Taxane Acute Pain Syndrome (TAPS) in Patients Receiving Taxane-Based Chemotherapy for Breast Cancer—A Systematic Review

Support Care Cancer DOI 10.1007/s00520-016-3256-5

REVIEW ARTICLE

Taxane acute pain syndrome (TAPS) in patients receiving taxane-based chemotherapy for breast cancer—a systematic review

Ricardo Fernandes1 & Sasha Mazzarello2 & Brian Hutton 3 & Risa Shorr4 & Habeeb Majeed5 & Mohammed FK Ibrahim1 & Carmel Jacobs1 & Michael Ong1 & Mark Clemons1,2

Received: 15 January 2016 /Accepted: 26 April 2016 # Springer-Verlag Berlin Heidelberg 2016

Abstract between study heterogeneity, a meta-analysis was not per- Background Taxane acute pain syndrome (TAPS) is charac- formed. The incidence of TAPS varied between taxanes: pac- terized by myalgias and arthralgias starting 24–48 h after litaxel (median 13.1 %, range 0.9–86 %), docetaxel (median taxane-based chemotherapy and lasting for 5–7days. 10.5 %, range 3.6–70 %), and nab-paclitaxel (26 %, range 14– Relatively little is known about its incidence and impact on 43 %). In the metastatic setting, median incidence was 30 % quality of life. (range 5.4–73 %), compared with 11.3 % (range 0.9–86 %) in Objectives A systematic review was conducted evaluating the the adjuvant setting. Three out of eight studies assessing qual- incidence of TAPS in breast cancer patients receiving taxane- ity of life demonstrated pain interference with daily activities. based chemotherapy. Conclusions The incidence of TAPS varies between taxanes, Methods Embase, Cochrane, and Ovid MEDLINE were regimens, and disease settings. In order to identify patients at searched from 1947 to July 2015. Data was sought from ran- the greatest risk of TAPS, and hence optimize its prevention domized controlled trials (RCTs), prospective and retrospec- and management, standardized methods of diagnosing and tive observational studies. Two reviewers independently measuring TAPS are needed. screened citations and full text articles. Outcomes of interest were the incidence of TAPS and its impact on quality of life. Keywords Breast cancer . Taxane chemotherapy . Pain . Results Of 980 citations identified, 51 relevant studies (27, Incidence . Quality of life 007 patients) were included. Data came from RCTs (12,357 patients), retrospective (6566 patients) and prospective observational studies (6210 patients). Study sample sizes ranged from 14 to 4149 patients (median 152). Given the significance Background

Taxanes such as docetaxel, paclitaxel, and nab-paclitaxel are – * Mark Clemons commonly used in the treatment of breast cancer [1 3]. A [email protected] commonly reported toxicity of taxanes is taxane acute pain syndrome (TAPS), also known as paclitaxel-associated acute 1 Department of Medicine, Division of Medical Oncology, The Ottawa pain syndrome or taxane-induced pain [4]. TAPS is typically Hospital Cancer Centre and University of Ottawa, 501 Smyth Road, characterized by myalgias and arthralgias appearing 24–48 h Ottawa, Canada after receiving taxane-based chemotherapy and lasting for 5– 2 Ottawa Hospital Research Institute and University of Ottawa, 7days[5]. TAPS can be debilitating for patients and lead to Ottawa, Canada dose delays, reductions, and discontinuation of potentially 3 Department of Epidemiology and Community Medicine, University curable therapy [4–7]. of Ottawa, Ottawa, Canada The incidence of TAPS varies between taxanes and is re- 4 The Ottawa Hospital, Ottawa, Canada portedly more common with docetaxel than with either pacli- 5 Department of Medicine, Division of Internal Medicine, The Ottawa taxel or nab-paclitaxel [4, 5, 8]. TAPS also appears to be more Hospital and University of Ottawa, Ottawa, Canada frequent in patients with breast cancer than in those with Support Care Cancer prostate, lung, or ovarian cancer [8–17]. The reasons for this Literature search variability in incidence are likely multi-factorial and reflect differences between taxanes, doses, combination regimens, An information specialist (RS) designed and executed an elec- patient populations, and variability in the co-administered tronic literature search to seek relevant citations from Embase, supportive care treatments that can themselves cause myalgias Cochrane, and Ovid MEDLINE from 1946 to July 7, 2015. (e.g., growth-colony stimulating factors) [2, 9, 10, 18]. The Key terms and their medical subject headings (MeSH) are use of different pain and toxicity assessment tools means that provided along with the full search strategy in Appendix 1. some studies report the incidence of chemotherapy-induced An independent PRESS review performed by a second librar- peripheral neuropathy (CIPN) as being the same as TAPS ian is provided in Appendix 1 [29]. [19, 20]. Clinically, TAPS is quite distinct from CIPN, with different mechanisms of action and temporal profiles. Study selection, data collection, and risk of bias However, the occurrence of TAPS can predispose to subse- assessment quent CIPN [21–24]. Thus, despite being relatively common in clinical Stage 1 screening was performed by three reviewers (SM, practice, the incidence of TAPS with different taxanes RF, and HM), who independently screened all citations and taxane-based regimens is not well established retrieved from the electronic search. Disagreements were [25–28]. Given the paucity of data addressing these discussed and resolved between reviewers. Stage 2 screen- knowledge gaps, the current systematic review was per- ing consisted of a full-text review of all potentially relevant formed. The objectives were to estimate the incidence citations by six reviewers working independently (SM, RF, of TAPS following a range of taxane-containing regi- HB, MC, CJ, and MI) to determine the final set of included mens in patients with breast cancer and to possibly articles. A PRISMA flow diagram was prepared to summa- identify potential predisposing factors for its occurrence. rize the process of study selection (Fig. 1), and a PRISMA Such risk factors could potentially be used to identify checklist was also completed during preparation of the re- patients a priori at greatest risk of experiencing TAPS port (Appendix 3)[30]. and to develop better prevention and treatment Once the final set of included studies was established, data strategies. were extracted by two reviewers independently using a pre- designed form implemented in Microsoft Excel version 2010 (Microsoft Corporation, Seattle, Washington, USA); any dis- crepancies were resolved by consensus discussion. The fol- Methods lowing information was collected from each study: authors, year and journal of publication, study design, number of pa- Research question and study eligibility criteria tients enrolled, patient eligibility criteria, relevant patient de- mographics, study duration, publication status, chemotherapy The systematic review was designed to summarize available duration and line, taxane type and frequency, stage of disease, information addressing the following research question: symptoms and incidence of TAPS, presence of concurrent BWhat are the incidence and risk factors of TAPS in steroid administration, rates of, and reasons for, chemotherapy breast cancer patients who have received taxane-based discontinuation, dose and type of analgesia, and quality of life chemotherapy?^ The Population-Intervention-Comparator- assessment. Authors were contacted to acquire other unpub- Outcome-Study Design (PICOS) framework was used to lished data. The Cochrane Collaboration’s tool for assessing structure the research question and its corresponding literature risk of bias in RCTs was used (Appendix 4)[31]. search. In the literature, breast cancer patients have the highest incidence of TAPS and hence were the population of interest. Data analysis Interventions of interest included any taxane-based chemotherapy. Outcomes of interest included measures of the inci- If deemed appropriate, following exploration of study and dence of TAPS and quality of life. We also sought information patient characteristics to ensure sufficient clinical and meth- related to potential risk factors such as type of taxane, gender, odological homogeneity across studies, we planned to con- stage of disease, single agent versus combination chemother- duct meta-analyses using random effects models to combine apy, and concurrent medications. Randomized controlled tri- TAPS incidence data across studies. Following inspection of als (RCTs) as well as retrospective and prospective observa- the characteristics of included studies, the research team felt tional studies were eligible. Data on the incidence of TAPS there was a high degree of study heterogeneity in terms of was also included from randomized trials where one arm did study populations, study design, disease stage, and chemo- not receive a taxane. Animal studies were excluded, as were therapy regimen. These differences were viewed by the au- studies investigating CIPN. thors to preclude the data from meta-analysis. To synthesize Support Care Cancer

