REVIEWARTICLE

Taxane acute pain syndrome (TAPS) in patients receivingtaxane-based chemotherapy for breast cancer—a systematicreview

Ricardo Fernandes1 & Sasha Mazzarello2 & Brian Hutton3& 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

AbstractBackground Taxane acute pain syndrome (TAPS) is charac-terized by myalgias and arthralgias starting 24–48 h aftertaxane-based chemotherapy and lasting for 5–7 days.Relatively little is known about its incidence and impact onquality of life.Objectives A systematic review was conducted evaluating theincidence of TAPS in breast cancer patients receiving taxane-based chemotherapy.Methods Embase, Cochrane, and Ovid MEDLINE weresearched from 1947 to July 2015. Data was sought from ran-domized controlled trials (RCTs), prospective and retrospec-tive observational studies. Two reviewers independentlyscreened citations and full text articles. Outcomes of interestwere the incidence of TAPS and its impact on quality of life.Results Of 980 citations identified, 51 relevant studies (27,007 patients) were included. Data came from RCTs (12,357patients), retrospective (6566 patients) and prospective obser-vational studies (6210 patients). Study sample sizes rangedfrom 14 to 4149 patients (median 152). Given the significance

between study heterogeneity, a meta-analysis was not per-formed. The incidence of TAPS varied between taxanes: pac-litaxel (median 13.1 %, range 0.9–86 %), docetaxel (median10.5%, range 3.6–70%), and nab-paclitaxel (26 %, range 14–43 %). In the metastatic setting, median incidence was 30 %(range 5.4–73 %), compared with 11.3 % (range 0.9–86 %) inthe adjuvant setting. Three out of eight studies assessing qual-ity of life demonstrated pain interference with daily activities.Conclusions The incidence of TAPS varies between taxanes,regimens, and disease settings. In order to identify patients atthe greatest risk of TAPS, and hence optimize its preventionand management, standardized methods of diagnosing andmeasuring TAPS are needed.

Keywords Breast cancer . Taxane chemotherapy . Pain .

Incidence . Quality of life

Background

Taxanes such as docetaxel, paclitaxel, and nab-paclitaxel arecommonly used in the treatment of breast cancer [1–3]. Acommonly reported toxicity of taxanes is taxane acute painsyndrome (TAPS), also known as paclitaxel-associated acutepain syndrome or taxane-induced pain [4]. TAPS is typicallycharacterized by myalgias and arthralgias appearing 24–48 hafter receiving taxane-based chemotherapy and lasting for 5–7 days [5]. TAPS can be debilitating for patients and lead todose delays, reductions, and discontinuation of potentiallycurable therapy [4–7].

The incidence of TAPS varies between taxanes and is re-portedly more common with docetaxel than with either pacli-taxel or nab-paclitaxel [4, 5, 8]. TAPS also appears to be morefrequent in patients with breast cancer than in those with

* Mark Clemonsmclemons@toh.on.ca

1 Department ofMedicine, Division ofMedical Oncology, The OttawaHospital Cancer Centre and University of Ottawa, 501 Smyth Road,Ottawa, Canada

2 Ottawa Hospital Research Institute and University of Ottawa,Ottawa, Canada

3 Department of Epidemiology and Community Medicine, Universityof Ottawa, Ottawa, Canada

4 The Ottawa Hospital, Ottawa, Canada5 Department of Medicine, Division of Internal Medicine, The Ottawa

Hospital and University of Ottawa, Ottawa, Canada

Support Care CancerDOI 10.1007/s00520-016-3256-5

prostate, lung, or ovarian cancer [8–17]. The reasons for thisvariability in incidence are likely multi-factorial and reflectdifferences between taxanes, doses, combination regimens,patient populations, and variability in the co-administeredsupportive care treatments that can themselves cause myalgias(e.g., growth-colony stimulating factors) [2, 9, 10, 18]. Theuse of different pain and toxicity assessment tools means thatsome studies report the incidence of chemotherapy-inducedperipheral neuropathy (CIPN) as being the same as TAPS[19, 20]. Clinically, TAPS is quite distinct from CIPN, withdifferent mechanisms of action and temporal profiles.However, the occurrence of TAPS can predispose to subse-quent CIPN [21–24].

Thus, despite being relatively common in clinicalpractice, the incidence of TAPS with different taxanesand taxane-based regimens is not well established[25–28]. Given the paucity of data addressing theseknowledge gaps, the current systematic review was per-formed. The objectives were to estimate the incidenceof TAPS following a range of taxane-containing regi-mens in patients with breast cancer and to possiblyidentify potential predisposing factors for its occurrence.Such risk factors could potentially be used to identifypatients a priori at greatest risk of experiencing TAPSand to develop better prevention and treatmentstrategies.

Methods

Research question and study eligibility criteria

The systematic review was designed to summarize availableinformation addressing the following research question:BWhat are the incidence and risk factors of TAPS inbreast cancer patients who have received taxane-basedchemotherapy?^ The Population-Intervention-Comparator-Outcome-Study Design (PICOS) framework was used tostructure the research question and its corresponding literaturesearch. In the literature, breast cancer patients have the highestincidence of TAPS and hence were the population of interest.Interventions of interest included any taxane-based chemo-therapy. Outcomes of interest included measures of the inci-dence of TAPS and quality of life. We also sought informationrelated to potential risk factors such as type of taxane, gender,stage of disease, single agent versus combination chemother-apy, and concurrent medications. Randomized controlled tri-als (RCTs) as well as retrospective and prospective observa-tional studies were eligible. Data on the incidence of TAPSwas also included from randomized trials where one arm didnot receive a taxane. Animal studies were excluded, as werestudies investigating CIPN.

Literature search

An information specialist (RS) designed and executed an elec-tronic literature search to seek relevant citations from Embase,Cochrane, and Ovid MEDLINE from 1946 to July 7, 2015.Key terms and their medical subject headings (MeSH) areprovided along with the full search strategy in Appendix 1.An independent PRESS review performed by a second librar-ian is provided in Appendix 1 [29].

Study selection, data collection, and risk of biasassessment

Stage 1 screening was performed by three reviewers (SM,RF, and HM), who independently screened all citationsretrieved from the electronic search. Disagreements werediscussed and resolved between reviewers. Stage 2 screen-ing consisted of a full-text review of all potentially relevantcitations by six reviewers working independently (SM, RF,HB, MC, CJ, and MI) to determine the final set of includedarticles. A PRISMA flow diagram was prepared to summa-rize the process of study selection (Fig. 1), and a PRISMAchecklist was also completed during preparation of the re-port (Appendix 3) [30].

Once the final set of included studies was established, datawere 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-lowing information was collected from each study: authors,year and journal of publication, study design, number of pa-tients enrolled, patient eligibility criteria, relevant patient de-mographics, study duration, publication status, chemotherapyduration and line, taxane type and frequency, stage of disease,symptoms and incidence of TAPS, presence of concurrentsteroid administration, rates of, and reasons for, chemotherapydiscontinuation, dose and type of analgesia, and quality of lifeassessment. Authors were contacted to acquire other unpub-lished data. The Cochrane Collaboration’s tool for assessingrisk of bias in RCTs was used (Appendix 4) [31].

Data analysis

If deemed appropriate, following exploration of study andpatient characteristics to ensure sufficient clinical and meth-odological homogeneity across studies, we planned to con-duct meta-analyses using random effects models to combineTAPS incidence data across studies. Following inspection ofthe characteristics of included studies, the research team feltthere was a high degree of study heterogeneity in terms ofstudy populations, study design, disease stage, and chemo-therapy regimen. These differences were viewed by the au-thors to preclude the data from meta-analysis. To synthesize

Support Care Cancer

the information collected, a narrative summary was preparedto document variations in TAPS incidence and to summarizepotential risk factors.

Results

Extent of evidence identified

Following the removal of duplicate citations, the literaturesearch identified 980 unique citations. Stage 1 screening wasperformed on the citations only and 122 potentially relevantstudies were identified. At stage 2 screening, a total of 76studies were reviewed in full text format. The total numberof trials included was 51 (n = 27,007 patients). Studies wereexcluded for the following reasons: no data on TAPS reported(n = 13), not breast cancer (n = 9), chemoradiation study(n = 1), TAPS not recorded (n = 1), and duplicate publication(n = 1). Figure 1 shows an overview of the study selectionprocess and Tables 1, 2, 3, and 4 summarize studycharacteristics.

