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Symptom Burden, Survival and Palliative Care in Advanced Soft Tissue Sarcoma

Symptom Burden, Survival and Palliative Care in Advanced Soft Tissue Sarcoma Hindawi Publishing Corporation Sarcoma Volume 2011, Article ID 325189, 8 pages doi:10.1155/2011/325189 Research Article Symptom Burden, Survival and Palliative Care in Advanced Soft Tissue Sarcoma 1, 2 1, 3 1, 3 1, 3 2, 4 Nicholas J. Gough, Clare Smith, Joy R. Ross, Julia Riley, and Ian Judson Palliative Care Department, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK Division of Medicine, Institute of Cancer Research, 123 Old Brompton Road, London SW7 3RP, UK National Heart and Lung Institute, Imperial College, London SW7 2AZ, UK Sarcoma Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK Correspondence should be addressed to Nicholas J. Gough, goughn79@yahoo.com Received 29 June 2011; Revised 16 August 2011; Accepted 31 August 2011 Academic Editor: Alessandro Gronchi Copyright © 2011 Nicholas J. Gough et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. The symptom burden and role of palliative care (PC) in patients with advanced soft tissue sarcoma (STS) are not well defined. Methods. This study retrospectively reviewed both symptoms and PC involvement in patients known to an STS referral centre who died in one calendar year. Results. 81 patients met inclusion criteria of which 27% had locally advanced disease and 73% metastases at initial referral. The median number of symptoms was slowly progressive ranging from 2 (range 0–5) before first-line chemotherapy (n = 50) to 3 (range 1–6) at the time of best supportive care (BSC) decision (n = 48). Pain and dyspnoea were the commonest symptoms. Median overall survival from BSC decision was 3.4 weeks. 88% had PC involvement (either hospital, community, or both) with median time from first PC referral to death of 16 (range 0–110) weeks. Conclusions. Patients with metastatic STS have a significant symptom burden which justifies early PC referral. Pain, including neuropathic pain, is a significant problem. Dyspnoea is common, progressive and appears to be undertreated. Time from BSC decision to death is short, and prospective studies are required to determine whether this is due to overtreatment or very rapid terminal disease progression. 1. Introduction chemotherapy has the potential for significant toxicity [10], and whilst this is routinely recorded as part of clinical Soft tissue sarcomas are malignant tumours of connective trials [11], there is a paucity of generalised STS symptom tissue comprising over 50 different histological subtypes prevalence data. A recent study of the STS population as a which vary in their clinical behaviour and response to whole in one United Kingdom (UK) sarcoma unit found a treatment [1, 2]. Surgery, often supplemented by adjuvant pain prevalence of 53% at the time of assessment of which radiotherapy, offers the only reliable chance of cure for 63% was described as inadequately controlled [12]. localised disease [2, 3]; however, over 50% of soft tissue Disease- or treatment-related symptoms are frequently sarcoma (STS) patients will develop metastases [4, 5]. managed by oncologists; however, more complex symptom Whilst metastasectomy is increasingly possible [6], palliative control can be challenging and require specialist input. treatment generally consists of radiotherapy for locally Given the potential for symptoms and limited prognosis, advanced “inoperable” recurrence and systemic chemother- there would seem a clear role for palliative care (PC) team apy for widespread metastatic disease [1–3]. The aim of involvement in the advanced STS population. such palliative treatments is to establish disease control thus Palliative care is defined by the World Health Organisa- improving survival and symptomatology [2]. tion (WHO) as “an approach that improves the quality of life Median overall survival (OS) from commencing first- of patients and their families facing the problems associated and second-line palliative chemotherapy is reported as 12 with life threatening illness, through the prevention and relief months [7, 8] and 8 months [9], respectively. Systemic of suffering by means of early identification and impeccable 2 Sarcoma assessment and treatment of pain and other problems, with surgery or palliative radiotherapy alone), if the STS physical, psychosocial and spiritual” [13]. PC teams in unit only provided a treatment opinion and if the death the UK provide a spectrum of services including (i) hospital was considered unrelated to the STS diagnosis. Patients advice/support teams, (ii) hospices providing admissions with Gastro-Intestinal Stromal Tumours (GIST) were also for symptom control, respite, or end of life care, and (iii) excluded as in this well-defined subgroup treatment with community PC teams who assess and treat patients in their molecularly targeted agents such as imatinib can provide a own homes. long-term survival benefit. Within UK health care policy, the 2006 National Insti- Data were collected from the hospital electronic patient tute for health and Clinical Excellence (NICE) guidance records and a hand search of paper notes. Missing data from Improving outcomes for people with sarcoma found no specific hospital records were obtained from the patient’s primary evidence supporting the role of PC teams in patients with care team. sarcoma [14]. However, it suggested much of its guidance Each patient’s records were analysed from first referral in the 2004 document improving supportive and palliative with advanced disease to death. Data collected included care for adults with cancer [15] was applicable. Specifically, demographic information, tumour-specific data, treatment this recommends the effectiveness of specialist PC team decisions, documented symptoms, and information relating