Download Treatment of taxane acute pain syndrome (TAPS) in cancer patients

Support Care Cancer (2016) 24:1583–1594
DOI 10.1007/s00520-015-2941-0
ORIGINAL ARTICLE
Treatment of taxane acute pain syndrome (TAPS) in cancer
patients receiving taxane-based chemotherapy—a systematic
review
Ricardo Fernandes 1 & Sasha Mazzarello 2 & Habeeb Majeed 3 &
Stephanie Smith 2 & Risa Shorr 4 & Brian Hutton 5 & Mohammed FK Ibrahim 1 &
Carmel Jacobs 1 & Michael Ong 1 & Mark Clemons 1,2,6
Received: 21 May 2015 / Accepted: 3 September 2015 / Published online: 19 September 2015
# Springer-Verlag Berlin Heidelberg 2015
Abstract
Background Taxane acute pain syndrome (TAPS) is characterized by myalgias and arthralgias starting 1–3 days and lasting 5–7 days after taxane-based chemotherapy. Despite negatively impacting patient’s quality of life, little is known about
the optimal TAPS management. A systematic review of treatment strategies for TAPS across all tumor sites was performed.
Methods Embase, Ovid MEDLINE(R), and the Cochrane
Central Register of Controlled Trials were searched from
1946 to October 2014 for trials reporting the effectiveness of
different treatments of TAPS in cancer patients receiving
taxane-based chemotherapy. Two individuals independently
screened citations and full-text articles for eligibility.
Outcome measures included type of treatment and response
of myalgias, arthralgias, pain, and quality of life (QoL).
Results Of 1614 unique citations initially identified, five studies met the pre-specified eligibility criteria. Two were randomized placebo-controlled trials (225 patients), two were
* Mark Clemons
[email protected]
randomized open-label trials 76 patients), and one was a retrospective study (10 patients). The agents investigated included gabapentin, amifostine, glutathione, and glutamine. Study
sizes ranged from 10 to 185 patients. Given the heterogeneity
of study designs, a narrative synthesis of results was performed. Neither glutathione (QoL, p = 0.30, no 95 % CI reported) nor glutamine (mean improvement in average pain
was 0.8 in both treatment arms, p = 0.84, no 95 % CI reported)
were superior to placebo. Response to amifostine (pain response) and gabapentin (reduction in taxane-induced arthralgias and myalgias) was 36 % (95 % CI, 16–61 %) and 90 %
(no 95 % CI data reported), respectively.
Conclusions Despite its prevalence in patients receiving
taxane-based chemotherapies, TAPS remains poorly
researched and few studies evaluate its optimal management.
If the management of patients is to be improved, more prospective trials are needed.
Keywords Taxane acute pain syndrome . Docetaxel .
Paclitaxel . Gabapentin . Amifostine . Glutathione .
Glutamine
1
Division of Medical Oncology, Department of Medicine, The Ottawa
Hospital and University of Ottawa, Ottawa, Ontario, Canada
Background
2
Ottawa Hospital Research Institute and University of Ottawa,
Ottawa, Ontario, Canada
3
Division of Internal Medicine, Department of Medicine, The Ottawa
Hospital, Ottawa, Ontario, Canada
4
The Ottawa Hospital, Ottawa, Ontario, Canada
5
Department of Epidemiology and Community Medicine, University
of Ottawa, Ottawa, Ontario, Canada
6
Division of Medical Oncology, The Ottawa Hospital Cancer Centre,
501 Smyth Road, Ottawa, Canada
Taxane-based chemotherapeutic agents, such as docetaxel,
paclitaxel, nab-paclitaxel, and cabazitaxel, are commonly
used in the treatment of many malignancies [1]. Taxanes have
been associated with taxane acute pain syndrome (TAPS), also
known as paclitaxel-associated acute pain (P-APS) and
taxane-induced pain. TAPS is characterized by myalgia and
arthralgia, starting 1–3 days after taxane-based treatment, and
usually lasting for 5–7 days [2]. While TAPS shares some
clinical characteristics with chemotherapy-induced peripheral
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neuropathy (CIPN) (and indeed TAPS can be associated with
subsequent CIPN) [3–13], TAPS is usually completely resolved prior to the next cycle of chemotherapy [2]. While
the incidence of TAPS varies according to tumor type and
taxane regimen (Table 1), its pathophysiology remains poorly
understood [2, 12, 13].
