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

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 Fernandes1 & Sasha Mazzarello2 & Habeeb Majeed3 & Stephanie Smith 2 & 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

Abstract randomized open-label trials 76 patients), and one was a ret- Background Taxane acute pain syndrome (TAPS) is charac- rospective study (10 patients). The agents investigated includ- terized by myalgias and arthralgias starting 1–3 days and lasted gabapentin, amifostine, glutathione, and glutamine. Study ing 5–7 days after taxane-based chemotherapy. Despite nega- sizes ranged from 10 to 185 patients. Given the heterogeneity tively impacting patient’s quality of life, little is known about of study designs, a narrative synthesis of results was per- the optimal TAPS management. A systematic review of treat- formed. Neither glutathione (QoL, p = 0.30, no 95 % CI re- ment strategies for TAPS across all tumor sites was performed. ported) nor glutamine (mean improvement in average pain Methods Embase, Ovid MEDLINE(R), and the Cochrane was 0.8 in both treatment arms, p = 0.84, no 95 % CI reported) Central Register of Controlled Trials were searched from were superior to placebo. Response to amifostine (pain re- 1946 to October 2014 for trials reporting the effectiveness of sponse) and gabapentin (reduction in taxane-induced arthral- different treatments of TAPS in cancer patients receiving gias and myalgias) was 36 % (95 % CI, 16–61 %) and 90 % taxane-based chemotherapy. Two individuals independently (no 95 % CI data reported), respectively. screened citations and full-text articles for eligibility. Conclusions Despite its prevalence in patients receiving Outcome measures included type of treatment and response taxane-based chemotherapies, TAPS remains poorly of myalgias, arthralgias, pain, and quality of life (QoL). researched and few studies evaluate its optimal management. Results Of 1614 unique citations initially identified, five stud- If the management of patients is to be improved, more pro- ies met the pre-specified eligibility criteria. Two were random- spective trials are needed. ized placebo-controlled trials (225 patients), two were Keywords Taxane acute pain syndrome . Docetaxel . Paclitaxel . Gabapentin . Amifostine . Glutathione . * Mark Clemons Glutamine [email protected]

1 Division of Medical Oncology, Department of Medicine, The Ottawa Background Hospital and University of Ottawa, Ottawa, Ontario, Canada 2 Ottawa Hospital Research Institute and University of Ottawa, Taxane-based chemotherapeutic agents, such as docetaxel, Ottawa, Ontario, Canada paclitaxel, nab-paclitaxel, and cabazitaxel, are commonly 3 Division of Internal Medicine, Department of Medicine, The Ottawa used in the treatment of many malignancies [1]. Taxanes have Hospital, Ottawa, Ontario, Canada been associated with taxane acute pain syndrome (TAPS), also 4 The Ottawa Hospital, Ottawa, Ontario, Canada known as paclitaxel-associated acute pain (P-APS) and 5 Department of Epidemiology and Community Medicine, University taxane-induced pain. TAPS is characterized by myalgia and of Ottawa, Ottawa, Ontario, Canada arthralgia, starting 1–3 days after taxane-based treatment, and 6 Division of Medical Oncology, The Ottawa Hospital Cancer Centre, usually lasting for 5–7 days [2]. While TAPS shares some 501 Smyth Road, Ottawa, Canada clinical characteristics with chemotherapy-induced peripheral 1584 Support Care Cancer (2016) 24:1583–1594 neuropathy (CIPN) (and indeed TAPS can be associated with combination) in the neoadjuvant, adjuvant, or metastatic set- subsequent CIPN) [3–13], TAPS is usually completely re- tings. Outcome measures of interest included the type of treat- solved prior to the next cycle of chemotherapy [2]. While ment for TAPS, as well as the response of myalgias, arthral- the incidence of TAPS varies according to tumor type and gias, pain, and quality of life using validated scales. taxane regimen (Table 1), its pathophysiology remains poorly Randomized, retrospective, or prospective studies published understood [2, 12, 13]. in English were included. Studies were excluded if they en- TAPS is clinically significant as it not only affects physical rolled patients with prior neurologic comorbidities. function and quality of life but can also lead to chemotherapy dose delays, reductions, and discontinuation [11]. A number Literature search of approaches for its prevention and treatment have been suggested, including non-steroidal anti-inflammatory drugs An information specialist (RS) designed and executed an elec- (NSAIDs) [17], corticosteroids [18], antihistamines [19], tronic literature search to identify relevant citations from gabapentin [20–21], pregabalin [22], and shakuyaku-kanzo- Embase Classic and Embase from 1947 to October 2014, to [23–24]. However, most of these agents have been evalu- Ovid MEDLINE(R) In-Process & other non-indexed cita- ated in the context of treatment for CIPN and not for TAPS. In tions, and Ovid MEDLINE(R) from 1946 to September order to establish the strength of evidence underlying different 2014. Search terms and their medical subject heading treatment options for TAPS, a systematic review was per- (MeSH) equivalents are shown in Appendix 1 where the formed. Although breast and prostate cancer have been most MEDLINE search strategy is provided. commonly reported in the literature to be associated with TAPS, a systematic review was performed including all tumor Study screening and selection sites for which taxane-based chemotherapy are used. Stage 1 screening consisted of titles and abstracts identified from the literature search by two independent reviewers (SM, Methods RF, HM). Disagreements were discussed and resolved between reviewers. Stage 2 screening consisted of a full-text Study objective and eligibility criteria review of all potentially relevant citations identified during Stage 1 screening by two independent reviewers (SM, RF, This systematic review was performed to identify and evaluate SS, MC, CJ, and MI). Results from the screening process strategies in the literature for the management of TAPS in are presented in a PRISMA flow diagram (Fig. 1). cancer patients receiving taxane-based chemotherapy. The population-intervention-comparator-outcome study design Data collection (PICOS) framework was used to structure the research ques- tion for the review and its corresponding literature search. The A pre-designed data collection form implemented in population of interest included patients diagnosed with cancer. Microsoft Excel was utilized for data extraction. All data No restrictions were placed on primary tumor sites. was extracted independently by two reviewers and subse- Interventions of interest incorporated any taxane-based che- quently compared for discrepancies which were resolved by motherapy regimen (either as a single agent or in discussion. We collected information related to publication

