Short-term and Low-dose Prednisolone Administration Reduces Aromatase Inhibitor-induced Arthralgia in Patients with Breast Cancer

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1 Short-term and Low-dose Prednisolone Administration Reduces Aromatase Inhibitor-induced Arthralgia in Patients with Breast Cancer MAKOTO KUBO 1*, HIDEYA ONISHI 2*, SYOJI KUROKI 3, MASAYUKI OKIDO 4, KAZUO SHIMADA 5, KAZUNORI YOKOHATA 6, SHUYO UMEDA 7, TAKAHIRO OGAWA 8, MASAO TANAKA 1 and MITSUO KATANO 2 Departments of 1 Surgery and Oncology, and 2 Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 3 Kuroki Breast Clinic, Fukuoka, Japan; 4 Breast Surgery, Hamanomachi Hospital, Fukuoka, Japan; 5 Shimada Breast Surgery Clinic, Kitakyushu, Fukuoka, Japan; 6 Fukuoka Red Cross Hospital, Fukuoka, Japan; 7 Kyushu Kosei Nenkin Hospital, Kitakyushu, Fukuoka, Japan; 8 Breast Surgery, Hara Sanshin Hospital, Fukuoka, Japan Abstract. Aromatase inhibitors (AIs) are important therapeutic drugs for postmenopausal women with hormone receptorpositive breast cancer. However, adverse effects of AIs such as arthralgia have been extensively reported. We performed a joint prospective, multi-institutional investigation to find out whether a low-dose and short-term prednisolone is effective against AIinduced arthralgia in 27 patients with breast cancer. Patients were administered 5 mg of oral prednisolone once a day in the morning for only one week. Patients were then asked to answer a questionnaire about joint pain symptoms at one week, one month and two months after the beginning of prednisolone use. Joint pain symptoms improved in 67% of patients immediately after prednisolone use, with 63% still reporting analgesic effect at one month, and 52% at two months after beginning internal use of prednisolone. At one week, one month and two months after the use of prednisolone, 30%, 30% and 26% of patients reported improved daily life, respectively. Our results suggest that prednisolone could substitute non-steroidal antiinflammatory drugs, acetoaminophen or cyclooxygenase-2 inhibitors in patients with AI-induced arthralgia. *These Authors contributed equally to this work. Correspondence to: Hideya Onishi, Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka , Japan. Tel: , Fax: , ohnishi@surg1.med.kyushuu.ac.jp Key Words: Aromatase inhibitor, steroid hormone, arthralgia, breast cancer. Aromatase inhibitors (AIs) effectively reduce estrogen levels in postmenopausal women by blocking the enzyme aromatase, which transforms androgenic precursors into estrogen in peripheral tissues (1). Third-generation AIs (anastrozole, letrozole, and exemestane) are superior in their effects on disease-free survival compared with tamoxifen, both as monotherapy and when used sequentially after tamoxifen therapy (2-4). Therefore, AIs have become the standard in the management of both early and advanced hormone-responsive breast cancer in postmenopausal women (5). More recently, trials of AIs have shown their benefits over tamoxifen in both metastatic (6) and subsequent adjuvant treatment settings (7-11). The two main adverse effects of AIs have been identified as a reduction in bone mineral density and joint symptoms or arthralgia (5). The link between AI therapy and arthralgia was first reported in 2001 (12). The mechanisms behind arthralgia are not clearly understood, but one mechanism is believed to be related to the deep estrogen deprivation induced by AIs (13). In fact, all three compounds of the third-generation AIs mentioned above, suppress whole-body aromatization by more than 96% at their clinically used dosage (14). There is evidence that estrogen may have antinociceptive and pain modulating effects for example, through opioid pain fibers in the central nervous system (15). Another mechanism is thought to be associated with mild soft-tissue thickening (16). Although the prevalence of arthralgia has been reported to be between 5% and 47% in different studies (7, 8, 10, 17-19), the true number is much higher, with up to 50% of AI-users complaining of arthralgia (14, 16). To date, AI-induced arthralgia is mostly managed /2012 $

