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Risk factors for joint symptoms in patients enrolled in the ATAC trial: a retrospective, exploratory analysis
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Risk factors for joint symptoms in patients enrolled in the ATAC trial: a retrospective, exploratory analysis Ivana Sestak, Jack Cuzick, Francisco Sapunar, Richard Eastell, John F Forbes, Angelo R Bianco, Aman U Buzdar, on behalf of the ATAC Trialists’ Group
Summary Lancet Oncol 2008; 9: 866–72 Published Online August 13, 2008 DOI:10.1016/S14702045(08)70182-7 See Reflection and Reaction page 817 Cancer Research UK, Centre for Epidemiology, Mathematics, and Statistics, Wolfson Institute of Preventive Medicine, London, UK (I Sestak PhD, Prof J Cuzick PhD); AstraZeneca, Macclesfield, UK (F Sapunar MD); Metabolic Bone Centre, Northern General Hospital, University of Sheffield, Sheffield, UK (Prof R Eastell MD); Department of Surgical Oncology, Newcastle Mater Hospital, University of Newcastle, Newcastle, NSW, Australia (Prof J F Forbes FRACS); Department of Clinical Oncology, School of Medicine, University Federico II, Naples, Italy (A R Bianco MD); Department of Breast Medical Oncology, MD Anderson Cancer Centre, University of Texas, Houston, TX, USA (A U Buzdar MD) Correspondence to: Ivana Sestak, Cancer Research UK, Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Queen Mary School of Medicine and Dentistry, University of London, London EC1M 6BQ, UK [email protected]
Background Joint symptoms (eg, arthralgia and arthritis) are a well-known side-effect of aromatase inhibitors. Low oestrogen concentrations and postmenopausal status are associated with the development of these symptoms. Chemotherapy can also induce joint symptoms, but tamoxifen seems to have little effect on their incidence. The aim of this study was to assess the relative importance of different risk factors for treatment-emergent joint symptoms in patients assigned to anastrozole or tamoxifen as adjuvant treatment for postmenopausal breast cancer. Methods The Arimidex Tamoxifen Alone or in Combination (ATAC) trial randomly assigned 9366 postmenopausal women to anastrozole (1 mg/day), to tamoxifen (20 mg/day), or to a combination of both. Our analyses were based on data from case reports of 5433 women who were randomly assigned to anastrozole or tamoxifen, who started with their allocated treatment, and who did not have joint symptoms at entry (anastrozole group: n=2698; tamoxifen group: n=2735). The analysis was restricted to the occurrence of joint symptoms at any time during active treatment or within 14 days of its discontinuation. Joint symptoms were defined as any report of arthralgia, arthrosis, arthritis, or joint disorder on a case-report form. Joint disorders were defined as reports of cervical spondylosis, osteoarthritis, and disc herniation. The date of occurrence was recorded, along with a severity score (ie, mild, moderate, or severe). Our analyses were done by use of logistic regression. The ATAC trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. Findings 777 of 1914 women (40·6%) who used hormone replacement therapy (HRT) before trial entry developed joint symptoms compared with 1001 of 3519 women (28·4%) without previous HRT use (odds ratio [OR] 1·72 [95% CI 1·53–1·93]). Women with hormone-receptor-negative breast cancer developed significantly fewer joint symptoms compared with those with hormone-receptor-positive tumours (124 of 461 [26·9%] vs 1556 of 4548 [34·2%]; OR 0·71 [0·57–0·88]). Women for whom chemotherapy was part of their initial treatment developed significantly more joint symptoms than those who did not receive it (461 of 1219 women [37·8%] vs 1317 of 4214 women [31·3%]; OR 1·34 [1·17–1·53]). Obese women (body-mass index [BMI] >30 kg/m²) reported more joint symptoms than women with a BMI of 25–30 kg/m² or those with a BMI <25 kg/m² (504 of 1354 women [37·2%] vs 502 of 1926 women [31·3%; OR 1·01 (0·88–1·16)] vs 592 of 1908 women [31·0%; OR 1·32 (1·14–1·53)]) and women on anastrozole reported more joint symptoms compared with those on tamoxifen (949 of 2698 women [35·2%] vs 829 of 2735 women [30·3%]; OR 1·25 [1·11–1·40]). All significant risk factors from the univariate analysis were included in a multivariate analysis and remained significant with little change. Interpretation In this trial, the major risk factors for developing joint symptoms were previous HRT, hormonereceptor positivity, previous chemotherapy, obesity, and treatment with anastrozole. Discussion of identified risk factors is appropriate when counselling women before initiation of adjuvant hormonal treatment. Funding This study was funded by Cancer Research UK and AstraZeneca (Macclesfield, UK).
Introduction Oestrogen deficiency has been associated with joint symptoms (eg, arthralgia and arthritis) in several different settings. In the general population, postmenopausal status and low oestrogen concentrations are associated with the development of joint pain and joint symptoms.1,2 These symptoms are most prominent around the ages of 50 to 59 years,1,2 are more common in postmenopausal women than in premenopausal and perimenopausal women of the same age,3 and often improve during use of hormone replacement therapy (HRT).4,5 Further evidence linking joint symptoms with decreased oestrogen concentrations comes from adjuvant trials of aromatase inhibitors in patients with early breast 866
cancer, where increased joint symptoms (eg, arthralgia and arthritis) have been noted for all three thirdgeneration aromatase inhibitors.6–8 Women treated with chemotherapy for breast cancer have also shown joint symptoms and other joint or muscle-related problems.9,10 However, tamoxifen does not seem to have an effect on joint symptoms. In the first International Breast Cancer Intervention Study,11 joint symptoms were similarly distributed between treatment groups in postmenopausal women (159 of 3579 women in the tamoxifen group vs 147 of 3575 women in the placebo group; p=0·5). Similar findings were shown in the Royal Marsden trial.12 In this retrospective, exploratory analysis, we investigate the relative importance of a range of risk factors for joint www.thelancet.com/oncology Vol 9 September 2008
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Safety population
Study population
Anastrozole* (N=3092) Tamoxifen (N=3094) OR (95% CI)
Anastrozole* (N=2698)
Tamoxifen (N=2735)
1128 (36·5)
957 (30·9)
1·28 (1·15–1·43)
949 (35·2%)
829 (30·3%)
1·25 (1·11–1·40)
Mild, n (%)
586 (19·0)
517 (16·7)
1·16 (1·02–1.33)
518 (19·2%)
472 (17·3%)
1·14 (0·99–1·31)
Moderate, n (%)
447 (14·5)
353 (11·4)
1·31 (1·13–1·53)
366 (13·6%)
296 (10·8%)
1·29 (1·09–1·53)
94 (3·0)
87 (2·8)
1·08 (0·79–1·47)
64 (2·4%)
61 (2·2%)
1·06 (0·73–1·54)
Overall, n (%)
Severe, n (%)
OR (95% CI)
OR=odds ratio. *One patient in the anastrozole group reported joint symptoms but severity was not provided.
Table 1: Patients with joint symptoms by severity and treatment first received for all women (safety population) and for those without joint symptoms at entry (study population)
symptoms in the Arimidex Tamoxifen Alone or in Combination (ATAC) trial,13 and assess whether these risk factors act differently in the presence of anastrozole treatment.
