Support Care (2015) 23:1473–1481 DOI 10.1007/s00520-015-2678-9

REVIEW ARTICLE

Pharmacological options for the management of refractory cancer —what is the evidence?

B. Afsharimani & K. Kindl & P. Good & J. Hardy

Received: 21 November 2014 /Accepted: 22 February 2015 /Published online: 7 March 2015 # Springer-Verlag Berlin Heidelberg 2015

Abstract Refractory cancer pain that does not respond to fashion according to the severity of pain [1]. These guidelines standard and/or co- therapy occurs in 10– are considered the world standard for pain control. It is gen- 20 % of patients. Risk factors include young age, neuropathic erally accepted that the use of these guidelines results in the pain type, incident pain, psychological distress, previous opi- control of pain in the majority of patients [2]. oid use, high tolerance, a history of and impaired Refractory cancer pain has been defined as pain related to cognition. The management of patients with refractory pain cancer or its treatment, of at least 3 months duration, that has remains a challenge. Treatment options include opioid manip- not responded to standard treatment with and co- ulation (parenteral delivery, rotation, combination, methadone [3]. There is no standard definition however, and and buprenorphine), non-opioids and co-analgesics (paracet- cancer pain that is difficult to control has been variously de- amol, non-steroidal anti-inflammatory agents, antidepressants scribed as difficult, persistent, intractable or opioid non- and ), NMDA receptor antagonists, cannabi- responsive in heterogeneous populations exposed to a range noids, lignocaine and corticosteroids. The evidence of benefit of different medications and interventions. It has been report- for any of these agents is weak, and each additional agent ed to occur in 10–20 % of cancer patients. [4]. The character- increases the risk of adverse events. Evidence-based guide- istics that lead to difficult pain control are said to include lines cannot, therefore, be developed at present. New ap- young age, type, incident pain, psychologi- proaches are recommended including targeted opioid therapy, cal distress, previous opioid use, high tolerance, a history of multimodal analgesia, a goal-oriented approach to pain man- addiction and impaired cognition [5]. The prognosis of cancer agement and increasing use of the multidisciplinary team and pain is reported to be worse in those with mixed pain type, support services. high pain severity, daily opioid use and poor emotional well- being [5]. With the goal of developing evidence-based guide- Keywords Cancer pain . Refractory . Evidence . Analgesia lines for refractory cancer , the evidence for the treatments and interventions commonly used for refractory cancer pain was examined.