Fig. 1 PRISMA flow diagram of Records identified and screened study selection process through database and abstract Records excluded due to searching after removal of irrelevancy duplicates (n=858)

(N=980) Identification Identification Excluded (n=46): No reported TAPS data First screening (n=23) (n= 122) Cancer related pain (n=7) Quality of life (n=1) CIPN (n=4) Combination therapy (n=4) Case series and reports (n=6) Second screening Duplication (n=1) Screening (n= 76) Excluded (n=25): Quality of life (n=1) No TAPS data reported (n=13) Other tumour sites (n=9) Full-text articles or abstracts Duplication (n=1) assessed for eligibility Chemoradiation therapy (n=1)

Eligibility (n= 51)

Studies included in qualitative and quantitative synthesis (n=51) Included

the information collected, a narrative summary was prepared retrospective analyses [5, 33, 34, 39, 40, 44, 46, 48, 50, 53, to document variations in TAPS incidence and to summarize 57, 64–66], and 5 prospective observational trials [38, 45, 51, potential risk factors. 52, 67]. Among RCTs, both phase 2 and 3 trials were included and all were completed. In terms of type of taxane chemotherapy, 27 (52%) studies included a group that evaluated doce- Results taxel [5, 32, 33, 35, 36, 38–59], 26 (50%) paclitaxel [5, 9, 27, 32–38, 40, 60–74], and 8 (13%) nab-paclitaxel [37, 39, Extent of evidence identified 75–80]. Studies included treatment in the neoadjuvant (8 studies) [41–43, 60–62, 75, 76], adjuvant (23 studies) [9, 11, Following the removal of duplicate citations, the literature 32–34, 44–52, 54–56, 63–67, 77], metastatic (18 studies) [5, search identified 980 unique citations. Stage 1 screening was 27, 35–37, 40, 57–59, 68–74, 78 , 79] settings, and not report- performed on the citations only and 122 potentially relevant ed in 2 studies [38, 39]. The symptoms of TAPS were usually studies were identified. At stage 2 screening, a total of 76 described as Bmyalgia^ and Barthralgia^ and measured using studies were reviewed in full text format. The total number the NCI Common Terminology Criteria for Adverse Events of trials included was 51 (n = 27,007 patients). Studies were version 3.0 (http://www.ctep.cancer.gov). This meant we were excluded for the following reasons: no data on TAPS reported unable to ascertain the timing of TAPS for either the adjuvant (n = 13), not breast cancer (n = 9), chemoradiation study or metastatic settings. Quality of life was assessed in eight (n = 1), TAPS not recorded (n = 1), and duplicate publication studies. The European Organization for Research and (n = 1). Figure 1 shows an overview of the study selection Treatment of Cancer (EORTC) quality of life questionnaire process and Tables 1, 2, 3,and4 summarize study (QLQC30), Rotterdam Symptom Checklist (RSCL), Brief characteristics. Pain Inventory (BPI), and Functional Assessment of Cancer Therapy–Taxane Scale (FACT-T) were used to evaluate pain Study characteristics intensity and its interference with quality of life in five [35, 45, 56, 70, 74], two [69, 80], and one studies [5], respectively. Of Of the 51 studies included, 32 were RCTs [9, 27, 32, 35–37, all included studies, the median age of patients ranged from 43 41–43, 47, 49, 51, 54–56, 58, 59, 61–63, 68–79], 14 were to 57 years. Support Care Cancer