Study characteristics

Of the 51 studies included, 32 were RCTs [9, 27, 32, 35–37,41–43, 47, 49, 51, 54–56, 58, 59, 61–63, 68–79], 14 were

retrospective analyses [5, 33, 34, 39, 40, 44, 46, 48, 50, 53,57, 64–66], and 5 prospective observational trials [38, 45, 51,52, 67]. Among RCTs, both phase 2 and 3 trials were includedand all were completed. In terms of type of taxane chemother-apy, 27 (52%) studies included a group that evaluated doce-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, 39,75–80]. Studies included treatment in the neoadjuvant (8 stud-ies) [41–43, 60–62, 75, 76], adjuvant (23 studies) [9, 11,32–34, 44–52, 54–56, 63–67, 77], metastatic (18 studies) [5,27, 35–37, 40, 57–59, 68–74, 78, 79] settings, and not report-ed in 2 studies [38, 39]. The symptoms of TAPS were usuallydescribed as Bmyalgia^ and Barthralgia^ and measured usingthe NCI Common Terminology Criteria for Adverse Eventsversion 3.0 (http://www.ctep.cancer.gov). This meant we wereunable to ascertain the timing of TAPS for either the adjuvantor metastatic settings. Quality of life was assessed in eightstudies. The European Organization for Research andTreatment of Cancer (EORTC) quality of life questionnaire(QLQC30), Rotterdam Symptom Checklist (RSCL), BriefPain Inventory (BPI), and Functional Assessment of CancerTherapy–Taxane Scale (FACT-T) were used to evaluate painintensity and its interference with quality of life in five [35, 45,56, 70, 74], two [69, 80], and one studies [5], respectively. Ofall included studies, the median age of patients ranged from 43to 57 years.

Records identified and screened

through database and abstract

searching after removal of

duplicates

(N=980)

Second screening

(n= 76)

Full-text articles or abstracts

assessed for eligibility

(n= 51)

Studies included in qualitative

and quantitative synthesis

(n=51)

Iden

tifi

cati

on

Scre

enin

gE

ligib

ility

Incl

uded

Excluded (n=25):

Quality of life (n=1)

No TAPS data reported (n=13)

Other tumour sites (n=9)

Duplication (n=1)

Chemoradiation therapy (n=1)

Records excluded due to

irrelevancy

(n=858)

First screening

(n= 122)

Excluded (n=46):

No reported TAPS data

(n=23)

Cancer related pain (n=7)

Quality of life (n=1)

CIPN (n=4)

Combination therapy (n=4)

Case series and reports (n=6)

Duplication (n=1)

Fig. 1 PRISMA flow diagram ofstudy selection process

Support Care Cancer

Risk of bias assessment

A risk of bias assessment was performed on the RCTs usingCochrane risk of bias scale (Appendix 4) [31]. Risk of biaswas high for all of the included trials due to incomplete out-come data [5, 41, 63]. The studies by Luck [70] and Moulder[71] were also judged to have high risk of performance anddetection bias with inadequate blinding of outcome assess-ment. As well, risk of bias was high due to random sequencegeneration in three studies [49, 62, 63].

Incidence of TAPS by taxane type

Docetaxel Among the 27 included studies (18,702 patients)[37, 39, 75–80], the incidence of TAPS with docetaxel rangedfrom 3.6 to 70.0 % (median 10.5 %) depending on dosing andchemotherapy regimen (Table 2.) For instance, with FEC-D

regimen (5-fluorouracil-epirubicin-cyclophosphamidefollowed by docetaxel), the incidence of TAPS varied from28 to 53% (median 13.6%), whereas with EC-D (epirubicin +cychophosphamide followed by docetaxel) the incidenceranged from 3 to 12.3 % (median 8.3 %) [49, 51, 52, 56].Regarding dosing, TAPS incidence with docetaxel 75 mg/m2

every 3 weeks was reported to be 4–28 % (median 9.3 %),whereas dosing of 100 mg/m2 showed a TAPS incidence of5.4–53.3 % (median 20.5 %) [42, 46, 47, 49, 51, 55–57].Withregard to disease stage, docetaxel was associated with higherTAPS incidence in the adjuvant setting (median 20.5 %) com-pared with the metastatic setting (median 14.8 %) [36, 39–44,46, 47, 49, 50, 57, 58].

Paclitaxel Paclitaxel was evaluated in 26 studies (12,284 pa-tients) [37, 39, 75–80]. The incidence of TAPS ranged from0.9 to 86 % (median 13.1 %). This varied according to both

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

Author[ref]

Study design Studysetting

N*pts

Medianage

Taxane type and dose Taxanefrequency

Tool used tomeasure TAPS

TAPS incidence

Fountzilas[32]

Randomizedphase III

Adjuvant 990 53 ArmA—Paclitaxel200 mg/m2

(3 weekly);Arm B—Paclitaxel

80 mg/m2 (weekly);Arm C—Docetaxel

30 mg/m2 (weekly)

Weekly and 3weekly

NCI CTCAEversion 3.0

Arm A: 5.2 %Arm B: 0.9 %Arm C: 1.6 %

Joensuu[33]

Retrospective Adjuvant 1496 NR PaclitaxelDocetaxel

q 3 weekly QLQ C30 1.9 %8 %

Kim [34] Retrospective,observational

Adjuvant 54 48.6 Paclitaxel 175 mg/m2

vs.Docetaxel 100 mg/m2

q 3 weekly NCI CTCAEversion 3.0

Paclitaxel = 30.8 %,Docetaxel = 6.7 %(3.8 and 0 % g3/4)

Wist [35] Randomizedphase II

Metastatic 37 53 Paclitaxel (80 mg/m2)vs.Docetaxel (75 mg/m2)

Paclitaxelweekly ×

Docetaxel q 3weekly

NR Paclitaxel 38.9 %Docetaxel 26.3 %

Lin [36] Randomized Metastatic 101 48 Docetaxel (60 mg/m2)vs.Paclitaxel(175 mg/m2)

3 weekly WHO Docetaxel 14 %Paclitaxel 25 %

Saibil [5] Retrospective,survey

Adjuvant 82 NR Pacitaxel or Docetaxelcontaining regimens

NR NR AC-T (43 %), FEC-D(43 %), AC-D (14 %)

Baselga[37]

Randomized Metastatic 363 52 Paclitaxel 80 mg/m2 vs.Nab-paclitaxel 50 mg/m2

Paclitaxelweekly

vs.Nab-paclitaxel

q3weekly

NCI CTCAEversion 3.0

10 % in each arm

Pasetka[38]

Prospective,observational

NR 275 52 Paclitaxel, DocetaxelNab-paclitaxel -

NR NR arthralgia = 67.9 %,myalgia = 63.8 %

Howell[39]

Retrospectiveanalysis

NR 81 NR Docetaxel (50, 75, or100 mg/m2),

Nab paclitaxel (260 mg/m2)

q 3 weekly NR 10 % docetaxel43 % nab-paclitaxel

Brammer[40]

Retrospective,observational

NR 1551 NR NR NR NR Docetaxel (9 %),Docetaxel +trastuzumab (16 %),paclitaxel (11 %)

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

Support Care Cancer

schedule and disease stage. In one study, paclitaxel (140 mg/m2) infused over 96 h caused less TAPS (30 %) when com-pared with paclitaxel (250 mg/m2) given over 3 h (59 %) [71].While the incidence of TAPS from weekly paclitaxel rangedfrom 7 to 38.9 % (median 17.6), a higher incidence was re-ported with three weekly treatments ranging from 39.2 to53.5% (median 52.7) [32, 35, 62, 63, 65, 66, 70].With respectto disease stage, paclitaxel was associated with higher TAPS

incidence in the metastatic (median 45.9) when compared tothe adjuvant setting (median 32.7) [9, 60, 62, 63, 65, 67, 68,70–74].