involvement for the control of pain and cancer symptoms. It to PC involvement. did not, however, suggest when or if PC referral for symptom More specifically, documented physical symptoms were control or holistic support might be appropriate. recorded from the notes prior to each new treatment deci- Early PC team involvement has been shown to improve sion, for example, before first line palliative chemotherapy quality of life, mood, and survival in patients with newly and were recorded in four categories; “present controlled”, diagnosed metastatic non-small-cell lung cancer, a condition “present uncontrolled”, “documented absent”, or “not docu- with a similar prognosis to metastatic STS [16]. However, mented”. in many instances PC is delivered too late to be effective The term symptom burden can be defined as symptoms [17, 18]. experienced by the patient as a result of the disease itself or There are anecdotal reports by both STS clinicians associated treatments [20]. and patients that, despite advanced disease, STS patients In this study, we assessed clinician documented physical maintain a good quality of life with moderate symptoms symptoms prior to the start of a new treatment decision. until a rapid decline to the final weeks [19]. Although there The impact of systemic therapy on symptom burden was are no data to support this, the deterioration has been not directly studied. Overall survival (OS) was measured suggested to differ from the more “predictable” gradual from the start of each new treatment decision until death. deterioration experienced by those with other cancers such Permission from the clinical audit committee was obtained as non-small cell-lung cancer [19]. If true, one might expect prior to data collection. that PC team referrals might occur too late to be of benefit to the STS population. It is important to evaluate symptom burden and PC input in locally advanced and metastatic 3. Results STS to provide recommendations for optimal timing of PC One hundred and forty-two STS patients with locally involvement. This paper presents the results of a retrospective review advanced/metastatic disease known to the STS unit died of physical symptoms and PC team involvement in patients during the review period 1st January 2009–31st December with locally advanced “inoperable”/metastatic STS treated at 2009. Sixty-One patients did not meet the inclusion criteria one tertiary referral centre in the UK. for review (see Figure 1) resulting in a total of eighty-one patient records analysed. The aims were to better define the number and severity of physical symptoms at the time of each new treat- ment decision, for example, before first-line chemotherapy, before second-line chemotherapy, and so forth for locally 3.1. Demographics and Tumour-Specific Information. The advanced/metastatic STS. We also wanted to establish the demographic- and tumour-specific details of these patients most common symptoms in each group, and the proportion are described in Table 1. Thirty-five patients (43%) were of patients referred to a PC team prior to death along with male with a median age at death of 55 years, range from their OS from the time of diagnosis with metastatic disease. 18 to 84. Seventy-six patients (94%) presented with “new” advanced “inoperable”/metastatic disease and 5 (6%) had already received treatment for advanced disease in other oncology centres prior to review by the STS medical oncol- 2. Materials and Methods ogy unit. Fifty-nine patients (73%) had metastatic disease at The records of all patients with a histological diagnosis of referral, with 17 (29%) having multiorgan disease. locally advanced/metastatic STS over the age of 18, known One hundred and fifty-six treatment decisions were to the unit and considered for palliative chemotherapy who made for the 81 patients and the notes reviewed prior died during the 2009 calendar year, were analysed. Patients to each of these decisions. Fifty patients received first-line were excluded from the analysis if management did not chemotherapy, 28 second line, 15 third line and 7 fourth line. include palliative chemotherapy assessment (those treated Eight patients were referred for phase 1 drug trials, and 48 Sarcoma 3 142 patient 61 patients excluded: deaths • 23 sarcomas highly sensitive to systemic treatment e.g, GISTs � 17 MDT opinion only � 11 treated with palliative surgery/ radiotherapy only and not seen by STS medical oncologists. � 6 non-STS-related deaths � 3 no STS diagnosis e.g, benign histology � 1 < 18 years old 81 patients records included and reviewed Figure 1: Profile of patients reviewed. Table 1: Demographics and tumour-specific details. 3.5 Demographic- and tumour-specific Number % 2.5 factors: Number: 81 1.5 Male 35 43.2 Female 46 56.8 Median age at death (Range) 55 (18–84) 0.5 Histology: Leiomyosarcoma 23 28.4 Liposarcoma 12 14.8 Angiosarcoma 7 8.6 Synovial sarcoma 6 7.4 Sarcoma—(Not other specified) 6 7.4 Treatment option Other 27 33.4 Figure 2: Median number of symptoms prior to each treatment Disease status at referral: decision. Locally advanced/“inoperable” 22 27.2 Metastatic 59 72.8 Metastasis at referral: received palliative radiotherapy at some point after referral Single organ 42 71.2 with the documented aims being reduction in primary Multiple organ 17 28.8 tumour size (7 patients), analgesia (5 patients), treatment of Site of metastases at referral: brain metastases (5 patients) and treatment of spinal cord Lung 38 64.4 compression (1 patient). Liver 12 20.3 Soft tissue 15 25.4 3.2. Symptom Burden. The median number of symptoms Bone 9 15.3 documented prior to each new treatment decision ranged Other 9 15.3 from 2 at the time of first-line chemotherapy to 3 at BSC (Figure 2). Table 2 shows all documented symptoms at the time of each new treatment decision: pain, dyspnoea, and patients had a best supportive care (BSC), that is, no further nausea/vomiting are the three commonest. Other symptoms active treatment decision made by the STS unit. include fatigue, constipation, and cough. Both figures show In addition, seven patients (9%) underwent metastasec- that before different lines of chemotherapy, symptom burden tomies after favourable responses to chemotherapy. 