Table 1 Overview of randomised studies reporting the incidence of TAPS with different taxanes in breast cancer patients

Author Study design Study N* Median Taxane type and dose Taxane Tool used to TAPS incidence [ref] setting pts age frequency measure TAPS

Fountzilas Randomized Adjuvant 990 53 ArmA—Paclitaxel Weekly and 3 NCI CTCAE Arm A: 5.2 % [32] phase III 200 mg/m2 weekly version 3.0 Arm B: 0.9 % (3 weekly); Arm C: 1.6 % Arm B—Paclitaxel 80 mg/m2 (weekly); Arm C—Docetaxel 30 mg/m2 (weekly) Joensuu Retrospective Adjuvant 1496 NR Paclitaxel q 3 weekly QLQ C30 1.9 % [33] Docetaxel 8% Kim [34] Retrospective, Adjuvant 54 48.6 Paclitaxel 175 mg/m2 q3weekly NCICTCAE Paclitaxel = 30.8 %, observational vs. version 3.0 Docetaxel = 6.7 % Docetaxel 100 mg/m2 (3.8 and 0 % g3/4) Wist [35]Randomized Metastatic 37 53 Paclitaxel (80 mg/m2) Paclitaxel NR Paclitaxel 38.9 % phase II vs. weekly × Docetaxel 26.3 % Docetaxel (75 mg/m2) Docetaxel q 3 weekly Lin [36] Randomized Metastatic 101 48 Docetaxel (60 mg/m2) 3 weekly WHO Docetaxel 14 % vs. Paclitaxel 25 % Paclitaxel(175 mg/m2) Saibil [5] Retrospective, Adjuvant 82 NR Pacitaxel or Docetaxel NR NR AC-T (43 %), FEC-D survey containing regimens (43 %), AC-D (14 %) Baselga Randomized Metastatic 363 52 Paclitaxel 80 mg/m2 vs. Paclitaxel NCI CTCAE 10 % in each arm [37] Nab-paclitaxel 50 mg/ weekly version 3.0 m2 vs. Nab-paclitaxel q3weekly Pasetka Prospective, NR 275 52 Paclitaxel, Docetaxel NR NR arthralgia = 67.9 %, [38] observational Nab-paclitaxel - myalgia = 63.8 % Howell Retrospective NR 81 NR Docetaxel (50, 75, or q 3 weekly NR 10 % docetaxel [39] analysis 100 mg/m2), 43 % nab-paclitaxel Nab paclitaxel (260 mg/ m2) Brammer Retrospective, NR 1551 NR NR NR NR Docetaxel (9 %), [40] observational Docetaxel + trastuzumab (16 %), paclitaxel (11 %)

NR not reported, QLQ C30 quality of life questionnaire, WHO World Health Organization

Risk of bias assessment regimen (5-fluorouracil-epirubicin-cyclophosphamide followed by docetaxel), the incidence of TAPS varied from A risk of bias assessment was performed on the RCTs using 28 to 53 % (median 13.6 %), whereas with EC-D (epirubicin + Cochrane risk of bias scale (Appendix 4)[31]. Risk of bias cychophosphamide followed by docetaxel) the incidence was high for all of the included trials due to incomplete out- ranged from 3 to 12.3 % (median 8.3 %) [49, 51, 52, 56]. come data [5, 41, 63]. The studies by Luck [70] and Moulder Regarding dosing, TAPS incidence with docetaxel 75 mg/m2 [71]werealsojudgedtohavehighriskofperformanceand every 3 weeks was reported to be 4–28 % (median 9.3 %), detection bias with inadequate blinding of outcome assess- whereas dosing of 100 mg/m2 showed a TAPS incidence of ment. As well, risk of bias was high due to random sequence 5.4–53.3 % (median 20.5 %) [42, 46, 47, 49, 51, 55–57]. With generation in three studies [49, 62, 63]. regard to disease stage, docetaxel was associated with higher TAPS incidence in the adjuvant setting (median 20.5 %) com- Incidence of TAPS by taxane type pared with the metastatic setting (median 14.8 %) [36, 39–44, 46, 47, 49, 50, 57, 58]. Docetaxel Among the 27 included studies (18,702 patients) [37, 39, 75–80], the incidence of TAPS with docetaxel ranged Paclitaxel Paclitaxel was evaluated in 26 studies (12,284 pa- from 3.6 to 70.0 % (median 10.5 %) depending on dosing and tients) [37, 39, 75–80]. The incidence of TAPS ranged from chemotherapy regimen (Table 2.) For instance, with FEC-D 0.9 to 86 % (median 13.1 %). This varied according to both Support Care Cancer

Table 2 Studies reporting the incidence of TAPS with docetaxel in breast cancer patients

Author [ref] Study design N* Median Taxane type and dose Taxane Instrument used to TAPS incidence pts age frequency measure TAPS