Table 1 Reported incidence of taxane acute pain syndrome from Taxane Chemotherapy regimen Study population Incidence of TAPS (%) past literature 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 Support Care Cancer (2016) 24:1583–1594 1585

Fig. 1 Systematic review Records identified and screened supplement: PRISMA flow through database and abstract diagram review supplement: searching after removal of PRISMA flow diagram. CIPN Identiﬁcation duplicates chemotherapy-induced peripheral (n=1608) neuropathy

Records excluded due to irrelevancy (n= 1571)

Record screened in full text Screening (n=39)

Full-text arcles or abstracts Excluded (n=33): Eligibility assessed for eligibility CIPN (n= 5) No TAPS treatment mention (n=5) (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 characteris- authors that there were significant clinical differences that pre- tics (performance status, median age, disease stage, and sites cluded the data from meta-analysis. In the light of these dif- of disease), intervention characteristics (chemotherapy line, ferences, a narrative strategy to summary of study-specific taxane type and frequency, and TAPS treatment), and out- results was performed. comes of interest (response of pain, myalgias, and arthralgias). Studies were also independently assessed for risk of bias by two reviewers using the Cochrane Collaboration’sriskofbias tool for randomized trials [25] which assesses for sources of Findings selection, performance, detection, attrition, reporting, and other sources of bias. Discrepancies in data collection were re- Quantity of evidence identified solved by discussion among the reviewers. Funding for the current study was from internal hospital sources; there was no From 1614 unique citations identified by the literature search, pharmaceutical company funding. 39 potentially relevant studies were identified during the first stage screening of titles and abstracts. These 39 studies were Data analysis subsequently reviewed in full text for the second stage of screening, and 5 met the eligibility criteria (Table 2). Studies If deemed appropriate, following exploration of study and were excluded because they evaluated chemotherapy-induced patient characteristics to ensure sufficient clinical and meth- peripheral neuropathy (n = 5), no TAPS treatment was men- odological homogeneity across studies, we planned to pursue tioned (n = 32), cancer-related pain (n = 1), evaluated arthrop- meta-analyses using random effects models to combine data athy post-chemotherapy rather than TAPS (n = 1), or duplicate for outcomes of interest across relevant studies, as described publication (n = 1). Of the 5 included studies, 4 were available in Cochrane book [25]. Statistical heterogeneity would be as peer-reviewed manuscripts [26–29] and one was available assessed using both the Cochrane Q statistic and the I2 statis- as a conference meeting abstract [30]. The manuscripts were tic. Following review of included studies’ characteristics, spe- published in 1999 [28], 2001 [29], 2003 [26], 2004 [30], and cifically regarding patient population, it was judged by the 2014 [27], respectively. 1586 Support Care Cancer (2016) 24:1583–1594

Study characteristics =0.45) National glutamine p

— Four studies were randomized prospective studies [26–29], 1.0 vs × placebo 0.5 ( − − differences between the two groups and one was a retrospective analysis [30]. The sample sizes Overall Not performed FACT-O: no ranged from 10 [30] to 185 patients [27]. Three trials included NCIC-CTG patients with breast cancer [26, 28, 30]andtwoincludedpa- 31 ] Not performed tients with different types of malignancies including breast, significant differences dizziness grade 2; nausea grade 2 significant differences lung, and ovarian cancers [27]aswellasgermcelltumors

Adverse events Quality of life results [29]. Paclitaxel was evaluated in four studies [25–28] and docetaxel in one [30]. Four of the five studies excluded

Eastern Cooperative Oncology Group. patients with pre-existing neuropathies or prior treatment – D/C rate due to TAPS Not reported No statistically 17.5 % Vomiting grade 3/4; Not reported Dizziness [ Not reported No statistically with neurotoxic chemotherapy [27 30]. Characteristics

ECOG of the individual studies which included study design, taxane acute pain syndrome,

one cancer site, taxane used, type of TAPS treatment, and — = 0.002 on no response TAPS =0.30on3- response rates are described in Table 3.Astherewas p — p considerable variability between studies in particular =0.79)

p with regard to patient populations, meta-analysis was considered inappropriate and a narrative summary of each two grade reduction/3 grade reduction/1 1.8 points (on a 10-point scale) ( vs 36.8 % (95 %to CI, 61.6 16.3 %) glutathione and placebo on a 10-point scale ( weekly arm) weekly arm and response rate, — study as well as a descriptive overview of common results is 6 Pain response to intervention Chemotherapy

RR presented below. a Risk of bias assessment Incidence of TAPS post- treatment 95 vs 90 % 22.2 % (95 % CI, 6.4 to 47.6 %) 90 % 35 vs 25 % Not reported None Not reported Not performed

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 common toxicity criteria toxicity scale common toxicity criteria

er therapy-ovarian cancer, trials due to incomplete reporting data [26]. The studies by TAPS ECOG toxicity score 74 vs 80 % Mean improvement 2.3 points vs NCIC-CTG modified EORTC-QLQ-CIPN20 38 vs 33 % Mean improvement 1 point both NCIC-expanded Gelmon [28], Leal [27], and Rick [29]werealsojudgedto =94) = 10) National Cancer Institute

= 20) have high risk of performance and detection bias with inade- = 18) n n n n = 20) vs quate blinding of patients and personnel [28, 29] and outcome n =18) =20) =91) =20) data [27–28]. n n n n vs placebo ( amifostine ( vs placebo ( vs no amifostine ( Glutamine ( Placebo ( Glutathione ( Amifostine ( Gabapentin (