Nab-paclitaxel Nab-paclitaxel resulted in different incidenceof TAPS based on dosing, schedule, and setting of disease,ranging from 13 to 43 % (median 26) in eight studies (997patients) [37, 39, 75–80]. When given in the metastatic

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

Author [ref] Study design N*pts

Medianage

Taxane type and dose Taxanefrequency

Instrument used tomeasure TAPS

TAPS incidence

Neoadjuvant

Coudert [41] Open-label,randomized

152 NR Docetaxel100 mg/m2

q 3 weekly NR 3.60 %

Yong WhaMoon [42]

Single arm phase 2 49 43 Docetaxel100 mg/m2

q 3 weekly NCI CTCAE version3.0

myalgia 14.3 % arthralgia4.1 %

Tuxen [43] Phase II 49 50 Docetaxel 100 mg/m2

q 3 weekly × 4q 3 weekly NCI CTCAE version

2.031 %

Adjuvant

Akinci [44] Retrospectiveanalysis

539 48 Docetaxel100 mg/m2

q 3 weekly NR 2 % with 3 cycles and1 % with 4 cycles

Hatam [45] ProspectiveObservational

100 48 Docetaxel 75 mg/m2 q 3 weekly NCI CTCAE version3.0

30 %

Eckhoff [46] Retrospectiveanalysis

1143 NR Docetaxel 100 mg/m2 q 3 weekly NCI CTCAE version2.0

53.3 %, all grades6.9 % grades 3/4

Eiermann[47]

Randomized phaseIII

3298 50 Docetaxel 75 mg/m2 × 6 or 100 mg/m2q 3 weekly × 4

q 3 weekly NCI CTCAE version2.0

35.8 % all grades4.9 % grades 3/4

Miura [48] Retrospectiveanalysis

85 NR Docetaxel 75 mg/m2 q 3 weekly NR 6 % rTC vs. 48 % TC

Schonerr[49]

Phase IIIprospective,randomized

1496 55 Docetaxel 100 mg/m2 q 3 weekly NCI CTCAE version3.0

12.3 % (EC-Docetaxel)vs. 1.4 % (FEC)

Thomson[50]

Retrospective 37 NR Docetaxel 100 mg/m2 NR NR D1: 70 %, D2: 53 %, D3:28 %

Thomssen[51]

Prospective 4149 NR Docetaxel 100 mg/m2 NR NR 4.3 % (FEC-D) <1 % (FEC)

Yau [52] Observational 1537 47 Docetaxel 100 mg/m2 q 3 weekly NR 0.63

Rodriguez-Abreu [53]

Retrospective 81 50 Docetaxel 100 mg/m2 q 3 weekly NR NR

Lee [54] Randomized 209 NR Docetaxel100 mg/m2

NR NR 67 % (TX) vs.28 % (AC)

Vriens [55] Randomized phaseIII

201 NR Docetaxel 75 mg/m2 q 3weekly × 6 or100 mg/m2 × 4

q 3 weekly NR TAC = 0 %,AC-T = 4 %

Coombes[56]

Randomized 803 NR Docetaxel 100 mg/m2 q 3 weekly NCI CTCAE version3.0

2 % (3 cycles Epirrubicin-Docetaxel vs 20.5 %(6 cycles Epirrubicin-Docetaxel)

Metastatic

Jacot [57] Retrospective 45 45 Docetaxel 100 mg/m2 q 2 weekly NCI CTCAE version2.0

5.4 % total

Morimoto[58]

Randomized phaseIII

62 NR Docetaxel100 mg/m2

q 3 weekly NCI CTCAE version3.0

45.2 %

Swain [59] Randomized phaseIII

808 54 Docetaxel100 mg/m2

q 3 weekly NCI CTCAE version3.0

Arm A: 15.6 %Arm B: 13.8 %

NR not reported, TX docetaxel plus capecitabinle, TC Docetaxel plus cyclophosphamide, rTC reverse Docetaxel plus cyclophosphamide

Support Care Cancer

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

Author [ref] Study design N*pts

Median age Taxane type anddose

Taxanefrequency

Instrumentused tomeasureTAPS

TAPS incidence

NeoadjuvantEarl [60] Randomized

open label,831 NR Paclitaxel 175 mg/

m2q 2 weekly NCI CTCAE

version 3.05 % each arm

Gonzalez-Angulo [61]

Randomizedphase II

50 Arm A: 52(T-FEC)

Arm B: 46(TR-FEC)

Paclitaxel 80 mg/m2

weekly NCI CTCAEversion 3.0

Arm A: 7 %Arm B: 13 %

Saura [62] Randomized,open-label,phase II

295 48 Paclitaxel 80 mg/m2

weekly NCI CTCAEversion 3.0

Myalgia 13.2 %/Arthralgia 9.7 %

AdjuvantCognetti [63] Randomized

phase III2091 NR Paclitaxel 80 mg/

m2q 2

weekly(D-D) ×

q 3weekly(SD)

NR Arms C,D: 53.5 %Arms A,B: 39.2 %

Richardet [64] Retrospectiveanalysis

76 57 Paclitaxel 80 mg/m2

weekly NR NR

Richardet [65] Retrospective,observational

50 53 Paclitaxel 80 mg/m2

q weekly 22 %

Haba-rodriguez[66]

Retrospectiveanalysis ofphase III

1246 NR Paclitaxel 100 mg/m2 q 1 week × 8

q1 weekly NR Arthralgia = 5.2 %/9.5 %/8.0 % by climateMyalgia = 10.3 %/12.5 %/8.5 % by climate

Jones [9] Randomized 1016 51 Paclitaxel 75 mg/m2

NR NCICCTCAEversion 3.0

33 % TC vs. 16 % AC

Palappallil [67] ProspectiveObservational

100 48 (FAC)40 (AC-P)

Paclitaxel 175 mg/m2

q 3weekly × 4

WHOtoxicitygrading

86 %

MetastaticEsteva [68] Open label

phase I63 53 Paclitaxel 80 mg/

m2 or70 mg/m2

Weekly NCICCTCAEversion 3.0

29 %

Moinpour [69] Randomizedphase III

529/366

55 Paclitaxel 175 mg/m2

q 3 weekly NR NR

Luck [70] Prospectivephase 3randomized

340 57 Paclitaxel 175 mg/m2

q 3 weekly NCI CTCAEversion 2.0

Myalgia: capecitabine +taxane 52 % vs.epirrubicin + taxane52.7 %

Athralgia: capecitabine +taxane 58.8 % vs.epirubicin + taxane55.7 %

Molder [71] Randomized 214 NR Paclitaxel 250 or140 mg/m2

3 h q 3 weeklyvs. 96 h q 3weekly

NCICCTCAEversion 2.0

59 % vs.30 %

Burstein [72] Randomized 81 55 Paclitaxel 80 mg/m2

weekly NR 20 %/44 %/25 %

Talbot [73] Randomized 44 52 Paclitaxel 175 mg/m2

NR NCICCTCAEversion 3.0

0 % Capecitabine vs. 5 %Paclitaxel

Jassem [74] Randomizedopen label,

267 50 Paclitaxel 220 mg/m2

q 3 weekly NR AT (73 %) vs. FAC (17 %)

Gelmon [27] Randomizedopen label,

42 49 Paclitaxel 250 mg/m2 (initial)and 175 mg/m2

(nonprogressingpatients)

q 3 weekly NCICCTCAEversion 3.0

Paclitaxel only (95 %) vs.Paclitaxel + amifostine

(90 %)

NR not reported

Support Care Cancer

setting, the incidence of TAPS ranged from 13 to 43 % (me-dian 21.85), compared to 14 and 35.7 % (median 21.2) in theneoadjuvant and adjuvant settings [37, 39, 75–77, 79], respec-tively. When given every 2 weeks (range 20–38.9 %; median21.85 %) nab-paclitaxel had a similar incidence of TAPSwhen compared with weekly treatment (range 14–35.7 %;median 17.7 %) [77, 79].