Neoadjuvant Coudert [41] Open-label, 152 NR Docetaxel q 3 weekly NR 3.60 % randomized 100 mg/m2 Yong Wha Single arm phase 2 49 43 Docetaxel q 3 weekly NCI CTCAE version myalgia 14.3 % arthralgia Moon [42] 100 mg/m2 3.0 4.1 % Tuxen [43] Phase II 49 50 Docetaxel 100 mg/m2 q 3 weekly NCI CTCAE version 31 % q3weekly×4 2.0 Adjuvant Akinci [44] Retrospective 539 48 Docetaxel q 3 weekly NR 2 % with 3 cycles and analysis 100 mg/m2 1 % with 4 cycles Hatam [45] Prospective 100 48 Docetaxel 75 mg/m2 q 3 weekly NCI CTCAE version 30 % Observational 3.0 Eckhoff [46] Retrospective 1143 NR Docetaxel 100 mg/m2 q 3 weekly NCI CTCAE version 53.3 %, all grades analysis 2.0 6.9 % grades 3/4 Eiermann Randomized phase 3298 50 Docetaxel 75 mg/ q 3 weekly NCI CTCAE version 35.8 % all grades [47] III m2 × 6 or 100 mg/m2 2.0 4.9 % grades 3/4 q3weekly×4 Miura [48] Retrospective 85 NR Docetaxel 75 mg/m2 q 3 weekly NR 6 % rTC vs. 48 % TC analysis Schonerr Phase III 1496 55 Docetaxel 100 mg/m2 q 3 weekly NCI CTCAE version 12.3 % (EC-Docetaxel) [49] prospective, 3.0 vs. 1.4 % (FEC) randomized Thomson Retrospective 37 NR Docetaxel 100 mg/m2 NR NR D1: 70 %, D2: 53 %, D3: [50] 28 % Thomssen Prospective 4149 NR Docetaxel 100 mg/m2 NR NR 4.3 % (FEC-D) <1 % (FEC) [51] Yau [52] Observational 1537 47 Docetaxel 100 mg/m2 q 3 weekly NR 0.63 Rodriguez- Retrospective 81 50 Docetaxel 100 mg/m2 q 3 weekly NR NR Abreu [53] Lee [54] Randomized 209 NR Docetaxel NR NR 67 % (TX) vs. 100 mg/m2 28 % (AC) Vriens [55] Randomized phase 201 NR Docetaxel 75 mg/m2 q3 q 3 weekly NR TAC = 0 %, III weekly × 6 or AC-T =4% 100 mg/m2 ×4 Coombes Randomized 803 NR Docetaxel 100 mg/m2 q 3 weekly NCI CTCAE version 2 % (3 cycles Epirrubicin- [56] 3.0 Docetaxel vs 20.5 % (6 cycles Epirrubicin- Docetaxel) Metastatic Jacot [57] Retrospective 45 45 Docetaxel 100 mg/m2 q 2 weekly NCI CTCAE version 5.4 % total 2.0 Morimoto Randomized phase 62 NR Docetaxel q 3 weekly NCI CTCAE version 45.2 % [58] III 100 mg/m2 3.0 Swain [59] Randomized phase 808 54 Docetaxel q 3 weekly NCI CTCAE version Arm A: 15.6 % III 100 mg/m2 3.0 Arm B: 13.8 %

NR not reported, TX docetaxel plus capecitabinle, TC Docetaxel plus cyclophosphamide, rTC reverse Docetaxel plus cyclophosphamide schedule and disease stage. In one study, paclitaxel (140 mg/ incidence in the metastatic (median 45.9) when compared to m2) infused over 96 h caused less TAPS (30 %) when com- the adjuvant setting (median 32.7) [9, 60, 62, 63, 65, 67, 68, pared with paclitaxel (250 mg/m2) given over 3 h (59 %) [71]. 70–74]. While the incidence of TAPS from weekly paclitaxel ranged from 7 to 38.9 % (median 17.6), a higher incidence was re- Nab-paclitaxel Nab-paclitaxel resulted in different incidence ported with three weekly treatments ranging from 39.2 to of TAPS based on dosing, schedule, and setting of disease, 53.5 % (median 52.7) [32, 35, 62, 63, 65, 66, 70]. With respect ranging from 13 to 43 % (median 26) in eight studies (997 to disease stage, paclitaxel was associated with higher TAPS patients) [37, 39, 75–80]. When given in the metastatic Support Care Cancer

Table 3 Studies reporting the incidence of TAPS with paclitaxel in breast cancer patients

Author [ref] Study design N* Median age Taxane type and Taxane Instrument TAPS incidence pts dose frequency used to measure TAPS