The ATAC trial13 was a double-blind randomised clinical trial in which postmenopausal women with early breast cancer were randomly assigned to oral daily anastrozole (1 mg) alone, tamoxifen (20 mg) alone, or a combination of both in a double-blind fashion, so that each woman took two tablets, at least one of which was active. Patients from the combination group were discontinued after 33 months of follow-up and are not included in this analysis. Women were followed-up at 3 months, 6 months, and then at 6 monthly intervals for the 5 years of active treatment. Details of trial design, methods, primary objectives, and outcome have been published elsewhere.13 Written informed consent was obtained from all participants before trial entry. Regulatory and ethics authorities for all participating centres in 21 countries approved the protocol before enrolment of participants. The trial was done in accordance with the Declaration of Helsinki (1996 revision) and under the principles of good clinical practice. Only women who started with their randomly assigned treatment and who did not report joint symptoms at entry were included in this analysis (anastrozole group: n=2698; tamoxifen group: n=2735). Women with joint symptoms at entry reported fewer symptoms during treatment. By excluding these women, we focused on newly reported joint symptoms, which are more likely to be related to endocrine treatment. Our analysis was based on the 100-month median follow-up data set, at which point all patients had completed their study medication.14 Because most symptoms occurred relatively early, and the effects of treatment and other variables were not constant with time, the analysis was restricted to the occurrence of joint symptoms at any time during active treatment or within 14 days of its discontinuation. Joint symptoms were defined as any report of arthralgia, arthrosis, arthritis, or joint disorder (Coding Symbols for a Thesaurus of Adverse Reaction terms)15 on a case-report form. Joint disorders were defined as reports of cervical spondylosis, www.thelancet.com/oncology Vol 9 September 2008
Anastrozole Tamoxifen
40
Patients (%)
Methods
50
30
20
10
0 0 Number at risk Anastrozole Tamoxifen
1
2
3
4
5
1534 1656
1354 1464
Follow-up time (years) 2698 2735
2239 2372
1950 2085
1710 1859
Figure 1: Patients (%) developing joint symptoms at or before a specified follow-up time during active treatment according to treatment first received in women without joint symptoms at entry (study population)
osteoarthritis, and disc herniation. The date of occurrence was recorded, along with a severity score (ie, mild, moderate, or severe). For the ATAC trial, all side-effect data were the result of elicited responses recorded on case-report forms and a specific symptom check list was not used. All reports were reviewed by the trial medical officer (FS), who was blinded to treatment allocation, to resolve any uncertain reports.
Statistical analysis Analyses of potential risk factors were based on comparisons of proportions by univariate and multivariate logistic regression. Interactions between treatment and subgroups were based on likelihood ratio tests for an added interaction term. Hazard plots were smoothed by use of an Epanechnikov kernel with the optimum bandwidth chosen by cross validation.16 All p values are two-sided, with level of significance set at 0·05, and all confidence intervals are at the 95% level. All calculations were done by use of STATA (version 9.2). The ATAC trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. 867
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Anastrozole Tamoxifen
16
Annual hazard rate (%)
14
Results
12
10
8
0 0
1
2
3
5
4
Follow-up time (years)
Figure 2: Smoothed annual hazard rates (%) of newly reported joint symptoms during active treatment according to treatment first received in women without joint symptoms at entry (study population)
Anastrozole (N=2698)
Tamoxifen (N=2735)
Previous HRT
941 (34·9)
973 (35·6)
Previous chemotherapy
627 (23·2)
592 (21·6)
Previous radiotherapy
1796 (66·6)
1780 (65·1)
History of smoking
1092 (40·5)
1118 (40·9)
BMI (kg/m2) <25
963 (35·7)
963 (35·2)
25–30
957 (35·5)
969 (35·4)
>30
654 (24·2)
700 (25·6)
Missing
124 (4·6)
121 (4·4)
Hormone-receptor status Positive (ER or PgR positive)
2264 (83·9)
2284 (83·5)
Negative
220 (8·2)
241 (8·8)
Unknown
214 (7·9)
210 (7·7)
Region UK
905 (33·5)
910 (33·3)
ROW
991 (36·7)
1016 (37·1)
North America*
802 (29·7)
809 (29·6)
Age (years) ≤60 61–70 >70
993 (36·8)
1016 (37·1)
1019 (37·8)
998 (36·5)
686 (25·4)
721 (26·4)
HRT=hormone replacement therapy. BMI=body-mass index. ER=oestrogen receptor. PgR=progesterone receptor. ROW=rest of world. *North America=USA and Canada.
Table 2: Selected baseline characteristics (%) according to treatment group (study population)
Role of the funding source This study was funded by Cancer Research UK and AstraZeneca (Macclesfield, UK). All authors were responsible for data interpretation and writing the report, and the decision to submit for publication was taken jointly with the Steering Committee. IS and JC had full 868
access to the data. The commercial sponsor was represented by two of the 28 members of the Steering Committee.
A total of 2085 of 6186 women in the safety population reported joint symptoms while on active treatment. Significantly more joint symptoms were noted in the anastrozole group compared with the tamoxifen group (1128 of 3092 (36·5%) vs 957 of 3094 (30·9%); odds ratio [OR] 1·28 [95% CI 1·15–1·43), p<0·0001). 394 women in the anastrozole group and 359 women in the tamoxifen group (OR 0·90 [0·77–1·05]) reported a history of joint symptoms at entry into the trial. These women have been excluded from further analyses. Table 1 shows exclusion of these women had little effect on the differences in joint symptoms between the two treatment groups. After exclusion, a total of 2698 women in the anastrozole group and 2735 women in the tamoxifen group remained for further analyses (study population). Figure 1 shows the higher prevalence of joint symptoms reported by women without a history of joint symptoms at study entry in the anastrozole group compared with the tamoxifen group. Most of the additional joint symptoms reported in the anastrozole group occurred during the first 2 years of treatment (figure 2). In both treatment groups, most joint symptoms were of mild or moderate severity, and the intensity of symptoms was similarly distributed in both treatment groups (table 1). 