Quality of life Quality of life (QoL) was assessed in eightstudies [4, 35, 45, 56, 69, 70, 74, 80]. There were six RCTs[35, 45, 56, 69, 70, 74], one prospective observational study[80], and one retrospective study [5]. Studies used three dif-ferent validated tools to measure QoL [19, 20, 81, 82]. TheEuropean Organization for Research and Treatment of Cancer(EORTC) quality of life questionnaire (QLQC30), RotterdamSymptom Checklist (RSCL), Brief Pain Inventory (BPI), andFunctional Assessment of Cancer Therapy–Taxane Scale(FACT-T) were used to evaluate pain intensity and its inter-ference with quality of life in five [35, 45, 56, 70, 74], two [69,80], and one studies [5], respectively. Among the randomizedtrials, five studies did not demonstrate statistically significantdifferences between two arms for results of the questionnairesin terms of adverse effect on pain relative to taxane-basedchemotherapy [35, 56, 69, 70, 74]. On the other hand, twoRCTs comparing two different taxane-based chemotherapyregimens FAC (doxorubicin, cyclophosphamide, and 5-fluorouracil) versus TAC (docetaxel, doxorubicin, and cyclo-phosphamide) or AT (docetaxel and doxorubicin) observed

higher deterioration of QoL in the latter [45, 74]. For instance,one trial showed a reduction of mean score of QoL in the FACfrom 74.5 to 68 (67.74 ± 26.11) and the TAC group decreasedfrom 74.5 to 64 (64.39 ± 29.56). In addition, in all the fiveaspects of patient’s functional status (physical, role, emotion-al, cognitive, and social functioning), the mean results weresignificantly less than that of the FAC group [45]. Finally, boththe prospective and retrospective studies surveyed breast can-cer patients through a completion of BPI and FACT-Taxanequestionnaires, respectively [5, 80]. While the analysis of theFACT-Taxane survey results did not demonstrate any signifi-cant differences in quality-of-life scores for patients receivingdocetaxel as comparedwith patients receiving paclitaxel in theretrospective survey [5], early 36 % of patients prospectivelyevaluated indicated interference with activities of daily living[80].

Discussion

Despite being a significant management issue in clinical prac-tice, relatively little is known about the incidence of TAPS [4,5]. To our knowledge, this is the first systematic review ex-ploring its incidence with different taxane-based regimens inbreast cancer patients. From the 27,007 patients accrued in the51 studies, several results became apparent. Perhaps the mostimportant being that there remains no clear and validated def-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*pts

Medianage

Taxane type and dose Taxane frequency Instrument used tomeasure TAPS

TAPS incidence

Neoadjuvant

Saracchini[75]

Randomizedphase II

15 52 Nab-paclitaxel single armN = 15

q 3 weekly NCI CTCAEversion 3.0

Grade 3–21 %

Tsugawa [76] Randomizedphase II

37 50 Nab-paclitaxel single armN = 37

Weekly NCI CTCAEversion 3.0

G3/4 14 %

Adjuvant

Seki [77] Randomizedphase II

14 NR Nab-paclitaxel single armN = 14

Weekly NCI CTCAEversion 3.0

Myalgia = G1/2:21.4 %,G3/4: 0 %Arthralgia =G1/2: 35.7 %, G3/4: 0 %

Metastatic

Schwartzberg[78]

Open label, phaseII

50 57 Nab-paclitaxel 125 mg/m2

D1 and D8 q 3weekly

NCI CTCAEversion 3.0

32%

Seidman[79]

Open label,randomizedphase II

212 56 Nab-paclitaxelArm A N = 75 vs.Arm B N = 54 vs.Arm C N = 79

Arm A (Weekly)N = 23

Arm B (q 2weekly)N = 21

Arm C(q 3weekly) N = 11

NCI CTCAEversion 3.0

weekly = 13.9 %q 2weekly = 38.9 %q 3weekly = 30.7 %

NR not reported

Support Care Cancer

and WHO scales were used to measure the incidence of my-algias and arthralgias. Similarly, a number of quality of lifetools (e.g., EORTC QLQC30, RSCL, and BPI) were used tomeasure the quality of life impact of TAPS. Thus, a significantchallenge with recording the incidence of TAPS is that thereremains no uniform definition with different studies usingdifferent assessment tools.While many of these tools are mea-suring taxane-induced arthralgia and myalgia, clinical experi-ence would suggest that many patients would describe TAPSas a diffuse aching discomfort typically beginning 24–48 hafter the taxane infusion and lasting for 3–5 days [5].

Despite the limitations posed by the use of different criteriato define and measure TAPS, our systematic review suggeststhat the incidence of TAPS varies between taxanes, taxane-containing regimens, doses used, and disease settings.Overall, the type of taxane appears to be the important riskfactor with paclitaxel being associated with a higher incidenceof TAPS then either docetaxel or nab-paclitaxel [37, 47, 55,63, 70, 71, 79]. The disease stage was also relevant, as taxanein the metastatic setting had a higher incidence compared tothe (neo) adjuvant setting. The chemotherapy schedule alsoappears important for example weekly taxane dosing showeda higher rate of TAPS than 3-weekly dosing.

There are limitations to the current study. First, the lack of auniform definition of TAPS meant that multiple tools wereused to define and measure TAPS. This may in part explainthe results that suggest that TAPS is more common with pac-litaxel, as clinical experience would suggest that it is morecommon with docetaxel. A second limitation is the lack ofspecific detailed information that was available from somestudies with regards to TAPS toxicity grading scale used.Given the heterogeneity between the studies, it was difficultto make comparisons between studies and their outcomes. Amultivariate analysis would have allowed us to investigateinteractions between various factors. However, the heteroge-neity of trials meant that this was not possible and hence thedata was presented as a narrative summary. This heterogeneityincluded different patient populations (metastatic and non-metastatic), different treatment intentions (palliative vs. cura-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 importantlimitation as clearly many of the potential risk factors maysimply reflect the populations being assessed, for example,patients with metastatic disease are more likely to receiveweekly paclitaxel than patients with early stage disease. Theheterogeneity in studies and their reporting also meant thatstratification by taxane type was not possible in a robustenough manner to allow valid comparisons. With the studiesreporting such a broad variety in incidence data further trialswith appropriate endpoint reporting are clearly required.

So where do these findings leave us? First, it is evident thatdespite the absence of a uniform definition for TAPS,

myalgias and arthralgias after taxane-based chemotherapyare common. Second, are we able to identify a priori thosepatients at greatest risk of TAPS so that some form of preven-tative strategies can be put in place? The heterogeneity of thetrials designs and populations meant that we were unable toidentify specific risk factors for TAPS in individual patients.However, some risk factors identified in the current studysuggest important differences between taxanes: TAPS wasmore commonwith paclitaxel, given in a weekly basis, shorterinfusion rate, and in metastatic disease. Unfortunately, due tothe variability of measuring and reporting of TAPS, we wereunable to quantify the impact of each of these factors.Essentially, identifying potential risk factors for the occur-rence of TAPS and useful preventative strategies, patients ata greater risk of developing TAPS could benefit from a pro-phylactic management approach to mitigate or avoid symp-toms later on. The optimal management of TAPS is also poor-ly studied, as are prophylactic strategies, and therefore thedevelopment of prevention and management strategies couldsignificantly enhance clinical practice [81].

The etiology of TAPS is poorly understood. It has beensuggested that it may result from nociceptor sensitization onthe basis of patient descriptors of pain [4]. Despite the molec-ular mechanisms involved in such sensitization being unclear,there is data to suggest that variations in as single nucleotidepolymorphisms (SNPs) and Copy Number Variations (CNVs)may partly explain tits incidence in genetically predispositionin individuals [82, 83]. Improving diagnostic assessments anddeveloping a scientific understanding of TAPS physiologywill underpin a greater understanding of the condition.Specifically, the need to standardize scales to measure symp-toms of TAPS would improve reporting among physicians.Ultimately, it might provide insight into the importance ofchemotherapy type on the incidence of TAPS and its impactclinical management. Finally, there is a need for prospectivestudies targeting high risk populations and identifying poten-tial mechanisms and treatments. We are currently trying toperform such a study in breast and prostate cancer patients[84].

