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ORIGINAL ARTICLE
Treatment of taxane acute pain syndrome (TAPS) in cancerpatients
receiving taxane-based chemotherapy—a systematicreview
Ricardo Fernandes1 & Sasha Mazzarello2 & Habeeb Majeed3
&Stephanie Smith2 & Risa Shorr4 & Brian Hutton5 &
Mohammed FK Ibrahim1 &Carmel Jacobs1 & Michael Ong1 &
Mark Clemons1,2,6
Received: 21 May 2015 /Accepted: 3 September 2015 /Published
online: 19 September 2015# Springer-Verlag Berlin Heidelberg
2015
AbstractBackground Taxane acute pain syndrome (TAPS) is
charac-terized by myalgias and arthralgias starting 1–3 days and
last-ing 5–7 days after taxane-based chemotherapy. Despite
nega-tively impacting patient’s quality of life, little is known
aboutthe optimal TAPS management. A systematic review of treat-ment
strategies for TAPS across all tumor sites was performed.Methods
Embase, Ovid MEDLINE(R), and the CochraneCentral Register of
Controlled Trials were searched from1946 to October 2014 for trials
reporting the effectiveness ofdifferent treatments of TAPS in
cancer patients receivingtaxane-based chemotherapy. Two individuals
independentlyscreened citations and full-text articles for
eligibility.Outcome measures included type of treatment and
responseof myalgias, arthralgias, pain, and quality of life
(QoL).Results Of 1614 unique citations initially identified, five
stud-ies met the pre-specified eligibility criteria. Twowere
random-ized placebo-controlled trials (225 patients), two were
randomized open-label trials 76 patients), and one was a
ret-rospective study (10 patients). The agents investigated
includ-ed gabapentin, amifostine, glutathione, and glutamine.
Studysizes ranged from 10 to 185 patients. Given the
heterogeneityof study designs, a narrative synthesis of results was
per-formed. Neither glutathione (QoL, p = 0.30, no 95 % CI
re-ported) nor glutamine (mean improvement in average painwas 0.8
in both treatment arms, p = 0.84, no 95%CI reported)were superior
to placebo. Response to amifostine (pain re-sponse) and gabapentin
(reduction in taxane-induced arthral-gias and myalgias) was 36 %
(95 % CI, 16–61 %) and 90 %(no 95 % CI data reported),
respectively.Conclusions Despite its prevalence in patients
receivingtaxane-based chemotherapies, TAPS remains poorlyresearched
and few studies evaluate its optimal management.If the management
of patients is to be improved, more pro-spective trials are
needed.
Keywords Taxane acute pain syndrome . Docetaxel .
Paclitaxel . Gabapentin . Amifostine . Glutathione .
Glutamine
Background
Taxane-based chemotherapeutic agents, such as
docetaxel,paclitaxel, nab-paclitaxel, and cabazitaxel, are
commonlyused in the treatment of many malignancies [1]. Taxanes
havebeen associatedwith taxane acute pain syndrome (TAPS),
alsoknown as paclitaxel-associated acute pain (P-APS)
andtaxane-induced pain. TAPS is characterized by myalgia
andarthralgia, starting 1–3 days after taxane-based treatment,
andusually lasting for 5–7 days [2]. While TAPS shares someclinical
characteristics with chemotherapy-induced peripheral
* Mark [email protected]
1 Division ofMedical Oncology, Department ofMedicine, The
OttawaHospital and University of Ottawa, Ottawa, Ontario,
Canada
2 Ottawa Hospital Research Institute and University of
Ottawa,Ottawa, Ontario, Canada
3 Division of Internal Medicine, Department of Medicine, The
OttawaHospital, Ottawa, Ontario, Canada
4 The Ottawa Hospital, Ottawa, Ontario, Canada5 Department of
Epidemiology and Community Medicine, University
of Ottawa, Ottawa, Ontario, Canada6 Division of Medical
Oncology, The Ottawa Hospital Cancer Centre,
501 Smyth Road, Ottawa, Canada
Support Care Cancer (2016) 24:1583–1594DOI
10.1007/s00520-015-2941-0
http://crossmark.crossref.org/dialog/?doi=10.1007/s00520-015-2941-0&domain=pdf
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neuropathy (CIPN) (and indeed TAPS can be associated
withsubsequent CIPN) [3–13], TAPS is usually completely re-solved
prior to the next cycle of chemotherapy [2]. Whilethe incidence of
TAPS varies according to tumor type andtaxane regimen (Table 1),
its pathophysiology remains poorlyunderstood [2, 12, 13].
TAPS is clinically significant as it not only affects
physicalfunction and quality of life but can also lead to
chemotherapydose delays, reductions, and discontinuation [11]. A
numberof approaches for its prevention and treatment have been
sug-gested, including non-steroidal anti-inflammatory drugs(NSAIDs)
[17], corticosteroids [18], antihistamines [19],gabapentin [20–21],
pregabalin [22], and shakuyaku-kanzo-to [23–24]. However, most of
these agents have been evalu-ated in the context of treatment for
CIPN and not for TAPS. Inorder to establish the strength of
evidence underlying differenttreatment options for TAPS, a
systematic review was per-formed. Although breast and prostate
cancer have been mostcommonly reported in the literature to be
associated withTAPS, a systematic review was performed including
all tumorsites for which taxane-based chemotherapy are used.
Methods
Study objective and eligibility criteria
This systematic reviewwas performed to identify and
evaluatestrategies in the literature for the management of TAPS
incancer patients receiving taxane-based chemotherapy.
Thepopulation-intervention-comparator-outcome study design(PICOS)
framework was used to structure the research ques-tion for the
review and its corresponding literature search. Thepopulation of
interest included patients diagnosed with cancer.No restrictions
were placed on primary tumor sites.Interventions of interest
incorporated any taxane-based che-motherapy regimen (either as a
single agent or in
combination) in the neoadjuvant, adjuvant, or metastatic
set-tings. Outcome measures of interest included the type of
treat-ment for TAPS, as well as the response of myalgias,
arthral-gias, pain, and quality of life using validated
scales.Randomized, retrospective, or prospective studies
publishedin English were included. Studies were excluded if they
en-rolled patients with prior neurologic comorbidities.