× Study-specific overviews and findings × 2 2 2 European Organization for Research and Treatment of Cancer Quality of Life, 2 (3 2

functional assessment of canc Jacobson et al. [26] four cycles followed by 175 mg/m weekly and weekly) four cycles (doses not mentioned) 200 mg/m In this randomized, placebo-controlled, crossover trial, pa- Paclitaxel 250 mg/m Paclitaxel 150 to Paclitaxel 175 mg/m FACT-O tients with breast cancer who had developed any grade of TAPS with prior paclitaxel treatment were randomized to re-

EORTC-QLQ-CIPN20 ceive 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 end- Canada Grants, Eli Lilly and Bristol-Myers Squibb, Canada. and National Cancer Institute grants points included quality of life (QoL) outcomes and toxicity Public Health Services grants Not reported profile (NCICCTC version 3.0) using the QoL parameters on linear analog self-assessment, a symptom-distress scale and linear analog self-assessment others tumor (LASA) questionnaire. LASA Cancer site Funding source Taxane Treatment of TAPS Scores to evaluate Breast Not reported Paclitaxel 175 mg/m Breast Not reported Docetaxel and paclitaxel Ovarian, lung, Germ cell Breast National Cancer Institute of Thirty-six patients were eligible for the study and were subsequently evaluated. The patient population reported grade ]; 26 ]; 28 30 ]; – Overview of included studies: 1 2 TAPS with prior paclitaxel treatment using symptom- 29 ]; 27 ]; phase distress scale and linear analog self-assessment (LASA) ques- discontinuation, tionnaire. There were no differences in worse/average pain phase II randomized (2003) retrospective (2004) III randomized (2014) prospective randomized (2001) phase II randomized (1999) Post-cycle 1 treatment only Cancer Institute of Canada Clinical Trials Group, Table 2 Study author (year); study type D/C a Jacobson et al. [ Rick et al. [ Leal et al. [ Nguyen et al. [ Gelmon et al. [ scores, daily pain relief, or physician-reported grades of Support Care Cancer (2016) 24:1583–1594 1587

Table 3 Risk of bias assessment of included randomized trials Study (ref) Random Allocation Blinding Blinding Incomplete Selective sequence concealment (participants (outcome outcome reporting generation and assessment) data personnel)

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 (−)=lowriskbias Red (+) = high risk bias Yellow (?) = unclear risk of bias

TAPS between treatment arms. The mean improvement in Results from the 185 randomized patients showed no dif- worst pain from baseline to the end of the first treatment peri- ference between the study arms for any of the reported toxic- od was 2.3 points with glutamine and 1.8 points with placebo, ities. In the glutathione arm, the incidence of acute pain was as measured on a 10-point scale (p =0.79).Meanimprove- 38 % (grade 2) and 5 % (grade 3), while in placebo arm, it was ment in average pain was 0.8 in both treatment arms (p =0.84, 33 % (grade 2) and 4 % (grade 3). Data was also reported in no 95 % CI data not reported). The crossover analysis did not this study on patient-reported acute pain syndrome (i.e., show evidence of benefit in regard to QoL and pain scores. In paclitaxel-induced arthralgia/myalgia). These results showed conclusion, this study showed that glutamine was no better no significant response to glutathione between the two study than placebo at prevention or alleviation of paclitaxel- arms (p = 0.30 for the every 3-week subset vs p =0.002forthe associated myalgias/arthralgias. weekly subset, in favor of the placebo arm). Thus, there was no evidence to support the use of glutathione for prevention of Leal et al. [27] paclitaxel-induced acute pain syndrome.

The North Central Cancer Treatment Group/Alliance Trial Gelmon et al. [28] N08CA was designed to evaluate the efficacy of glutathione for preventing CIPN in a cohort of patients undergoing This randomized, open label, multicenter, phase II study eval- paclitaxel/carboplatin chemotherapy. This was a phase 3 ran- uated the possible effects of adding amifostine (910 mg/m2 domized, double-blind, placebo-controlled study, in which pa- intravenously over 15 min prior to paclitaxel infusion) to pac- tients with ovarian, lung, and other cancer sites scheduled to litaxel (250 mg/m2 intravenously every 3 weeks for four receive paclitaxel (150–200 mg/m2,weeklyorevery3weeks) courses then 175 mg/m2 intravenously every 3 weeks) in pa- and carboplatin (AUC 5–7every3or4weeksforsixcourses) tients with metastatic breast cancer. Forty patients were ran- were enrolled. Eligible patients could not have pre-existing domized 1:1 to either paclitaxel alone (group 1) or paclitaxel history of peripheral neuropathy greater than 1 (NCICTCAE preceded by amifostine (group 2). The primary objective was version 4) nor concurrent use of any agents to prevent or treat to compare the toxicity profile of the two arms, particularly neuropathy. Patients were randomized to either intravenous neurologic symptoms. Comparison of response of myalgias glutathione (1.5 g/m2) or placebo, given immediately before (using NCIC-CTG modified common toxicity criteria) was a chemotherapy. secondary objective. Eligible patients could not have had a The study’s primary outcome was the occurrence of senso- pre-existing neuropathy or prior treatment with a neurotoxic ry CIPN as measured by the sensory subscale (yes/no) of the chemotherapy. European Organization for Research and Treatment of Cancer Thirty-seven patients had myalgia during the course of Quality of life (EORTC-QLQ-CIPN20) during the first six treatment, and therefore they were analyzed for response. cycles of treatment. Quality of life was also assessed using Eighteen patients, who received paclitaxel alone and 19 pa- the Functional Assessment of Cancer Therapy for patients tients who received combination treatment, were assessable with ovarian cancer (FACT-O) obtained at baseline and 1 week for response. The difference in response rate between the after each dose of chemotherapy. two arms of 1.6 % favoring amifostine arm was not significant 1588 Support Care Cancer (2016) 24:1583–1594

(arm 1: response rate of 22.2 %—95 % CI, 6.4–47.6 %; arm 2: asymptomatic and six had mild symptoms specifically myal- response rate of 36.8 %—95 % CI, 16.3–61.6 %). The results gias and arthralgias(at least two grade reductions in symp- showed no differences between arms 1 and 2 on any of the toms). Given the encouraging findings reported by this study, measures of neurotoxicity nor myalgia (incidence of myalgia: the authors suggested that gabapentin is a viable treatment arm 1–95 % vs arm 2–90 %). The authors concluded that option in the prevention of taxane-induced arthralgias and amifostine did not prevent or reduce the incidence of TAPS myalgias. when given in this schedule..