Conclusion

While TAPS is relatively poorly researched, it is a clinicallysignificant adverse event as it can interfere with activities ofdaily living, decrease quality of life, and in some cases, lead todose reductions, delays, and discontinuation of treatment.This systematic review may help to quantify the incidence ofTAPS among breast cancer patients undergoing taxane-basedtreatment, however, until standardized and validated tools areavailable for its diagnosis it is going to be challenging todevelop optimal strategies for its prevention and treatment.

Support Care Cancer

Compliance with ethical standards

Conflict of interest Brian Hutton has previously received consultantfees from Amgen Canada and Cornerstone Research Group for method-ological advice related to systematic reviews and meta-analyses. All otherauthors have no conflicts to declare.

Appendix 1 Systematic review supplement:electronic literature search strategyDatabase: Embase Classic + Embase 1947 to September 29 2014, Ovid

MEDLINE(R) In-Process & Other Non-Indexed Citations and OvidMEDLINE(R) 1946 to September 29, 2014.

Searches Results

1. docetaxel

2. paclitaxel

3. *taxoid

4. docetaxel or paclitaxel or taxane

5. taxotere or docecad

6. or/1–5

7. or/1–5

8. breast adj cancer or neoplasms or carcinoma

9. exp. prostate cancer

10. prostate adj cancer or neoplasm$ or carcinoma

11. or/7–10

12. 6 and 11

13. exp. *pain

14. pain

15. exp. *myalgia

16. myalgia

17. exp. *arthralgia/

18. arthralgia

19. or/13–18

20. 12 and 19

21. risk or mortality or cohort

22. *cohort analysis

23. prevalence

24. incidence

25. incidence or prevalence or frequency or proportion or rate or numberor percent

26. or/21–25

27. 20 and 26

28. limit 27 to english language

29. 28 use emczd

30. exp. Taxoids

31. docetaxel or paclitaxel or taxane

32. taxotere or docecad

33. or/30–32

34. exp. Breast Neoplasms/

35. breast adj cancer or neoplasm$ or carcinoma

36. exp. Prostatic Neoplasms/

37. prostate adj cancer or neoplasm or carcinoma

38. or/34–37

39. 33 and 38

40. exp. Pain/

41. pain

42. Myalgia/or Myalgia

43. exp. Arthralgia/or Arthralgia

44. or/40–43

45. 39 and 44

46. prevalence/or incidence/

47. incidence or prevalence or frequenc or proportion or rate or number orpercent

48. risk or mortality.mp. or cohort

49. exp. Cohort Studies/

50. or/46–49

51. 45 and 50

52. limit 51 to english language

53. 52 use prmz MEDLINE

54. 29 or 53

55. remove duplicates from 54

ID Search Hits

1 MeSH descriptor: [Taxoids] explode all trees

2 docetaxel:ti,ab,kw or taxotere:ti,ab,kw or docecad:ti,ab,kw(Wordvariations have been searched)

3 paclitaxel:ti,ab,kw or taxane*:ti,ab,kw (Word variations havebeensearched)

4 #1 or #2 or #3

5 MeSH descriptor: [Breast Neoplasms] explode all trees

6 MeSH descriptor: [Prostatic Neoplasms] explode all trees

7 breast near/2 cancer:ti,ab,kw or breast near/2 neoplasm*:ti,ab,kw orbreast near/2 carcinoma*:ti,ab,kw (Word variations have beensearched)

8 prostat* near/2 cancer:ti,ab,kw or prostat* near/2 neoplasm*:ti,ab,kwor prostat* near/2 carcinoma*:ti,ab,kw (Word variations havebeen searched)

9 #5 or #6 or #7 or #8

10 #4 and #9

11 MeSH descriptor: [Pain] explode all trees

12 pain:ti,ab,kw or Arthralgia*:ti,ab,kw or myalgia*:ti,ab,kw (Wordvariations have been searched)

13 MeSH descriptor: [Myalgia] explode all trees

14 MeSH descriptor: [Arthralgia] explode all trees

15 #11 or #12 or #13 or #14

16 #10 and #15

17 prevalence:ti,ab,kw or incidence:ti,ab,kw or frequenc*:ti,ab,kw or“proportion”:ti,ab,kw or rate*:ti,ab,kw (Word variations havebeen searched)

18 number:ti,ab,kw or “percentage”:ti,ab,kw (Word variations havebeen searched)

19 risk:ti,ab,kw or “mortality” or cohort:ti,ab,kw (Word variations havebeen searched)

20 #17 or #18 or #19

21 #16 and #20

Support Care Cancer

Database: Embase Classic + Embase 1947 to September 29 2014,Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations andOvid MEDLINE(R) 1946 to September 29, 2014

Searches Results

1. exp. Taxoids/

2. (docetaxel or paclitaxel or taxane$ or cabazitaxel).mp.

3. (taxotere or docecad).tw.

4. or/1–3

5. exp. Breast Neoplasms/

6. (breast adj2 (cancer or neoplasm$ or carcinoma$)).tw.

7. exp. Prostatic Neoplasms/

8. (prostat$ adj2 (cancer or neoplasm$ or carcinoma$)).tw.

9. or/5–8

10. 4 and 9

11. exp. Pain/

12. pain.tw.

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$ ornumber$ 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.

7 or/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/

19 arthralgia$.tw.

20 or/14–19

21 13 and 20

22. (risk or mortalit$ or cohort).tw.

23. *cohort analysis/

24. prevalence/

25. incidence/

26. (incidence or prevalence or frequenc$ or proportion$ or rate$ ornumber$ or percent$).tw.

27. or/22–26

28. 21 and 27

29. limit 28 to english language

30. 2015$.em.

31. 20,141$.dd.

32. (“201,443” or “201,444” or “201,445” or “201,446” or “201,447” or“201,448” or “201,449” or 20,145$).em.

33. or/30–32

34. 29 not 33

Support Care Cancer

Appendix 2 PRESS EBC Search Submission

Searcher’s Name: Risa E-mail: rshorr@toh.on.ca

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

EBSCO

OVID PubMED

Other _________________

__

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

Ageline

AMED

C2-SPCTRE

CINAHL

Cochrane Database of Systematic

Reviews (CDSR; Cochrane

Reviews)

Cochrane Central Register of

Controlled Trials (CENTRAL;

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)

LILACS (Latin American and

Caribbean Health Sciences

Literature)

MEDLINE

PreMEDLINE

PsycINFO

Other

Biosis Previews

Other

Support Care Cancer

Peer Review Assessment

[For peer reviewers only]

Peer reviewer’s name: Sascha Davis

E-mail: adavis@toh.on.ca

Date completed:

Please select the one most appropriate answer for each elementAdequate Adequate with

revisions*Needs revision*

1. Translation of the research

question

x

2. Boolean and proximity operators x

3. Subject headings x

4. Natural language / free-text x

5. Spelling, syntax and line

numbers

x

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 onpage #

TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both. 1ABSTRACTStructured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility

criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusionsand implications of key findings; systematic review registration number.

2

INTRODUCTIONRationale 3 Describe the rationale for the review in the context of what is already known. 3–4Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions,

comparisons, outcomes, and study design (PICOS).3

METHODSProtocol and

registration5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide

registration information including registration number.N/A

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,language, publication status) used as criteria for eligibility, giving rationale.

4

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identifyadditional studies) in the search and date last searched.

4–5

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could berepeated.

29–32

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,included in the meta-analysis).

5

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processesfor obtaining and confirming data from investigators.

5–6

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions andsimplifications made.

5–6

Risk of bias inindividual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this wasdone at the study or outcome level), and how this information is to be used in any data synthesis.

5

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). N/ASynthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency

(e.g., I2) for each meta-analysis.N/A

Risk of bias acrossstudies

15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selectivereporting within studies).

5

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicatingwhich were pre-specified.

N/A

RESULTSStudy selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at

each stage, ideally with a flow diagram.6–7

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) andprovide the citations.

6–7

Risk of bias withinstudies

19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 7,38

Results of individualstudies

20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each inter-vention group (b) effect estimates and confidence intervals, ideally with a forest plot.

8–10, 24–28

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. N/ARisk of bias across

studies22 Present results of any assessment of risk of bias across studies (see Item 15). 7,38

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). N/ADISCUSSIONSummary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to

key groups (e.g., healthcare providers, users, and policy makers).10–13

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval ofidentified research, reporting bias).