TAPS is clinically significant as it not only affects physical
function and quality of life but can also lead to chemotherapy
dose delays, reductions, and discontinuation [11]. A number
of approaches for its prevention and treatment have been suggested, including non-steroidal anti-inflammatory drugs
(NSAIDs) [17], corticosteroids [18], antihistamines [19],
gabapentin [20–21], pregabalin [22], and shakuyaku-kanzoto [23–24]. However, most of these agents have been evaluated in the context of treatment for CIPN and not for TAPS. In
order to establish the strength of evidence underlying different
treatment options for TAPS, a systematic review was performed. Although breast and prostate cancer have been most
commonly reported in the literature to be associated with
TAPS, a systematic review was performed including all tumor
sites for which taxane-based chemotherapy are used.
Methods
Study objective and eligibility criteria
This systematic review was performed to identify and evaluate
strategies in the literature for the management of TAPS in
cancer patients receiving taxane-based chemotherapy. The
population-intervention-comparator-outcome study design
(PICOS) framework was used to structure the research question for the review and its corresponding literature search. The
population of interest included patients diagnosed with cancer.
No restrictions were placed on primary tumor sites.
Interventions of interest incorporated any taxane-based chemotherapy regimen (either as a single agent or in
Table 1 Reported incidence of
taxane acute pain syndrome from
past literature
combination) in the neoadjuvant, adjuvant, or metastatic settings. Outcome measures of interest included the type of treatment for TAPS, as well as the response of myalgias, arthralgias, pain, and quality of life using validated scales.
Randomized, retrospective, or prospective studies published
in English were included. Studies were excluded if they enrolled patients with prior neurologic comorbidities.
Literature search
An information specialist (RS) designed and executed an electronic literature search to identify relevant citations from
Embase Classic and Embase from 1947 to October 2014,
Ovid MEDLINE(R) In-Process & other non-indexed citations, and Ovid MEDLINE(R) from 1946 to September
2014. Search terms and their medical subject heading
(MeSH) equivalents are shown in Appendix 1 where the
MEDLINE search strategy is provided.
Study screening and selection
Stage 1 screening consisted of titles and abstracts identified
from the literature search by two independent reviewers (SM,
RF, HM). Disagreements were discussed and resolved between reviewers. Stage 2 screening consisted of a full-text
review of all potentially relevant citations identified during
Stage 1 screening by two independent reviewers (SM, RF,
SS, MC, CJ, and MI). Results from the screening process
are presented in a PRISMA flow diagram (Fig. 1).
Data collection
A pre-designed data collection form implemented in
Microsoft Excel was utilized for data extraction. All data
was extracted independently by two reviewers and subsequently compared for discrepancies which were resolved by
discussion. We collected information related to publication
Taxane
Chemotherapy regimen
Study population
Incidence of TAPS (%)
Paclitaxel [8]
Docetaxel [3–6]
AC-T
TC
FEC-D
TAC
Single agent
Single agent
Single agent
Single agent
Carboplatin plus docetaxel
CT or PT
Adjuvant breast cancer
Adjuvant breast cancer
12
10–22
33
10–28
26
7–26
1–10
1.5–16.1
31
9.6–36.7
Docetaxel [7]
Nab-paclitaxel [9]
Docetaxel [10]
Docetaxel [14]
Docetaxel [15]
Paclitaxel [16]
Metastatic breast cancer
Metastatic breast cancer
Metastatic prostate cancer
Metastatic lung cancer
Metastatic ovarian cancer
Adjuvant ovarian cancer
TC docetaxel/cyclophosphamide; FEC-D docetaxel after prior 5-fluorouracil-epirubicin-cyclophosphamide; ACT docetaxel after prior doxorubicin-cyclophosphamide; CT carboplatin/paclitaxel; PT cisplatin/paclitaxel
Support Care Cancer (2016) 24:1583–1594
Fig. 1 Systematic review
supplement: PRISMA flow
diagram review supplement:
PRISMA flow diagram. CIPN
chemotherapy-induced peripheral
neuropathy
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Records identified and screened
through database and abstract
searching after removal of
duplicates
Identification
(n=1608)
Records excluded due to
irrelevancy
(n= 1571)
Record screened in full text
Screening
(n=39)
Full-text arcles or abstracts
assessed for eligibility
(n=5)
Eligibility
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)
Studies included in qualitative synthesis
Included
(n=5)
CIPN - chemotherapy induced peripheral neuropathy
characteristics (year, journal, and authors), patient characteristics (performance status, median age, disease stage, and sites
of disease), intervention characteristics (chemotherapy line,
taxane type and frequency, and TAPS treatment), and outcomes of interest (response of pain, myalgias, and arthralgias).