Introduction Methods World Health Organisation (WHO) analgesic guidelines rec- Strategies for the management of refractory cancer pain were ommend a limited number of drugs titrated in a step-wise obtained from a survey of physicians [6], from reviews of refractory cancer pain management [7] and from B. Afsharimani : K. Kindl : P. Good : J. Hardy (*) Department of Palliative and Supportive Care , Mater Health personal experience of the authors and palliative care col- Services, and Mater Research Institute, University of Queensland, leagues. Evidence for the effectiveness of each intervention Brisbane, Australia was sought primarily from the Cochrane data base and from e-mail: [email protected] published systematic reviews searched via Cochrane, P. Good EMBASE, PUBMED and the Joanna Briggs Institute. In the St Vincent’s Private Hospital, Brisbane, Australia absence of a formal Cochrane review, systematic reviews, 1474 Support Care Cancer (2015) 23:1473–1481 randomised and non-randomised controlled trials were accept- other opioids or routes of administration found subcutaneous ed. Unless specified otherwise, all trials discussed are to be well tolerated and effective in the management randomised controlled trials (RCTs). The quality of included of refractory pain [21]. In a small retrospective study of cancer studies was not formally assessed or scored. Non- patients who could not tolerate subcutaneous , sub- pharmacological interventions including interventional tech- cutaneous fentanyl infusion was used to achieve analgesia niques, complementary therapies and psychological support with limited side effects [22]. have not been included and will be the subject of a subsequent At present, there is no evidence to support the superiority of review. parenteral versus oral opioid administration in controlling in- tractable cancer pain. Based on available evidence, the Euro- pean Association of Palliative Care (EAPC) recommends the Results use of parenteral opioid infusions in cases where oral or trans- dermal opioids fail to provide effective analgesia [15]. Opioids Opioid rotation Opioids remain the only analgesics with proven benefit in severe cancer pain [8, 9]. Opioid dose escalation in the face Changing or switching from one opioid to another has been of increasing pain is often limited by adverse effects. Several reported in many uncontrolled trials and descriptive studies to approaches have been proposed to address this including the lead to improved pain relief and/or reduction in toxicity. Pro- proactive and aggressive management of side effects, the use posed mechanisms include incomplete cross-tolerance, varia- of co-analgesics, alternative routes of administration or tion in intrinsic opioid receptor activity, inter and intra-patient switching to a different opioid (opioid rotation) [10]. variation in pharmacokinetics/dynamics and relative Parenteral opioids desensitisation of opioid receptors [23]. A Cochrane review identified multiple case studies, retro- spective reviews and prospective uncontrolled trials all of High serum concentrations of opioids can be achieved rapidly which showed benefit [24]. None of the studies was of suffi- by parenteral administration although the correlation between cient quality to be included in a meta-analysis. A subsequent serum opioid concentrations and analgesia is poor [11–13]. systematic review identified eleven new trials, of which the Clinical studies have shown similar efficacy and tolerability majority showed opioid switching to be highly effective in for both intravenous and subcutaneous delivery [14]. Subcu- controlling cancer pain and reducing adverse effects [25]. taneous injection is generally preferred due to ease of admin- All of the studies were of limited quality and lacked istration, but the intravenous route can provide faster pain randomisation or controls. relief [15]. Few studies have explored the possibility that refractory cancer pain responds to a rapid and intensive analgesic inter- Opioids in combination vention. In a small open-label RCT assessing the use of par- enteral morphine titration for pain exacerbations, pain was Theoretically, patients with pain refractory to a single opioid controlled in 77 % of the cases with no difference between might benefit from the addition of a second opioid, especially the subcutaneous and intravenous routes [16]. In patients with when using drugs with different characteristics such as differ- severe pain from advanced cancer, intravenous morphine was ent lipid solubility, routes of metabolism, degree of receptor shown to be safe and to result in better immediate analgesia activation/antagonism or opioid receptor type affinity. Animal than oral morphine [17]. studies have confirmed the benefit of using a combination of The peak onset of action of morphine is seen after about different opioids in improving analgesia and reducing depen- 30 min, even when administered intravenously [18]. More dence [26]. Human studies on the benefit of combination opi- lipophilic opioids such as fentanyl readily cross the blood oid analgesia are contradictory. A prospective clinical trial brain barrier and provide effective analgesia more rapidly. comparing combination opioid therapy and opioid rotation One small RCT studied the benefit of subcutaneous fentanyl in cancer patients with uncontrolled pain showed similar ben- compared to morphine in cancer patients and found both drugs efit in pain reduction and adverse effects for both manoeuvres to be equally efficacious [19]. An uncontrolled observational [27]. In contrast, a systematic review on the efficacy and safe- study in patients seen in emergency rooms with severe pain ty of a combination of strong opioids in controlling cancer showed fast opioid titration with bolus intravenous fentanyl