2 Table I. Profile of patients who participated in this study. Patients (n=27) Figure 1. Patient flow diagram. Age, years Mean 62.8 Range Type of AI used Anastrozole 25 Letrozole 2 Time from AI use to prednisolone use Mean (months) 24.8 Range (months) 2-60 Time from AI use to pain appearance Mean (months) 16 Range (months) 1-59 Time from pain appearance to prednisolone use Mean (months) 8.8 Mean (months) 0-30 AI: Aromatase inhibitor. with non-steroidal anti-inflammatory drugs (NSAIDS), acetoaminophen or cyclooxygenase-2 (cox-2) inhibitors (20). Other strategies consist of drug holidays, switching to another AI (or tamoxifen) and acupuncture (21-24). Autoimmune diseases, particularly rheumatoid arthritis and Sjögren s syndrome, are reportedly associated with AI therapy (25, 26), while steroid hormones (SH) are effective on these diseases. However, to our knowledge, SH treatment for AI-induced arthralgia has not been reported. In the present study, we used low-dose prednisolone for AI-induced arthralgia, since we had a patient whose arthralgia was well-controlled by short-term use of low-dose prednisolone, and we performed a follow-up survey of subjective symptoms over a two-month period. Patients and Methods Patients. We performed multi-institutional joint research as to whether prednisolone is effective against AI-induced arthralgia with 27 patients who suffered from AI-induced arthralgia. Twenty-seven patients (9 cases: Department of Surgery and Oncology, Kyushu University, Fukuoka; 12 cases: Kuroki Clinic, Fukuoka; 5 cases: Hamanomachi Hospital, Fukuoka; and 1 case: Shimada Clinic, Kitakyushu) with primary breast cancer who suffered from AI-induced arthralgia were enrolled in this study (see Figure 1 for patient flow diagram). Patients ranged in age from 51 to 81 years (mean=62.8 years old). Patients began taking anastrozole (25 cases, Astro Zeneca, Osaka, Japan), or letrozole (two cases, Novartis Pharma, Tokyo, Japan) orally between December 2007 and July The patients profiles are summarized in Table I. All patients were provided written informed consent before treatment. Patients took 5 mg of oral prednisolone (Takeda Pharmaceutical Co. Ltd, Osaka, Japan) once a day in the morning for one week. Patients were then required to fill in a questionnaire (Table II) about their joint pain symptoms at one week, one month and two months after the beginning of prednisolone use. To estimate the degree of the pain subjectively, a visual analogue scale (VAS) was used (27). Table II. Questionnaire used for assessment of arthralgia. Q1. Does stiffened joint pain weigh on your mind? (a subjective symptom) 1. Not at all 2. A little 3. Sometimes 4. Often 5. Always Q2. At which joint do you feel stiffened pain? Q3. How much is your pain when you use VAS? Q4. How much does your stiffened joint pain affect your quality of life? 1. Not at all 2. A little 3. Sometimes 4. Often 5. Always Q5. When did you begin to take anastrozole/letrozole? Q6. When did symptoms of arthralgia appear? Statistical analysis. An unpaired two-tailed Student s t-test was used for statistical analysis. p<0.05 was considered significant. Results Symptoms of AI-induced arthralgia improved after the use of prednisolone. Out of the 27 patients, 68% and 29% suffered from pain of their finger and knee joints, respectively (Figure 2). Subjective symptoms in 67% of patients improved immediately after the use of prednisolone (Figure 2); subjective symptoms in 41% and 33% of patients had ameliorated one month and two months, respectively, after the beginning of oral 2332

Kubo et al: Prednisolone Reduces Aromatase Inhibitor-induced Arthralgia Figure 2. Location of pain was estimated by use of a questionnaire. prednisolone use (Figure 3).

2 months, respectively, after beginning of oral prednisolone use (Figure 4).

The percentage of patients whose daily life improved was 30%, 30% and 26% at one week, one month and two months, after the use of prednisolone, respectively (Figure 6). Figure 3.

3 Kubo et al: Prednisolone Reduces Aromatase Inhibitor-induced Arthralgia Figure 2. Location of pain was estimated by use of a questionnaire. prednisolone use (Figure 3). When a VAS was used to estimate the subjective degree of pain, symptoms in 67% of patients also improved immediately after prednisolone use (Figure 4); 63% and 52% of patients improved at 1 month and 2 months, respectively, after beginning of oral prednisolone use (Figure 4). Consistently, the value of VAS after one week and after one month was significantly lower compared to that before prednisolone use (Figure 5). The percentage of patients whose daily life improved was 30%, 30% and 26% at one week, one month and two months, after the use of prednisolone, respectively (Figure 6). Figure 3. Change in subjective symptoms after the use of steroid hormone was analysed by use of a questionnaire. There was no correlation of time among AI use, pain appearance and prednisolone use with respect to the effect of prednisolone. There was no significant difference in time between AI use and prednisolone use in improved patients and non-improved patients, nor was there a correlation for time from AI use to pain appearance, or time from pain appearance to prednisolone use and the effect of prednisolone on AI-induced arthralgia (Table III). Discussion AIs reduce recurrence rates in women treated for early-stage postmenopausal breast cancer (7-11). Therefore, AIs are becoming widely used in breast cancer treatment and are being explored to prevent disease in women at high risk (28). Cancellation of AI therapy due to AI-induced arthralgia is, thus, a very serious problem. In the present study, low-dose short-term oral prednisolone therapy improved AI-induced arthralgia significantly. Low-dose (5 mg) of oral prednisolone administration once a day in the morning for only seven days is a safe method that does not require steroid coverage. Figure 4. Change of symptoms after the use of steroid hormone was analyzed by totaling Visual Analogue (VAS) values. Aromatase inhibitor-induced musculoskeletal syndrome (AIMSS) includes musculoskeletal pain, carpal tunnel syndrome, joint stiffness, joint pain and parenthesia as well as arthralgia. We prospectively focused on changes in 2333