Studies were also independently assessed for risk of bias by
two reviewers using the Cochrane Collaboration’s risk of bias
tool for randomized trials [25] which assesses for sources of
selection, performance, detection, attrition, reporting, and other sources of bias. Discrepancies in data collection were resolved by discussion among the reviewers. Funding for the
current study was from internal hospital sources; there was no
pharmaceutical company funding.
Data analysis
If deemed appropriate, following exploration of study and
patient characteristics to ensure sufficient clinical and methodological homogeneity across studies, we planned to pursue
meta-analyses using random effects models to combine data
for outcomes of interest across relevant studies, as described
in Cochrane book [25]. Statistical heterogeneity would be
assessed using both the Cochrane Q statistic and the I2 statistic. Following review of included studies’ characteristics, specifically regarding patient population, it was judged by the
authors that there were significant clinical differences that precluded the data from meta-analysis. In the light of these differences, a narrative strategy to summary of study-specific
results was performed.
Findings
Quantity of evidence identified
From 1614 unique citations identified by the literature search,
39 potentially relevant studies were identified during the first
stage screening of titles and abstracts. These 39 studies were
subsequently reviewed in full text for the second stage of
screening, and 5 met the eligibility criteria (Table 2). Studies
were excluded because they evaluated chemotherapy-induced
peripheral neuropathy (n = 5), no TAPS treatment was mentioned (n = 32), cancer-related pain (n = 1), evaluated arthropathy post-chemotherapy rather than TAPS (n = 1), or duplicate
publication (n = 1). Of the 5 included studies, 4 were available
as peer-reviewed manuscripts [26–29] and one was available
as a conference meeting abstract [30]. The manuscripts were
published in 1999 [28], 2001 [29], 2003 [26], 2004 [30], and
2014 [27], respectively.
Study characteristics
Four studies were randomized prospective studies [26–29],
and one was a retrospective analysis [30]. The sample sizes
ranged from 10 [30] to 185 patients [27]. Three trials included
patients with breast cancer [26, 28, 30] and two included patients 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] and
docetaxel in one [30]. Four of the five studies excluded
patients with pre-existing neuropathies or prior treatment
with neurotoxic chemotherapy [27–30]. Characteristics
of the individual studies which included study design,
cancer site, taxane used, type of TAPS treatment, and
response rates are described in Table 3. As there was
considerable variability between studies in particular
with regard to patient populations, meta-analysis was
considered inappropriate and a narrative summary of each
study as well as a descriptive overview of common results is
presented below.
Risk of bias assessment
A risk of bias assessment was performed on the four randomized trials included in the review using Cochrane assessment
(Table 3) [31]. Risk of bias was high for one of the included
trials due to incomplete reporting data [26]. The studies by
Gelmon [28], Leal [27], and Rick [29] were also judged to
have high risk of performance and detection bias with inadequate blinding of patients and personnel [28, 29] and outcome
data [27–28].
Study-specific overviews and findings
Post-cycle 1 treatment only
Jacobson et al. [26]
a
D/C discontinuation, LASA linear analog self-assessment, FACT-O functional assessment of cancer therapy-ovarian cancer, RR response rate, TAPS taxane acute pain syndrome, NCIC-CTG National
Cancer Institute of Canada Clinical Trials Group, EORTC-QLQ-CIPN20 European Organization for Research and Treatment of Cancer Quality of Life, ECOG Eastern Cooperative Oncology Group.