Literature search
An information specialist (RS) designed and executed an
elec-tronic literature search to identify relevant citations
fromEmbase Classic and Embase from 1947 to October 2014,Ovid
MEDLINE(R) In-Process & other non-indexed cita-tions, and Ovid
MEDLINE(R) from 1946 to September2014. Search terms and their
medical subject heading(MeSH) equivalents are shown in Appendix 1
where theMEDLINE search strategy is provided.
Study screening and selection
Stage 1 screening consisted of titles and abstracts
identifiedfrom the literature search by two independent reviewers
(SM,RF, HM). Disagreements were discussed and resolved be-tween
reviewers. Stage 2 screening consisted of a full-textreview of all
potentially relevant citations identified duringStage 1 screening
by two independent reviewers (SM, RF,SS, MC, CJ, and MI). Results
from the screening processare presented in a PRISMA flow diagram
(Fig. 1).
Data collection
A pre-designed data collection form implemented inMicrosoft
Excel was utilized for data extraction. All datawas extracted
independently by two reviewers and subse-quently compared for
discrepancies which were resolved bydiscussion. We collected
information related to publication
Table 1 Reported incidence oftaxane acute pain syndrome frompast
literature
Taxane Chemotherapy regimen Study population Incidence of TAPS
(%)
Paclitaxel [8] AC-T Adjuvant breast cancer 12
Docetaxel [3–6] TC Adjuvant breast cancer 10–22
FEC-D 33
TAC 10–28
Docetaxel [7] Single agent Metastatic breast cancer 26
Nab-paclitaxel [9] Single agent Metastatic breast cancer
7–26
Docetaxel [10] Single agent Metastatic prostate cancer 1–10
Docetaxel [14] Single agent Metastatic lung cancer 1.5–16.1
Docetaxel [15] Carboplatin plus docetaxel Metastatic ovarian
cancer 31
Paclitaxel [16] CT or PT Adjuvant ovarian cancer 9.6–36.7
TC docetaxel/cyclophosphamide; FEC-D docetaxel after prior
5-fluorouracil-epirubicin-cyclophosphamide; AC-T docetaxel after
prior doxorubicin-cyclophosphamide; CT carboplatin/paclitaxel; PT
cisplatin/paclitaxel
1584 Support Care Cancer (2016) 24:1583–1594
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characteristics (year, journal, and authors), patient
characteris-tics (performance status, median age, disease stage,
and sitesof disease), intervention characteristics (chemotherapy
line,taxane type and frequency, and TAPS treatment), and out-comes
of interest (response of pain, myalgias, and arthralgias).Studies
were also independently assessed for risk of bias bytwo reviewers
using the Cochrane Collaboration’s risk of biastool for randomized
trials [25] which assesses for sources ofselection, performance,
detection, attrition, reporting, and oth-er sources of bias.
Discrepancies in data collection were re-solved by discussion among
the reviewers. Funding for thecurrent study was from internal
hospital sources; there was nopharmaceutical company funding.
Data analysis
If deemed appropriate, following exploration of study andpatient
characteristics to ensure sufficient clinical and meth-odological
homogeneity across studies, we planned to pursuemeta-analyses using
random effects models to combine datafor outcomes of interest
across relevant studies, as describedin Cochrane book [25].
Statistical heterogeneity would beassessed using both the Cochrane
Q statistic and the I2 statis-tic. Following review of included
studies’ characteristics, spe-cifically regarding patient
population, it was judged by the
authors that there were significant clinical differences that
pre-cluded the data from meta-analysis. In the light of these
dif-ferences, a narrative strategy to summary of
study-specificresults was performed.
Findings
Quantity of evidence identified
From 1614 unique citations identified by the literature
search,39 potentially relevant studies were identified during the
firststage screening of titles and abstracts. These 39 studies
weresubsequently reviewed in full text for the second stage
ofscreening, and 5 met the eligibility criteria (Table 2).
Studieswere excluded because they evaluated
chemotherapy-inducedperipheral neuropathy (n = 5), no TAPS
treatment was men-tioned (n = 32), cancer-related pain (n = 1),
evaluated arthrop-athy post-chemotherapy rather than TAPS (n = 1),
or duplicatepublication (n = 1). Of the 5 included studies, 4 were
availableas peer-reviewed manuscripts [26–29] and one was
availableas a conference meeting abstract [30]. The manuscripts
werepublished in 1999 [28], 2001 [29], 2003 [26], 2004 [30],
and2014 [27], respectively.
CIPN - chemotherapy induced peripheral neuropathy
Records identified and screened through database and
abstract
searching after removal of duplicates
(n=1608)
Records excluded due to irrelevancy(n= 1571)
Studies included in qualitative synthesis
(n=5)
Full-text ar�cles or abstracts assessed for eligibility
(n=5)
Screening
Included
Eligibility
Record screened in full text
(n=39)
Identification
Excluded (n=33):CIPN (n= 5)No TAPS treatment mention
(n=26)Late arthropathy treatment
(n= 1)Cancer related pain (n=1)Duplicate publication (n= 1)
Fig. 1 Systematic reviewsupplement: PRISMA flowdiagram review
supplement:PRISMA flow diagram. CIPNchemotherapy-induced
peripheralneuropathy
Support Care Cancer (2016) 24:1583–1594 1585
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Study characteristics
Four studies were randomized prospective studies [26–29],and one
was a retrospective analysis [30]. The sample sizesranged from 10
[30] to 185 patients [27]. Three trials includedpatients with
breast cancer [26, 28, 30] and two included pa-tients with
different types of malignancies including breast,lung, and ovarian
cancers [27] as well as germ cell tumors[29]. Paclitaxel was
evaluated in four studies [25–28] anddocetaxel in one [30]. Four of
the five studies excludedpatients with pre-existing neuropathies or
prior treatmentwith neurotoxic chemotherapy [27–30].