Rick et al. [29] Discussion This prospective randomized single-center, open-label study was performed to assess whether the addition of Taxane acute pain syndrome (TAPS) has been described as a amifostine (500 mg intravenously over 30 min before distinct toxicity occurring with taxane treatment. Its incidence paclitaxel) would have a protective effect of chemotherapy- varies not only between agents but also between tumor types. induced toxicities after conventional-dose and high-dose che- For example, with docetaxel use, it is reported in 1–10 % of motherapy in patients with germ cell tumors. Forty patients prostate cancer patients [10] and in 10–33 % of breast cancer were randomized 1:1 either to receive amifostine or no patients [3–7]. In lung cancer patients treated with docetaxel, amifostine. Evaluations of toxicities were done after TAPS has been reported up to 16.1 % [17]. As well, both each cycle and classified according to modified criteria paclitaxel and docetaxel are being used for ovarian cancer of World Health Organization (WHO) and National therapy and their TAPS incidence varies from 9.6 up to 36.7 Cancer Institute of Canada Expanded Common Toxicity and 31 % in the metastatic and adjuvant settings, respectively Criteria (NCICTC). Among patients undergoing conventional [15, 16]. Similarly, its incidence varies with the choice of dose with TIP-based chemotherapy (paclitaxel 175 mg/m2 taxane from 12 % in patients receiving paclitaxel following day 1, ifosfamide 1.2 g/m2 × 5 days, and cisplatin 20 mg/ doxorubicin-cyclophosphamide (AC-T) chemotherapy [8] m2 × 5 days), there were no statistically significant difference and 7–26 % post-nab-paclitaxel chemotherapy [9]. This vari- of response of myalgias between patients treated with and ation may reflect not only differing dosing schedules of without amifostine (groups A—35 % vs group B—25 %). In taxanes and concurrent steroid co-administration [11] but also conclusion, with respect to the reduction of chemotherapy- differences in taxane metabolism in patients with prostate can- related toxicities after conventional-dose TIP, the study could cer who are castrated [32]. Interestingly, TAPS has not been not observe any benefit of amifostine. reported in prostate cancer patients receiving cabazitaxel [33]. As TAPS can affect physical function, quality of life, and the Nguyen et al. [30] patient’s desire to continue treatment, it is essential that optimal treatment strategies are identified [11, 34]. In this retrospective study, patients diagnosed with breast can- Despite the fact that numerous agents have been identified cer who had received a taxane (docetaxel or paclitaxel) and as potential therapies for TAPS such as corticosteroids, gabapentin between April 1998 and February 2003 were iden- pregabalin, gabapentin, glutamine, shakuyaku-kanzo-to, and tified through a survey of oncologists and oncology-nurse glutathione, in our systematic review, there was no strong practitioners and with a search of local electronic health re- evidence of benefit from these interventions, but rather these cords. Ten patients were identified, and among them, nine treatments seem to be extrapolated from trials pertaining to the developed myalgias and arthralgias following the first cycle treatment of CIPN rather than TAPS [17–35]. of taxane-based chemotherapy (and one following the second Five studies were identified using four different agents in cycle). These symptoms started 2 to 3 days following taxane our systematic review. Only the retrospective study by infusion and lasted up to 7 days. Four patients reported dis- Nguyen et al. reported any significant improvement in TAPS abling pain graded at 4 according to the National Cancer with the use of gabapentin [30], reporting that 90 % of patients Institute Toxicity Criteria (NCITC) while the remaining pa- had a reduction in symptoms. Further larger scale prospective tients complained of moderate to severe pain. studies would need to be undertaken to confirm this effect Dexamethasone20mgwasgiven20minbeforeeach before gabapentin could be recommended. taxane infusion in addition of dexamethasone 4 to 8 mg There are a number of limitations to the current study. First bid for 2 to 3 days after chemotherapy. and rather surprisingly is that despite the widespread global Gabapentin 300 mg was given orally, three times a day use of taxanes for many decades in cancer chemotherapy, (tid), 2 days before and for 5 days after taxane infusion in nine there appears to be a paucity of high-quality literature on the patients. One patient did not take the gabapentin post-chemo- incidence, measurement, and treatment of TAPS [11]. The therapy. Nine patients responded, three of whom became identified studies also lacked detailed, consistent outcome Support Care Cancer (2016) 24:1583–1594 1589 data and indeed one was published in abstract form only, 11 exp. *arthralgia/ which leads to a risk of bias in these trials (Table 2). 12 arthralgia Our study does however identify important areas for future 13 or/7–12 research. First, we need to have more consistent and validated 14 6 and 13 measurement of TAPS. Only with consistent scores can we 15 random or placebo or double-blind possibly evaluate treatment responses in different tumor types. 16 cohort analysis/ Studies of treatments need to also be double-blind, prospec- 17 longitudinal study/ tive, and report toxicity data in a standardized fashion [11]. In 18 prospective study/ addition, as we do not know the mechanism and cause of 19 follow up/ TAPS, further study into the pathophysiology is required. It 20 cohort has been suggested that one of the mechanisms may result 21 retrospective study/ from nociceptor sensitization on the basis of patient descrip- 22 case adj (control or series) tors of pain [2], which in turn could be related to single nucle- 23 exp. *case control study/ otide polymorphisms (SNPs) in cytochrome p-450 (CYP) and 24 *controlled clinical trial/or *clinical trial/ multi-drug resistance genes (MDR1), and variability in drug 25 *randomized controlled trial/ metabolism [3–4]. Potential preventative strategies could be 26 or/15–25 developed if genetic factors for TAPS could be identified. 27 14 and 26 28 27 use emczd 29 exp. Taxoids/ Conclusion 30 docetaxel or paclitaxel or taxane 31 taxotere or docetaxel Despite its frequency, TAPS remains an important, poorly 32 or/29–31 researched and challenging issue for cancer patients. Despite 33 exp. Pain/ this systematic review, we are currently unable to recommend 34 pain any agents for the treatment or prevention of TAPS. This 35 exp. Arthralgia/or Arthralgia knowledge gap warrants urgent research, so that we will be 36 Myalgia/or Myalgia able to offer our patients the optimally effective and safe care. 37 or/33–36 TC docetaxel/cyclophosphamide, FEC-D docetaxel after 38 or/33–36 prior 5-fluorouracil-epirubicin-cyclophosphamide, AC-T do- 39 32 and 38 cetaxel after prior doxorubicin-cyclophosphamide, CT 40 randomized controlled trial.pt. carboplatin/paclitaxel, PT cisplatin/paclitaxel 41 controlled clinical trial.pt. 42 placebo.ab. 43 clinical trials as topic/ 44 trial.ti. Appendix 1: Systematic review supplement: 45 random Summary of electronic literature search 46 exp. Cohort Studies/ 47 cohort Database: Embase Classic + Embase 1947 to October 20 2014, 48 case-control studies/ Ovid MEDLINE(R) In-Process & Other Non-indexed 49 case adj (control or series) Citations and Ovid MEDLINE(R) 1946 to September 29, 2014. 50 or/40–49 51 39 and 50 Searches 52 51 use prmz 1docetaxel/ 53 28 or 52 2 paclitaxel/ 54 limit 53 to english language 3 *taxoid/ 55 remove duplicates from 54 4 docetaxel or paclitaxel or taxane 5 taxotere or docetaxel ID Search Hits 6or/1–5 #1 MeSH descriptor: [Taxoids] explode all trees 7 exp. *pain/ #2 docetaxel:ti,ab,kw or taxotere:ti,ab,kw or docecad:ti,ab,kw (Word 8pain variations have been searched) 9 exp. *myalgia/ #3 paclitaxel:ti,ab,kw or taxane*:ti,ab,kw (Word variations have been 10 myalgia searched) 3541 1590 Support Care Cancer (2016) 24:1583–1594