Neoadjuvant Earl [60]Randomized831 NR Paclitaxel 175 mg/ q 2 weekly NCI CTCAE 5 % each arm open label, m2 version 3.0 Gonzalez- Randomized 50 Arm A: 52 Paclitaxel 80 mg/ weekly NCI CTCAE Arm A: 7 % Angulo [61] phase II (T-FEC) m2 version 3.0 Arm B: 13 % Arm B: 46 (TR-FEC) Saura [62]Randomized,295 48 Paclitaxel 80 mg/ weekly NCI CTCAE Myalgia 13.2 %/ open-label, m2 version 3.0 Arthralgia 9.7 % phase II Adjuvant Cognetti [63]Randomized 2091 NR Paclitaxel 80 mg/ q2 NR Arms C,D: 53.5 % phase III m2 weekly(D- Arms A,B: 39.2 % D) × q3 weekly(SD) Richardet [64]Retrospective 76 57 Paclitaxel 80 mg/ weekly NR NR analysis m2 Richardet [65] Retrospective, 50 53 Paclitaxel 80 mg/ q weekly 22 % observational m2 Haba-rodriguez Retrospective 1246 NR Paclitaxel 100 mg/ q1 weekly NR Arthralgia = 5.2 %/9.5 %/ [66] analysis of m2 q1week×8 8.0 % by climate phase III Myalgia = 10.3 %/ 12.5 %/8.5 % by climate Jones [9] Randomized 1016 51 Paclitaxel 75 mg/ NR NCIC 33 % TC vs. 16 % AC m2 CTCAE version 3.0 Palappallil [67]Prospective 100 48 (FAC) Paclitaxel 175 mg/ q3 WHO 86 % Observational 40 (AC-P) m2 weekly × 4 toxicity grading Metastatic Esteva [68]Openlabel 63 53 Paclitaxel 80 mg/ Weekly NCIC 29 % phase I m2 or CTCAE 70 mg/m2 version 3.0 Moinpour [69]Randomized 529/ 55 Paclitaxel 175 mg/ q 3 weekly NR NR phase III 366 m2 Luck [70]Prospective340 57 Paclitaxel 175 mg/ q 3 weekly NCI CTCAE Myalgia: capecitabine + phase 3 m2 version 2.0 taxane 52 % vs. randomized epirrubicin + taxane 52.7 % Athralgia: capecitabine + taxane 58.8 % vs. epirubicin + taxane 55.7 % Molder [71] Randomized 214 NR Paclitaxel 250 or 3hq3weekly NCIC 59 % vs. 140 mg/m2 vs.96hq3 CTCAE 30 % weekly version 2.0 Burstein [72] Randomized 81 55 Paclitaxel 80 mg/ weekly NR 20 %/44 %/25 % m2 Talbot [73] Randomized 44 52 Paclitaxel 175 mg/ NR NCIC 0 % Capecitabine vs. 5 % m2 CTCAE Paclitaxel version 3.0 Jassem [74]Randomized267 50 Paclitaxel 220 mg/ q 3 weekly NR AT (73 %) vs. FAC (17 %) open label, m2 Gelmon [27]Randomized 42 49 Paclitaxel 250 mg/ q 3 weekly NCIC Paclitaxel only (95 %) vs. open label, m2 (initial) CTCAE Paclitaxel + amifostine and 175 mg/m2 version 3.0 (90 %) (nonprogressing patients)

NR not reported Support Care Cancer setting, the incidence of TAPS ranged from 13 to 43 % (me- higher deterioration of QoL in the latter [45, 74]. For instance, dian 21.85), compared to 14 and 35.7 % (median 21.2) in the one trial showed a reduction of mean score of QoL in the FAC neoadjuvant and adjuvant settings [37, 39, 75–77, 79], respec- from 74.5 to 68 (67.74 ± 26.11) and the TAC group decreased tively. When given every 2 weeks (range 20–38.9 %; median from 74.5 to 64 (64.39 ± 29.56). In addition, in all the five 21.85 %) nab-paclitaxel had a similar incidence of TAPS aspects of patient’s functional status (physical, role, emotion- when compared with weekly treatment (range 14–35.7 %; al, cognitive, and social functioning), the mean results were median 17.7 %) [77, 79]. significantly less than that of the FAC group [45]. Finally, both the prospective and retrospective studies surveyed breast cancer patients through a completion of BPI and FACT-Taxane Quality of life Quality of life (QoL) was assessed in eight questionnaires, respectively [5, 80]. While the analysis of the studies [4, 35, 45, 56, 69, 70, 74, 80]. There were six RCTs FACT-Taxane survey results did not demonstrate any signifi- [35, 45, 56, 69, 70, 74], one prospective observational study cant differences in quality-of-life scores for patients receiving [80], and one retrospective study [5]. Studies used three dif- docetaxel as compared with patients receiving paclitaxel in the ferent validated tools to measure QoL [19, 20, 81, 82]. The retrospective survey [5], early 36 % of patients prospectively European Organization for Research and Treatment of Cancer evaluated indicated interference with activities of daily living (EORTC) quality of life questionnaire (QLQC30), Rotterdam [80]. Symptom Checklist (RSCL), Brief Pain Inventory (BPI), and Functional Assessment of Cancer Therapy–Taxane Scale (FACT-T) were used to evaluate pain intensity and its interference with quality of life in five [35, 45, 56, 70, 74], two [69, Discussion 80], and one studies [5], respectively. Among the randomized trials, five studies did not demonstrate statistically significant Despite being a significant management issue in clinical prac- differences between two arms for results of the questionnaires tice, relatively little is known about the incidence of TAPS [4, in terms of adverse effect on pain relative to taxane-based 5]. To our knowledge, this is the first systematic review ex- chemotherapy [35, 56, 69, 70, 74]. On the other hand, two ploring its incidence with different taxane-based regimens in RCTs comparing two different taxane-based chemotherapy breast cancer patients. From the 27,007 patients accrued in the regimens FAC (doxorubicin, cyclophosphamide, and 5- 51 studies, several results became apparent. Perhaps the most fluorouracil) versus TAC (docetaxel, doxorubicin, and cyclo- important being that there remains no clear and validated def- phosphamide) or AT (docetaxel and doxorubicin) observed inition for TAPS and various tools including the NCI CTCAE

Table 4 Studies reporting the incidence of TAPS with nab-paclitaxel in breast cancer patients

Author Study design N* Median Taxane type and dose Taxane frequency Instrument used to TAPS incidence pts age measure TAPS

Neoadjuvant Saracchini Randomized 15 52 Nab-paclitaxel single arm q 3 weekly NCI CTCAE Grade 3–21 % [75] phase II N =15 version 3.0 Tsugawa [76]Randomized 37 50 Nab-paclitaxel single arm Weekly NCI CTCAE G3/4 14 % phase II N =37 version 3.0 Adjuvant Seki [77]Randomized14 NR Nab-paclitaxel single arm Weekly NCI CTCAE Myalgia = G1/2: phase II N =14 version 3.0 21.4 %, G3/4: 0 % Arthralgia = G1/2: 35.7 %, G3/ 4: 0 % Metastatic Schwartzberg Open label, phase 50 57 Nab-paclitaxel 125 mg/ D1 and D8 q 3 NCI CTCAE 32% [78] II m2 weekly version 3.0 Seidman Open label, 212 56 Nab-paclitaxel Arm A (Weekly) NCI CTCAE weekly = 13.9 % [79] randomized Arm A N =75vs. N =23 version 3.0 q2weekly=38.9% phase II Arm B N =54vs. Arm B (q 2weekly) q3weekly=30.7% Arm C N =79 N =21 Arm C (q 3weekly) N =11