Characteristicsof the individual studies which included study
design,cancer site, taxane used, type of TAPS treatment,
andresponse rates are described in Table 3. As there
wasconsiderable variability between studies in particularwith
regard to patient populations, meta-analysis wasconsidered
inappropriate and a narrative summary of eachstudy as well as a
descriptive overview of common results ispresented below.
Risk of bias assessment
A risk of bias assessment was performed on the four random-ized
trials included in the review using Cochrane assessment(Table 3)
[31]. Risk of bias was high for one of the includedtrials due to
incomplete reporting data [26]. The studies byGelmon [28], Leal
[27], and Rick [29] were also judged tohave high risk of
performance and detection bias with inade-quate blinding of
patients and personnel [28, 29] and outcomedata [27–28].
Study-specific overviews and findings
Jacobson et al. [26]
In this randomized, placebo-controlled, crossover trial,
pa-tients with breast cancer who had developed any grade ofTAPS
with prior paclitaxel treatment were randomized to re-ceive
glutamine 10 g PO TID or matching placebo for 5 dayswith the next
paclitaxel treatment. The primary endpoint of thestudy was a change
in the severity or duration of TAPS mea-sured daily using the ECOG
toxicity score. Secondary end-points included quality of life (QoL)
outcomes and toxicityprofile (NCICCTC version 3.0) using the QoL
parameters ona symptom-distress scale and linear analog
self-assessment(LASA) questionnaire.
Thirty-six patients were eligible for the study and
weresubsequently evaluated. The patient population reported
grade1–2 TAPS with prior paclitaxel treatment using
symptom-distress scale and linear analog self-assessment (LASA)
ques-tionnaire. There were no differences in worse/average
painscores, daily pain relief, or physician-reported grades
ofTa
ble2
Overviewof
included
studies:
Studyauthor
(year);
studytype
Cancersite
Fundingsource
Taxane
Treatmento
fTA
PSScores
toevaluate
TAPS
Incidenceof
TAPS
post-
treatm
ent
Pain
response
tointervention
Chemotherapy
D/C
ratedue
toTA
PS
Adverse
events
Qualityof
liferesults
Jacobson
etal.[26];
phaseIIrandom
ized
(2003)
Breast
Not
reported
Paclitaxel1
75mg/m
2Glutamine(n
=18)
vsplacebo
(n=18)
ECOGtoxicity
score
74vs
80%
Meanim
provem
ent2
.3pointsvs
1.8points(ona10-point
scale)(p
=0.79)
Not
reported
Nostatistically
significant
differences
Overall—
glutam
ine
−1.0vs
×placebo
−0.5(p
=0.45)
Lealetal.[27];p
hase
IIIrandom
ized
(2014)
Ovarian,lung,
others
PublicHealth
Services
grants
andNationalC
ancer
Institutegrants
Paclitaxel1
50to
200mg/m
2(3
weeklyandweekly)
Glutathione
(n=94)
vsplacebo
(n=91)
EORTC-Q
LQ-CIPN20
38vs
33%
Meanim
provem
ent1
pointb
oth
glutathioneandplaceboon
a10-pointscale(p
=0.30
on3-
weeklyarm
andp=0.002on
weeklyarm)
Not
reported
Nostatistically
significant
differences
FACT-O:n
odifferences
betweenthetwo
groups
Gelmon
etal.[28];
phaseIIrandom
ized
(1999)
Breast
NationalC
ancerInstituteof
CanadaGrants,EliLillyand
Bristol-M
yersSquibb,C
anada.
Paclitaxel2
50mg/m
2×
four
cycles
followed
by175mg/m
2
Placebo(n
=20)vs
amifostine
(n=20)
NCIC-CTGmodified
common
toxicity
criteria
95vs
90%
22.2
%(95%
CI,6.4to
47.6
%)
vs36.8
%(95%
CI,16.3
to61.6
%)
17.5
%Vom
iting
grade3/4;
dizzinessgrade
2;nauseagrade2
Not
performed
Ricketal.[29];
prospective
random
ized
(2001)
Germ
cell
tumor
Not
reported
Paclitaxel175
mg/m2×
fourcycles
Amifostine(n
=20)
vsno
amifostine
(n=20)
NCIC-expanded
common
toxicity
criteria
35vs
25%
Not
reported
None
Not
reported
Not
performed
Nguyenetal.[30];
retrospective(2004)
Breast
Not
reported
Docetaxelandpaclitaxel
(dosesnotm
entioned)
Gabapentin
(n=10)
NationalC
ancerInstitute
toxicityscale
90%
a6—
twogradereduction/3—
one
gradereduction/1—
noresponse
Not
reported
Dizziness[31]
Not
performed
D/C
discontin
uatio
n,LA
SAlin
earanalog
self-assessm
ent,FA
CT-O
functio
nalassessmentof
cancer
therapy-ovariancancer,RRresponse
rate,TA
PStaxane
acutepain
syndrome,NCIC-CTG
National
CancerInstitu
teof
CanadaClin
icalTrialsGroup,E
ORTC
-QLQ-CIPN20
EuropeanOrganizationforResearchandTreatmento
fCancerQualityof
Life,ECOGEastern
Cooperativ
eOncologyGroup.
aPo
st-cycle1treatm
ento
nly
1586 Support Care Cancer (2016) 24:1583–1594
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TAPS between treatment arms. The mean improvement inworst pain
from baseline to the end of the first treatment peri-od was 2.3
points with glutamine and 1.8 points with placebo,as measured on a
10-point scale (p = 0.79). Mean improve-ment in average pain was
0.8 in both treatment arms (p = 0.84,no 95 % CI data not reported).
The crossover analysis did notshow evidence of benefit in regard to
QoL and pain scores. Inconclusion, this study showed that glutamine
was no betterthan placebo at prevention or alleviation of
paclitaxel-associated myalgias/arthralgias.