1067 of 1778 patients (60%) who reported joint symptoms received treatment, with 960 of these patients (90%) using a non-steroidal anti-inflammatory drug alone or in combination with a mild analgesic. Potential risk factors for developing joint symptoms are shown for each treatment group in table 2. After exclusion of women with baseline joint symptoms, 949 of 2698 women (35·2%) reported joint symptoms in the anastrozole group compared with 829 of 2735 women (30·3%) in the tamoxifen group (OR 1·25 [95% CI 1·11–1·40; p<0·0001]; table 3). For women who previously used HRT, 777 of 1914 (40·6%) developed joint symptoms compared with 1001 of 3519 women (28·4%) without previous HRT use (OR 1·72 [1·53–1·93]; p<0·0001). Joint symptoms were increased by a similar amount for women who stopped HRT less than 6 months before trial entry compared with those who stopped HRT more than 6 months before entry (502 of 1201 women (41·8%) vs 142 of 335 women (42·4%); OR 1·08 [0·84–1·40]; p=0·54). 133 patients with joint symptoms and 245 patients without joint symptoms had missing data for date of last use. Women with hormone-receptor-negative breast cancer developed significantly fewer joint symptoms than those with hormone-receptor-positive tumours (124 of 461 (26·9%) vs 1556 of 4548 (34·2%); OR 0·71 [0·57–0·88]; p=0·002; table 3). Previous chemotherapy was also a strong risk factor for developing joint symptoms (461 of 1219 women (37·8%) with history of previous www.thelancet.com/oncology Vol 9 September 2008
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chemotherapy vs 1317 of 4214 women (31·3%) with history of no chemotherapy; OR 1·34 [1·17–1·53]; p<0·0001). Women with a BMI over 30 kg/m² and those who smoked reported more joint symptoms than their counterparts (table 3). Age and radiotherapy showed no detectable effect on the development of joint symptoms. When all significant variables in the univariate models were entered into a multivariate model, the odds ratios were similar to the univariate findings, except for smoking status, which became non-significant (table 3). Similar findings for the univariate and multivariate analyses of risk factors were obtained if the population was restricted to hormone-receptor-positive women (data
not shown). Additionally, there were no significant interactions of any factors with treatment, except for a weak interaction between treatment and previous HRT use (pinteraction=0·05; table 4). Women from the USA and Canada (grouped as North America) reported significantly more joint symptoms than those from the UK or the reference group of the rest of the world (738 of 1611 (45·8%; OR 2·44 [2·12–2·80]; p<0·0001) vs 523 of 1815 (28·8%; OR 1·17 [1·01–1·35]; p=0·03) vs 517 of 2007 (25·8%); table 3). This difference was unchanged in the multivariate model. To explore further baseline characteristics, interactions of region with other key variables were added to the model. Overall,
Women with joint symptoms, n (%)
Univariate analysis OR (95% CI)
Multivariate analysis p value
OR (95% CI)
p value
<0·0001
1·26 (1·12–1·42)
<0·0001
1·53 (1·35–1·74)
<0·0001
··
··
Treatment Tamoxifen (n=2735)
829 (30·3)
1
Anastrozole (n=2698)
949 (35·2)
1·25 (1·11–1·40)
1 <0·0001
Previous HRT No (n=3519)
1001 (28·4)
Yes (n=1914)*
777 (40·6)
1 1·72 (1·53–1·93)
Stopped ≤6 months† (n=1201)
502 (41·8)
1
Stopped >6 months† (n=335)
142 (42·4)
1·08 (0·84–1·40)
1
0·54‡
Chemotherapy No (n=4214)
1317 (31·3)
Yes (n=1219)
461 (37·8)
1 1·34 (1·17–1·53)
1 <0·0001
1·24 (1·07–1·43)
0·004
Hormone-receptor status Positive (ER or PgR positive; n=4548)
1556 (34·2)
1
1
Negative (n=461)
124 (26·9)
0·71 (0·57–0·88)
0·002
0·78 (0·62–0·98)
0·03
Unknown (n=424)
98 (23·1)
0·58 (0·46–0·73)
<0·0001
0·76 (0·59–0·97)
0·028
Region ROW (n=2007)
517 (25·8)
1
UK (n=1815)
523 (28·8)
1·17 (1·01–1·35)
0·03
1·20 (1·02–1·40)
1 0·025
North America§ (n=1611)
738 (45·8)
2·44 (2·12–2·80)
<0·0001
2·09 (1·79–2·43)
<0·0001
BMI (kg/m2)¶ <25 (n=1908)
592 (31·0)
1
25–30 (n=1926)
602 (31·3)
1·01 (0·88–1·16)
0·88
1·08 (0·94–1·24)
1 0·28
>30 (n=1354)
504 (37·2)
1·32 (1·14–1·53)
<0·0001
1·33 (1·14–1·55)
<0·0001
0·05
0·99 (0·88–1·12)
Ever smoker No (n=3223)
1030 (32·0)
Yes (n=2210)
747 (33·8)
1 1·12 (1·00–1·26)
1
≤60 (n=2009)
661 (32·9)
1
··
··
61–70 (n=2017)
638 (31·6)
0·94 (0·83–1·08)
0·39
··
··
>70 (n=1407)
479 (34·0)
1·05 (0·91–1·22)
0·49
··
··
No (n=1857)
644 (34·7)
1
··
··
Yes (n=3576)
1134 (31·7)
0·40
··
··
0·9
Age (years)
Radiotherapy 1·05 (0·93–1·18)
Reference group is represented by an odds ratio (OR) of 1. Multivariate analysis includes only significant factors from the univariate model. HRT=hormone-replacement therapy. ER=oestrogen recepetor. PgR=progesterone receptor. ROW=rest of world. BMI=body-mass index. *Stop-date data missing for 133 patients with joint symptoms and 245 patients without joint symptoms. †Before trial entry. ‡Comparison with those who used HRT and excludes 133 patients with missing data for stop date. §North America=USA and Canada. ¶Data missing for 245 patients.
Table 3: Risk factors at baseline for developing joint symptoms in women without joint symptoms at trial entry (study population)
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Anastrozole (N=2698)
Tamoxifen (N=2735)
949 (35·2)
829 (30·3)
No
525/1757 (29·9)
476/1762 (27·0)
··
Yes
424/941 (45·1)
353/973 (36·3)
0·05
No
687/2071 (33·2)
630/2143 (29·4)
··
Yes
262/627 (41·8)
199/592 (33·6)
0·20
All
pinteraction
Previous HRT
Chemotherapy
Hormone-receptor status Positive (ER or PgR positive)
840/2264 (37·1)
716/2284 (31·3)
Negative
59/220 (26·8)
65/241 (27·0)
0·23
··
Unknown
50/214 (23·3)
48/210 (22·9)
0·31
Region ROW
284/991 (28·7)
233/1016 (22·9)
UK
269/905 (29·7)
254/910 (27·9)
·· 0·15
North America*
396/802 (49·4)
342/809 (42·3)
0·94
<25
324/963 (33·6)
268/945 (28·4)
··
25–30
335/957 (35·0)
267/969 (27·6)
0·48
>30
246/654 (37·6)
258/700 (36·9)
0·21
BMI (kg/m2)†
HRT=hormone replacement therapy. ER=oestrogen receptor. PgR=progesterone receptor. ROW=rest of world. BMI=body-mass index *North America=USA and Canada. †Data missing for 245 patients.
Table 4: Number (%) of women reporting joint symptoms at any time during treatment according to treatment first received and selected risk factors in women without joint symptoms at entry (study population)
no significant interactions of key variables in the univariate model were seen with region in the multivariate model (data not shown).