#4 #1 or #2 or #3 Hara F, Matsubara N, Saito T, Takano T, Park Y,Toyama T, #5 MeSH descriptor: [Pain] explode all trees et al. Randomized phase III study of taxane versus TS-1 as #6 pain:ti,ab,kw or Arthralgia*:ti,ab,kw or myalgia*:ti,ab,kw (Word first-line treatment for metastatic breast cancer (SELECT BC). variations have been searched) J Clin Oncol. 2014; 32(15 SUPPL. 1). #7 MeSH descriptor: [Myalgia] explode all trees Bulent Akinci M, Algin E, Inal A, Odabas H, Berk V, #8 MeSH descriptor: [Arthralgia] explode all trees Coskun U, et al. Sequential adjuvant docetaxel and #9 #5 or #6 or #7 or #8 anthracycline chemotherapy for node positive breast cancers: #10 #4 and #9 a retrospective study. J Balk Union Oncol 2013;18[2]:314–20. #11 CCRT Fenlon D, Cranfield D, Powers C, Recio-Sauceda A. Joint Aches Cohort Study (JACS): The impact of joint pain in Appendix 2: Excluded studies from full text women on adjuvant therapy for primary breast cancer. Eur J screening Cancer. 2013; 49:S376. Hanaoka M, Kawabata H, Iwatani T, Takano T, Miura D. Reduction of toxicity by reversing the order of infusion of Reason for exclusion: docetaxel and cyclophosphamide. Chemotherapy 2013;59[2]:93–8. Article describes chemotherapy-induced peripheral Mirzaei HR, Nasrollahi F, Sabet RP, Akbari TZ, Moein neuropathy: HR, Ghaffari PT, et al. Dose-dense epirubicin and cyclophosphamide followed by docetaxel as adjuvant chemotherapy in Lavoie Smith EM, Pang H, Cirrincione C, Fleishman node-positive breast cancer. Int J Breast Cancer. 2013; 2013. SB, Paskett ED, Fadul CE, et al. CALGB 170601: A Hervonen P, Joensuu H, Joensuu T, Ginman C, McDermott phase III double blind trial of duloxetine to treat painful R, Harmenberg U, et al. Biweekly docetaxel is better tolerated chemotherapy-induced peripheral neuropathy (CIPN). J than conventional three-weekly dosing for advanced Clin Oncol. 2012; 30 (18 SUPPL.1). hormone-refractory prostate cancer. Anticancer Res Argyriou AA, Chroni E, Koutras A, Iconomou G, 2012;32[3]:953–6. Papapetropoulos S, Polychronopoulos P, et al. Preventing Logothetis CJ, Basch E, Molina A, Fizazi K, North SA, Paclitaxel-Induced Peripheral Neuropathy: A Phase II Trial Chi KN, et al. Effect of abiraterone acetate and prednisone of Vitamin E. compared with placebo and prednisone on pain control Chiechio S, Copani A, Nicoletti F, Gereau IV RW. and skeletal-related events in patients with metastatic L-Acetylcarnitine: A proposed therapeutic agent for castration-resistant prostate cancer: exploratory analysis painful peripheral neuropathies. Curr Neuropharmacol. of data from the COU-AA-301 randomised trial. Lancet 2006; 4[3]:233–237. Oncol 2012;13[12]:1210–7. Neuropathic pain and balance problems are poorly evalu- Pond GR, Armstrong AJ, Wood BA, Leopold LH, Galsky ated in patients receiving taxane-based chemotherapy. J MD, Sonpavde G. Efficacy of docetaxel and prednisone in Support Oncol 2005;3[6]:412. men with metastatic castration-resistant prostate cancer Smith EML et al. Effect of duloxetine on pain, function, (mCRPC) exposed to prior ketoconazole (KC). J Clin and quality of life among patients with chemotherapy-induced Oncol. 2012; 30(5 SUPPL. 1). painful peripheral neuropathy: a randomized clinical trial. Svensson H, Hatschek T, Johansson H, Einbeigi Z, JAMA 2013;309(13):1359–67 Brandberg Y. Health-related quality of life as prognostic factor for response, progression-free survival, and survival in women with metastatic breast cancer. Med Oncol No mention of TAPS treatment 2012;29[2]:432–8. Fizazi K, De BJ, Haqq C, Logothetis CC, Jones RJ, Chi K, Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela et al. Abiraterone acetate plus low-dose prednisone has a fa- M, et al. Effects of the addition of gemcitabine, and paclitaxel- vorable safety profile in metastatic castration-resistant prostate first sequencing, in neoadjuvant sequential epirubicin, cyclo- cancer progressing after docetaxel-based chemotherapy: phosphamide, and paclitaxel for women with high-risk early Results from COU-AA-301, a randomized, double-blind, pla- breast cancer (Neo-tAnGo): an open-label, 2 × 2 factorial cebo controlled, phase III study. Eur Urol Suppl. 2011; randomised phase 3 trial. Lancet Oncol 2014;15:201–12. 10[2]:338. Gravis G, Marino P, Joly F, Oudard S, Priou F, Esterni B, Hervonen P, Joensuu H, Joensuu K, Nyandoto P, Luukkaa et al. Patients' self-assessment versus investigators' evaluation M, Nilsson S, et al. Phase III, randomized, open-label study of in a phase III trial in non-castrate metastatic prostate cancer triweekly docetaxel versus biweekly docetaxel as treatments (GETUG-AFU 15). Eur J Cancer 2014;50[5]:953–62. for advanced hormone-refractory prostate cancer: Findings Support Care Cancer (2016) 24:1583–1594 1591 from an interim safety analysis of the Finnish Uro-oncological trial of BMS-275,291 in patients with early stage breast can- Group Study 1–2003. J Clin Oncol. 