Leal et al. [27]
The North Central Cancer Treatment Group/Alliance TrialN08CA was
designed to evaluate the efficacy of glutathionefor preventing CIPN
in a cohort of patients undergoingpaclitaxel/carboplatin
chemotherapy. This was a phase 3 ran-domized, double-blind,
placebo-controlled study, in which pa-tients with ovarian, lung,
and other cancer sites scheduled toreceive paclitaxel (150–200
mg/m2, weekly or every 3 weeks)and carboplatin (AUC 5–7 every 3 or
4 weeks for six courses)were enrolled. Eligible patients could not
have pre-existinghistory of peripheral neuropathy greater than 1
(NCICTCAEversion 4) nor concurrent use of any agents to prevent or
treatneuropathy. Patients were randomized to either
intravenousglutathione (1.5 g/m2) or placebo, given immediately
beforechemotherapy.
The study’s primary outcome was the occurrence of senso-ry CIPN
as measured by the sensory subscale (yes/no) of theEuropean
Organization for Research and Treatment of CancerQuality of life
(EORTC-QLQ-CIPN20) during the first sixcycles of treatment. Quality
of life was also assessed usingthe Functional Assessment of Cancer
Therapy for patientswith ovarian cancer (FACT-O) obtained at
baseline and 1weekafter each dose of chemotherapy.
Results from the 185 randomized patients showed no dif-ference
between the study arms for any of the reported toxic-ities. In the
glutathione arm, the incidence of acute pain was38% (grade 2) and
5% (grade 3), while in placebo arm, it was33 % (grade 2) and 4 %
(grade 3). Data was also reported inthis study on patient-reported
acute pain syndrome (i.e.,paclitaxel-induced arthralgia/myalgia).
These results showedno significant response to glutathione between
the two studyarms (p = 0.30 for the every 3-week subset vs p =
0.002 for theweekly subset, in favor of the placebo arm). Thus,
there wasno evidence to support the use of glutathione for
prevention ofpaclitaxel-induced acute pain syndrome.
Gelmon et al. [28]
This randomized, open label, multicenter, phase II study
eval-uated the possible effects of adding amifostine (910 mg/m2
intravenously over 15 min prior to paclitaxel infusion) to
pac-litaxel (250 mg/m2 intravenously every 3 weeks for fourcourses
then 175 mg/m2 intravenously every 3 weeks) in pa-tients with
metastatic breast cancer. Forty patients were ran-domized 1:1 to
either paclitaxel alone (group 1) or paclitaxelpreceded by
amifostine (group 2). The primary objective wasto compare the
toxicity profile of the two arms, particularlyneurologic symptoms.
Comparison of response of myalgias(using NCIC-CTG modified common
toxicity criteria) was asecondary objective. Eligible patients
could not have had apre-existing neuropathy or prior treatment with
a neurotoxicchemotherapy.
Thirty-seven patients had myalgia during the course oftreatment,
and therefore they were analyzed for response.Eighteen patients,
who received paclitaxel alone and 19 pa-tients who received
combination treatment, were assessablefor response. The difference
in response rate between thetwo arms of 1.6 % favoring amifostine
armwas not significant
Table 3 Risk of bias assessment of included randomized
trials
Study (ref) Random
sequence
generation
Allocation
concealment
Blinding
(participants
and
personnel)
Blinding
(outcome
assessment)
Incomplete
outcome
data
Selective
reporting
Jacobson (26) - - - - + -
Gelmon (28) - - + + + -
Leal (27) - - - + + -
Rick (29) - + + + - -Trials at low risk of bias (green), high
risk of bias (red), or unclear risk of bias (yellow)
Green (−) = low risk biasRed (+) = high risk bias
Yellow (?) = unclear risk of bias
Support Care Cancer (2016) 24:1583–1594 1587
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(arm 1: response rate of 22.2%—95%CI, 6.4–47.6%; arm 2:response
rate of 36.8 %—95 % CI, 16.3–61.6 %). The resultsshowed no
differences between arms 1 and 2 on any of themeasures of
neurotoxicity nor myalgia (incidence of myalgia:arm 1–95 % vs arm
2–90 %). The authors concluded thatamifostine did not prevent or
reduce the incidence of TAPSwhen given in this schedule..
Rick et al. [29]
This prospective randomized single-center, open-labelstudy was
performed to assess whether the addition ofamifostine (500 mg
intravenously over 30 min beforepaclitaxel) would have a protective
effect of chemotherapy-induced toxicities after conventional-dose
and high-dose che-motherapy in patients with germ cell tumors.
Forty patientswere randomized 1:1 either to receive amifostine or
noamifostine. Evaluations of toxicities were done aftereach cycle
and classified according to modified criteriaof World Health
Organization (WHO) and NationalCancer Institute of Canada Expanded
Common ToxicityCriteria (NCICTC). Among patients undergoing
conventionaldose with TIP-based chemotherapy (paclitaxel 175
mg/m2
day 1, ifosfamide 1.2 g/m2 × 5 days, and cisplatin 20 mg/m2 × 5
days), there were no statistically significant differenceof
response of myalgias between patients treated with andwithout
amifostine (groups A—35 % vs group B—25 %). Inconclusion, with
respect to the reduction of chemotherapy-related toxicities after
conventional-dose TIP, the study couldnot observe any benefit of
amifostine.
Nguyen et al. [30]
In this retrospective study, patients diagnosed with breast
can-cer who had received a taxane (docetaxel or paclitaxel)
andgabapentin between April 1998 and February 2003 were iden-tified
through a survey of oncologists and oncology-nursepractitioners and
with a search of local electronic health re-cords. Ten patients
were identified, and among them, ninedeveloped myalgias and
arthralgias following the first cycleof taxane-based chemotherapy
(and one following the secondcycle). These symptoms started 2 to 3
days following taxaneinfusion and lasted up to 7 days. Four
patients reported dis-abling pain graded at 4 according to the
National CancerInstitute Toxicity Criteria (NCITC) while the
remaining pa-tients complained of modera te to severe pa in
.Dexamethasone 20 mg was given 20 min before eachtaxane infusion in
addition of dexamethasone 4 to 8 mgbid for 2 to 3 days after
chemotherapy.
Gabapentin 300 mg was given orally, three times a day(tid), 2
days before and for 5 days after taxane infusion in ninepatients.