10–13

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 10–13FUNDINGFunding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the

systematic review.N/A

Support Care Cancer

Appendix 4 Risk of bias assessment of includedrandomized trials

Trials at low risk of bias (green), high risk of bias (red), or unclear riskof bias (yellow).

Green (−) = low risk bias.Red (+) = high risk bias.Yellow (?) = unclear risk of bias.

Author

[ref]

Random

sequence

generation

Allocation

concealment

Blinding

(participants

and personnel)

Blinding

(outcome

assessment)

Incomplete

outcome

data

Selective

reporting

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]

- ? ? - - -

Support Care Cancer

References

1. Dumontet C, Jordan M (2010) Microtubule-binding agents: a dy-namic field of cancer therapeutics. Nat Rev Drug Discov 9(10):790–803

2. Bahl A, Oudard S, Tombal B, Özgürog M, Lu HS, et al. (2013)Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate can-cer treated in the TROPIC trial. Ann Oncol 24:2402–2408

3. Trudeau M, Sinclair SE, Clemons M, et al. (2005) Neoadjuvanttaxanes in the treatment of non-metastatic breast cancer: a system-atic review. Cancer Treat Rev 31(4):283–302

4. Loprinzi CL, Reeves BN, Dakhil SR, Sloan JA, Wolf SL, BurgerKN, et al. (2011) Natural history of paclitaxel-associated acute painsyndrome: prospective cohort study NCCTG N08C1. J Clin Oncol29:1472–1478

5. Saibil S (2010) Incidence of taxane-induced pain and distress inpatients receiving chemotherapy for early-stage breast cancer: aretrospective, outcomes-based survey. Curr Oncol 17(4):42–47

6. Beusterien K, Grinspan J, Kuchuk I, Mazzarello S, Dent S, GertlerS, et al. (2014) Use of conjoint analysis to assess breast cancerpatient preferences for chemotherapy side effects. Oncologist19(2):127–134

7. Kuchuk I, Bouganim N, Beusterien K, et al. (2013) Preferenceweights for chemotherapy side effects from the perspective ofwomen with breast cancer. Breast Cancer Res Treat 142(1):101–107

8. Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, ManikhasGM, Clawson A, et al. (2009) Significantly longer progression-freesurvival with nab-paclitaxel compared with docetaxel as first-linetherapy for metastatic breast cancer. J Clin Oncol 27:3611–3619

9. Jones SE, Savin MA, Holmes FA, ‘shaughnessy JAO, Blum JL,Vukelja S, et al. (2006) Phase III trial comparing doxorubicin pluscyclophosphamide with docetaxel plus cyclophosphamide as adju-vant therapy for operable breast cancer. J Clin Oncol 24:5381–5387

10. Roché H, Fumoleau P, Spielmann M, Canon J-L, Delozier T, SerinD, et al. (2006) Sequential adjuvant epirubicin-based and docetaxelchemotherapy for node-positive breast cancer patients: theFNCLCC PACS 01 trial. J Clin Oncol 24:5664–5671

11. Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla J-P,Weaver C, et al. (2005) Adjuvant docetaxel for node-positive breastcancer. N Engl J Med 352(22):2302–2313

12. Smith RE, Anderson SJ, Brown A, Scholnik AP, Desai AM,Kardinal CG, et al. (2002) Phase II trial of doxorubicin/docetaxel/cyclophosphamide for locally advanced and metastatic breast can-cer: results from NSABP trial BP-58. Clin Breast Cancer 3(5):333–340

13. Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, SedlacekSM, Fisher B, et al. (2005) Paclitaxel after doxorubicin plus cyclo-phosphamide as adjuvant chemotherapy for node-positive breastcancer: results from NSABP B-28. J Clin Oncol 23:3686–3696

14. Borghaei H (2015) Nivolumab versus docetaxel in advancedNonsquamous non-small cell lung cancer. N Engl J Med 373(17):1627–1639

15. Mok TS, Wu Y-L, Thongprasert S, Yang C-H, Chu D-T, Saijo N,et al. (2009) Gefitinib or carboplatin–paclitaxel in pulmonary ade-nocarcinoma. N engl j med. Chinese AcadMed Sci Shanghai— allChina Maharaj Nakorn Chiang N Engl J Med 361(10):947–957

16. Tannock IF, De Wit R, Berry WR, Horti J, Pluzanska A, Chi KN,et al. (2004) Docetaxel plus prednisone or Mitoxantrone plus pred-nisone for advanced prostate cancer. N Engl J Med 351(15):1502–1512

17. Pignata S, Scambia G, Katsaros D, Gallo C, Pujade-Lauraine E, DePlacido S, et al. (2014) Carboplatin plus paclitaxel once a weekversus every 3 weeks in patients with advanced ovarian cancer

(MITO-7): a randomised, multicentre, open-label, phase 3 trial.Lancet Oncol 15(4):396–405

18. Jacobs C, Hutton B, Mazzarello S, Smith S, Joy A, Amir E, et al.(2015) Optimisation of steroid prophylaxis schedules in breast can-cer patients receiving docetaxel chemotherapy—a survey of healthcare providers and patients. Support Care Cancer 23(11):3269–3275

19. Chow E, Nguyen J, Zhang L, Tseng L-M, Hou M-F, Fairchild A,et al. (2012) International field testing of the reliability and validityof the EORTC QLQ-BM22 module to assess health-related qualityof life in patients with bone metastases. Cancer 118(5):1457–1465

20. Cella D, Peterman A, Hudgens S, Webster K, Socinski MA (2003)Measuring the side effects of taxane therapy in oncology the func-tional assessment of cancer therapy–taxane (FACT-taxane). Cancer98(4):822–831

21. Reeves BN, Dakhil SR, Sloan JA, Wolf SL, Burger KN, Kamal A,et al. (2012) Further data supporting that the paclitaxel-associatedacute pain syndrome is associated with the development of periph-eral neuropathy: NCCTG trial N08C1 1. Hematol Oncol Dayt18(20):5171–5178

22. Loprinzi CL, Maddocks-Christianson K, Wolf SL, Rao RD, DyckPJB,Mantyh P, Dyck P (2007) The paclitaxel acute pain syndrome:sensitization of nociceptors as the putative mechanism. Cancer J13(6):399–403

23. New PZ, Jackson CE, Rinaldi D, et al. (1996) Peripheral neuropa-thy secondary to docetaxel. Neurology 46:108–111

24. Hilkens PH, Verweij J, Stoter G, et al. (1996) Peripheral neurotox-icity induced by docetaxel. Neurology 46:104–108

25. Nguyen V, Lawrence H (2004) Use of gabapentin in the preventionof taxane-induced arthralgias and myalgias. J Clin Oncol 22(9):1767–1769

26. Jacobson SD, Loprinzi CL, Sloan JA, Wilke JL, Novotny PJ,Okuno SH, Jatoi AMT (2003) Glutamine does not preventpaclitaxel-associated myalgias and arthralgiasas. J Support Oncol1(4):274–278

27. Gelmon K, Eisenhauer E, Bryce C, Tolcher A, Mayer L, TomlinsonE, et al. (1999) Randomized phase II study of high-dose paclitaxelwith or without amifostine in patients with metastatic breast cancer.J Clin Oncol 17(10):3038–3047

28. Leal AD, Qin R, Atherton PJ, Haluska P, Behrens RJ, Tiber C, et al.(2014) NCCTG N08CA (alliance): the use of glutathione for pre-vention of paclitaxel/carboplatin induced peripheral neuropathy: aphase III randomized, double-blind placebo-controlled study andfor the alliance for clinical trials in oncology. Cancer 120(12):1890–1897

29. Sampson M, McGowan J, Cogo E, Grimshaw J, Moher DLC(2009) An evidence-based practice guideline for the peer reviewof electronic search. J Clin Epidemiol 62(9):944–952

30. Moher D, Liberati A, Tetzlaff J, et al. (2009) Preferred reportingitems for systematic reviews andmeta-analyses: the PRISMA state-ment. Ann Intern Med 151(4):264–269

31. Higgins Senior Statistician JPT, Altman Director DG, GøtzscheDirector PC, Jüni P. (2011) The Cochrane Collaboration’s tool forassessing risk of bias in randomised trials. BMJ 343(d5928).