2011; 29(7 SUPPL. 1). cer. Clin Cancer Res 2004;10[6]:1971–5. Hoque E, Karim S, Reza MDS, Ahmed TU, Adnan RA. Pusztai L, Mendoza TR, Reuben JM, Martinez MM, Clinical experience of docetaxel in combination with prednis- Willey JS, Lara J, et al. Changes in plasma levels of inflam- olone and zoledronic acid for hormone-refractory prostate matory cytokines in response to paclitaxel chemotherapy. cancer (HRPC): A Bangladesh perspective. J Clin Oncol. Cytokine 2004;25[3]:94–102. 2011; 29(15 SUPPL. 1). Markman M. Management of toxicities associated Meulenbeld HJ, van Werkhoven ED, Coenen JLLM, with the administration of taxanes. Expert Opin Drug Creemers G, Loosveld OJL, de Jong PC, et al. Randomized Saf 2003;2[2]:141–6. phase III study of docetaxel with or without risedronate in Penson DF. Assessment of patients with castrate- patients with bone metastases from castration-resistant pros- resistant prostate cancer. Clin Adv Hematol Oncol tate cancer (CRPC): The Netherlands Prostate Study (NePro). 20119[7]:4–6. J Clin Oncol. 2011; 29(15 SUPPL. 1). Sartor O. Prognosis of patients with castrate-resistant pros- Ou Y, Michaelson MD, Sengelov L, Saad F, Houede N, tate cancer. Clin Adv Hematol Oncol 20119[7]:7–9. Ostler PJ, et al. Randomized, placebo-controlled, phase III Gardner TA, Elzey BD, Hahn NM. Sipuleucel-T trial of sunitinib in combination with prednisone (SU + P) (Provenge) autologous vaccine approved for treatment of versus prednisone (P) alone in men with progressive metasta- men with asymptomatic or minimally symptomatic castrate- tic castration-resistant prostate cancer (mCRPC). J Clin resistant metastatic prostate cancer. Hum Vaccines Oncol. 2011; 29(15 SUPPL. 1). Immunother 20128[4]:526 –531. Pond GR, Armstrong AJ, Wood BA, Brookes M, Seal B, Puto K, Allen PD, Asche CV. Patient- Leopold LH, Burke JM, et al. Assessment of two prog- reported outcomes (PROS) and tolerability of therapeu- nostic risk group methods to predict outcomes with tic agents in patients with metastatic prostate cancer docetaxel-based therapy in men with metastatic castration- (MPC): A systematic literature review. Value Health resistant prostate cancer (mCRPC). J Clin Oncol. 2011; 29(7 201215[4]:A226. SUPPL. 1). Wilson LS, Zhong L, Pon V, Srinivas S, Frear M, Nguyen Saad F, De Bono JS, Haqq CM, Logothetis CJ, Fizazi K, N, et al. Cost effectiveness analysis of new treatments for Jones RJ, et al. Abiraterone acetate plus low-dose prednisone metastatic castration-resistant prostate cancer: Does severity has a favorable safety profile, improves survival and produces matter? Value Health 201215[4]:A220-A221. PSA and radiographic responses in metastatic castration- Merseburger AS, Scher HI, De WR, Bellmunt J, resistant prostate cancer progressing after docetaxel-based Miller K, Mulders P, et al. Enzalutamide (ENZA) has chemotherapy: Results from COU-AA-301, a randomized, similareffectinEuropean(EU)andNorthAmerican double-blind, placebo-controlled, phase III study. J Urol. (NA) men despite regional differences in diagnosis and 2011; 185(4 SUPPL. 1):e283-e284. treatment: AFFIRM trial subanalysis. Urologe Ausg A Moulder SL, Holmes FA, Tolcher AW, Thall P, Broglio K, 201352(1 SUPPL. 1):76. Valero V, et al. A randomized phase 2 trial comparing 3-h versus 96-h infusion schedules of paclitaxel for the treatment Article describes arthropathy post-chemotherapy of metastatic breast cancer. Cancer 2010;116[4]:814–21. Eaton KD, Frieze DA. Cancer pain: Perspectives of a med- Kim M-J, Ye Y-M, Park H-S, Suh C-H. Chemotherapy-related ical oncologist. Curr Pain Headache Rep. 2008; 12[4]:270–276. arthropathy. J Rheumatol. 2006; 33[7]:1364–1368 Ledeboer A, Hutchinson MR, Watkins LR, Johnson KW. Ibudilast (AV-411): A new class therapeutic candidate for neu- Cancer-related pain ropathic pain and opioid withdrawal syndromes. Expert Opin Investig Drugs. 2007; 16[7]:935–950. Basch EM, De Bono JS, Scher HI, Molina A, Sternberg CN, Gilron I, Flatters SJL. Gabapentin and pregabalin for the Fizazi K, et al. Pain control and delay in time to skeletal- treatment of neuropathic pain: A review of laboratory and related events (SREs) in patients with metastatic castration- clinical evidence. Pain Res Manage. 2006; 11(SUPPL. resistant prostate cancer (mCRPC) treated with abiraterone A):16A-29A. acetate (AA): Long-term follow-up. J Clin Oncol. 2012; Chao TC, Chu Z, Tseng LM, Chiou TJ, Hsieh RK, Wang 30(5 SUPPL. 1) WS, et al. Paclitaxel in a novel formulation containing less Cremophor EL as first-line therapy for advanced breast can- Duplicate publication cer: a phase II trial. Invest New Drugs 2005;23[2]:171–7. Miller KD, Saphner TJ, Waterhouse DM, Chen TT, Rush- Markman M. Prevention of paclitaxel-associated arthralgias Taylor A, Sparano JA, et al. A randomized phase II feasibility and myalgias. J Support Oncol. 2003; 1[4]:233–234. 1592 Support Care Cancer (2016) 24:1583–1594