One patient did not take the gabapentin post-chemo-therapy. Nine
patients responded, three of whom became
asymptomatic and six had mild symptoms specifically myal-gias
and arthralgias(at least two grade reductions in symp-toms). Given
the encouraging findings reported by this study,the authors
suggested that gabapentin is a viable treatmentoption in the
prevention of taxane-induced arthralgias andmyalgias.
Discussion
Taxane acute pain syndrome (TAPS) has been described as
adistinct toxicity occurring with taxane treatment. Its
incidencevaries not only between agents but also between tumor
types.For example, with docetaxel use, it is reported in 1–10 %
ofprostate cancer patients [10] and in 10–33 % of breast
cancerpatients [3–7]. In lung cancer patients treated with
docetaxel,TAPS has been reported up to 16.1 % [17]. As well,
bothpaclitaxel and docetaxel are being used for ovarian
cancertherapy and their TAPS incidence varies from 9.6 up to
36.7and 31 % in the metastatic and adjuvant settings,
respectively[15, 16]. Similarly, its incidence varies with the
choice oftaxane from 12 % in patients receiving paclitaxel
followingdoxorubicin-cyclophosphamide (AC-T) chemotherapy [8]and
7–26 % post-nab-paclitaxel chemotherapy [9]. This vari-ation may
reflect not only differing dosing schedules oftaxanes and
concurrent steroid co-administration [11] but alsodifferences in
taxane metabolism in patients with prostate can-cer who are
castrated [32]. Interestingly, TAPS has not beenreported in
prostate cancer patients receiving cabazitaxel [33].As TAPS can
affect physical function, quality of life, and thepatient’s desire
to continue treatment, it is essential that opti-mal treatment
strategies are identified [11, 34].
Despite the fact that numerous agents have been identifiedas
potential therapies for TAPS such as corticosteroids,pregabalin,
gabapentin, glutamine, shakuyaku-kanzo-to, andglutathione, in our
systematic review, there was no strongevidence of benefit from
these interventions, but rather thesetreatments seem to be
extrapolated from trials pertaining to thetreatment of CIPN rather
than TAPS [17–35].
Five studies were identified using four different agents inour
systematic review. Only the retrospective study byNguyen et al.
reported any significant improvement in TAPSwith the use of
gabapentin [30], reporting that 90% of patientshad a reduction in
symptoms. Further larger scale prospectivestudies would need to be
undertaken to confirm this effectbefore gabapentin could be
recommended.
There are a number of limitations to the current study. Firstand
rather surprisingly is that despite the widespread globaluse of
taxanes for many decades in cancer chemotherapy,there appears to be
a paucity of high-quality literature on theincidence, measurement,
and treatment of TAPS [11]. Theidentified studies also lacked
detailed, consistent outcome
1588 Support Care Cancer (2016) 24:1583–1594
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data and indeed one was published in abstract form only,which
leads to a risk of bias in these trials (Table 2).
Our study does however identify important areas for
futureresearch. First, we need to have more consistent and
validatedmeasurement of TAPS. Only with consistent scores can
wepossibly evaluate treatment responses in different tumor
types.Studies of treatments need to also be double-blind,
prospec-tive, and report toxicity data in a standardized fashion
[11]. Inaddition, as we do not know the mechanism and cause ofTAPS,
further study into the pathophysiology is required. Ithas been
suggested that one of the mechanisms may resultfrom nociceptor
sensitization on the basis of patient descrip-tors of pain [2],
which in turn could be related to single nucle-otide polymorphisms
(SNPs) in cytochrome p-450 (CYP) andmulti-drug resistance genes
(MDR1), and variability in drugmetabolism [3–4]. Potential
preventative strategies could bedeveloped if genetic factors for
TAPS could be identified.
Conclusion
Despite its frequency, TAPS remains an important,
poorlyresearched and challenging issue for cancer patients.
Despitethis systematic review, we are currently unable to
recommendany agents for the treatment or prevention of TAPS.
Thisknowledge gap warrants urgent research, so that we will beable
to offer our patients the optimally effective and safe care.
TC docetaxel/cyclophosphamide, FEC-D docetaxel afterprior
5-fluorouracil-epirubicin-cyclophosphamide, AC-T do-cetaxel after
prior doxorubicin-cyclophosphamide, CTcarboplatin/paclitaxel, PT
cisplatin/paclitaxel
Appendix 1: Systematic review supplement:Summary of electronic
literature search
Database: Embase Classic + Embase 1947 to October 20 2014,Ovid
MEDLINE(R) In-Process & Other Non-indexedCitations
andOvidMEDLINE(R) 1946 to September 29, 2014.
Searches1 docetaxel/
2 paclitaxel/
3 *taxoid/
4 docetaxel or paclitaxel or taxane
5 taxotere or docetaxel
6 or/1–5
7 exp. *pain/
8 pain
9 exp. *myalgia/
10 myalgia
11 exp. *arthralgia/
12 arthralgia
13 or/7–12
14 6 and 13
15 random or placebo or double-blind
16 cohort analysis/
17 longitudinal study/
18 prospective study/
19 follow up/
20 cohort
21 retrospective study/
22 case adj (control or series)
23 exp. *case control study/
24 *controlled clinical trial/or *clinical trial/
25 *randomized controlled trial/
26 or/15–25
27 14 and 26
28 27 use emczd
29 exp. Taxoids/
30 docetaxel or paclitaxel or taxane
31 taxotere or docetaxel
32 or/29–31
33 exp. Pain/
34 pain
35 exp. Arthralgia/or Arthralgia
36 Myalgia/or Myalgia
37 or/33–36
38 or/33–36
39 32 and 38
40 randomized controlled trial.pt.
41 controlled clinical trial.pt.
42 placebo.ab.
43 clinical trials as topic/
44 trial.ti.