NR not reported Support Care Cancer and WHO scales were used to measure the incidence of my- myalgias and arthralgias after taxane-based chemotherapy algias and arthralgias. Similarly, a number of quality of life are common. Second, are we able to identify a priori those tools (e.g., EORTC QLQC30, RSCL, and BPI) were used to patients at greatest risk of TAPS so that some form of preven- measure the quality of life impact of TAPS. Thus, a significant tative strategies can be put in place? The heterogeneity of the challenge with recording the incidence of TAPS is that there trials designs and populations meant that we were unable to remains no uniform definition with different studies using identify specific risk factors for TAPS in individual patients. different assessment tools. While many of these tools are mea- However, some risk factors identified in the current study suring taxane-induced arthralgia and myalgia, clinical experi- suggest important differences between taxanes: TAPS was ence would suggest that many patients would describe TAPS more common with paclitaxel, given in a weekly basis, shorter as a diffuse aching discomfort typically beginning 24–48 h infusion rate, and in metastatic disease. Unfortunately, due to after the taxane infusion and lasting for 3–5days[5]. the variability of measuring and reporting of TAPS, we were Despite the limitations posed by the use of different criteria unable to quantify the impact of each of these factors. to define and measure TAPS, our systematic review suggests Essentially, identifying potential risk factors for the occur- that the incidence of TAPS varies between taxanes, taxane- rence of TAPS and useful preventative strategies, patients at containing regimens, doses used, and disease settings. a greater risk of developing TAPS could benefit from a pro- Overall, the type of taxane appears to be the important risk phylactic management approach to mitigate or avoid symp- factor with paclitaxel being associated with a higher incidence toms later on. The optimal management of TAPS is also poor- of TAPS then either docetaxel or nab-paclitaxel [37, 47, 55, ly studied, as are prophylactic strategies, and therefore the 63, 70, 71, 79]. The disease stage was also relevant, as taxane development of prevention and management strategies could in the metastatic setting had a higher incidence compared to significantly enhance clinical practice [81]. the (neo) adjuvant setting. The chemotherapy schedule also The etiology of TAPS is poorly understood. It has been appears important for example weekly taxane dosing showed suggested that it may result from nociceptor sensitization on a higher rate of TAPS than 3-weekly dosing. the basis of patient descriptors of pain [4]. Despite the molec- There are limitations to the current study. First, the lack of a ular mechanisms involved in such sensitization being unclear, uniform definition of TAPS meant that multiple tools were there is data to suggest that variations in as single nucleotide used to define and measure TAPS. This may in part explain polymorphisms (SNPs) and Copy Number Variations (CNVs) the results that suggest that TAPS is more common with pac- may partly explain tits incidence in genetically predisposition litaxel, as clinical experience would suggest that it is more in individuals [82, 83]. Improving diagnostic assessments and common with docetaxel. A second limitation is the lack of developing a scientific understanding of TAPS physiology specific detailed information that was available from some will underpin a greater understanding of the condition. studies with regards to TAPS toxicity grading scale used. Specifically, the need to standardize scales to measure symp- Given the heterogeneity between the studies, it was difficult toms of TAPS would improve reporting among physicians. to make comparisons between studies and their outcomes. A Ultimately, it might provide insight into the importance of multivariate analysis would have allowed us to investigate chemotherapy type on the incidence of TAPS and its impact interactions between various factors. However, the heteroge- clinical management. Finally, there is a need for prospective neity of trials meant that this was not possible and hence the studies targeting high risk populations and identifying poten- data was presented as a narrative summary. This heterogeneity tial mechanisms and treatments. We are currently trying to included different patient populations (metastatic and non- perform such a study in breast and prostate cancer patients metastatic), different treatment intentions (palliative vs. cura- [84]. tive), different pain scores to assess TAPS, different taxanes (docetaxel, paclitaxel, and nab paclitaxel), and their integra- tion into different regimens [38, 39, 50]. This is an important limitation as clearly many of the potential risk factors may Conclusion simply reflect the populations being assessed, for example, patients with metastatic disease are more likely to receive While TAPS is relatively poorly researched, it is a clinically weekly paclitaxel than patients with early stage disease. The significant adverse event as it can interfere with activities of heterogeneity in studies and their reporting also meant that daily living, decrease quality of life, and in some cases, lead to stratification by taxane type was not possible in a robust dose reductions, delays, and discontinuation of treatment. enough manner to allow valid comparisons. With the studies This systematic review may help to quantify the incidence of reporting such a broad variety in incidence data further trials TAPS among breast cancer patients undergoing taxane-based with appropriate endpoint reporting are clearly required. treatment, however, until standardized and validated tools are So where do these findings leave us? First, it is evident that available for its diagnosis it is going to be challenging to despite the absence of a uniform definition for TAPS, develop optimal strategies for its prevention and treatment. Support Care Cancer