Discussion In this trial, the major risk factors for developing joint symptoms in women not reporting them at entry were previous HRT use, hormone-receptor positivity, previous chemotherapy, obesity, and treatment with anastrozole versus tamoxifen, leading to significant absolute increases of 12·1%, 7·3%, 6·5%, 6·2%, and 4·9%, respectively. All these factors are potentially linked with greater decreases in oestrogen concentrations near to the time when endocrine treatment is started. Women with pre-existing joint symptoms were excluded from this analysis to focus on new treatment-emergent symptoms. The effect of previous HRT was especially striking, which could be because most women previously using HRT, for whom we had data, came off it within 6 months before entry into the study (1201 of 1536 women [78·2%]), although the effect was similar in women who had stopped their HRT treatment earlier. Furthermore, the effects of HRT seemed to be additive, resulting in an 18·1% increase in joint symptoms in women who previously used HRT and were on anastrozole compared with those on tamoxifen with no previous HRT use. Recent users of HRT (ie, those who stopped use less than 6 months ago) are likely to have a greater decrease in 870
oestrogen concentrations with endocrine treatment than those who stopped use more than 6 months ago, and most,17,18 but not all studies,19 have shown that they are more likely than never users to have oestrogen-receptorpositive tumours. In our study, women with hormonereceptor-positive tumours reported more joint symptoms than those with hormone-receptor-negative tumours, but, paradoxically, the few women with tumours of unknown hormone-receptor status had the lowest number of joint symptoms. Several studies have shown that women with high oestrogen concentrations are more likely to develop oestrogen-receptor-positive tumours than those with low oestrogen concentrations.20, 21 Obese women tend to have higher oestrogen concentrations than non-obese women as a result of aromatisation from the adipose tissue,22 so the decrease in oestrogen concentration is likely to be greater in this group as well. Obesity itself is also a risk factor for joint symptoms independent of endocrine treatment.23 However, Crew and colleagues24 reported that women with a BMI between 25 and 30 kg/m² developed fewer joint symptoms than those with a lower BMI. Our data do not confirm this finding, with significantly more joint symptoms being noted with increasing BMI. Chemotherapy is well known to induce arthralgia or myalgia and has been reported in several trials independently of endocrine treatment.10,25–27 Chemotherapy is known to damage ovarian function in premenopausal women, and the effects seen here could be a result of the ablation of any residual ovarian production of oestrogen in these postmenopausal women. Again, the findings were additive in anastrozole users so that the use of previous chemotherapy and anastrozole together resulted in a 12·4% increase in joint symptoms when compared with women on tamoxifen without previous chemotherapy. Reports have suggested that side-effects, such as joint symptoms, are under-reported in clinical trials compared with patient-recorded side-effects.28,29 The ATAC trial was an international study, involving 21 countries. Joint symptoms were collected in free-text format on the casereport forms. Because of the nature of the collection, in which uniform definition of symptoms was not provided, subcategories of joint symptoms were not thought to be reliable and were, therefore, not reported during the ATAC trial. Additionally, the duration of symptoms and date of resolution of symptoms could not be assessed in detail, because data were collected at 3 months, 6 months, and at 6-monthly intervals thereafter, so dates within these intervals were not recorded. Because the study was blinded, there would have been no bias in relative rates, but the overall reporting rates for specific symptoms could have been affected. However, this approach did seem to be sensitive, because known minor side-effects, and some previously unknown ones, were clearly detectable.30 The symptoms were assessed by clinicians and mapped to the relevant COSTART www.thelancet.com/oncology Vol 9 September 2008
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terms.15 This ascertainment of joint symptoms needs to be taken into account when interpreting these findings. Although various joint symptoms were reported during the study, only 1% of them led to treatment withdrawal. By contrast, a higher drop-out rate caused by joint symptoms was reported in two smaller uncontrolled studies,31,32 but it is difficult to attribute all these events to an aromatase inhibitor, because joint symptoms are common in postmenopausal women (eg, 31% of women receiving tamoxifen in the ATAC trial reported joint symptoms). The increased incidence of joint symptoms in the North American population is most probably consistent with different practices for recording symptoms. Although more patients had previous HRT use, previous chemotherapy, and a higher BMI in North America, compared with the UK and the rest of the world, the effects of region were only slightly diminished when they were adjusted for in the multivariate model. No significant interactions between region and risk factors were identified, suggesting that the differences noted between regions were most probably due to different thresholds for reporting these symptoms in North America, especially because adverse events overall were more often reported in North American participants. In conclusion, several factors other than treatment with anastrozole were associated with the development of joint symptoms in this trial. The effects are additive and thus need to be taken into account when counselling women about the use of aromatase inhibitors. Joint symptoms were generally of mild to moderate intensity and for most women they do not override the clear benefits of anastrozole over tamoxifen in terms of decreased recurrence and fewer other major side-effects, including venous thromboembolic events and gynaecological complications (eg, endometrial cancer).14 However, for women with serious side-effects on anastrozole, tamoxifen remains a viable option. Awareness of risk factors for joint symptoms will help both clinicians and patients to anticipate and manage these symptoms and ensure optimum adherence to endocrine treatment. Conflicts of interest IS declared no conflicts of interest. JC has received research funds from AstraZeneca and acted as a consultant to AstraZeneca and Novartis. FS is an employee and has stock ownership with AstraZeneca. RE has received honoraria and research grants, and has acted as a consultant for AstraZeneca. JFF has received honoraria from AstraZeneca. ARB has received research funding from AstraZeneca. AUB has received honoraria and other research grants from AstraZeneca, Pfizer, Genentech, Lilly, Taiko, and Amgen. Contributors IS was involved in the data analysis and interpretation. JC was responsible for the conception and design of the study, and assembly and analysis of the data. FS and RE were involved with the assembly and interpretation of the data. JFF, ARB, and AUB were involved in the design of the study, provision of patients, and interpretation of the data. All contributors took part in writing the paper and approved the final version.
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Acknowledgments This research was supported by Cancer Research UK and AstraZeneca (Macclesfield, UK). We thank all the patients for their participation in the trial. We also thank the trial investigators, other supporting staff, and the members of the International Steering Committee. References 1 Croft P, Rigby AS, Boswell R, Schollum J, Silman A. The prevalence of chronic widespread pain in the general population. J Rheumatol 1993; 20: 710–13. 2 Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum 1995; 38: 19–28. 3 Felson DT, Cummings SR. Aromatase inhibitors and the syndrome of arthralgias with estrogen deprivation. Arthritis Rheum 2005; 52: 2594–98. 4 Jansson C, Johansson S, Lindh-Astrand L, Hoffmann M, Hammar M. The prevalence of symptoms possibly related to the climacteric in pre- and postmenopausal women in Linkoping, Sweden. Maturitas 2003; 45: 129–35. 5 Carlsten H. Immune responses and bone loss: the estrogen connection. Immunol Rev 2005; 208: 194–206. 6 Coates AS, Keshaviah A, Thurlimann B, et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 2007; 25: 486–92. 7 Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004; 350: 1081–92. 8 Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005; 365: 60–62. 9 Smith RE, Anderson SJ, Lembersky BC, Brown A, Mamounas E. Phase II trial of a doxorubicin/docetaxel doublet for locally advanced and metastatic breast cancer: results from national surgical adjuvant breast and bowel project trial BP-57. Clin Breast Cancer 2004; 5: 208–15. 10 Jones SE, Savin MA, Holmes FA, et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 2006; 24: 5381–87. 11 Cuzick J, Forbes JF, Sestak I, et al. Long-term results of tamoxifen prophylaxis for breast cancer—96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst 2007; 99: 272–82. 12 Powles TJ, Ashley S, Tidy A, Smith IE, Dowsett M. Twenty-year follow-up of the Royal Marsden Randomized, Double-Blinded Tamoxifen Breast Cancer Prevention Trial. J Natl Cancer Inst 2007; 99: 283–90. 13 The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’ Group Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359: 2131–39. 14 Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M. Effect of anastrozole and tamoxifen as adjuvant treatment for earlystage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008; 9: 45–53. 15 Food and Drug Administration. (COSTART ) The coding symbols for thesaurus of adverse reaction terms. Rockville, MD: National Press Office, 1995. 16 Jones MC, Wand MP. Kernel smoothing. Boca Raton, Florida: CRC Press, 1994. 17 Holli K, Isola J, Cuzick J. Low biologic aggressiveness in breast cancer in women using hormone replacement therapy. J Clin Oncol 1998; 16: 3115–20. 18 Delgado RC, Lubian Lopez DM. Prognosis of breast cancer detected in women receiving hormone replacement therapy. Maturitas 2001; 38: 147–56. 19 Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 2003; 289: 3243–53.