18 (22%) was consistent but increased prior to both decision to refer Median symptom number prior to decision First line chemo (n = 50) Second-line chemo (n = 28) Third line chemo (n = 15) Forth line chemo (n = 7) Phase 1 trail (n = 8) Best supportive care (n = 48) 4 Sarcoma Table 2: Alldocumentedsymptomsprior to different palliative treatment decisions. (Due to the small numbers, only documented symptoms at the time of first- and second-line chemotherapy and best supportive care decision are displayed). First-line palliative Second-line palliative Best supportive care chemotherapy chemotherapy Symptom (n = 48) (n = 50) (n = 28) Symptom prevalence Symptom prevalence Symptom prevalence Pain 25 (50%) 23 (82%) 38 (79%) Breathlessness 10 (20%) 11 (40%) 21 (44%) Nausea and vomiting 11 (22%) 5 (18%) 17 (35%) Fatigue 9 (18%) 5 (18%) 16 (33%) Constipation 6 (12%) 2 (7%) 8 (17%) Cough 3 (6%) 3 (11%) 9 (19%) Feeling bloated 9 (18%) 2 (7%) 3 (6%) Weight loss 6 (12%) 0 (0%) 1 (2%) Low appetite 4 (8%) 0 (0%) 9 (19%) Diarrhoea 1 (2%) 0 (0%) 4 (8%) Drymouth 1(2%) 1 (4%) 3(6%) Trouble sleeping 2 (4%) 0 (0%) 4 (8%) Numbness/tingling in hands/feet 0 (0%) 1 (4%) 3 (6%) Problems with urination 2 (4%) 0 (0%) 2 (4%) Sweats 0 (0%) 0 (0%) 1 (2%) to the Phase 1 trial unit (median 2.5 symptoms) and a best dyspnoea at first-line chemotherapy compared to 31% supportive treatment decision (median 3). The two most (15/48) of patients at BSC decision. Overall, medications common documented symptoms were pain and dyspnoea. specifically documented for palliation of dyspnoea (opioids or benzodiazepines) were prescribed in only 15% (12/81) of patients, suggesting that this symptom is undertreated. (a) Pain. Pain was the most common symptom across all treatment decisions/stages of disease. Fifty percent of patients starting first-line chemotherapy experienced pain; 3.3. Overall Survival. MedianOSfromfirstreferralirre- however, the proportion of patients with pain rose to 82% spective of treatment (n = 81) was 38.7 weeks (Table 5) (23/28) at second-line chemotherapy and remained similar indicating the relatively poor prognosis of this STS cohort. at BSC decision (79%, 38/48). Twenty percent (10/50) of The median OS times from start of first- and second-line patients were documented as having uncontrolled pain at chemotherapy mirror established data [7–9]. Of the 59% first-line chemotherapy compared to 48% (23/48) of patients with a documented BSC decision, OS from decision was 3.4 at BSC decision (Table 3). The gold standard for the effective weeks (range 1–62). management of cancer pain is to follow the WHO 3- step analgesic ladder [21]. Table 4 describes the overall use 3.4. Palliative Care Team Involvement. 71 patients (88%) had of analgesia in these patients. It shows 86% (70/81) of a PC team referral made either to the hospital team alone patients were using a regular “step 1” analgesic, for example, (7/71), a community team alone (26/71), or both (38/71). paracetamol a median of 40 weeks before death, whereas 64% The median time before death from first PC team referral (52/81) required a regular “step 3” analgesic—for example, was 15.8 weeks (range 0.1–110.3). a strong opioid, such as oral morphine a median 14 weeks before death. Interestingly, 28% (23/81) were prescribed a neuropathic agent such as gabapentin, implying that the 4. Discussion proportion experiencing neuropathic pain was at least 28%. Patients with locally advanced/metastatic STS generally (b) Dyspnoea. Dyspnoea was the second most common undergo chemotherapy to palliate not cure. This paper shows symptom across all treatment decisions/stages of disease that these patients experience a significant symptom burden except at first-line chemotherapy. Twenty percent of patients that can be difficult to control. The authors, hope these starting first-line chemotherapy experienced dyspnoea; how- symptom prevalence data are generalisable and therefore, of ever, the proportion of patients rose to 39% (11/28) at value to oncologists treating STS. second-line chemotherapy, and rose further (44%, 21/48) The median number of documented symptoms ranged at BSC decision (see Table 2). This correlates with lung from 2 at first-line chemotherapy to 3 at BSC decision being the most common site of STS metastasis. Six percent suggesting sustained and slowly progressive symptoms. The (3/50) of patients were documented as having uncontrolled prevalence of documented pain before different palliative Sarcoma 5 Table 3: The documentation of symptoms. (Due to the small numbers, only the three commonest documented symptoms at the time of first- and second-line chemotherapy and best supportive care decision are shown here). First-line palliative Second-line palliative Best supportive care Symptom chemotherapy chemotherapy (n = 48) (n = 50) (n = 28) Pain documented as: Present controlled 15 (30%) 19 (68%) 15 (31%) Present uncontrolled 10 (20%) 4 (14%) 23 (48%) Absent documented 15 (30%) 2 (7%) 7 (15%) Not recorded 10 (20%) 3 (11%) 3 (6%) Breathlessness documented as: Present controlled 7 (14%) 10 (36%) 6 (13%) Present uncontrolled 3 (6%) 1 (4%) 15 (31%) Absent documented 20 (40%) 8 (28%) 20 (43%) Not recorded 20 (40%) 9 (32%) 7 (15%) Nausea and Vomiting documented as: Present controlled 8 (16%) 4 (14%) 15 (31%) Present uncontrolled 3 (6%) 1 (4%) 2 (4%) Absent documented 21 (42%) 15 (54%) 21 (44%) Not recorded 18 (36%) 8 (28%) 10 (21%) Table 4: Symptom control drug use. WHO Class 1 WHO Class 2 WHO Class 3 Agent specified for Agent specified for