Not performed
Dizziness [31]
Not reported
Docetaxel and paclitaxel
(doses not mentioned)
Not reported
Breast
Gelmon et al. [28];
phase II randomized
(1999)
Germ cell
Rick et al. [29];
tumor
prospective
randomized (2001)
Nguyen et al. [30];
Breast
retrospective (2004)
Paclitaxel 250 mg/m2 ×
National Cancer Institute of
Canada Grants, Eli Lilly and
four cycles followed
Bristol-Myers Squibb, Canada.
by 175 mg/m2
Not reported
Paclitaxel 175 mg/m2 ×
four cycles
Placebo (n = 20) vs
amifostine
(n = 20)
Amifostine (n = 20)
vs no amifostine
(n = 20)
Gabapentin (n = 10)
95 vs 90 %
NCIC-CTG modified
common toxicity
criteria
35 vs 25 %
NCIC-expanded
common toxicity
criteria
National Cancer Institute 90 % a
toxicity scale
6—two grade reduction/3—one
grade reduction/1—no response
No statistically
significant
differences
Mean improvement 1 point both Not reported
glutathione and placebo on a
10-point scale (p = 0.30 on 3weekly arm and p = 0.002 on
weekly arm)
22.2 % (95 % CI, 6.4 to 47.6 %) 17.5 %
vs 36.8 % (95 % CI, 16.3
to 61.6 %)
Not reported
None
38 vs 33 %
Glutathione (n = 94) EORTC-QLQ-CIPN20
vs placebo
(n = 91)
Paclitaxel 150 to
200 mg/m2 (3
weekly and weekly)
Ovarian, lung, Public Health Services grants
others
and National Cancer
Institute grants
Leal et al. [27]; phase
III randomized
(2014)
Paclitaxel 175 mg/m2
Not reported
Breast
Jacobson et al. [26];
phase II randomized
(2003)
Vomiting grade 3/4; Not performed
dizziness grade
2; nausea grade 2
Not reported
Not performed
Overall—glutamine
−1.0 vs × placebo
−0.5 (p = 0.45)
No statistically
significant
differences
Not reported
Mean improvement 2.3 points vs
1.8 points (on a 10-point
scale) (p = 0.79)
74 vs 80 %
ECOG toxicity score
Glutamine (n = 18)
vs placebo
(n = 18)
FACT-O: no
differences
between the two
groups
Quality of life results
Chemotherapy Adverse events
D/C rate due
to TAPS
Incidence of Pain response to intervention
TAPS posttreatment
Funding source
Cancer site
Study author (year);
study type
Table 2
Overview of included studies:
Taxane
Scores to evaluate
TAPS
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Treatment of TAPS
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In this randomized, placebo-controlled, crossover trial, patients with breast cancer who had developed any grade of
TAPS with prior paclitaxel treatment were randomized to receive glutamine 10 g PO TID or matching placebo for 5 days
with the next paclitaxel treatment. The primary endpoint of the
study was a change in the severity or duration of TAPS measured daily using the ECOG toxicity score. Secondary endpoints included quality of life (QoL) outcomes and toxicity
profile (NCICCTC version 3.0) using the QoL parameters on
a symptom-distress scale and linear analog self-assessment
(LASA) questionnaire.
Thirty-six patients were eligible for the study and were
subsequently evaluated. The patient population reported grade
1–2 TAPS with prior paclitaxel treatment using symptomdistress scale and linear analog self-assessment (LASA) questionnaire. There were no differences in worse/average pain
scores, daily pain relief, or physician-reported grades of
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Table 3
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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
-
+
+
+
+
+
+
+
+
+
-
Jacobson (26)
Gelmon (28)
Leal (27)
Rick (29)
Selective
reporting
-
Trials at low risk of bias (green), high risk of bias (red), or unclear risk of bias (yellow)
Green (−) = low risk bias
Red (+) = high risk bias
Yellow (?) = unclear risk of bias
TAPS between treatment arms. The mean improvement in
worst pain from baseline to the end of the first treatment period was 2.3 points with glutamine and 1.8 points with placebo,
as measured on a 10-point scale (p = 0.79). Mean improvement in average pain was 0.8 in both treatment arms (p = 0.84,
no 95 % CI data not reported). The crossover analysis did not
show evidence of benefit in regard to QoL and pain scores. In
conclusion, this study showed that glutamine was no better
than placebo at prevention or alleviation of paclitaxelassociated myalgias/arthralgias.