45 random
46 exp. Cohort Studies/
47 cohort
48 case-control studies/
49 case adj (control or series)
50 or/40–49
51 39 and 50
52 51 use prmz
53 28 or 52
54 limit 53 to english language
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 have
beensearched) 3541
Support Care Cancer (2016) 24:1583–1594 1589
-
#4 #1 or #2 or #3
#5 MeSH descriptor: [Pain] explode all trees
#6 pain:ti,ab,kw or Arthralgia*:ti,ab,kw or myalgia*:ti,ab,kw
(Wordvariations have been searched)
#7 MeSH descriptor: [Myalgia] explode all trees
#8 MeSH descriptor: [Arthralgia] explode all trees
#9 #5 or #6 or #7 or #8
#10 #4 and #9
#11 CCRT
Appendix 2: Excluded studies from full textscreening
Reason for exclusion:
Article describes chemotherapy-induced peripheralneuropathy:
Lavoie Smith EM, Pang H, Cirrincione C, FleishmanSB, Paskett ED,
Fadul CE, et al. CALGB 170601: Aphase III double blind trial of
duloxetine to treat painfulchemotherapy-induced peripheral
neuropathy (CIPN). JClin Oncol. 2012; 30 (18 SUPPL.1).
Argyriou AA, Chroni E, Koutras A, Iconomou G,Papapetropoulos S,
Polychronopoulos P, et al. PreventingPaclitaxel-Induced Peripheral
Neuropathy: A Phase II Trialof Vitamin E.
Chiechio S, Copani A, Nicoletti F, Gereau IV
RW.L-Acetylcarnitine: A proposed therapeutic agent forpainful
peripheral neuropathies. Curr Neuropharmacol.2006;
4[3]:233–237.
Neuropathic pain and balance problems are poorly evalu-ated in
patients receiving taxane-based chemotherapy. JSupport Oncol
2005;3[6]:412.
Smith EML et al. Effect of duloxetine on pain, function,and
quality of life among patients with chemotherapy-inducedpainful
peripheral neuropathy: a randomized clinical trial.JAMA
2013;309(13):1359–67
No mention of TAPS treatment
Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, IddawelaM, et
al. Effects of the addition of gemcitabine, and paclitaxel-first
sequencing, in neoadjuvant sequential epirubicin,
cyclo-phosphamide, and paclitaxel for women with high-risk
earlybreast cancer (Neo-tAnGo): an open-label, 2 × 2
factorialrandomised phase 3 trial. Lancet Oncol 2014;15:201–12.
Gravis G, Marino P, Joly F, Oudard S, Priou F, Esterni B,et al.
Patients' self-assessment versus investigators' evaluationin a
phase III trial in non-castrate metastatic prostate
cancer(GETUG-AFU 15). Eur J Cancer 2014;50[5]:953–62.
Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T,et al.
Randomized phase III study of taxane versus TS-1 asfirst-line
treatment for metastatic breast cancer (SELECTBC).J Clin Oncol.
2014; 32(15 SUPPL. 1).
Bulent Akinci M, Algin E, Inal A, Odabas H, Berk V,Coskun U, et
al. Sequential adjuvant docetaxel andanthracycline chemotherapy for
node positive breast cancers:a retrospective study. J Balk
UnionOncol 2013;18[2]:314–20.
Fenlon D, Cranfield D, Powers C, Recio-Sauceda A. JointAches
Cohort Study (JACS): The impact of joint pain inwomen on adjuvant
therapy for primary breast cancer. Eur JCancer. 2013; 49:S376.
Hanaoka M, Kawabata H, Iwatani T, Takano T, Miura D.Reduction of
toxicity by reversing the order of infusion ofdocetaxel and
cyclophosphamide. Chemotherapy2013;59[2]:93–8.
Mirzaei HR, Nasrollahi F, Sabet RP, Akbari TZ, MoeinHR, Ghaffari
PT, et al. Dose-dense epirubicin and cyclophos-phamide followed by
docetaxel as adjuvant chemotherapy innode-positive breast cancer.
Int J Breast Cancer. 2013; 2013.
Hervonen P, Joensuu H, Joensuu T, Ginman C,McDermottR,
Harmenberg U, et al. Biweekly docetaxel is better toleratedthan
conventional three-weekly dosing for advancedhormone-refractory
prostate cancer. Anticancer Res2012;32[3]:953–6.
Logothetis CJ, Basch E, Molina A, Fizazi K, North SA,Chi KN, et
al. Effect of abiraterone acetate and prednisonecompared with
placebo and prednisone on pain controland skeletal-related events
in patients with metastaticcastration-resistant prostate cancer:
exploratory analysisof data from the COU-AA-301 randomised trial.
LancetOncol 2012;13[12]:1210–7.
Pond GR, Armstrong AJ, Wood BA, Leopold LH, GalskyMD, Sonpavde
G. Efficacy of docetaxel and prednisone inmen with metastatic
castration-resistant prostate cancer(mCRPC) exposed to prior
ketoconazole (KC). J ClinOncol. 2012; 30(5 SUPPL. 1).
Svensson H, Hatschek T, Johansson H, Einbeigi Z,Brandberg Y.
Health-related quality of life as prognosticfactor for response,
progression-free survival, and sur-vival in women with metastatic
breast cancer. Med Oncol2012;29[2]:432–8.
Fizazi K, De BJ, Haqq C, Logothetis CC, Jones RJ, Chi K,et al.
Abiraterone acetate plus low-dose prednisone has a fa-vorable
safety profile in metastatic castration-resistant prostatecancer
progressing after docetaxel-based chemotherapy:Results from
COU-AA-301, a randomized, double-blind, pla-cebo controlled, phase
III study. Eur Urol Suppl. 2011;10[2]:338.
Hervonen P, Joensuu H, Joensuu K, Nyandoto P, LuukkaaM, Nilsson
S, et al. Phase III, randomized, open-label study oftriweekly
docetaxel versus biweekly docetaxel as treatmentsfor advanced
hormone-refractory prostate cancer: Findings
1590 Support Care Cancer (2016) 24:1583–1594
-
from an interim safety analysis of the Finnish
Uro-oncologicalGroup Study 1–2003. J Clin Oncol. 2011; 29(7 SUPPL.
1).