Analgesic, Analgesic, Analgesic, neuropathic pain, dyspnoea, for example, for example, for example, for example, for example, Paracetamol Codeine Morphine sulphate Gabapentin Lorazepam Patients using 70 52 52 23 12 %86 64 64 28 15 Median time started before 39.7 32.3 13.9 11.1 3.4 death in weeks (Range) (1–202) (2–206) (1–106) (1–83) (1–56) treatment decisions was consistently above 50%. This cor- why these drugs (e.g., opiates or benzodiazepines) were relates with a systematic review by van den Beuken-van prescribed. Everdingen et al. suggesting pain prevalence to be 64% One striking statistic is that those who had a BSC decision in those with advanced/metastatic/terminal cancer of any (48/81) had a median OS of only 3.4 weeks. This may suggest type [22]. Furthermore, a recent study investigating pain “active” treatment is being continued late into the disease prevalence in the STS population as a whole found a trajectory, against recommendations arising from a national prevalence of 53% [12]ofwhich 36% were foundtohave UK report reviewing deaths within 30 days of receiving neuropathic pain. Whilst documented interpretation of pain systemic anticancer therapy [24]. Conversely, it may also type was not recorded, 28% of patients in this paper were add support to the anecdotal observation that STS patients prescribed neuropathic analgesic agents correlating with this remain relatively well with good quality of life until late into recent published data. their illness before a rapid deterioration towards the terminal Dyspnoea can be multifactorial in aetiology; however, phase [19]. the high prevalence of documented breathlessness correlates Importantly, the median OS for all patients was signif- with lung as the commonest site of metastases in STS. icantly less than one year. The UK Department of Health At referral, 38 of the 59 patients (64%) with metastatic EndofLifeCareStrategy[25] advocates the importance of disease had lung metastases; this is comparable to findings individualised care plans and PC involvement in the last year from other studies [7, 8, 23]. The increasing prevalence of life. Given this policy, all the patients in this paper should of dyspnoea through lines of chemotherapy likely reflects have had some PC involvement. Encouragingly, 88% of disease progression in the lungs. The small number of patients were referred to a PC team, with a high proportion patients on a medication specifically to palliate dyspnoea of these (64/71, 90%) known to community PC teams. (12 patients) may represent clinicians’ lack of confidence in Although not reviewed, this may have enabled advanced care treating this symptom or a lack of documentation clarifying planning such as a patients preferred place of care and death 6 Sarcoma Table 5: Overall survival. Best First-line Second-line Third-line Fourth-line Phase 1 drug Overall supportive chemo chemo chemo chemo trial care Number of patients 81 50 28 15 7 8 48 Overallsurvivalin 38.7 48.6 43.0 15.8 13.6 14.9 3.4 weeks (Range) (1–212) (3–200) (1–151) (5–100) (9–27) (1–46) (1–62) to be established and facilitated. The median time from first documentation where factors such as inadequate assessment, PC referral to death of 15.8 weeks may suggest patients at time pressure, and selective documentation of positive this centre are being referred early enough to potentially findings may all contribute to inaccuracy. Recording symp- benefit from the PC service. The data also suggest that the toms prospectively using validated patient reported outcome majority of patients experience symptoms earlier, often from measures may lead to more accurate assessment/outcomes the initial diagnosis of locally advanced/metastatic disease [43]. Patients whose death was not thought attributable to which, therefore, adds further weight to considering PC STS were excluded: this is difficult to establish; therefore, all sooner. deaths should have been analysed. There are no guidelines at this centre regarding the appropriateness or timing of referral to a PC team. Decisions 5. Conclusions to refer are made on an individual basis by the oncology team or general practitioner after patient consultation. A Locally advanced “inoperable”/metastatic STS patients have nationwide survey of American doctors suggested 13 weeks a significant symptom burden which is slowly progressive before death as the most appropriate time to refer to a and commonly includes pain and dyspnoea. The level hospice care program [26]. However, studies in America and and timing of PC team referrals in this UK single centre other countries have shown physicians refer cancer patients evaluation was encouraging. However, pain was documented to PC teams/hospice care programs much nearer death— as uncontrolled in 48% of patients at the time of first- with median survival from initial referral ranging from 3 line chemotherapy and patients had at least two symptoms to 8 weeks [27–32]. Barriers to early PC referrals include at the time of all treatment decisions. There was also a (i) limitations in PC access between and within countries, suggestion that dyspnoea was undertreated. The short time (ii) reluctance of patients/families to be referred because from documented BSC decision to death is a concern: of misunderstandings of what PC may offer/its perceived this could suggest that patients continue active treatment association with imminent death, and (iii) resistance by clin- too long, or that this is due to extremely rapid disease icians to refer patients still having “active” treatment/their progression in the terminal phase. reluctance to discuss end of life issues [33–35]. Interestingly, Given the prevalence of symptoms, potential for treat- our data show that 48% (23/48) of patients in this review ment toxicity, and poor OS, prospective quality of life data had documented uncontrolled pain and 31% (15/48) had could aid decision making in the STS population. Given the uncontrolled dyspnoea at the time of a BSC decision. 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Symptom Burden, Survival and Palliative Care in Advanced Soft Tissue Sarcoma