Leal et al. [27]
The North Central Cancer Treatment Group/Alliance Trial
N08CA was designed to evaluate the efficacy of glutathione
for preventing CIPN in a cohort of patients undergoing
paclitaxel/carboplatin chemotherapy. This was a phase 3 randomized, double-blind, placebo-controlled study, in which patients with ovarian, lung, and other cancer sites scheduled to
receive 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-existing
history of peripheral neuropathy greater than 1 (NCICTCAE
version 4) nor concurrent use of any agents to prevent or treat
neuropathy. Patients were randomized to either intravenous
glutathione (1.5 g/m2) or placebo, given immediately before
chemotherapy.
The study’s primary outcome was the occurrence of sensory CIPN as measured by the sensory subscale (yes/no) of the
European Organization for Research and Treatment of Cancer
Quality of life (EORTC-QLQ-CIPN20) during the first six
cycles of treatment. Quality of life was also assessed using
the Functional Assessment of Cancer Therapy for patients
with ovarian cancer (FACT-O) obtained at baseline and 1 week
after each dose of chemotherapy.
Results from the 185 randomized patients showed no difference between the study arms for any of the reported toxicities. In the glutathione arm, the incidence of acute pain was
38 % (grade 2) and 5 % (grade 3), while in placebo arm, it was
33 % (grade 2) and 4 % (grade 3). Data was also reported in
this study on patient-reported acute pain syndrome (i.e.,
paclitaxel-induced arthralgia/myalgia). These results showed
no significant response to glutathione between the two study
arms (p = 0.30 for the every 3-week subset vs p = 0.002 for the
weekly subset, in favor of the placebo arm). Thus, there was
no evidence to support the use of glutathione for prevention of
paclitaxel-induced acute pain syndrome.
Gelmon et al. [28]
This randomized, open label, multicenter, phase II study evaluated the possible effects of adding amifostine (910 mg/m2
intravenously over 15 min prior to paclitaxel infusion) to paclitaxel (250 mg/m2 intravenously every 3 weeks for four
courses then 175 mg/m2 intravenously every 3 weeks) in patients with metastatic breast cancer. Forty patients were randomized 1:1 to either paclitaxel alone (group 1) or paclitaxel
preceded by amifostine (group 2). The primary objective was
to compare the toxicity profile of the two arms, particularly
neurologic symptoms. Comparison of response of myalgias
(using NCIC-CTG modified common toxicity criteria) was a
secondary objective. Eligible patients could not have had a
pre-existing neuropathy or prior treatment with a neurotoxic
chemotherapy.
Thirty-seven patients had myalgia during the course of
treatment, and therefore they were analyzed for response.
Eighteen patients, who received paclitaxel alone and 19 patients who received combination treatment, were assessable
for response. The difference in response rate between the
two arms of 1.6 % favoring amifostine arm was not significant
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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 results
showed no differences between arms 1 and 2 on any of the
measures of neurotoxicity nor myalgia (incidence of myalgia:
arm 1–95 % vs arm 2–90 %). The authors concluded that
amifostine did not prevent or reduce the incidence of TAPS
when given in this schedule..
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asymptomatic and six had mild symptoms specifically myalgias and arthralgias(at least two grade reductions in symptoms). Given the encouraging findings reported by this study,
the authors suggested that gabapentin is a viable treatment
option in the prevention of taxane-induced arthralgias and
myalgias.
Rick et al. [29]
Discussion
This prospective randomized single-center, open-label
study was performed to assess whether the addition of
amifostine (500 mg intravenously over 30 min before
paclitaxel) would have a protective effect of chemotherapyinduced toxicities after conventional-dose and high-dose chemotherapy in patients with germ cell tumors. Forty patients
were randomized 1:1 either to receive amifostine or no
amifostine. Evaluations of toxicities were done after
each cycle and classified according to modified criteria
of World Health Organization (WHO) and National
Cancer Institute of Canada Expanded Common Toxicity
Criteria (NCICTC). Among patients undergoing conventional
dose 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 difference
of response of myalgias between patients treated with and
without amifostine (groups A—35 % vs group B—25 %). In
conclusion, with respect to the reduction of chemotherapyrelated toxicities after conventional-dose TIP, the study could
not observe any benefit of amifostine.