to pain included two studies that showed better pain relief and be safe and effective in controlling pain [20]. A retrospective lower side effects when a second opioid was added to the analysis of cancer patients commenced on subcutaneous fen- original [28]. Unfortunately, due to methodological problems tanyl infusions because of toxicity or uncontrolled pain from in study design, only a weak recommendation could be made Support Care Cancer (2015) 23:1473–1481 1475 towards the use of combination strong opioids in controlling study in patients with advanced cancer, switching to metha- cancer pain. done from was successful in improving pain and/ or adverse effects and distress [35]. Methadone Methadone may contribute to the management of refracto- ry pain, but to date, there remains considerable uncertainty Methadone is often used as a second-line agent in difficult regarding dose equivalence, how best to titrate and concern pain, instead of, or in conjunction with, other opioids. Inhibi- over potential toxicity. tion of NMDA receptors and monoamine reuptake plus acti- vation of kappa and delta opioid receptors is postulated to lead to additional analgesia and reversal of opioid tolerance. Anec- Buprenorphine dotally, methadone has benefit in patients with predominantly neuropathic pain [29]. Buprenorphine is a semi-synthetic partial agonist of the mu This opioid is difficult to use because of significant inter- opioid receptor with proven efficacy in controlling chronic patient variation in efficacy and unpredictable adverse effects. pain. In patients requiring escalating doses of opioids for pain Dose titration is complex due to the highly variable pharma- management, buprenorphine may stabilise opioid dosing, pro- cokinetic profile of the drug. Patients must be closely moni- vide effective pain relief and improve quality of life (QoL) tored because of the possibility of drug accumulation and [36]. unintended overdose. Methadone is frequently used in the Transdermal buprenorphine has been shown to have a more scenario of opioid rotation or switching. The morphine dose favourable profile compared to pure mu ago- equivalence of methadone is not clear. It has been suggested nists such as morphine or fentanyl [37, 38]. Buprenorphine that the morphine-to-methadone equipotent ratio varies de- transdermal patches resulted in better analgesia compared to pending on the prior dosage of opioids administered, and that and rescue buprenorphine in 157 patients with severe in patients on higher doses of morphine, lower doses of meth- uncontrolled pain from cancer or other disorders [39]. In 137 adone are needed to achieve the same analgesic effect [30]. patients (including 45 cancer patients) with severe chronic A Cochrane review of methadone versus opioid compara- pain, there was a trend towards better pain relief in patients tors included nine RCTs and 459 participants. A number of randomised to transdermal buprenorphine [40]. Compared to different dose and titration schedules were used along with placebo (with rescue analgesia), transdermal buprenorphine various pain scales. No superiority over morphine was shown administration resulted in lower pain intensity, less need for nor superiority with respect to the treatment of neuropathic rescue analgesics and fewer discontinuations [41]. In an open pain. Patients on methadone had a higher rate of withdrawal observational surveillance study in 13,179 patients with due to adverse events [31]. (including 3690 cancer patients), effective pain More recently, two RCTs showed a benefit for switching to relief, good tolerability and less need for rescue therapy were methadone. In cancer patients with refractory pain, sustained- seen in patients receiving buprenorphine patches [42]. release morphine, methadone and transdermal fentanyl were Compared to sustained-release morphine administration, similarly effective in controlling pain, but the need for opioid transdermal buprenorphine was more effective in providing escalation was significantly less with methadone [31]. A com- long-term pain control and improving QoL in cancer patients bination of epidural methadone and lidocaine has been com- assessed by a randomised prospective study [43]. pared to epidural lidocaine alone in cancer patients whose pain Buprenorphine is also reported to be effective in control- was not adequately controlled with oral morphine. The addi- ling neuropathic and breakthrough pain in cancer patients and tion of methadone to lidocaine reduced the need for oral mor- to be an option in opioid rotation [37]. Unfortunately, three phine consumption in a dose-dependent manner. This was systematic reviews have concluded that due to the poor quality improved when epidural dexamethasone was added to the of evidence, a definitive conclusion cannot be made on the regimen [32]. efficacy of this drug in moderate-to-severe cancer pain The additive effect of acetaminophen on the analgesic ef- [44–46]. ficacy of methadone in cancer patients has been studied. Par- ticipants were switched from a stable dose of morphine to methadone and plus either acetaminophen or placebo. Al- Non-opioid analgesics and co-analgesics though acetaminophen showed no advantage over placebo, switching to methadone significantly improved pain scores, The WHO analgesic ladder supports the use of non-opioid constipation and xerostomia [33]. Switching to methadone analgesics ( and NSAIDs) and adjuvant analge- from other opioid analgesics was also shown to be safe and sics as monotherapy for mild cancer pain and as adjunct for effective in a prospective uncontrolled study in 21 opioid- improving opioid analgesia in moderate-to-severe pain in can- tolerant cancer patients [34]. In a prospective uncontrolled cer patients [47]. 1476 Support Care Cancer (2015) 23:1473–1481