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Hindawi Publishing Corporation
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Copyright © 2011 Nicholas J. Gough et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2011/325189
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Hindawi Publishing Corporation Sarcoma Volume 2011, Article ID 325189, 8 pages doi:10.1155/2011/325189 Research Article Symptom Burden, Survival and Palliative Care in Advanced Soft Tissue Sarcoma 1, 2 1, 3 1, 3 1, 3 2, 4 Nicholas J. Gough, Clare Smith, Joy R. Ross, Julia Riley, and Ian Judson Palliative Care Department, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK Division of Medicine, Institute of Cancer Research, 123 Old Brompton Road, London SW7 3RP, UK National Heart and Lung Institute, Imperial College, London SW7 2AZ, UK Sarcoma Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK Correspondence should be addressed to Nicholas J. Gough, goughn79@yahoo.com Received 29 June 2011; Revised 16 August 2011; Accepted 31 August 2011 Academic Editor: Alessandro Gronchi Copyright © 2011 Nicholas J. Gough et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. The symptom burden and role of palliative care (PC) in patients with advanced soft tissue sarcoma (STS) are not well defined. Methods. This study retrospectively reviewed both symptoms and PC involvement in patients known to an STS referral centre who died in one calendar year. Results. 81 patients met inclusion criteria of which 27% had locally advanced disease and 73% metastases at initial referral. The median number of symptoms was slowly progressive ranging from 2 (range 0–5) before first-line chemotherapy (n = 50) to 3 (range 1–6) at the time of best supportive care (BSC) decision (n = 48). Pain and dyspnoea were the commonest symptoms. Median overall survival from BSC decision was 3.4 weeks. 88% had PC involvement (either hospital, community, or both) with median time from first PC referral to death of 16 (range 0–110) weeks. Conclusions. Patients with metastatic STS have a significant symptom burden which justifies early PC referral. Pain, including neuropathic pain, is a significant problem. Dyspnoea is common, progressive and appears to be undertreated. Time from BSC decision to death is short, and prospective studies are required to determine whether this is due to overtreatment or very rapid terminal disease progression. 1. Introduction chemotherapy has the potential for significant toxicity [10], and whilst this is routinely recorded as part of clinical Soft tissue sarcomas are malignant tumours of connective trials [11], there is a paucity of generalised STS symptom tissue comprising over 50 different histological subtypes prevalence data. A recent study of the STS population as a which vary in their clinical behaviour and response to whole in one United Kingdom (UK) sarcoma unit found a treatment [1, 2]. Surgery, often supplemented by adjuvant pain prevalence of 53% at the time of assessment of which radiotherapy, offers the only reliable chance of cure for 63% was described as inadequately controlled [12]. localised disease [2, 3]; however, over 50% of soft tissue Disease- or treatment-related symptoms are frequently sarcoma (STS) patients will develop metastases [4, 5]. managed by oncologists; however, more complex symptom Whilst metastasectomy is increasingly possible [6], palliative control can be challenging and require specialist input. treatment generally consists of radiotherapy for locally Given the potential for symptoms and limited prognosis, advanced “inoperable” recurrence and systemic chemother- there would seem a clear role for palliative care (PC) team apy for widespread metastatic disease [1–3]. The aim of involvement in the advanced STS population. such palliative treatments is to establish disease control thus Palliative care is defined by the World Health Organisa- improving survival and symptomatology [2]. tion (WHO) as “an approach that improves the quality of life Median overall survival (OS) from commencing first- of patients and their families facing the problems associated and second-line palliative chemotherapy is reported as 12 with life threatening illness, through the prevention and relief months [7, 8] and 8 months [9], respectively. Systemic of suffering by means of early identification and impeccable 2 Sarcoma assessment and treatment of pain and other problems, with surgery or palliative radiotherapy alone), if the STS physical, psychosocial and spiritual” [13]. PC teams in unit only provided a treatment opinion and if the death the UK provide a spectrum of services including (i) hospital was considered unrelated to the STS diagnosis. Patients advice/support teams, (ii) hospices providing admissions with Gastro-Intestinal Stromal Tumours (GIST) were also for symptom control, respite, or end of life care, and (iii) excluded as in this well-defined subgroup treatment with community PC teams who assess and treat patients in their molecularly targeted agents such as imatinib can provide a own homes. long-term survival benefit. Within UK health care policy, the 2006 National Insti- Data were collected from the hospital electronic patient tute for health and Clinical Excellence (NICE) guidance records and a hand search of paper notes. Missing data from Improving outcomes for people with sarcoma found no specific hospital records were obtained from the patient’s primary evidence supporting the role of PC teams in patients with care team. sarcoma [14]. However, it suggested much of its guidance Each patient’s records were analysed from first referral in the 2004 document