4 Figure 5. Visual Analogue (VAS) value after steroid hormone use was compared with that before the use of steroid hormone. *p<0.05 compared with the value before steroid hormone use. rheumatological symptoms, such as morning stiffness, joint pain and grip strength, because of prednisolone use. As a result, we assessed joint symptoms of fingers and knees, from which 68% and 29% of suffering patients (Figure 2). Joint symptoms in peri- and postmenopausal women are well recognized; prevalence varies by country: 14.5%, Japan; 31.4%, Canada; and 38.6%, USA (29). A proposed etiology for these symptoms is estrogen deprivation. In the case of AI treatment, it is also probable that the accompanying large and rapid drop in estrogen may provide a direct pro-nociceptive stimulus for joint pain and/or remove the protective antinociceptive role of estrogen (30). Estrogen also has multiple roles in the immune system. Th17 cell-mediated chronic inflammation is derived from estrogen effects on other T-cell cytokines (31). However, in a case control study, Henry et al. reported that AIMSS may be negatively associated with alterations in serum concentrations of pro-inflammatory mediators, and suggested that AIMSS is due to a localized or non-inflammatory process (32). Steroid hormones have been used to treat rheumatoid arthritis (RA) for several decades, but adequate dosing and timing of these medications remain controversial because of varied mechanisms action of and serious side-effects. Steroid hormones are very potent and fast-acting antiinflammatory drugs which provide immediate symptomatic relief. When this pilot study was designed, no clear evidence was available regarding whether a low-dose and short-term SH therapy has persistent efficacy in AI-induced arthralgia. In 2005, Wassenberg et al. reported that a single daily oral dose of 5 mg prednisolone, as an adjunct to diseasemodifying anti-rheumatic drug therapy, reduces radiographic progression in early RA with an acceptable level of risk (33). Futhermore, we expected that low-dose SH treatment could improve the patients psychological state. This preliminary and prospective trial was, therefore, designed to Figure 6. Change in quality of daily life was estimated by use of a questionnaire. Table III. Correlation with time among AI use, pain appearance and prednisolone use. Time Months p-value From AI use to prednisolone use Improved (n=13) 24.8±18.3 Not improved (n=11) 24.4± From AI use to pain appearance Improved (n=13) 16±17.9 Not improved (n=11) 18.6± From pain appearance to prednisolone use Improved (n=13) 8.8±9.1 Not improved (n=11) 5.7± Not improved includes no change and deterioration. test the hypothesis that a low-dose short-term SH that seemed to be almost harmless would retard AI-induced arthralgia as in RA. There was little discrepancy between subjective symptoms and VAS results. One reason may be that the degree of pain can be more closely expressed by using numerical values. Another reason may be that patients had forgotten the degree of pain which they had felt two months earlier. We think that the VAS is a good index to estimate the pain in AI-induced arthralgia objectively. On the other hand, improvement of daily life was approximately 30% after two months. We do not believe that many patients feel their daily life was 2334

5 Kubo et al: Prednisolone Reduces Aromatase Inhibitor-induced Arthralgia hindered by AI-induced arthralgia in this study. Our results suggest that timing of prednisolone treatment is not an important factor, as short-term use of prednisolone shows persistent efficacy in AI-induced arthralgia in 50% of patients (Figure 4). However, we believe that prednisolone treatment for AI-induced arthralgia should be given as soon as pain occurs. The mechanism of the efficacy of prednisolone in AIinduced arthralgia is unclear; however, our aim is to reduce cases of AI-induced arthralgia that are severe enough to force patients off of AI therapy. Clearly, patient education is the first step towards managing AI-induced arthralgia successfully, as it is important that patients comprehend the significance of total adherence to AI regimens. The findings of this study are limited by its small sample size and by the lack of a concurrent control group. However, despite these limitations, our results suggest that low-dose/short term prednisolone is a substitute for NSAIDs, acetoaminophen and COX-2 inhibitors for patients who suffer from AI-induced arthralgia, and may prevent patients from dropping out of AI treatment. Conflict of Interest Statement The Authors declare no conflict of interest regarding this work. Acknowledgements We thank Ms Kaori Nomiyama, Norie Shigematsu, and Yuka Miyazoe for technical assistance. References 1 Dizdar O, Ozçakar L, Malas FU, Harputluoglu H, Bulut N, Aksoy S, Ozisik Y and Altundag K: Sonographic and electrodiagnostic evaluations in patients with aromatase inhibitor-related arthralgia. 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Should aromatase inhibitors be used as initial adjuvant treatment or sequenced after tamoxifen?

British Journal of Cancer (26) 94, 46 464 & 26 Cancer Research UK All rights reserved 7 92/6 $3. www.bjcancer.com Minireview Should aromatase inhibitors be used as initial adjuvant treatment or sequenced