Paracetamol and NSAIDs and amitriptyline [59] in treatment-related neuropathic pain in cancer patients demonstrated effectiveness. In patients with Paracetamol and/or NSAIDs are used in patients with cancer- advanced cancer, there was no improvement in pain control related pain because of their postulated opioid-sparing effect when amitriptyline was added to an opioid analgesic regimen [48, 49]. Although effective in mild to moderate cancer pain, [60]. In pain related to bone metastases, a combination of low- these preparations have limited value in severe pain as dose dose antidepressants (imipramine or mirtazapine) with an an- escalation is restricted by adverse effects. A Cochrane review ticonvulsant (pregabalin) provided better pain control com- found 14 studies that compared the efficacy of opioids and pared to pregabalin alone [61]. There is recent evidence for NSAIDs or paracetamol, alone or in combination, in cancer the benefit of duloxetine in -induced painful pain. Nine studies showed a slight advantage, one insignifi- [62]. cant advantage and four no advantage for combinations of A systematic review analysed 14 RCTs and 16 non- opioids and NSAIDs/paracetamol over each drug used alone randomised studies of neuropathic cancer pain based on abso- [50]. A more recent systematic review identified two other lute risk benefit and absolute risk harm. Overall, absolute risk studies that showed a benefit of adding NSAIDs/paracetamol benefit of antidepressants, anticonvulsants, other adjuvant an- to an opioid analgesic regimen in cancer patients [48]. One algesics or opioids outweighed absolute risk harm [63]. RCT assessed the outcome of adding oral ketorolac to mor- Although guidelines recommend using antidepressants for phine treatment in patients with advanced cancer. Ketorolac neuropathic pain especially in cancer patients with mood dis- (60 mg/day) led to better analgesia and reduced the need for orders, rigorous data are lacking to endorse the use of antide- opioid dose escalation [51]. The introduction of dipyrone to a pressants as co-analgesics in cancer pain and current practice morphine regimen significantly improved analgesia compared is mainly based on clinical experience. to placebo in another small RCT [52]. In summary, NSAIDs can have an opioid-sparing effect Anticonvulsants and might improve analgesia. However, since clinical studies are of insufficient number or quality, they can only weakly Anticonvulsants, particularly gabapentin and pregabalin, are support the use of NSAIDs as co-analgesics in the manage- commonly used as first-line treatment in neuropathic pain ment of cancer pain [48]. [64]. Their effect is thought to be exerted through binding to presynaptic calcium channels, decreasing calcium influx and Antidepressants neurotransmitter release [65]. A systematic review that analysed five RCTs and three Neuropathic pain accounts for about one third of refractory non-randomised studies on the benefit of combining antide- pain associated with cancer [5]. Opioid analgesics alone often pressants or antiepileptic drugs with opioid analgesics in neu- fail to control pain completely [7]. Historically, antidepres- ropathic cancer pain found the strongest evidence for the ef- sants have been used as co-analgesics for the management fectiveness of gabapentin [66] although a recent RCT showed of neuropathic pain. Any analgesic effect is independent of similar analgesic efficacy for both gabapentin and amitripty- the psychological impact and is thought to be due to enhanced line when used as co-analgesics in this setting [67]. In a RCT norepinephrine and serotonin-mediated descending inhibitory in cancer patients, neuropathic pain intensity was significantly output and possibly blockade of sodium channels [53]. The lower in patients treated with pregabalin as compared to pla- evidence of benefit in the management of pain comes largely cebo [68]. Similarly, pregabalin provided better control of from trials of non-malignant pain. neuropathic cancer pain compared to placebo, gabapentin or A Cochrane review of tricyclic antidepressants in all pain amitriptyline and reduced opioid consumption [69]. types suggested that the number needed to treat (NNT) for at Pregabalin also provides better pain relief and patient satisfac- least moderate pain reduction was 3.6. The number needed to tion compared to transdermal fentanyl [70]. High quality con- harm (NNH) for minor and major adverse events was 3.7 and trolled trials are still needed to support the safety and efficacy 22, respectively. These results are similar to those for the of these drugs in cancer patients [71]. newer antidepressants such as venlafaxine (NNT=3.1) [54]. A systematic review of amitriptyline showed evidence of ben- N-methyl-D-aspartate (NMDA) receptor antagonists efit in some non-malignant pain scenarios but failed to find any unbiased well-designed clinical studies to support its use Ketamine is a general anaesthetic agent that is often used at in cancer pain, [55]. Duloxetine has been shown in three subanaesthetic doses as a co-analgesic, usually in combination double-blind RCTs to be effective in controlling diabetic pe- with opioids, particularly in neuropathic pain [72]. It interacts ripheral neuropathic pain [56]. with multiple receptors thought to be involved in pain percep- Very few studies have been performed in cancer-related tion. NMDA receptor activation is thought to result in neuro- neuropathic pain. Three small RCTs of venlafaxine [57, 58] nal hyperexcitability and the development of opioid tolerance. Support Care Cancer (2015) 23:1473–1481 1477