improving supportive and palliative with advanced disease to death. Data collected included care for adults with cancer [15] was applicable. Specifically, demographic information, tumour-specific data, treatment this recommends the effectiveness of specialist PC team decisions, documented symptoms, and information relating involvement for the control of pain and cancer symptoms. It to PC involvement. did not, however, suggest when or if PC referral for symptom More specifically, documented physical symptoms were control or holistic support might be appropriate. recorded from the notes prior to each new treatment deci- Early PC team involvement has been shown to improve sion, for example, before first line palliative chemotherapy quality of life, mood, and survival in patients with newly and were recorded in four categories; “present controlled”, diagnosed metastatic non-small-cell lung cancer, a condition “present uncontrolled”, “documented absent”, or “not docu- with a similar prognosis to metastatic STS [16]. However, mented”. in many instances PC is delivered too late to be effective The term symptom burden can be defined as symptoms [17, 18]. experienced by the patient as a result of the disease itself or There are anecdotal reports by both STS clinicians associated treatments [20]. and patients that, despite advanced disease, STS patients In this study, we assessed clinician documented physical maintain a good quality of life with moderate symptoms symptoms prior to the start of a new treatment decision. until a rapid decline to the final weeks [19]. Although there The impact of systemic therapy on symptom burden was are no data to support this, the deterioration has been not directly studied. Overall survival (OS) was measured suggested to differ from the more “predictable” gradual from the start of each new treatment decision until death. deterioration experienced by those with other cancers such Permission from the clinical audit committee was obtained as non-small cell-lung cancer [19]. If true, one might expect prior to data collection. that PC team referrals might occur too late to be of benefit to the STS population. It is important to evaluate symptom burden and PC input in locally advanced and metastatic 3. Results STS to provide recommendations for optimal timing of PC One hundred and forty-two STS patients with locally involvement. This paper presents the results of a retrospective review advanced/metastatic disease known to the STS unit died of physical symptoms and PC team involvement in patients during the review period 1st January 2009–31st December with locally advanced “inoperable”/metastatic STS treated at 2009. Sixty-One patients did not meet the inclusion criteria one tertiary referral centre in the UK. for review (see Figure 1) resulting in a total of eighty-one patient records analysed. The aims were to better define the number and severity of physical symptoms at the time of each new treat- ment decision, for example, before first-line chemotherapy, before second-line chemotherapy, and so forth for locally 3.1. Demographics and Tumour-Specific Information. The advanced/metastatic STS. We also wanted to establish the demographic- and tumour-specific details of these patients most common symptoms in each group, and the proportion are described in Table 1. Thirty-five patients (43%) were of patients referred to a PC team prior to death along with male with a median age at death of 55 years, range from their OS from the time of diagnosis with metastatic disease. 18 to 84. Seventy-six patients (94%) presented with “new” advanced “inoperable”/metastatic disease and 5 (6%) had already received treatment for advanced disease in other oncology centres prior to review by the STS medical oncol- 2. Materials and Methods ogy unit. Fifty-nine patients (73%) had metastatic disease at The records of all patients with a histological diagnosis of referral, with 17 (29%) having multiorgan disease. locally advanced/metastatic STS over the age of 18, known One hundred and fifty-six treatment decisions were to the unit and considered for palliative chemotherapy who made for the 81 patients and the notes reviewed prior died during the 2009 calendar year, were analysed. Patients to each of these decisions. Fifty patients received first-line were excluded from the analysis if management did not chemotherapy, 28 second line, 15 third line and 7 fourth line. include palliative chemotherapy assessment (those treated Eight patients were referred for phase 1 drug trials, and 48 Sarcoma 3 142 patient 61 patients excluded: deaths • 23 sarcomas highly sensitive to systemic treatment e.g, GISTs � 17 MDT opinion only � 11 treated with palliative surgery/ radiotherapy only and not seen by STS medical oncologists. � 6 non-STS-related deaths � 3 no STS diagnosis e.g, benign histology � 1 < 18 years old 81 patients records included and reviewed Figure 1: Profile of patients reviewed. Table 1: Demographics and tumour-specific details. 3.5 Demographic- and tumour-specific Number % 2.5 factors: Number: 81 1.5 Male 35 43.2 Female 46 56.8 Median age at death (Range) 55 (18–84) 0.5 Histology: Leiomyosarcoma 23 28.4 Liposarcoma 12 14.8 Angiosarcoma 7 8.6 Synovial sarcoma 6 7.4 Sarcoma—(Not other specified) 6 7.4 Treatment option Other 27 33.4 Figure 2: Median number of symptoms prior to each treatment Disease status at referral: decision. Locally advanced/“inoperable” 22 27.2 Metastatic 59 72.8 Metastasis at referral: received palliative radiotherapy at some point after referral Single organ 42 71.2 with the documented aims being reduction in primary Multiple organ 17 28.8 tumour size (7 patients), analgesia (5 patients), treatment of Site of metastases at referral: brain metastases (5 patients) and treatment of spinal cord Lung 38 64.4 compression (1 patient). Liver 12 20.3 Soft tissue 15 25.4 3.2. Symptom Burden. The median number of symptoms Bone 9 15.3 documented prior to each new treatment decision ranged Other 9 15.3 from 2 at the time of first-line chemotherapy to 3 at BSC (Figure 2). Table 2 shows all documented symptoms at the time of each new treatment decision: pain, dyspnoea, and patients had a best supportive care (BSC), that is, no further nausea/vomiting are the three commonest. Other symptoms active treatment decision made by the STS unit. include fatigue, constipation, and cough. Both figures show In addition, seven patients (9%) underwent metastasec- that before different lines of chemotherapy, symptom burden tomies after favourable responses to chemotherapy. 