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Numazaki R, Miyagi E, Onose R, et al. Historical control study of paclitaxel-carboplatin (TJ) versus conventional platinum-based chemotherapy (CAP) for epithelial ovarian cancer. Int J Clin Oncol 2006; 11: 221–28. Basch E, Iasonos A, McDonough T, et al. Patient versus clinician symptom reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events: results of a questionnairebased study. Lancet Oncol 2006; 7: 903–09. Dent S, DeValentin T, Vandermeer L, et al. Long-term toxicities in women with early stage breast cancer treated with aromatase inhibitors: data from a tertiary care center. Breast Cancer Res Treat 2006; 100 (suppl 1): abstract 4057. Buzdar A, Howell A, Cuzick J, et al. Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for earlystage breast cancer: long-term safety analysis of the ATAC trial. Lancet Oncol 2006; 7: 633–43. Henry NL, Giles JT, Ang D, et al. Prospective characterization of musculoskeletal symptoms in early stage breast cancer patients treated with aromatase inhibitors. Breast Cancer Res Treat 2008; 111: 365–72. Fontaine C, Meulemans A, Huizing M, et al. Tolerance of adjuvant letrozole outside of clinical trials. Breast 2008; published online May 2. DOI: 10.1016/j.breast.2008.02.006.
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Risk factors for joint symptoms in patients enrolled in the ATAC trial: a retrospective, exploratory analysis Ivana Sestak, Jack Cuzick, Francisco Sapunar, Richard Eastell, John F Forbes, Angelo R Bianco, Aman U Buzdar, on behalf of the ATAC Trialists’ Group
Summary Lancet Oncol 2008; 9: 866–72 Published Online August 13, 2008 DOI:10.1016/S14702045(08)70182-7 See Reflection and Reaction page 817 Cancer Research UK, Centre for Epidemiology, Mathematics, and Statistics, Wolfson Institute of Preventive Medicine, London, UK (I Sestak PhD, Prof J Cuzick PhD); AstraZeneca, Macclesfield, UK (F Sapunar MD); Metabolic Bone Centre, Northern General Hospital, University of Sheffield, Sheffield, UK (Prof R Eastell MD); Department of Surgical Oncology, Newcastle Mater Hospital, University of Newcastle, Newcastle, NSW, Australia (Prof J F Forbes FRACS); Department of Clinical Oncology, School of Medicine, University Federico II, Naples, Italy (A R Bianco MD); Department of Breast Medical Oncology, MD Anderson Cancer Centre, University of Texas, Houston, TX, USA (A U Buzdar MD) Correspondence to: Ivana Sestak, Cancer Research UK, Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Queen Mary School of Medicine and Dentistry, University of London, London EC1M 6BQ, UK [email protected]
Background Joint symptoms (eg, arthralgia and arthritis) are a well-known side-effect of aromatase inhibitors. Low oestrogen concentrations and postmenopausal status are associated with the development of these symptoms. Chemotherapy can also induce joint symptoms, but tamoxifen seems to have little effect on their incidence. The aim of this study was to assess the relative importance of different risk factors for treatment-emergent joint symptoms in patients assigned to anastrozole or tamoxifen as adjuvant treatment for postmenopausal breast cancer. Methods The Arimidex Tamoxifen Alone or in Combination (ATAC) trial randomly assigned 9366 postmenopausal women to anastrozole (1 mg/day), to tamoxifen (20 mg/day), or to a combination of both. Our analyses were based on data from case reports of 5433 women who were randomly assigned to anastrozole or tamoxifen, who started with their allocated treatment, and who did not have joint symptoms at entry (anastrozole group: n=2698; tamoxifen group: n=2735). The analysis was restricted to the occurrence of joint symptoms at any time during active treatment or within 14 days of its discontinuation. Joint symptoms were defined as any report of arthralgia, arthrosis, arthritis, or joint disorder on a case-report form. Joint disorders were defined as reports of cervical spondylosis, osteoarthritis, and disc herniation. The date of occurrence was recorded, along with a severity score (ie, mild, moderate, or severe). Our analyses were done by use of logistic regression. The ATAC trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. Findings 777 of 1914 women (40·6%) who used hormone replacement therapy (HRT) before trial entry developed joint symptoms compared with 1001 of 3519 women (28·4%) without previous HRT use (odds ratio [OR] 1·72 [95% CI 1·53–1·93]). Women with hormone-receptor-negative breast cancer developed significantly fewer joint symptoms compared with those with hormone-receptor-positive tumours (124 of 461 [26·9%] vs 1556 of 4548 [34·2%]; OR 0·71 [0·57–0·88]). Women for whom chemotherapy was part of their initial treatment developed significantly more joint symptoms than those who did not receive it (461 of 1219 women [37·8%] vs 1317 of 4214 women [31·3%]; OR 1·34 [1·17–1·53]). Obese women (body-mass index [BMI] >30 kg/m²) reported more joint symptoms than women with a BMI of 25–30 kg/m² or those with a BMI <25 kg/m² (504 of 1354 women [37·2%] vs 502 of 1926 women [31·3%; OR 1·01 (0·88–1·16)] vs 592 of 1908 women [31·0%; OR 1·32 (1·14–1·53)]) and women on anastrozole reported more joint symptoms compared with those on tamoxifen (949 of 2698 women [35·2%] vs 829 of 2735 women [30·3%]; OR 1·25 [1·11–1·40]). All significant risk factors from the univariate analysis were included in a multivariate analysis and remained significant with little change. Interpretation In this trial, the major risk factors for developing joint symptoms were previous HRT, hormonereceptor positivity, previous chemotherapy, obesity, and treatment with anastrozole. Discussion of identified risk factors is appropriate when counselling women before initiation of adjuvant hormonal treatment. Funding This study was funded by Cancer Research UK and AstraZeneca (Macclesfield, UK).