Ketamine has been used commonly in palliative care for the decreased pain scores and morphine consumption compared management of refractory or difficult pain, usually in combi- to untreated patients [84]. nation with opioids [73]. There is great variation in practice (Sativex®) is an oromucosal spray containing with respect to the type of pain treated with this drug, the dose, a 1:1 combination of tetrahydrocannabinol (THC), the princi- route and frequency of delivery. pal psychoactive constituent of the cannabis plant and A Cochrane review updated in 2012 included two RCTs cannabidiol. It is approved in some countries for the treatment that evaluated the effectiveness of adding ketamine to opioids of neuropathic pain in multiple sclerosis (MS) and refractory in cancer patients with refractory pain. Both studies found pain in cancer [85]. A placebo-controlled randomised trial ketamine administered intravenously [74] or intrathecally assessed the effect of different doses of nabiximols on [75] to be effective in improving analgesia. Pooling of data opioid-unresponsive refractory pain in 360 cancer patients. was not possible due to the small size and clinical heteroge- Low and medium doses of nabiximols were well-tolerated neity of the studied populations. The review concluded that and improved analgesia after 5 weeks of treatment [86]. The the current evidence was insufficient to support the use of safety and efficacy of this combination preparation was shown ketamine as an adjuvant to opioids for refractory cancer pain in another RCTcomparing nabiximols and THC with placebo. [76]. While pain scores in patients receiving THC were similar to More recently, two multicentre double-blind RCTs found placebo, nabiximols significantly reduced pain [87]. This ef- no benefit for the addition of ketamine to opioids in treating fect persisted with long-term use as shown by a subsequent cancer pain. The effect of parenteral ketamine as an adjuvant open-label follow-up study [88]. The primary adverse effects analgesic was studies in 185 adult patients with refractory pain at therapeutic doses are drowsiness, somnolence and dry due to cancer or its treatment. Ketamine did not result in any mouth, and there remain concerns about psychoactive effects improvement in pain over placebo and was associated with and potential for addiction and abuse [89]. The limited avail- significantly more adverse events [4]. The other RCT, per- ability of cannabinoids in many countries precludes its use for formed in a smaller number of patients, compared analgesic refractory pain in most situations. outcome after intravenous morphine with or without a contin- uous intravenous infusion of ketamine. The addition of keta- Lignocaine mine failed to provide any advantage over morphine alone [77]. Lignocaine, a local anaesthetic used topically to relieve per- Soto et al. reviewed randomised and non-randomised clin- sistent focal pain, has been used as an adjunct analgesic in ical data on the use of oral ketamine in cancer and neuropathic neuropathic pain caused by cancer or its treatment [89]. Sys- pain and found mixed results on the safety and efficacy of oral temic administration of lignocaine and other antiarrhythmic ketamine in these settings [78]. A recent systematic review drugs (such as flecainide and mexiletine) have also been used evaluated clinical data on the use of ketamine for cancer pain. for the control of postoperative or cancer pain. Preclinical and Five RCTs and six uncontrolled studies in adult cancer pa- clinical findings have indicated analgesic efficacy for tients were included. The findings in relation to effectiveness lignocaine in neuropathic pain [90]. A Cochrane review con- were contradictory [79]. cluded that current evidence endorses the safety and efficacy Overall, clinical opinion remains divided regarding keta- of parenteral lignocaine and its oral analogues in controlling mine as adjuvant analgesic in refractory cancer pain. Robust neuropathic pain [91]. However, as very few studies reported evidence to support its benefit in this setting is lacking. their outcome in cancer patients, no definite conclusion could be made about the use of these drugs for the management of Cannabinoids cancer pain.