18 (22%) was consistent but increased prior to both decision to refer Median symptom number prior to decision First line chemo (n = 50) Second-line chemo (n = 28) Third line chemo (n = 15) Forth line chemo (n = 7) Phase 1 trail (n = 8) Best supportive care (n = 48) 4 Sarcoma Table 2: Alldocumentedsymptomsprior to different palliative treatment decisions. (Due to the small numbers, only documented symptoms at the time of first- and second-line chemotherapy and best supportive care decision are displayed). First-line palliative Second-line palliative Best supportive care chemotherapy chemotherapy Symptom (n = 48) (n = 50) (n = 28) Symptom prevalence Symptom prevalence Symptom prevalence Pain 25 (50%) 23 (82%) 38 (79%) Breathlessness 10 (20%) 11 (40%) 21 (44%) Nausea and vomiting 11 (22%) 5 (18%) 17 (35%) Fatigue 9 (18%) 5 (18%) 16 (33%) Constipation 6 (12%) 2 (7%) 8 (17%) Cough 3 (6%) 3 (11%) 9 (19%) Feeling bloated 9 (18%) 2 (7%) 3 (6%) Weight loss 6 (12%) 0 (0%) 1 (2%) Low appetite 4 (8%) 0 (0%) 9 (19%) Diarrhoea 1 (2%) 0 (0%) 4 (8%) Drymouth 1(2%) 1 (4%) 3(6%) Trouble sleeping 2 (4%) 0 (0%) 4 (8%) Numbness/tingling in hands/feet 0 (0%) 1 (4%) 3 (6%) Problems with urination 2 (4%) 0 (0%) 2 (4%) Sweats 0 (0%) 0 (0%) 1 (2%) to the Phase 1 trial unit (median 2.5 symptoms) and a best dyspnoea at first-line chemotherapy compared to 31% supportive treatment decision (median 3). The two most (15/48) of patients at BSC decision. Overall, medications common documented symptoms were pain and dyspnoea. specifically documented for palliation of dyspnoea (opioids or benzodiazepines) were prescribed in only 15% (12/81) of patients, suggesting that this symptom is undertreated. (a) Pain. Pain was the most common symptom across all treatment decisions/stages of disease. Fifty percent of patients starting first-line chemotherapy experienced pain; 3.3. Overall Survival. MedianOSfromfirstreferralirre- however, the proportion of patients with pain rose to 82% spective of treatment (n = 81) was 38.7 weeks (Table 5) (23/28) at second-line chemotherapy and remained similar indicating the relatively poor prognosis of this STS cohort. at BSC decision (79%, 38/48). Twenty percent (10/50) of The median OS times from start of first- and second-line patients were documented as having uncontrolled pain at chemotherapy mirror established data [7–9]. Of the 59% first-line chemotherapy compared to 48% (23/48) of patients with a documented BSC decision, OS from decision was 3.4 at BSC decision (Table 3). The gold standard for the effective weeks (range 1–62). management of cancer pain is to follow the WHO 3- step analgesic ladder [21]. Table 4 describes the overall use 3.4. Palliative Care Team Involvement. 71 patients (88%) had of analgesia in these patients. It shows 86% (70/81) of a PC team referral made either to the hospital team alone patients were using a regular “step 1” analgesic, for example, (7/71), a community team alone (26/71), or both (38/71). paracetamol a median of 40 weeks before death, whereas 64% The median time before death from first PC team referral (52/81) required a regular “step 3” analgesic—for example, was 15.8 weeks (range 0.1–110.3). a strong opioid, such as oral morphine a median 14 weeks before death. Interestingly, 28% (23/81) were prescribed a neuropathic agent such as gabapentin, implying that the 4. Discussion proportion experiencing neuropathic pain was at least 28%. Patients with locally advanced/metastatic STS generally (b) Dyspnoea. Dyspnoea was the second most common undergo chemotherapy to palliate not cure. This paper shows symptom across all treatment decisions/stages of disease that these patients experience a significant symptom burden except at first-line chemotherapy. Twenty percent of patients that can be difficult to control. The authors, hope these starting first-line chemotherapy experienced dyspnoea; how- symptom prevalence data are generalisable and therefore, of ever, the proportion of patients rose to 39% (11/28) at value to oncologists treating STS. second-line chemotherapy, and rose further (44%, 21/48) The median number of documented symptoms ranged at BSC decision (see Table 2). This correlates with lung from 2 at first-line chemotherapy to 3 at BSC decision being the most common site of STS metastasis. Six percent suggesting sustained and slowly progressive symptoms. The (3/50) of patients were documented as having uncontrolled prevalence of documented pain before different palliative Sarcoma 5 Table 3: The documentation of symptoms. (Due to the small numbers, only the three commonest documented symptoms at the time of first- and second-line chemotherapy and best supportive care decision are shown here). First-line palliative Second-line palliative Best supportive care Symptom chemotherapy chemotherapy (n = 48) (n = 50) (n = 28) Pain documented as: Present controlled 15 (30%) 19 (68%) 15 (31%) Present uncontrolled 10 (20%) 4 (14%) 23 (48%) Absent documented 15 (30%) 2 (7%) 7 (15%) Not recorded 10 (20%) 3 (11%) 3 (6%) Breathlessness documented as: Present controlled 7 (14%) 10 (36%) 6 (13%) Present uncontrolled 3 (6%) 1 (4%) 15 (31%) Absent documented 20 (40%) 8 (28%) 20 (43%) Not recorded 20 (40%) 9 (32%) 