1
0.11
69 (29.0)
31 (81.6) 12 (31.6) 19 (50.0) 5 (13.2) 21 (55.3)
26 (83.9) 6 (19.4) 12 (38.7) 7 (22.6) 15 (48.4)
0,80 0.25 0.35 0.30 0.57
57 18 31 12 36
3 (2) 2 (1) 2,5 (3) 2 (2) 5 (6)
3 3 2 2 4
0.87 0.98 1.00 0.69 0.68 0.59
27 (71.0) 10 (26.3) 1 (2.6)
24 (77.4) 7 (22.6) 0
(1) (1) (2) (2) (4)
(82.6) (26.1) (44.9) (17.4) (52.2)
51 (73.9) 17 (24.6) 1 (1.4) 0.090
19 (50.0) 14 (36.8) 5 (13.2) 6 (15.8)
11 (35.5) 9 (29.0) 11 (35.5) 5 (16.1)
0.97
30 23 16 11
(43.5) (33.3) (23.2) (15.9)
5 (13.2)
3 (9.7)
0.65
8 (11.6)
27 (23.2)
26 (20.6)
0.75
53 (21.8)
28 (26.4)
48 (40.7)
0.02
76 (33.9)
Abbreviations: NRS: numerical rating scale. a Worst pain rating across all measured localizations. b Worst pain across all measured localizations, light pain: NRS 1e3, moderate pain: NRS 4e7, severe pain: NRS 8e10. c missing data on 3 patients, 1 in the EBRT group, 2 in the IORT group. d missing data on 14 patients, 6 in the EBRT group, 8 in the IORT group.
significantly higher in patients treated with TARGIT, but there is no pathophysiological explanation that IORT should give more pain in general, since pain elsewhere was described as headache, neckshoulder pain and low-back pain. Such unspecific pain complaints in the joints and muscles are a common side effect of aromatase inhibitors,7 but the use of aromatase inhibitors in the two groups was similar. However, general pain complaints have previously been shown to be associated with a higher risk of PPBCT1,3 and may therefore support that IORT may not increase the risk of PPBCT. Only 20% of the patients received adjuvant endocrine therapy due to inclusion of only patients with a low risk diagnose, and the relatively conservative treatment guidelines in Denmark in the study period. The nature of the TARGIT treatment precluded a blinding of patients, and may have introduced bias in the IORT population. However, the higher prevalence of pain elsewhere argues against this. The intensity of treatment related pain between the two treatment groups was similar, with most patients having light pain. The frequency of pain was high, with most patients experiencing pain on a weekly basis. Patients treated with EBRT experienced pain more frequently (P ¼ 0.044), suggesting a favorable effect of TARGIT. The pathophysiological background for the increased risk of PPBCT with radiation therapy is yet to be described, but it is reasonable to assume the impact on nerves is larger with a more extensive radiation field. Thus, with TARGIT, the smaller radiation field may reduce harm on nerves damage, as radiation is focused on breast tissue. However, sensory disturbances in the two groups were similar (about 22%), and somewhat lower than in the comparable population in the study by Gärtner et al, which found a prevalence of sensory disturbances of 31%.1 The explanations for this may be that the present cohort has an older population and with a shorter follow-up time, 17 months versus 26 months. The late effects of radiotherapy is reported to be accumulating with time.8 The strengths of our study are that it is a homogenous population in terms of treatment and disease status, and that the patients were randomized to IORT or EBRT, and a very high participation rate. The primary limitation of this study is that it is a retrospective questionnaire study, without pretreated baseline pain evaluation. Furthermore, it is a limitation that blinding of the patients was not possible, which is a potential source of bias. Since the patients were homogenous in terms of ethnicity, and are treated in a health care system with universal coverage for all, the results may not be generalized to other population with other ethnic composition or other health care systems.
K.G. Andersen et al. / The Breast 21 (2012) 46e49
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Conclusion
References
This study is the first to compare IORT and EBRT in terms of the risk developing PPBCT in a randomized study, and show that IORT does not increase risk of developing PPBCT compared with EBRT, but with a tendency towards a positive effect of TARGIT with regard to prevalence and frequency of PPBCT.
1. Gartner R, Jensen MB, Nielsen J, Ewertz M, Kroman N, Kehlet, H. Prevalence of and factors associated with persistent pain following breast cancer surgery. JAMA 2009;302(18):1985e92. 2. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet 2006;367(9522):1618e25. 3. Andersen KG, Kehlet H. Persistent pain after breast cancer treatment: a critical review of risk factors and strategies for prevention. J Pain 2011;12(7):725e46. 4. Vaidya JS, Tobias JS, Baum M, Keshtgar M, Wenz F, Hough, J, et al. Intraoperative radiotherapy for breast cancer. Lancet Oncol 2004;5(3):165e73. 5. Vaidya JS, Joseph DJ, Tobias JS, Bulsara M, Wenz F, Saunders C, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. Lancet 2010;376(9735):91e102. 6. Veronesi U, Orecchia R, Luini A, Galimberti V, Zurrida S, Intra M, et al. Intraoperative radiotherapy during breast conserving surgery: a study on 1,822 cases treated with electrons. Breast Cancer Res Treat 2010;124(1):141e51. 7. Coleman RE, Bolten WW, Lansdown M, Dale S, Jackisch C, Merkel D, et al. Aromatase inhibitor-induced arthralgia: clinical experience and treatment recommendations. Cancer Treat Rev 2008;34(3):275e82. 8. Bajrovic A, Rades D, Fehlauer F, Tribius S, Hoeller U, Rudat V, et al. Is there a lifelong risk of brachial plexopathy after radiotherapy of supraclavicular lymph nodes in breast cancer patients? Radiother Oncol 2004;71(3):297e301.
Conflict of interests The authors declare no conflict of interests. Acknowledgements This study is a part of the Europain project, funded by the Innovative Medicines Initiative Joint Undertaking (IMI JU) Grant no 115007 (www.imi.europa.eu), and was also supported by a grant from the Lundbeck Foundation and The Danish Cancer Society.