According to one systematic review, the existing data from Corticosteroids several RCTs suggest that cannabinoids are safe and effective in controlling different types of chronic pain, particularly neu- The analgesic effect of corticosteroids, particularly in inflam- ropathic pain [80]. Activation of cannabinoid receptors at pre- matory and neuropathic pain, may result from inhibition of synaptic sites and interaction with opioid, serotonergic and cytokine-mediated perception of pain [92]. A systematic re- dopaminergic signalling are thought to result in an analgesic view of literature found four RCTs that assessed the outcome effect [81]. of corticosteroid administration in cancer patients [93]. Two of Early findings from RCTs published in the 1970s found these studies did not adequately report the pain outcome [94, moderate analgesic efficacy for cannabinoids in cancer pain, 95]; one study showed significant improvement in analgesia comparable to , but with dose-limiting adverse effects and a reduction of analgesic consumption while another [82, 83]. A non-randomised prospective observational study showed no beneficial effect for corticosteroids [96, 97]. In in patients with advanced cancer suggested that nabinol another RCT, the addition of epidural dexamethasone 1478 Support Care Cancer (2015) 23:1473–1481 enhanced the analgesic efficacy of epidural methadone and pain transmission. This approach aims to minimise individual lidocaine with lower consumption of morphine by cancer pa- drug doses and target multiple receptors [100]. tients with refractory pain [32]. In a more recent study, cancer patients on opioids were randomised to methylprednisolone or Influence of pain duration placebo. Methylprednisolone did not provide additional anal- gesia but improved and appetite [98]. Considering the Some studies [101] have suggested that the longer a patient limited evidence on efficacy in controlling cancer pain and the experiences pain, the harder it is to achieve adequate analge- potential for serious toxicity with long-term use, a careful risk- sia. This may be related to the development of benefit analysis should be undertaken before using corticoste- or drug dependence. Future studies need to determine how roids for cancer pain. important timing of pain relief is as a predictive factor and emphasises the need for early pain control. Discussion A goal-orientated approach rather than a number/score-based The management of refractory cancer pain remains a chal- approach to pain management lenge. Current strategies often involve the addition of a suc- cession of unproven medications or interventions to standard To date, a response to pain has been measured numerically. It opioids and co-analgesics. Each additional medication has a is generally considered that a 2-point improvement on an 11- reduced likelihood of controlling pain and an increased poten- point numerical rating scale constitutes a clinically relevant tial for added toxicity [3]. As demonstrated in this review, improvement in pain [102]. Improving or maintaining an in- there is a paucity of high level evidence to guide refractory dividual’s function and their achievement of daily goals may cancer pain management. Clinicians are largely reliant on ev- be more important. idence extrapolated from non-cancer pain scenarios, anec- dotes or uncontrolled and low-quality studies. Unproven in- Increasing use of support services and the inter-disciplinary terventions should only be considered in the context of a clin- team ical trial or be subject to rigorous prospective evaluation using standardised tools and data collection systems. The focus of Individualised inter-disciplinary palliative care is believed to future pain management should be on new approaches and improve patient outcomes in cancer and end-of-life patients optimising the use of currently available drugs and techniques [103]. Anecdotally, the ability of a patient or carer in distress as illustrated below. to be able to contact a health professional to discuss an issue or problem can contribute significantly to symptom relief. Sev- Targeted opioid therapy eral studies have shown the benefit of telephone support [104]. Similarly, the involvement of an inter-disciplinary team Opioids remain the only analgesics with proven benefit in to provide holistic care may be the most effective means of severe pain. Rather than the current practice of slow dose treating ‘total pain’ [105]. titration of one drug until effect or toxicity in all patients, the emphasis should be towards ‘personalised medicine’ or . Very little is known about the The development of standard definitions pharmacokinetics/pharmacodynamics of opioids in patients with cancer. The challenge is to determine which opioids are The lack of international consensus for the classification and best suited to each individual. This will require further re- assessment of pain for both research and clinical practice is search into what factors determine the pharmacokinetic profile acknowledged and may contribute to failures in pain manage- of opioids in individual patients [99]. Genomics may play a ment [106]. A generally accepted definition of refractory pain role, but to date, genetic variation has not been shown to have is essential when assessing future treatment modalities. major effect on response to opioid therapy. Acknowledgment The authors wish to thank A/Prof John Hooper and Multimodal analgesia Prof CR Pinkerton for their advice and help in this project.

Rather than relying solely on opioids for all painful condi- Funding BA was supported from a grant from the Mater Research tions, a combination of medications that work at different sites Institute. or mechanisms of pain should be considered. Opioids can be Disclosures JH sits on the medical advisory boards of Mundipharma combined with anti-inflammatory medications, co-analgesics Pty Ltd and Menarini Australia Pty Ltd. She has contributed to the opioid and/or agents working through other receptors involved in educational modules of Mundipharma Pty Ltd. Support Care Cancer (2015) 23:1473–1481 1479

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