Compliance with ethical standards 37. prostate adj cancer or neoplasm or carcinoma 38. or/34–37 Conflict of interest Brian Hutton has previously received consultant 39. 33 and 38 fees from Amgen Canada and Cornerstone Research Group for method- ological advice related to systematic reviews and meta-analyses. All other 40. exp. Pain/ authors have no conflicts to declare. 41. pain 42. Myalgia/or Myalgia 43. exp. Arthralgia/or Arthralgia – Appendix 1 Systematic review supplement: 44. or/40 43 electronic literature search strategy 45. 39 and 44 46. prevalence/or incidence/ Database: Embase Classic + Embase 1947 to September 29 2014, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid 47. incidence or prevalence or frequenc or proportion or rate or number or MEDLINE(R) 1946 to September 29, 2014. percent 48. risk or mortality.mp. or cohort 49. exp. Cohort Studies/ Searches Results 50. or/46–49 1. docetaxel 51. 45 and 50 2. paclitaxel 52. limit 51 to english language 3. *taxoid 53. 52 use prmz MEDLINE 4. docetaxel or paclitaxel or taxane 54. 29 or 53 5. taxotere or docecad 55. remove duplicates from 54 6. or/1–5 7. or/1–5 ID Search Hits 8. breast adj cancer or neoplasms or carcinoma 1 MeSH descriptor: [Taxoids] explode all trees 9. exp. prostate cancer 2 docetaxel:ti,ab,kw or taxotere:ti,ab,kw or docecad:ti,ab,kw 10. prostate adj cancer or neoplasm$ or carcinoma (Wordvariations have been searched) 11. or/7–10 3 paclitaxel:ti,ab,kw or taxane*:ti,ab,kw (Word variations have 12. 6 and 11 beensearched) 13. exp. *pain 4#1or#2or#3 14. pain 5 MeSH descriptor: [Breast Neoplasms] explode all trees 15. exp. *myalgia 6 MeSH descriptor: [Prostatic Neoplasms] explode all trees 16. myalgia 7 breast near/2 cancer:ti,ab,kw or breast near/2 neoplasm*:ti,ab,kw or 17. exp. *arthralgia/ breast near/2 carcinoma*:ti,ab,kw (Word variations have been 18. arthralgia searched) 19. or/13–18 8 prostat* near/2 cancer:ti,ab,kw or prostat* near/2 neoplasm*:ti,ab,kw or prostat* near/2 carcinoma*:ti,ab,kw (Word variations have 20. 12 and 19 been searched) 21. risk or mortality or cohort 9 #5or#6or#7or#8 22. *cohort analysis 10 #4 and #9 23. prevalence 11 MeSH descriptor: [Pain] explode all trees 24. incidence 12 pain:ti,ab,kw or Arthralgia*:ti,ab,kw or myalgia*:ti,ab,kw (Word 25. incidence or prevalence or frequency or proportion or rate or number variations have been searched) or percent 13 MeSH descriptor: [Myalgia] explode all trees – 26. or/21 25 14 MeSH descriptor: [Arthralgia] explode all trees 27. 20 and 26 15 #11 or #12 or #13 or #14 28. limit 27 to english language 16 #10 and #15 29. 28 use emczd 17 prevalence:ti,ab,kw or incidence:ti,ab,kw or frequenc*:ti,ab,kw or 30. exp. Taxoids “proportion”:ti,ab,kw or rate*:ti,ab,kw (Word variations have 31. docetaxel or paclitaxel or taxane been searched) 32. taxotere or docecad 18 number:ti,ab,kw or “percentage”:ti,ab,kw (Word variations have been searched) 33. or/30–32 19 risk:ti,ab,kw or “mortality” or cohort:ti,ab,kw (Word variations have 34. exp. Breast Neoplasms/ been searched) 35. breast adj cancer or neoplasm$ or carcinoma 20 #17 or #18 or #19 36. exp. Prostatic Neoplasms/ 21 #16 and #20 Support Care Cancer

Database: Embase Classic + Embase 1947 to September 29 2014, 19 arthralgia$.tw. Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and 20 or/14–19 Ovid MEDLINE(R) 1946 to September 29, 2014 21 13 and 20 22. (risk or mortalit$ or cohort).tw. 23. *cohort analysis/ Searches Results 24. prevalence/ 1. exp. Taxoids/ 25. incidence/ 2. (docetaxel or paclitaxel or taxane$ or cabazitaxel).mp. 26. (incidence or prevalence or frequenc$ or proportion$ or rate$ or 3. (taxotere or docecad).tw. number$ or percent$).tw. 4. or/1–3 27. or/22–26 5. exp. Breast Neoplasms/ 28. 21 and 27 6. (breast adj2 (cancer or neoplasm$ or carcinoma$)).tw. 29. limit 28 to english language 7. exp. Prostatic Neoplasms/ 30. 2015$.em. 8. (prostat$ adj2 (cancer or neoplasm$ or carcinoma$)).tw. 31. 20,141$.dd. 9. or/5–8 32. (“201,443” or “201,444” or “201,445” or “201,446” or “201,447” or 10. 4 and 9 “201,448” or “201,449” or 20,145$).em. 11.exp.Pain/ 33. or/30–32 12. pain.tw. 34. 29 not 33 13. Myalgia/or Myalgia$.tw. 14. exp. Arthralgia/or Arthralgia$.tw. 15. or/11–14 16. 10 and 15 17. prevalence/or incidence/ 18. (incidence or prevalence or frequenc$ or proportion$ or rate$ or number$ or percent$).tw. 19. (risk or mortality).mp. or cohort.tw. 20. exp. Cohort Studies/ 21. or/17–20 22. 16 and 21 23. limit 22 to english language 24. (2,014,102$ or 20,141$ or 2015$).ed,dc. 25. 23 not 24