Appendix 3: PRISMA Checklist

Section/topic # Checklist item Reported on page # Title Title 1 Identify the report as a systematic review, meta-analysis, or both. 1 Abstract Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data 2–3 sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. Introduction Rationale 3 Describe the rationale for the review in the context of what is already known. 4–5 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, 5–6 interventions, comparisons, outcomes, and study design (PICOS). Methods Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, N/A if available, provide registration information including registration number. Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., 5 years considered, language, publication status) used as criteria for eligibility, giving rationale. Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study 5–6 authors to identify additional studies) in the search and date last searched. Search 8 Present full electronic search strategy for at least one database, including any limits used, 20–22 such that it could be repeated. Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic 5–6 review, and, if applicable, included in the meta-analysis). Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in 5–6 duplicate) and any processes for obtaining and confirming data from investigators. Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and 5 any assumptions and simplifications made. Risk of bias in 12 Describe methods used for assessing risk of bias of individual studies (including 7,17 individual studies specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). NA Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including NA measures of consistency (e.g., I2) for each meta-analysis. Risk of bias across 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., 7,17 studies publication bias, selective reporting within studies). Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta- NA regression), if done, indicating which were pre-specified. Results Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with 6,7, 19 reasons for exclusions at each stage, ideally with a flow diagram. Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, 8–13,18 PICOS, follow-up period) and provide the citations. Risk of bias within 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see 7,17 studies item 12). Results of individual 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary 8–13 studies data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of NA consistency. Risk of bias across 22 Present results of any assessment of risk of bias across studies (see Item 15). 7,17 studies Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta- NA regression [see Item 16]). Discussion Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; 14 consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., 14–16 incomplete retrieval of identified research, reporting bias). Support Care Cancer (2016) 24:1583–1594 1593

(continued)

Section/topic # Checklist item Reported on page # Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and 16 implications for future research. Funding Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of 7 data); role of funders for the systematic review.