Nguyen et al. [30]
In this retrospective study, patients diagnosed with breast cancer who had received a taxane (docetaxel or paclitaxel) and
gabapentin between April 1998 and February 2003 were identified through a survey of oncologists and oncology-nurse
practitioners and with a search of local electronic health records. Ten patients were identified, and among them, nine
developed myalgias and arthralgias following the first cycle
of taxane-based chemotherapy (and one following the second
cycle). These symptoms started 2 to 3 days following taxane
infusion and lasted up to 7 days. Four patients reported disabling pain graded at 4 according to the National Cancer
Institute Toxicity Criteria (NCITC) while the remaining patients complained o f m o d e r a t e t o s e v e r e p a i n .
Dexamethasone 20 mg was given 20 min before each
taxane infusion in addition of dexamethasone 4 to 8 mg
bid 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 nine
patients. One patient did not take the gabapentin post-chemotherapy. Nine patients responded, three of whom became
Taxane acute pain syndrome (TAPS) has been described as a
distinct toxicity occurring with taxane treatment. Its incidence
varies not only between agents but also between tumor types.
For example, with docetaxel use, it is reported in 1–10 % of
prostate cancer patients [10] and in 10–33 % of breast cancer
patients [3–7]. In lung cancer patients treated with docetaxel,
TAPS has been reported up to 16.1 % [17]. As well, both
paclitaxel and docetaxel are being used for ovarian cancer
therapy and their TAPS incidence varies from 9.6 up to 36.7
and 31 % in the metastatic and adjuvant settings, respectively
[15, 16]. Similarly, its incidence varies with the choice of
taxane from 12 % in patients receiving paclitaxel following
doxorubicin-cyclophosphamide (AC-T) chemotherapy [8]
and 7–26 % post-nab-paclitaxel chemotherapy [9]. This variation may reflect not only differing dosing schedules of
taxanes and concurrent steroid co-administration [11] but also
differences in taxane metabolism in patients with prostate cancer who are castrated [32]. Interestingly, TAPS has not been
reported in prostate cancer patients receiving cabazitaxel [33].
As TAPS can affect physical function, quality of life, and the
patient’s desire to continue treatment, it is essential that optimal treatment strategies are identified [11, 34].
Despite the fact that numerous agents have been identified
as potential therapies for TAPS such as corticosteroids,
pregabalin, gabapentin, glutamine, shakuyaku-kanzo-to, and
glutathione, in our systematic review, there was no strong
evidence of benefit from these interventions, but rather these
treatments seem to be extrapolated from trials pertaining to the
treatment of CIPN rather than TAPS [17–35].
Five studies were identified using four different agents in
our systematic review. Only the retrospective study by
Nguyen et al. reported any significant improvement in TAPS
with the use of gabapentin [30], reporting that 90 % of patients
had a reduction in symptoms. Further larger scale prospective
studies would need to be undertaken to confirm this effect
before gabapentin could be recommended.
There are a number of limitations to the current study. First
and rather surprisingly is that despite the widespread global
use of taxanes for many decades in cancer chemotherapy,
there appears to be a paucity of high-quality literature on the
incidence, measurement, and treatment of TAPS [11]. The
identified studies also lacked detailed, consistent outcome
Support Care Cancer (2016) 24:1583–1594
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 future
research. First, we need to have more consistent and validated
measurement of TAPS. Only with consistent scores can we
possibly evaluate treatment responses in different tumor types.
Studies of treatments need to also be double-blind, prospective, and report toxicity data in a standardized fashion [11]. In
addition, as we do not know the mechanism and cause of
TAPS, further study into the pathophysiology is required. It
has been suggested that one of the mechanisms may result
from nociceptor sensitization on the basis of patient descriptors of pain [2], which in turn could be related to single nucleotide polymorphisms (SNPs) in cytochrome p-450 (CYP) and
multi-drug resistance genes (MDR1), and variability in drug
metabolism [3–4]. Potential preventative strategies could be
developed if genetic factors for TAPS could be identified.