ID Search Hits 1. docetaxel/ 2. paclitaxel/ 3. *taxoid/ 4 cabazitaxel/ 5 (docetaxel or paclitaxel or taxane$ or cabazitaxel).tw. 6 (taxotere or docecad).tw. 7or/1–6 8 exp breast cancer/ 9 (breast adj2 (cancer or neoplasms$ or carcinoma$)).tw. 10 exp prostate cancer/ 11 (prostat$ adj2 (cancer or neoplasm$ or carcinoma$)).tw. 12 or/8–11 13 7 and 12 14 exp *pain/ 15 pain.tw. 16 exp *myalgia/ 17 myalgia$.tw. 18 exp *arthralgia/ Support Care Cancer

Appendix 2 PRESS EBC Search Submission

Searcher’s Name: Risa E-mail: [email protected] Date submitted: September 26, 2014 Date needed by: October 2, 2014

Note to peer reviewers – please enter your information in the Peer Review Assessment area

Remember: this peer review only pertains to your MEDLINE search strategy.

Search question (Describe the purpose of the search)

1. What is the incidence/risk of taxane acute pain syndrome in breast cancer patients undergoing docetaxel chemotherapy?

PICO format (Outline the PICO for your question, i.e., the Patient, Intervention, Comparison and Outcome)

P: Breast cancer I: docetaxel C: O: Taxane acute pain syndrome Inclusion criteria (List criteria such as age groups, study designs, to be included)

English language only

Exclusion criteria (List criteria such as study designs, to be excluded)

Was a search filter applied? (Remember this pertains only to the MEDLINE strategy) Support Care Cancer

Yes No

If yes, which one?

Cochrane hedge: PUBMED clinical query:

Haynes/McKibbon et al: SIGN (Scottish):

CRD (UK): Robinson and Dickerson:

Other: MEDLINE search interface used

EBSC OVID PubME Other ______O D __

Has the search strategy been adapted (i.e., subject heading and terms reviewed) for other databases? Please check all that apply.

Ageline LILACS (Latin American and Caribbean Health Sciences AMED Literature)

C2-SPCTRE MEDLINE

CINAHL PreMEDLINE

Cochrane Database of Systematic PsycINFO Reviews (CDSR; Cochrane Reviews) Other Biosis Previews Cochrane Central Register of Controlled Trials (CENTRAL; Other Clinical Trials)

Cochrane Methodology Register (CMR; Methods Studies)

Cochrane Library (all databases)

Database of Abstracts of Reviews of Effects (DARE; Other Reviews)

Embase

ERIC

ICTRP (International Clinical Trials Registry Platform) Support Care Cancer

Peer Review Assessment

[For peer reviewers only]

Peer reviewer’s name: Sascha Davis E-mail: [email protected] Date completed:

Please select the one most appropriate answer for each element Adequate Adequate with Needs revisions* revision*

1. Translation of the research x question

2. Boolean and proximity operators x

3. Subject headings x

4. Natural language / free-text x

5. Spelling, syntax and line x numbers

6. Limits and filters x

7. Search strategy adaptations x

* Provide an explanation or example for “Adequate with revisions” and “needs revision”: Support Care Cancer

Appendix 3 PRISMA Checklist

Section/topic # Checklist item Reported on page # TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both. 1 ABSTRACT Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility 2 criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. 3–4 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, 3 comparisons, outcomes, and study design (PICOS). METHODS Protocol and 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide N/A registration registration information including registration number. Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, 4 language, publication status) used as criteria for eligibility, giving rationale. Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify 4–5 additional studies) in the search and date last searched. Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be 29–32 repeated. Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, 5 included in the meta-analysis). Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes 5–6 for obtaining and confirming data from investigators. Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and 5–6 simplifications made. Risk of bias in 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was 5 individual studies done at the study or outcome level), and how this information is to be used in any data synthesis. Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). N/A Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency N/A (e.g., I2) for each meta-analysis. Risk of bias across 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective 5 studies reporting within studies). Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating N/A which were pre-specified. RESULTS Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at 6–7 each stage, ideally with a flow diagram. Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and 6–7 provide the citations. Risk of bias within 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 7,38 studies Results of individual 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each inter- 8–10, 24–28 studies vention group (b) effect estimates and confidence intervals, ideally with a forest plot. Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. N/A Risk of bias across 22 Present results of any assessment of risk of bias across studies (see Item 15). 7,38 studies Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). N/A DISCUSSION Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to 10–13 key groups (e.g., healthcare providers, users, and policy makers). Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of 10–13 identified research, reporting bias). Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 10–13 FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the N/A systematic review. Support Care Cancer

Appendix 4 Risk of bias assessment of included randomized trials

Author Random Allocation Blinding Blinding Incomplete Selective [ref] sequence concealment (participants (outcome outcome reporting generation and personnel) assessment) data

Baselga -+ + - - - [38] Coudert ?+ + - + - [40] Earl [79] - + - - - - Fountzilas -+ + - - - [35] Gonzales- -+ + - - - Angulo [56] Swain ------[58] Cognetti ++ + - + - [49] Luck [45] - + + + - - Saura [46] + + + - - - Seidman -+ + - - - [39] Moinpour -+ + - - - [44] Schonherr ++ + - - - [43] Coombes -+ + - - - [52] Moulder ?+ + + - - [47] Saibil [5] ? ? ? - + - Lee [48] - + + - - - Burstein ?? ? - - - [50] Lin [37] ? + + - - - Jones [9] ? + + - - - Talbot -+ + - - - [54] Jassem -? ? - - - [57]

Trials at low risk of bias (green), high risk of bias (red), or unclear risk of bias (yellow). Green (−)=lowriskbias. Red (+) = high risk bias. Yellow (?) = unclear risk of bias. Support Care Cancer

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