Introduction Oestrogen deficiency has been associated with joint symptoms (eg, arthralgia and arthritis) in several different settings. In the general population, postmenopausal status and low oestrogen concentrations are associated with the development of joint pain and joint symptoms.1,2 These symptoms are most prominent around the ages of 50 to 59 years,1,2 are more common in postmenopausal women than in premenopausal and perimenopausal women of the same age,3 and often improve during use of hormone replacement therapy (HRT).4,5 Further evidence linking joint symptoms with decreased oestrogen concentrations comes from adjuvant trials of aromatase inhibitors in patients with early breast 866
cancer, where increased joint symptoms (eg, arthralgia and arthritis) have been noted for all three thirdgeneration aromatase inhibitors.6–8 Women treated with chemotherapy for breast cancer have also shown joint symptoms and other joint or muscle-related problems.9,10 However, tamoxifen does not seem to have an effect on joint symptoms. In the first International Breast Cancer Intervention Study,11 joint symptoms were similarly distributed between treatment groups in postmenopausal women (159 of 3579 women in the tamoxifen group vs 147 of 3575 women in the placebo group; p=0·5). Similar findings were shown in the Royal Marsden trial.12 In this retrospective, exploratory analysis, we investigate the relative importance of a range of risk factors for joint www.thelancet.com/oncology Vol 9 September 2008
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Safety population
Study population
Anastrozole* (N=3092) Tamoxifen (N=3094) OR (95% CI)
Anastrozole* (N=2698)
Tamoxifen (N=2735)
1128 (36·5)
957 (30·9)
1·28 (1·15–1·43)
949 (35·2%)
829 (30·3%)
1·25 (1·11–1·40)
Mild, n (%)
586 (19·0)
517 (16·7)
1·16 (1·02–1.33)
518 (19·2%)
472 (17·3%)
1·14 (0·99–1·31)
Moderate, n (%)
447 (14·5)
353 (11·4)
1·31 (1·13–1·53)
366 (13·6%)
296 (10·8%)
1·29 (1·09–1·53)
94 (3·0)
87 (2·8)
1·08 (0·79–1·47)
64 (2·4%)
61 (2·2%)
1·06 (0·73–1·54)
Overall, n (%)
Severe, n (%)
OR (95% CI)
OR=odds ratio. *One patient in the anastrozole group reported joint symptoms but severity was not provided.
Table 1: Patients with joint symptoms by severity and treatment first received for all women (safety population) and for those without joint symptoms at entry (study population)
symptoms in the Arimidex Tamoxifen Alone or in Combination (ATAC) trial,13 and assess whether these risk factors act differently in the presence of anastrozole treatment.
The ATAC trial13 was a double-blind randomised clinical trial in which postmenopausal women with early breast cancer were randomly assigned to oral daily anastrozole (1 mg) alone, tamoxifen (20 mg) alone, or a combination of both in a double-blind fashion, so that each woman took two tablets, at least one of which was active. Patients from the combination group were discontinued after 33 months of follow-up and are not included in this analysis. Women were followed-up at 3 months, 6 months, and then at 6 monthly intervals for the 5 years of active treatment. Details of trial design, methods, primary objectives, and outcome have been published elsewhere.13 Written informed consent was obtained from all participants before trial entry. Regulatory and ethics authorities for all participating centres in 21 countries approved the protocol before enrolment of participants. The trial was done in accordance with the Declaration of Helsinki (1996 revision) and under the principles of good clinical practice. Only women who started with their randomly assigned treatment and who did not report joint symptoms at entry were included in this analysis (anastrozole group: n=2698; tamoxifen group: n=2735). Women with joint symptoms at entry reported fewer symptoms during treatment. By excluding these women, we focused on newly reported joint symptoms, which are more likely to be related to endocrine treatment. Our analysis was based on the 100-month median follow-up data set, at which point all patients had completed their study medication.14 Because most symptoms occurred relatively early, and the effects of treatment and other variables were not constant with time, the analysis was restricted to the occurrence of joint symptoms at any time during active treatment or within 14 days of its discontinuation. Joint symptoms were defined as any report of arthralgia, arthrosis, arthritis, or joint disorder (Coding Symbols for a Thesaurus of Adverse Reaction terms)15 on a case-report form. Joint disorders were defined as reports of cervical spondylosis, www.thelancet.com/oncology Vol 9 September 2008
Anastrozole Tamoxifen
40
Patients (%)
Methods
50
30
20
10
0 0 Number at risk Anastrozole Tamoxifen
1
2
3
4
5
1534 1656
1354 1464
Follow-up time (years) 2698 2735
2239 2372
1950 2085
1710 1859
Figure 1: Patients (%) developing joint symptoms at or before a specified follow-up time during active treatment according to treatment first received in women without joint symptoms at entry (study population)
osteoarthritis, and disc herniation. The date of occurrence was recorded, along with a severity score (ie, mild, moderate, or severe). For the ATAC trial, all side-effect data were the result of elicited responses recorded on case-report forms and a specific symptom check list was not used. All reports were reviewed by the trial medical officer (FS), who was blinded to treatment allocation, to resolve any uncertain reports.
Statistical analysis Analyses of potential risk factors were based on comparisons of proportions by univariate and multivariate logistic regression. Interactions between treatment and subgroups were based on likelihood ratio tests for an added interaction term. Hazard plots were smoothed by use of an Epanechnikov kernel with the optimum bandwidth chosen by cross validation.16 All p values are two-sided, with level of significance set at 0·05, and all confidence intervals are at the 95% level. All calculations were done by use of STATA (version 9.2). The ATAC trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. 867
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Anastrozole Tamoxifen
16
Annual hazard rate (%)
14
Results
12
10
8
0 0
1
2
3
5
4
Follow-up time (years)
Figure 2: Smoothed annual hazard rates (%) of newly reported joint symptoms during active treatment according to treatment first received in women without joint symptoms at entry (study population)
Anastrozole (N=2698)
Tamoxifen (N=2735)
Previous HRT
941 (34·9)
973 (35·6)
Previous chemotherapy
627 (23·2)
592 (21·6)
Previous radiotherapy
1796 (66·6)
1780 (65·1)
History of smoking
1092 (40·5)
1118 (40·9)
BMI (kg/m2) <25
963 (35·7)
963 (35·2)
25–30
957 (35·5)
969 (35·4)
>30
654 (24·2)
700 (25·6)
Missing
124 (4·6)
121 (4·4)
Hormone-receptor status Positive (ER or PgR positive)
2264 (83·9)
2284 (83·5)
Negative
220 (8·2)
241 (8·8)
Unknown
214 (7·9)
210 (7·7)
Region UK
905 (33·5)
910 (33·3)
ROW
991 (36·7)
1016 (37·1)
North America*
802 (29·7)
809 (29·6)
Age (years) ≤60 61–70 >70
993 (36·8)
1016 (37·1)
1019 (37·8)
998 (36·5)
686 (25·4)
721 (26·4)
HRT=hormone replacement therapy. BMI=body-mass index. ER=oestrogen receptor. PgR=progesterone receptor. ROW=rest of world. *North America=USA and Canada.
Table 2: Selected baseline characteristics (%) according to treatment group (study population)
Role of the funding source This study was funded by Cancer Research UK and AstraZeneca (Macclesfield, UK). All authors were responsible for data interpretation and writing the report, and the decision to submit for publication was taken jointly with the Steering Committee. IS and JC had full 868
access to the data. The commercial sponsor was represented by two of the 28 members of the Steering Committee.