Hoque E, Karim S, Reza MDS, Ahmed TU, Adnan RA.Clinical
experience of docetaxel in combination with prednis-olone and
zoledronic acid for hormone-refractory prostatecancer (HRPC): A
Bangladesh perspective. J Clin Oncol.2011; 29(15 SUPPL. 1).
Meulenbeld HJ, van Werkhoven ED, Coenen JLLM,Creemers G,
Loosveld OJL, de Jong PC, et al. Randomizedphase III study of
docetaxel with or without risedronate inpatients with bone
metastases from castration-resistant pros-tate cancer (CRPC): The
Netherlands Prostate Study (NePro).J Clin Oncol. 2011; 29(15 SUPPL.
1).
Ou Y, Michaelson MD, Sengelov L, Saad F, Houede N,Ostler PJ, et
al. Randomized, placebo-controlled, phase IIItrial of sunitinib in
combination with prednisone (SU + P)versus prednisone (P) alone in
men with progressive metasta-tic castration-resistant prostate
cancer (mCRPC). J ClinOncol. 2011; 29(15 SUPPL. 1).
Pond GR, Armstrong AJ, Wood BA, Brookes M,Leopold LH, Burke JM,
et al. Assessment of two prog-nostic risk group methods to predict
outcomes withdocetaxel-based therapy in men with metastatic
castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2011;
29(7SUPPL. 1).
Saad F, De Bono JS, Haqq CM, Logothetis CJ, Fizazi K,Jones RJ,
et al. Abiraterone acetate plus low-dose prednisonehas a favorable
safety profile, improves survival and producesPSA and radiographic
responses in metastatic castration-resistant prostate cancer
progressing after docetaxel-basedchemotherapy: Results from
COU-AA-301, a randomized,double-blind, placebo-controlled, phase
III study. J Urol.2011; 185(4 SUPPL. 1):e283-e284.
Moulder SL, Holmes FA, Tolcher AW, Thall P, Broglio K,Valero V,
et al. A randomized phase 2 trial comparing 3-hversus 96-h infusion
schedules of paclitaxel for the treatmentof metastatic breast
cancer. Cancer 2010;116[4]:814–21.
Eaton KD, Frieze DA. Cancer pain: Perspectives of a med-ical
oncologist. Curr Pain Headache Rep. 2008; 12[4]:270–276.
Ledeboer A, Hutchinson MR, Watkins LR, Johnson KW.Ibudilast
(AV-411): A new class therapeutic candidate for neu-ropathic pain
and opioid withdrawal syndromes. Expert OpinInvestig Drugs. 2007;
16[7]:935–950.
Gilron I, Flatters SJL. Gabapentin and pregabalin for
thetreatment of neuropathic pain: A review of laboratory
andclinical evidence. Pain Res Manage. 2006;
11(SUPPL.A):16A-29A.
Chao TC, Chu Z, Tseng LM, Chiou TJ, Hsieh RK, WangWS, et al.
Paclitaxel in a novel formulation containing lessCremophor EL as
first-line therapy for advanced breast can-cer: a phase II trial.
Invest New Drugs 2005;23[2]:171–7.
Miller KD, Saphner TJ, Waterhouse DM, Chen TT, Rush-Taylor A,
Sparano JA, et al. A randomized phase II feasibility
trial of BMS-275,291 in patients with early stage breast
can-cer. Clin Cancer Res 2004;10[6]:1971–5.
Pusztai L, Mendoza TR, Reuben JM, Martinez MM,Willey JS, Lara J,
et al. Changes in plasma levels of inflam-matory cytokines in
response to paclitaxel chemotherapy.Cytokine 2004;25[3]:94–102.
Markman M. Management of toxicities associatedwith the
administration of taxanes. Expert Opin DrugSaf 2003;2[2]:141–6.
Penson DF. Assessment of patients with castrate-resistant
prostate cancer. Clin Adv Hematol Oncol20119[7]:4–6.
Sartor O. Prognosis of patients with castrate-resistant
pros-tate cancer. Clin Adv Hematol Oncol 20119[7]:7–9.
Gardner TA, Elzey BD, Hahn NM. Sipuleucel-T(Provenge) autologous
vaccine approved for treatment ofmen with asymptomatic or minimally
symptomatic castrate-resistant metastatic prostate cancer. Hum
VaccinesImmunother 20128[4]:526–531.
Seal B, Puto K, Allen PD, Asche CV. Patient-reported outcomes
(PROS) and tolerability of therapeu-tic agents in patients with
metastatic prostate cancer(MPC): A systematic literature review.
Value Health201215[4]:A226.
Wilson LS, Zhong L, Pon V, Srinivas S, Frear M, NguyenN, et al.
Cost effectiveness analysis of new treatments formetastatic
castration-resistant prostate cancer: Does severitymatter? Value
Health 201215[4]:A220-A221.
Merseburger AS, Scher HI, De WR, Bellmunt J,Miller K, Mulders P,
et al. Enzalutamide (ENZA) hassimilar effect in European (EU) and
North American(NA) men despite regional differences in diagnosis
andtreatment: AFFIRM trial subanalysis. Urologe Ausg A201352(1
SUPPL. 1):76.
Article describes arthropathy post-chemotherapy
KimM-J, Ye Y-M, Park H-S, Suh C-H.
Chemotherapy-relatedarthropathy. J Rheumatol. 2006;
33[7]:1364–1368
Cancer-related pain
Basch EM, De Bono JS, Scher HI, Molina A, Sternberg CN,Fizazi K,
et al. Pain control and delay in time to skeletal-related events
(SREs) in patients with metastatic castration-resistant prostate
cancer (mCRPC) treated with abirateroneacetate (AA): Long-term
follow-up. J Clin Oncol. 2012;30(5 SUPPL. 1)
Duplicate publication
Markman M. Prevention of paclitaxel-associated arthralgiasand
myalgias. J Support Oncol. 2003; 1[4]:233–234.
Support Care Cancer (2016) 24:1583–1594 1591
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Appendix 3: PRISMA Checklist
Section/topic # Checklist item Reported onpage #
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; datasources; study eligibility
criteria, participants, and interventions; study appraisal
andsynthesis methods; results; limitations; conclusions and
implications of key findings;systematic review registration
number.