References cancer patients who were previously treated with platinum-based chemotherapy. Cancer Res Treat 37(6):339–343 15. Wang Yet al (2014) A multicenter, non-randomized, phase II study 1. Dumontet C, Jordan MA (2010) Microtubule-binding agents: a of docetaxel and carboplatin administered every 3 weeks as second dynamic field of cancer therapeutics. Nat Rev Drug Discov 9: line chemotherapy in patients with first relapse of platinum sensitive – 790 803 epithelial ovarian, peritoneal or fallopian tube cancer. BMC Cancer. 2. Charles L (2011) Loprinzi et al. Natural history of paclitaxel- 14:937 associated acute pain syndrome: prospective cohort study 16. Bois D et al. (2003) A randomized clinical trial of cisplatin/ – NCCTG N08C1. J Clin Oncol 29:1472 1478 paclitaxel versus carboplatin/paclitaxel as first-line treatment of 3. Roché H et al. (2006) Sequential adjuvant epirubicin-based and ovarian cancer. J Natl Cancer Inst 95(17):1320–1329 docetaxel chemotherapy for node-positive breast cancer patients: 17. Sarris AH et al. (1996) Cyclosporin A does not reverse clinical – the FNCLCC PACS 01 trial. J Clin Oncol 24:5664 5671 resistance to paclitaxel in patients with relapsed non-Hodgkin’s 4. Jones SE, Savin MA, Holmes FA, et al. (2006) Phase III trial com- lymphoma. J Clin Oncol 14(1):233–239 paring doxorubicin plus cyclophosphamide with docetaxel plus cy- 18. Markman M, Kennedy A, Webster K, et al (1999) Use of low-dose clophosphamide as adjuvant therapy for operable breast cancer. J oral prednisone to prevent paclitaxel-induced arthralgias and myal- – Clin Oncol 24:5381 5387 gias. Gynecol Oncol 72:100–101 5. Miguel Martin et al. (2005) Adjuvant Docetaxel for Node-Positive 19. Martoni A, Zamagni C, Gheka A, et al (1993) Antihistamines in the Breast Cancer. NEJM 352;22 treatment of Taxol-induced paroxystic pain syndrome. J Natl 6. Smith RE, Anderson SJ, Brown A, et al. (2002) Phase II trial Cancer Inst 85:676 doxorrubicin/docetaxel/cyclophosphamide for locally advanced 20. Van Deventer H, Bernard S. Use of gabapentin to treat taxane- and metastatic breast cancer: results from nsabp trial BP-58. Clin induced arthralgias and myalgias.DOI:10.1200/Jco.2004.99.298 Breast Cancer 3:333–340 21. Van Deventer H (1999) Use of Gabapentin to treat taxane-induced 7. Rivera E et al. (2008) Phase 3 study comparing the use of docetaxel myalgias. Jco 17(1) January:434–435 on an every-3-week versus weekly schedule in the treatment of 22. Imai A et al. (2012) Proposed medications for taxane-induced my- metastatic breast cancer. Cancer 112:1455 algia and arthralgia. Oncology Letters 3:1181–1185 8. Mamounas EP, Bryant J, Lembersky B, et al. (2005) Paclitaxel after 23. Strasser F, Demmer R, Böhme C, Schmitz SF, Thuerlimann B, doxorubicin plus cyclophosphamide as adjuvant chemotherapy for Cerny T, Gillessen S (2008) Prevention of docetaxel- or node-positive breast cancer: results from nsabp B-28. J Clin Oncol paclitaxel-associated taste alterations in cancer patients with oral 23:3686–3696 glutamine: a randomized, placebo-controlled, double-blind study. 9. William J, Gradishar A, et al (2009) Significantly longer Oncologist 13:337–346 progression-free survival with nab-paclitaxel compared with doce- 24. Fujiwara H. (2001) Prevention of arthralgias and myalgias from taxel as first-line therapy for metastatic. Breast Cancer J Clin Oncol paclitaxel andCBDCA combination chemotherapy with 27:3611–3619 shakuyaku-kanzo-to and L-glutamine. Proc Am Soc Clin Oncol 10. Ian F. Tannock et al. Tolerability and efficacy of docetaxel in older 20:299b, (abstr 2948) men with metastatic castrate-resistant prostate cancer (mCRPC) in 25. Higgins JPT, Green S. (2011) (editors). Cochrane Handbook for the TAX 327 trial Systematic Reviews of Intreventions Version 5.1.0. The Cochrane 11. Saibil S et al. (2010) Incidence of taxane-induced pain and Collaboration distress in patients receiving chemotherapy for early-stage 26. Jacobson SD, Loprinzi CL, Sloan JA, Wilke JL, Novotny PJ, breast cancer: a retrospective, outcomes-based survey. Curr Okuno SH, et al. (2003) Glutamine does not prevent paclitaxel- Oncol 17(4):42–47 associated myalgias and arthralgias. J Support Oncol 1(4):274–278 12. Damaraju S, Ghosh S, Tuszynski J, Greiner R, Lai R, Cass C, 27. Leal AD, Qin R, Atherton PJ, Haluska P, Behrens RJ, Tiber CH, Mackey J (2010) JCYP3A5*3 (rs776746) is associated with et al. (2014) North Central cancer treatment group/alliance trial docetaxel-specific toxicities during adjuvant breast cancer chemo- N08CA-the use of glutathione for prevention of paclitaxel/ therapy. European J of Cancer 8(7):p 175 carboplatin-induced peripheral neuropathy: a phase 3 randomized, 13. Damaraju S, Sehrawat BS, Ghosh S, Pituskin E, Tuszynski J, Cass double-blind, placebo-controlled study. Cancer 120(12):1890– CE, Mackey JR (2010) Germline Copy Number Polymorphisms 1897 Associated with Toxicity from Adjuvant Docetaxel. Cancer 28. Gelmon K, Eisenhauer E, Bryce C, Tolcher A, Mayer L, Tomlinson Research 70(24):p258s E, et al. (1999) Randomized phase II study of high-dose paclitaxel 14. Shim A et al (2005) The safety and efficacy of second-line single 2 with or without amifostine in patients with metastatic breast cancer. docetaxel (75 mg/m ) therapy in advanced non-small cell lung J Clin Oncol 17(10):3038–3047 1594 Support Care Cancer (2016) 24:1583–1594

29. Rick O, Beyer J, Schwella N, Schubart H, Schleicher J, Siegert W 32. Ryan M, Franke, et al (2010) Castration-dependent pharmacokinet- (2001) Assessment of amifostine as protection from chemotherapy- ics of docetaxel in patients with prostate cancer. J Clin Oncol 28: induced toxicities after conventional-dose and high-dose chemo- 4562–4567 therapy in patients with germ cell tumor. Ann Oncol 12(8):1151– 33. Bahl A et al. (2013) Impact of cabazitaxel on 2-year survival and 1155 palliation of tumour-related pain in men with metastatic castration- 30. Nguyen VH, Lawrence HJ (2004) Use of gabapentin in the preven- resistant prostate cancer treated in the TROPIC trial. Ann Oncol 24: tion of taxane-induced arthralgias and myalgias. J Clin Oncol 22(9): 2402–2408 1767–1769 34. Kuchuk I et al. (2013) Preference weights for chemotherapy side 31. Higgins Julian PT, Altman Douglas G, Gøtzsche Peter C, Peter J, effects from the perspective of women with breast cancer. Breast David M, Oxman Andrew D, et al (2011) The Cochrane Cancer Res Treat 142(1):101–107 Collaboration’s Tool for Assessing Risk of Bias in Randomised 35. Yamamoto K, Hoshiai H, Noda K (2001) Effects of shakuyaku- Trials. BMJ 343:d5928 kanzo-to on muscle pain from combination chemotherapy with paclitaxel and carboplatin (letter). Gynecol Oncol 81:333–334