A total of 2085 of 6186 women in the safety population reported joint symptoms while on active treatment. Significantly more joint symptoms were noted in the anastrozole group compared with the tamoxifen group (1128 of 3092 (36·5%) vs 957 of 3094 (30·9%); odds ratio [OR] 1·28 [95% CI 1·15–1·43), p<0·0001). 394 women in the anastrozole group and 359 women in the tamoxifen group (OR 0·90 [0·77–1·05]) reported a history of joint symptoms at entry into the trial. These women have been excluded from further analyses. Table 1 shows exclusion of these women had little effect on the differences in joint symptoms between the two treatment groups. After exclusion, a total of 2698 women in the anastrozole group and 2735 women in the tamoxifen group remained for further analyses (study population). Figure 1 shows the higher prevalence of joint symptoms reported by women without a history of joint symptoms at study entry in the anastrozole group compared with the tamoxifen group. Most of the additional joint symptoms reported in the anastrozole group occurred during the first 2 years of treatment (figure 2). In both treatment groups, most joint symptoms were of mild or moderate severity, and the intensity of symptoms was similarly distributed in both treatment groups (table 1). 1067 of 1778 patients (60%) who reported joint symptoms received treatment, with 960 of these patients (90%) using a non-steroidal anti-inflammatory drug alone or in combination with a mild analgesic. Potential risk factors for developing joint symptoms are shown for each treatment group in table 2. After exclusion of women with baseline joint symptoms, 949 of 2698 women (35·2%) reported joint symptoms in the anastrozole group compared with 829 of 2735 women (30·3%) in the tamoxifen group (OR 1·25 [95% CI 1·11–1·40; p<0·0001]; table 3). For women who previously used HRT, 777 of 1914 (40·6%) developed joint symptoms compared with 1001 of 3519 women (28·4%) without previous HRT use (OR 1·72 [1·53–1·93]; p<0·0001). Joint symptoms were increased by a similar amount for women who stopped HRT less than 6 months before trial entry compared with those who stopped HRT more than 6 months before entry (502 of 1201 women (41·8%) vs 142 of 335 women (42·4%); OR 1·08 [0·84–1·40]; p=0·54). 133 patients with joint symptoms and 245 patients without joint symptoms had missing data for date of last use. Women with hormone-receptor-negative breast cancer developed significantly fewer joint symptoms than those with hormone-receptor-positive tumours (124 of 461 (26·9%) vs 1556 of 4548 (34·2%); OR 0·71 [0·57–0·88]; p=0·002; table 3). Previous chemotherapy was also a strong risk factor for developing joint symptoms (461 of 1219 women (37·8%) with history of previous www.thelancet.com/oncology Vol 9 September 2008
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chemotherapy vs 1317 of 4214 women (31·3%) with history of no chemotherapy; OR 1·34 [1·17–1·53]; p<0·0001). Women with a BMI over 30 kg/m² and those who smoked reported more joint symptoms than their counterparts (table 3). Age and radiotherapy showed no detectable effect on the development of joint symptoms. When all significant variables in the univariate models were entered into a multivariate model, the odds ratios were similar to the univariate findings, except for smoking status, which became non-significant (table 3). Similar findings for the univariate and multivariate analyses of risk factors were obtained if the population was restricted to hormone-receptor-positive women (data
not shown). Additionally, there were no significant interactions of any factors with treatment, except for a weak interaction between treatment and previous HRT use (pinteraction=0·05; table 4). Women from the USA and Canada (grouped as North America) reported significantly more joint symptoms than those from the UK or the reference group of the rest of the world (738 of 1611 (45·8%; OR 2·44 [2·12–2·80]; p<0·0001) vs 523 of 1815 (28·8%; OR 1·17 [1·01–1·35]; p=0·03) vs 517 of 2007 (25·8%); table 3). This difference was unchanged in the multivariate model. To explore further baseline characteristics, interactions of region with other key variables were added to the model. Overall,
Women with joint symptoms, n (%)
Univariate analysis OR (95% CI)
Multivariate analysis p value
OR (95% CI)
p value
<0·0001
1·26 (1·12–1·42)
<0·0001
1·53 (1·35–1·74)
<0·0001
··
··
Treatment Tamoxifen (n=2735)
829 (30·3)
1
Anastrozole (n=2698)
949 (35·2)
1·25 (1·11–1·40)
1 <0·0001
Previous HRT No (n=3519)
1001 (28·4)
Yes (n=1914)*
777 (40·6)
1 1·72 (1·53–1·93)
Stopped ≤6 months† (n=1201)
502 (41·8)
1
Stopped >6 months† (n=335)
142 (42·4)
1·08 (0·84–1·40)
1
0·54‡
Chemotherapy No (n=4214)
1317 (31·3)
Yes (n=1219)
461 (37·8)
1 1·34 (1·17–1·53)
1 <0·0001
1·24 (1·07–1·43)
0·004
Hormone-receptor status Positive (ER or PgR positive; n=4548)
1556 (34·2)
1
1
Negative (n=461)
124 (26·9)
0·71 (0·57–0·88)
0·002
0·78 (0·62–0·98)
0·03
Unknown (n=424)
98 (23·1)
0·58 (0·46–0·73)
<0·0001
0·76 (0·59–0·97)
0·028
Region ROW (n=2007)
517 (25·8)
1
UK (n=1815)
523 (28·8)
1·17 (1·01–1·35)
0·03
1·20 (1·02–1·40)
1 0·025
North America§ (n=1611)
738 (45·8)
2·44 (2·12–2·80)
<0·0001
2·09 (1·79–2·43)
<0·0001
BMI (kg/m2)¶ <25 (n=1908)
592 (31·0)
1
25–30 (n=1926)
602 (31·3)
1·01 (0·88–1·16)
0·88
1·08 (0·94–1·24)
1 0·28
>30 (n=1354)
504 (37·2)
1·32 (1·14–1·53)
<0·0001
1·33 (1·14–1·55)
<0·0001
0·05
0·99 (0·88–1·12)
Ever smoker No (n=3223)
1030 (32·0)
Yes (n=2210)
747 (33·8)
1 1·12 (1·00–1·26)
1
≤60 (n=2009)
661 (32·9)
1
··
··
61–70 (n=2017)
638 (31·6)
0·94 (0·83–1·08)
0·39
··
··
>70 (n=1407)
479 (34·0)
1·05 (0·91–1·22)
0·49
··
··
No (n=1857)
644 (34·7)
1
··
··
Yes (n=3576)
1134 (31·7)
0·40
··
··
0·9
Age (years)
Radiotherapy 1·05 (0·93–1·18)
Reference group is represented by an odds ratio (OR) of 1. Multivariate analysis includes only significant factors from the univariate model. HRT=hormone-replacement therapy. ER=oestrogen recepetor. PgR=progesterone receptor. ROW=rest of world. BMI=body-mass index. *Stop-date data missing for 133 patients with joint symptoms and 245 patients without joint symptoms. †Before trial entry. ‡Comparison with those who used HRT and excludes 133 patients with missing data for stop date. §North America=USA and Canada. ¶Data missing for 245 patients.