2–3
Introduction
Rationale 3 Describe the rationale for the review in the context
of what is already known. 4–5
Objectives 4 Provide an explicit statement of questions being
addressed with reference to participants,interventions,
comparisons, outcomes, and study design (PICOS).
5–6
Methods
Protocol and registration 5 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.
5
Information sources 7 Describe all information sources (e.g.,
databases with dates of coverage, contact with studyauthors to
identify additional studies) in the search and date last
searched.
5–6
Search 8 Present full electronic search strategy for at least
one database, including any limits used,such that it could be
repeated.
20–22
Study selection 9 State the process for selecting studies (i.e.,
screening, eligibility, included in systematicreview, and, if
applicable, included in the meta-analysis).
5–6
Data collection process 10 Describe method of data extraction
from reports (e.g., piloted forms, independently, induplicate) and
any processes for 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) andany assumptions and
simplifications made.
5
Risk of bias inindividual studies
12 Describe methods used for assessing risk of bias of
individual studies (includingspecification of whether this was done
at the study or outcome level), and how thisinformation is to be
used in any data synthesis.
7,17
Summary measures 13 State the principal summary measures (e.g.,
risk ratio, difference in means). NA
Synthesis of results 14 Describe the methods of handling data
and combining results of studies, if done, includingmeasures of
consistency (e.g., I2) for each meta-analysis.
NA
Risk of bias acrossstudies
15 Specify any assessment of risk of bias that may affect the
cumulative evidence (e.g.,publication bias, selective reporting
within studies).
7,17
Additional analyses 16 Describe methods of additional analyses
(e.g., sensitivity or subgroup analyses, meta-regression), if done,
indicating which were pre-specified.
NA
Results
Study selection 17 Give numbers of studies screened, assessed
for eligibility, and included in the review, withreasons for
exclusions at each stage, ideally with a flow diagram.
6,7, 19
Study characteristics 18 For each study, present characteristics
for which data were extracted (e.g., study size,PICOS, follow-up
period) and provide the citations.
8–13,18
Risk of bias withinstudies
19 Present data on risk of bias of each study and, if available,
any outcome level assessment (seeitem 12).
7,17
Results of individualstudies
20 For all outcomes considered (benefits or harms), present, for
each study: (a) simple summarydata for each intervention group (b)
effect estimates and confidence intervals, ideally witha forest
plot.
8–13
Synthesis of results 21 Present results of each meta-analysis
done, including confidence intervals and measures
ofconsistency.
NA
Risk of bias acrossstudies
22 Present results of any assessment of risk of bias across
studies (see Item 15). 7,17
Additional analysis 23 Give results of additional analyses, if
done (e.g., sensitivity or subgroup analyses, meta-regression [see
Item 16]).
NA
Discussion
Summary 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).
14
Limitations 25 Discuss limitations at study and outcome level
(e.g., risk of bias), and at review-level (e.g.,incomplete
retrieval of identified research, reporting bias).
14–16
1592 Support Care Cancer (2016) 24:1583–1594
-
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3. Roché H et al. (2006) Sequential adjuvant epirubicin-based
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10. Ian F. Tannock et al. Tolerability and efficacy of docetaxel
in oldermen with metastatic castrate-resistant prostate cancer
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11. Saibil S et al. (2010) Incidence of taxane-induced pain
anddistress in patients receiving chemotherapy for
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27. Leal AD, Qin R, Atherton PJ, Haluska P, Behrens RJ, Tiber
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(continued)
Section/topic # Checklist item Reported onpage #
Conclusions 26 Provide a general interpretation of the results
in the context of other evidence, andimplications for future
research.
16
Funding
Funding 27 Describe sources of funding for the systematic review
and other support (e.g., supply ofdata); role of funders for the
systematic review.
7
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29. Rick O, Beyer J, Schwella N, Schubart H, Schleicher J,
Siegert W(2001) Assessment of amifostine as protection from
chemotherapy-induced toxicities after conventional-dose and
high-dose chemo-therapy in patients with germ cell tumor. Ann Oncol
12(8):1151–1155
30. Nguyen VH, Lawrence HJ (2004) Use of gabapentin in the
preven-tion of taxane-induced arthralgias andmyalgias. J Clin Oncol
22(9):1767–1769
31. Higgins Julian PT, Altman Douglas G, Gøtzsche Peter C, Peter
J,David M, Oxman Andrew D, et al (2011) The CochraneCollaboration’s
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343:d5928
32. Ryan M, Franke, et al (2010) Castration-dependent
pharmacokinet-ics of docetaxel in patients with prostate cancer. J
Clin Oncol 28:4562–4567
33. Bahl A et al. (2013) Impact of cabazitaxel on 2-year
survival andpalliation of tumour-related pain in men with
metastatic castration-resistant prostate cancer treated in the
TROPIC trial. Ann Oncol 24:2402–2408
34. Kuchuk I et al. (2013) Preference weights for chemotherapy
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1594 Support Care Cancer (2016) 24:1583–1594
Treatment of taxane acute pain syndrome (TAPS) in cancer
patients receiving taxane-based chemotherapy—a systematic
reviewAbstractAbstractAbstractAbstractAbstractBackgroundMethodsStudy
objective and eligibility criteriaLiterature searchStudy screening
and selectionData collectionData analysis
FindingsQuantity of evidence identifiedStudy characteristicsRisk
of bias assessmentStudy-specific overviews and findingsJacobson
etal. [26]Leal etal. [27]Gelmon etal. [28]Rick etal. [29]Nguyen
etal. [30]
DiscussionConclusionAppendix 1: Systematic review supplement:
Summary of electronic literature searchAppendix 2: Excluded studies
from full text screeningReason for exclusion:Article describes
chemotherapy-induced peripheral neuropathy:No mention of TAPS
treatmentArticle describes arthropathy
post-chemotherapyCancer-related painDuplicate publication
Appendix 3: PRISMA ChecklistReferences