32. Fountzilas G, Dafni U, Papadimitriou C, Timotheadou E, Gogas H,Eleftheraki AG, et al. (2014) Dose-dense sequential adjuvant che-motherapy followed, as indicated, by trastuzumab for one year inpatients with early breast cancer: first report at 5-year medianfollow-up of a Hellenic cooperative oncology group randomizedphase III trial. BMC Cancer 14:515

33. Joensuu H, Kellokumpu-Lehtinen P, Huovinen R, Kokko R, AsolaR. (2009) Significant improvement in recurrence-free survival(RFS) when capecitabine (X) is integrated into docetaxel(T)– > 5FU + epirubicin + cyclophosphamide (CEF) adjuvant ther-apy for high-risk early breast cancer (BC): Interim analysis of theFinXX-trial. Cancer Res 69:2 Suppl S).

Support Care Cancer

34. Kim WY, Woo U, Seo JH, Son GS, Lee JB, Bae JW (2011)Toxicities, dose reduction and delay of docetaxel and paclitaxelchemotherapy in breast cancer without distant metastases. JCancer Res Ther 7(4):412–415

35. Wist EA, Mjaaland I, Løkkevik E, Sommer HH (2012) Clinicalstudy weekly paclitaxel plus capecitabine versus docetaxel every3 weeks plus capecitabine in metastatic breast cancer. J OncolHindawi Publishing Corporation. doi:10.1155/2012/862921

36. Lin Y-C, Chang H-K, Chen J-S, Wang H-M, Yang T-S, Liaw C-C(2007) A phase II randomized study of two taxanes and cisplatin formetastatic breast cancer after anthracycline: a final analysis. Jpn JClin Oncol 37(1):23–29

37. Baselga J, Manikhas A, Cortés J, Llombart A, Roman L,Semiglazov VF, et al. (2014) Phase III trial of nonpegylated lipo-somal doxorubicin in combination with trastuzumab and paclitaxelin HER2-positive metastatic breast cancer. Ann Oncol 25(3):592–598

38. Pasekta M, Giotis A (2011) Characterization of taxane-inducedarthralgias and myalgias in breast cancer patients at two ambulatorycancer centres: a prospective observational study. Support CareCancer 19(Suppl.1):S312

39. Howell SJ, Armstrong ACAL (2012) Retrospective analysis of therelative efficacy and toxicity of nab-paclitaxel and docetaxel inmetastatic breast cancer. Eur J Cancer 48:S115–S116

40. Brammer M, Lalla D, Guerin A, Yu A,Wu E (2011) Complicationsassociated with chemotherapy in patients with metastatic breastcancer. Eur J Cancer 47:S330

41. Coudert BP, Pierga J-Y, Mouret-Reynier M-A, Kerrou K, Ferrero J-M, Petit T et al. (2014) An open-label, randomized, multicenterstudy investigating the addition of bevacizumab to neoadjuvanttrastuzumab plus docetaxel in patients with early stage HER2-positive breast cancer stratified according to PET change after onetherapy cycle. J Clini Oncol 32(15(Suppl. 1)).

42. Moon YW, Lee S, Park B-W, Kim E-K, Kim SI, Koo JS, et al.(2013) S-1 combined with docetaxel following doxorubicin pluscyclophosphamide as neoadjuvant therapy in breast cancer: phaseII trial. BMC Cancer 13:583

43. Malgorzata KT, Soeren C, Ulla BT, Soendergaard S, Nielsen D(2012) Phase II study of neoadjuvant pegylated liposomal doxoru-bicin and cyclophosphamide+/−trastuzumab followed by docetaxelin locally advanced breast cancer. Eur J Cancer 48:S173

44. Bulent AM, Algin E, Inal A, et al. (2013) Sequential adjuvantdocetaxel and anthracycline chemotherapy for node positive breastcancers: a retrospective study. J BUON 18(2):314–320

45. Hatam N, Ahmadloo N, Ahmad KDA, Daliri A, et al. (2011)Quality of life and toxicity in breast cancer patients using adjuvantTAC (docetaxel, doxorubicin, cyclophosphamide), in comparisonwith FAC (doxorubicin, cyclophosphamide, 5-fluorouracil). ArchGynecol Obstet 284(1):215–220

46. Eckhoff L, Nielsen M, Moeller S, Knoop A (2011) TAXTOX – aretrospective study regarding the side effects of docetaxel given aspart of the adjuvant treatment to patients with primary breast cancerin Denmark from 2007 to 2009. Acta Oncol 50(7):1075–1082

47. Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martin M, ChanA, et al. (2011) Phase III Study of Doxorubicin/CyclophosphamideWith Concomitant Versus Sequential Docetaxel As AdjuvantTreatment in Patients With Human Epidermal Growth FactorReceptor 2–Normal, Node-Positive Breast Cancer: BCIRG-005Trial. J Clin Oncol 10;29(29):3877–84.

48. Miura D, Fujii M, Iwatani T, Takano T, Kawabata H. (2011)Reduction of toxicity by reversing the order of infusion in docetaxeland cyclophosphamide (TC). J Clin Oncol 29(15):Suppl 3.

49. Schönherr A, Aivazova-Fuchs V, Annecke K, et al. (2012) Toxicityanalysis in the ADEBAR trial: sequential anthracycline-taxane ther-apy compared with FEC120 for the adjuvant treatment of high-riskbreast cancer. Breast Care 7:289–295

50. Boekel N, Schaapveld M, Aleman BMP, et al. (2010)Musculoskeletal pain in the FEC-D regimen is common and fre-quently severe—experiences in an outer metropolitan oncologyunit. Eur J Cancer Suppl 8:163–164

51. Kantelhardt EJ, Vetter M, Schmidt M, Veyret C, Augustin D, HanfV, et al. (2011) Prospective evaluation of prognostic factors uPA/PAI-1 in node-negative breast cancer: phase III NNBC3-Europetrial (AGO, GBG, EORTC-PBG) comparing 6 × FEC versus3 × FEC/3 × docetaxel. BMC Cancer 11:140

52. Yau TK, Sayeed A, Shen ZZ, Kim SB, Ali SM, Villalon AH, et al.(2010) Patterns of care and safety profiles of adjuvant docetaxel-based chemotherapy regimens in a large breast cancer registry studyin Asia Pacific. Eur J Cancer Suppl 8(3):216

53. Rodriguez-Abreu D,Murias A, García M et al. (2009) Neoadjuvantbiweekly dose-dense chemotherapy with fluouracil, epirubicin, andcyclophosphamide (FEC 90), followed by docetaxel in patientswith HER2-neu negative primary breast cancer. J Clin Oncol27(15s):suppl;abstr 596.

54. Lee KS, Ro J, Nam BH, et al. (2008) A randomized phase-III trialof docetaxel/capecitabine versus doxorubicin/cyclophosphamide asprimary chemotherapy for patients with stage II/III breast cancer.Breast Cnacer Res Treat 109(3):481–489

55. Vriens B, Smilde T, Van de Vjiver K. (2011) Sequential versusupfront intensified neoadjuvant chemotherapy in patients with largeresectable or locally advanced breast cancer (INTENS), toxicityresults from a phase III study of the dutch breast cancer triallistsgroup (BOOG). Cancer Res 71(24):Suppl. 1.