Table 3: Risk factors at baseline for developing joint symptoms in women without joint symptoms at trial entry (study population)
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Anastrozole (N=2698)
Tamoxifen (N=2735)
949 (35·2)
829 (30·3)
No
525/1757 (29·9)
476/1762 (27·0)
··
Yes
424/941 (45·1)
353/973 (36·3)
0·05
No
687/2071 (33·2)
630/2143 (29·4)
··
Yes
262/627 (41·8)
199/592 (33·6)
0·20
All
pinteraction
Previous HRT
Chemotherapy
Hormone-receptor status Positive (ER or PgR positive)
840/2264 (37·1)
716/2284 (31·3)
Negative
59/220 (26·8)
65/241 (27·0)
0·23
··
Unknown
50/214 (23·3)
48/210 (22·9)
0·31
Region ROW
284/991 (28·7)
233/1016 (22·9)
UK
269/905 (29·7)
254/910 (27·9)
·· 0·15
North America*
396/802 (49·4)
342/809 (42·3)
0·94
<25
324/963 (33·6)
268/945 (28·4)
··
25–30
335/957 (35·0)
267/969 (27·6)
0·48
>30
246/654 (37·6)
258/700 (36·9)
0·21
BMI (kg/m2)†
HRT=hormone replacement therapy. ER=oestrogen receptor. PgR=progesterone receptor. ROW=rest of world. BMI=body-mass index *North America=USA and Canada. †Data missing for 245 patients.
Table 4: Number (%) of women reporting joint symptoms at any time during treatment according to treatment first received and selected risk factors in women without joint symptoms at entry (study population)
no significant interactions of key variables in the univariate model were seen with region in the multivariate model (data not shown).
Discussion In this trial, the major risk factors for developing joint symptoms in women not reporting them at entry were previous HRT use, hormone-receptor positivity, previous chemotherapy, obesity, and treatment with anastrozole versus tamoxifen, leading to significant absolute increases of 12·1%, 7·3%, 6·5%, 6·2%, and 4·9%, respectively. All these factors are potentially linked with greater decreases in oestrogen concentrations near to the time when endocrine treatment is started. Women with pre-existing joint symptoms were excluded from this analysis to focus on new treatment-emergent symptoms. The effect of previous HRT was especially striking, which could be because most women previously using HRT, for whom we had data, came off it within 6 months before entry into the study (1201 of 1536 women [78·2%]), although the effect was similar in women who had stopped their HRT treatment earlier. Furthermore, the effects of HRT seemed to be additive, resulting in an 18·1% increase in joint symptoms in women who previously used HRT and were on anastrozole compared with those on tamoxifen with no previous HRT use. Recent users of HRT (ie, those who stopped use less than 6 months ago) are likely to have a greater decrease in 870
oestrogen concentrations with endocrine treatment than those who stopped use more than 6 months ago, and most,17,18 but not all studies,19 have shown that they are more likely than never users to have oestrogen-receptorpositive tumours. In our study, women with hormonereceptor-positive tumours reported more joint symptoms than those with hormone-receptor-negative tumours, but, paradoxically, the few women with tumours of unknown hormone-receptor status had the lowest number of joint symptoms. Several studies have shown that women with high oestrogen concentrations are more likely to develop oestrogen-receptor-positive tumours than those with low oestrogen concentrations.20, 21 Obese women tend to have higher oestrogen concentrations than non-obese women as a result of aromatisation from the adipose tissue,22 so the decrease in oestrogen concentration is likely to be greater in this group as well. Obesity itself is also a risk factor for joint symptoms independent of endocrine treatment.23 However, Crew and colleagues24 reported that women with a BMI between 25 and 30 kg/m² developed fewer joint symptoms than those with a lower BMI. Our data do not confirm this finding, with significantly more joint symptoms being noted with increasing BMI. Chemotherapy is well known to induce arthralgia or myalgia and has been reported in several trials independently of endocrine treatment.10,25–27 Chemotherapy is known to damage ovarian function in premenopausal women, and the effects seen here could be a result of the ablation of any residual ovarian production of oestrogen in these postmenopausal women. Again, the findings were additive in anastrozole users so that the use of previous chemotherapy and anastrozole together resulted in a 12·4% increase in joint symptoms when compared with women on tamoxifen without previous chemotherapy. Reports have suggested that side-effects, such as joint symptoms, are under-reported in clinical trials compared with patient-recorded side-effects.28,29 The ATAC trial was an international study, involving 21 countries. Joint symptoms were collected in free-text format on the casereport forms. Because of the nature of the collection, in which uniform definition of symptoms was not provided, subcategories of joint symptoms were not thought to be reliable and were, therefore, not reported during the ATAC trial. Additionally, the duration of symptoms and date of resolution of symptoms could not be assessed in detail, because data were collected at 3 months, 6 months, and at 6-monthly intervals thereafter, so dates within these intervals were not recorded. Because the study was blinded, there would have been no bias in relative rates, but the overall reporting rates for specific symptoms could have been affected. However, this approach did seem to be sensitive, because known minor side-effects, and some previously unknown ones, were clearly detectable.30 The symptoms were assessed by clinicians and mapped to the relevant COSTART www.thelancet.com/oncology Vol 9 September 2008
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terms.15 This ascertainment of joint symptoms needs to be taken into account when interpreting these findings. Although various joint symptoms were reported during the study, only 1% of them led to treatment withdrawal. By contrast, a higher drop-out rate caused by joint symptoms was reported in two smaller uncontrolled studies,31,32 but it is difficult to attribute all these events to an aromatase inhibitor, because joint symptoms are common in postmenopausal women (eg, 31% of women receiving tamoxifen in the ATAC trial reported joint symptoms). The increased incidence of joint symptoms in the North American population is most probably consistent with different practices for recording symptoms. Although more patients had previous HRT use, previous chemotherapy, and a higher BMI in North America, compared with the UK and the rest of the world, the effects of region were only slightly diminished when they were adjusted for in the multivariate model. No significant interactions between region and risk factors were identified, suggesting that the differences noted between regions were most probably due to different thresholds for reporting these symptoms in North America, especially because adverse events overall were more often reported in North American participants. In conclusion, several factors other than treatment with anastrozole were associated with the development of joint symptoms in this trial. The effects are additive and thus need to be taken into account when counselling women about the use of aromatase inhibitors. Joint symptoms were generally of mild to moderate intensity and for most women they do not override the clear benefits of anastrozole over tamoxifen in terms of decreased recurrence and fewer other major side-effects, including venous thromboembolic events and gynaecological complications (eg, endometrial cancer).14 However, for women with serious side-effects on anastrozole, tamoxifen remains a viable option. Awareness of risk factors for joint symptoms will help both clinicians and patients to anticipate and manage these symptoms and ensure optimum adherence to endocrine treatment. Conflicts of interest IS declared no conflicts of interest. JC has received research funds from AstraZeneca and acted as a consultant to AstraZeneca and Novartis. FS is an employee and has stock ownership with AstraZeneca. RE has received honoraria and research grants, and has acted as a consultant for AstraZeneca. JFF has received honoraria from AstraZeneca. ARB has received research funding from AstraZeneca. AUB has received honoraria and other research grants from AstraZeneca, Pfizer, Genentech, Lilly, Taiko, and Amgen. Contributors IS was involved in the data analysis and interpretation. JC was responsible for the conception and design of the study, and assembly and analysis of the data. FS and RE were involved with the assembly and interpretation of the data. JFF, ARB, and AUB were involved in the design of the study, provision of patients, and interpretation of the data. All contributors took part in writing the paper and approved the final version.
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