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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
Conclusion
29 exp. Taxoids/
30 docetaxel or paclitaxel or taxane
31 taxotere or docetaxel
Despite its frequency, TAPS remains an important, poorly
researched and challenging issue for cancer patients. Despite
this systematic review, we are currently unable to recommend
any agents for the treatment or prevention of TAPS. This
knowledge gap warrants urgent research, so that we will be
able to offer our patients the optimally effective and safe care.
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
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.
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-indexed
Citations and Ovid MEDLINE(R) 1946 to September 29, 2014.
Searches
1 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
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 (Word
variations have been searched)
#3 paclitaxel:ti,ab,kw or taxane*:ti,ab,kw (Word variations have been
searched) 3541
1590
#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 (Word
variations 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 text
screening
Reason for exclusion:
Article describes chemotherapy-induced peripheral
neuropathy:
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Appendix 3: PRISMA Checklist
Section/topic
#
Checklist item
Reported on
page #
1
Identify the report as a systematic review, meta-analysis, or both.
1
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; conclusions and implications of key findings;
systematic review registration number.
2–3
3
4
Describe the rationale for the review in the context of what is already known.
Provide an explicit statement of questions being addressed with reference to participants,
interventions, comparisons, outcomes, and study design (PICOS).
4–5
5–6
Protocol and registration
5
N/A
Eligibility criteria
6
Information sources
7
Search
8
Study selection
9
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.
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.
Describe all information sources (e.g., databases with dates of coverage, contact with study
authors to identify additional studies) in the search and date last searched.
Present full electronic search strategy for at least one database, including any limits used,
such that it could be repeated.
State the process for selecting studies (i.e., screening, eligibility, included in systematic
review, and, if applicable, included in the meta-analysis).
Describe method of data extraction from reports (e.g., piloted forms, independently, in
duplicate) and any processes for obtaining and confirming data from investigators.
List and define all variables for which data were sought (e.g., PICOS, funding sources) and
any assumptions and simplifications made.
Describe methods used for assessing risk of bias of individual studies (including
specification of whether this was done at the study or outcome level), and how this
information is to be used in any data synthesis.
State the principal summary measures (e.g., risk ratio, difference in means).
Describe the methods of handling data and combining results of studies, if done, including
measures of consistency (e.g., I2) for each meta-analysis.
Specify any assessment of risk of bias that may affect the cumulative evidence (e.g.,
publication bias, selective reporting within studies).
Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, metaregression), if done, indicating which were pre-specified.
Title
Title
Abstract
Structured summary
Introduction
Rationale
Objectives
Methods
Data collection process
10
Data items
11
Risk of bias in
individual studies
12
Summary measures
Synthesis of results
13
14
Risk of bias across
studies
Additional analyses
15
Results
Study selection
16
17
20–22
5–6
5–6
5
7,17
NA
NA
7,17
NA
6,7, 19
23
Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, metaregression [see Item 16]).
NA
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).
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
18
Risk of bias within
studies
Results of individual
studies
19
Synthesis of results
21
Risk of bias across
studies
Additional analysis
22
Limitations
5–6
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.
For each study, present characteristics for which data were extracted (e.g., study size,
PICOS, follow-up period) and provide the citations.
Present data on risk of bias of each study and, if available, any outcome level assessment (see
item 12).
For all outcomes considered (benefits or harms), present, for each study: (a) simple summary
data for each intervention group (b) effect estimates and confidence intervals, ideally with
a forest plot.
Present results of each meta-analysis done, including confidence intervals and measures of
consistency.
Present results of any assessment of risk of bias across studies (see Item 15).
Study characteristics
Discussion
Summary of evidence
5
20
25
8–13,18
7,17
8–13
NA
7,17
14–16
Support Care Cancer (2016) 24:1583–1594
1593
(continued)
Section/topic
Conclusions
#
Checklist item
26
Provide a general interpretation of the results in the context of other evidence, and
implications for future research.
27
Describe sources of funding for the systematic review and other support (e.g., supply of
data); role of funders for the systematic review.
Reported on
page #
16
Funding
Funding
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