56. Coombes RC, Bliss JM, Espie M, Erdkamp F, Wals J, Tres A, et al.(2011) Randomized, phase III trial of sequential epirubicin anddocetaxel versus epirubicin alone in postmenopausal patients withnode-positive breast cancer. J Clin Oncol 29(24):3247–3254

57. Jacot W, Bibeau F, Gourgou-Bourgade S, Gutowski M, ColomboP-E, Bleuse J-P, et al. (2010) Phase II trial of dose dense docetaxelfollowed by FEC100 as neoadjuvant chemotherapy in patients withoperable breast cancer. Am J Clin Oncol 33:544–549

58. Morimoto M, Nakagawa M, Takechi H, Tadokoro YT (2014) Aphase II study with S-1 + docetaxel (N-1 study) for advanced breastcancer. Eur J Cancer 50(S51)

59. Swain S, Baselga J,Miles D, Knott A, Clark E, Ross G, et al. (2014)Safety profile of Pertuzumab with trastuzumab and docetaxel inpatients from Asia with human epidermal growth factor receptor2- positive metastatic breast cancer: results form the phase III trialCLEOPATRA. Oncologist 19:693–701

60. Earl H, Vallier A, Hiller L, Fenwick N, Young J, IddawelaM (2014)Effects of the addition of gemcitabine, and paclitaxel-first sequenc-ing, in neoadjuvant sequential epirubicin, cyclophosphamide, andpaclitaxel for women with high-risk early breast cancer (neo-tAnGo): an open-label, 2 × 2 factorial randomised phase 3 trial.Lancet Oncol 15:201–212

61. Gonzalez-Angulo A, Akcakanat A, Liu S, Green M, Murray J,Chen H (2014) Open-label randomized clinical trial of standardneoadjuvant chemotherapy with paclitaxel followed by FEC versusthe combination of paclitaxel and everolimus followed by FEC inwomen with triple receptor-negative breast cancer. Ann Oncol 25:1122–1127

62. Saura C, Pusztain L (2013) Neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or paclitaxel en earlystage breast cancer and evaluation of BIII-tubulin expression as apredictive marker. Oncologist 18:787–794

63. Cognetti F, Bruzzi P, De PS, De LM, Boni C, Aitini E et al. (2013)Epirubicin and cyclophosphamide followed by paclitaxel (T) versusfluorouracil, epirubicin and cyclophosphamide followed by T innode-positive early breast cancer patients. Final results of thegruppo Italiano mammella 2 randomized phase III study. CancerRes 73(24):suppl 1.

Support Care Cancer

64. Richardet E, Richardet M, Brombin R, Cortes MN,MolinaM, RisoAA et al. (2014) Concurrent chemoradiotherapy (CRT) with pacli-taxel in breast cancer stage II-III. J Clin Oncol 32(15):Suppl 1.

65. Eduardo arnoldo Richardet, Perelli Laura, Martin EduardoRichardet, Nicolas Castagneris, Matias Nicolas Cortes MM.(2012) Concomitant chemoradiotherapy in women with stage II-III breast cancer. J Clin Oncol 30:suppl;abstr e11501.

66. De La Haba-Rodríguez J, Rodríguez-Lescure A, Ruiz A, et al.(2011) Regional and seasonal influence in patient’s toxicity to ad-juvant chemotherapy for early breast cancer. Breast Cancer ResTreat 125(1):273–278

67. Palappallil DS, Nair BL, Jayakumar KL, et al. (2011) Comparatives tudy of the toxic i ty of 5- f luorourac i l -adr iamycin-cyclophosphamide versus adriamycin-cyclophosphamide followedby paclitaxel in carcinoma breast. Indian J Cancer 48(1):68–73

68. Esteva FJ, Franco SX, Hagan MK, et al. (2013) An open-labelsafety study of lapatinib plus trastuzumab plus paclitaxel in first-line HER2-positive metastatic breast cancer. Oncologist 18(6):661–666

69. Moinpour C, Donaldson G, Liepa A, Albain K (2012) Evaluatinghealth-related quality of life therapeutic effectiveness in a clinicaltrial with extensive nonignorable missing data and heterogeneousresponse: results from a phase III randomized trial of gemcitabineplus paclitaxel versus paclitaxel monothe. Qual Life Res 21:765–775

70. Lück H-J, Andreas Du Bois B, Sibylle Loibl B, Iris Schrader B,Jens Huober B, Volker Heilmann B, et al. (2013) Capecitabine pluspaclitaxel versus epirubicin plus paclitaxel as first-line treatment formetastatic breast cancer: efficacy and safety results of a random-ized, phase III trial by the AGO breast cancer study group. BreastCancer Res Treat 139:779–787

71. Moulder SL, Holmes FA, Tolcher AW, Thall P, Broglio K, Valero V,et al. (2010) A randomized phase II trial comparing 3-h versus 96-hinfusion schedules of paclitaxel for the treatment of metastaticbreast cancer. Cancer 116 (4):814–821.

72. Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R,Kelly Marcom P, et al. (2007) Trastuzumab plus Vinorelbine ortaxane chemotherapy for HER2-overexpressing metastatic breastcancer: the trastuzumab and Vinorelbine or taxane study. Cancer110(5):965–972

73. Talbot D, Moiseyenko V, Van BS, O ‘reilly S, Conejo EA, AcklandS, et al. (2002) Randomised, phase II trial comparing oral capecit-abine (Xeloda 1) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines. Br JCancer 86(9):1367–1372

74. Jassem J, Pienkowski T (2001) Doxorubicin and paclitaxel versusfluorouracil, doxorubicin, and cyclophosphamide as first-line

therapy for women with metastatic breast cancer: final results of arandomized phase III multicenter trial. J Clin Oncol 19:1707–1715

75. Saracchini S, Foltran L, Bassini A, Sulfaro S, LorenzonM,MicheliE et al. (2014) Neoadjuvant chemotherapy with nonpegylatedliposome-encapsulated doxorubicin (NPLD) plus cyclophospha-mide followed by trastuzumab plus nabpaclitaxel for HER2-positive breast cancer (BC). J Clin Oncol 32(15):suppl 1

76. Tsugawa K, Kawamoto H, Kojima Y, Tsuchiya K, Shimo A,Hayami R et al. (2014) Feasibility study of weekly nanoparticlealbumin-bound (nab)-paclitaxel (150 mg/m2) followed by 5FU,epirubicin, plus cyclophosphamide (FEC) as neoadjuvant chemo-therapy for HER2-negative breast cancer. Eur J Cancer 50(S51).

77. Seki H, Asanuma F, YamadaY, Hirata Y, KanedaM, Suzuki K et al.(2014) Safety of weekly administration of nanoparticle albumin-bound paclitaxel in patients with breast cancer. Eur J Cancer50(e.41).

78. Schwartzberg LS, Arena FP, Mintzer DM, Epperson AL, WalkerMS (2012) Phase II multicenter trial of albumin-bound paclitaxeland capecitabine in first-line treatment of patients with metastaticbreast cancer. Clinical Breast Cancer 12(2):87–93

79. Seidman AD, Conlin AK, Bach A, Moynahan ME, Lake D, ForeroA, et al. (2013) Randomized Phase II Trial of Weekly vs. Every 2Weeks vs. Every 3 Weeks Nanoparticle Albumin-Bound PaclitaxelWith Bevacizumab as First-Line Chemotherapy for MetastaticBreast Cancer. Clinical Breast Cancer 13(4):239–46.e1.

80. Pasekta M, De Angelis C, Van Draanen J, Stacey E, Dent R (2011)Characterization of taxane-induced arthralgias and myalgias inbreast cancer patients at two ambulatory cancer centres: aProspecrtive observational study. Support Care Cancer 19(supp2):s67–370

81. Fernandes R, Mazzarello S, Majeed H, Smith S, Shorr R,Hutton B, et al. (2016) Treatment of taxane acute pain syn-drome (TAPS) in cancer patients receiving taxane-based chemo-therapy—a systematic review. Support Care Cancer 24(4):1583–1594

82. Damaraju S, Ghosh S, Tuszynski J, Greiner R, et al. (2010)CYP3A5*3 (rs776746) is associated with docetaxel-specific toxic-ities during adjuvant breast cancer chemotherapy. Eur J Cancer8(suppl 7):175

83. Damaraju S, Sehrawat BS, Ghosh S, Pituskin E, et al. (2010)Germline Copy Number Polymorphisms Associated with Toxicityfrom Adjuvant Docetaxel. Cancer Res 70(suppl(24)):258s

84. clinicaltrials.gov A Multi-Centre Study to Investigate the NaturalHistory of Taxane Acute Pain Syndrome (TAPS) in PatientsReceiving Taxane Chemotherapy for Breast or Prostate Cancer.NCT02362087 https://clinicaltrials.gov/ct2/show/NCT02362087

Support Care Cancer