7 (15%) Nausea and Vomiting documented as: Present controlled 8 (16%) 4 (14%) 15 (31%) Present uncontrolled 3 (6%) 1 (4%) 2 (4%) Absent documented 21 (42%) 15 (54%) 21 (44%) Not recorded 18 (36%) 8 (28%) 10 (21%) Table 4: Symptom control drug use. WHO Class 1 WHO Class 2 WHO Class 3 Agent specified for Agent specified for Analgesic, Analgesic, Analgesic, neuropathic pain, dyspnoea, for example, for example, for example, for example, for example, Paracetamol Codeine Morphine sulphate Gabapentin Lorazepam Patients using 70 52 52 23 12 %86 64 64 28 15 Median time started before 39.7 32.3 13.9 11.1 3.4 death in weeks (Range) (1–202) (2–206) (1–106) (1–83) (1–56) treatment decisions was consistently above 50%. This cor- why these drugs (e.g., opiates or benzodiazepines) were relates with a systematic review by van den Beuken-van prescribed. Everdingen et al. suggesting pain prevalence to be 64% One striking statistic is that those who had a BSC decision in those with advanced/metastatic/terminal cancer of any (48/81) had a median OS of only 3.4 weeks. This may suggest type [22]. Furthermore, a recent study investigating pain “active” treatment is being continued late into the disease prevalence in the STS population as a whole found a trajectory, against recommendations arising from a national prevalence of 53% [12]ofwhich 36% were foundtohave UK report reviewing deaths within 30 days of receiving neuropathic pain. Whilst documented interpretation of pain systemic anticancer therapy [24]. Conversely, it may also type was not recorded, 28% of patients in this paper were add support to the anecdotal observation that STS patients prescribed neuropathic analgesic agents correlating with this remain relatively well with good quality of life until late into recent published data. their illness before a rapid deterioration towards the terminal Dyspnoea can be multifactorial in aetiology; however, phase [19]. the high prevalence of documented breathlessness correlates Importantly, the median OS for all patients was signif- with lung as the commonest site of metastases in STS. icantly less than one year. The UK Department of Health At referral, 38 of the 59 patients (64%) with metastatic EndofLifeCareStrategy[25] advocates the importance of disease had lung metastases; this is comparable to findings individualised care plans and PC involvement in the last year from other studies [7, 8, 23]. The increasing prevalence of life. Given this policy, all the patients in this paper should of dyspnoea through lines of chemotherapy likely reflects have had some PC involvement. Encouragingly, 88% of disease progression in the lungs. The small number of patients were referred to a PC team, with a high proportion patients on a medication specifically to palliate dyspnoea of these (64/71, 90%) known to community PC teams. (12 patients) may represent clinicians’ lack of confidence in Although not reviewed, this may have enabled advanced care treating this symptom or a lack of documentation clarifying planning such as a patients preferred place of care and death 6 Sarcoma Table 5: Overall survival. Best First-line Second-line Third-line Fourth-line Phase 1 drug Overall supportive chemo chemo chemo chemo trial care Number of patients 81 50 28 15 7 8 48 Overallsurvivalin 38.7 48.6 43.0 15.8 13.6 14.9 3.4 weeks (Range) (1–212) (3–200) (1–151) (5–100) (9–27) (1–46) (1–62) to be established and facilitated. The median time from first documentation where factors such as inadequate assessment, PC referral to death of 15.8 weeks may suggest patients at time pressure, and selective documentation of positive this centre are being referred early enough to potentially findings may all contribute to inaccuracy. Recording symp- benefit from the PC service. The data also suggest that the toms prospectively using validated patient reported outcome majority of patients experience symptoms earlier, often from measures may lead to more accurate assessment/outcomes the initial diagnosis of locally advanced/metastatic disease [43]. Patients whose death was not thought attributable to which, therefore, adds further weight to considering PC STS were excluded: this is difficult to establish; therefore, all sooner. deaths should have been analysed. There are no guidelines at this centre regarding the appropriateness or timing of referral to a PC team. Decisions 5. Conclusions to refer are made on an individual basis by the oncology team or general practitioner after patient consultation. A Locally advanced “inoperable”/metastatic STS patients have nationwide survey of American doctors suggested 13 weeks a significant symptom burden which is slowly progressive before death as the most appropriate time to refer to a and commonly includes pain and dyspnoea. The level hospice care program [26]. However, studies in America and and timing of PC team referrals in this UK single centre other countries have shown physicians refer cancer patients evaluation was encouraging. However, pain was documented to PC teams/hospice care programs much nearer death— as uncontrolled in 48% of patients at the time of first- with median survival from initial referral ranging from 3 line chemotherapy and patients had at least two symptoms to 8 weeks [27–32]. Barriers to early PC referrals include at the time of all treatment decisions. There was also a (i) limitations in PC access between and within countries, suggestion that dyspnoea was undertreated. The short time (ii) reluctance of patients/families to be referred because from documented BSC decision to death is a concern: of misunderstandings of what PC may offer/its perceived this could suggest that patients continue active treatment association with imminent death, and (iii) resistance by clin- too long, or that this is due to extremely rapid disease icians to refer patients still having “active” treatment/their progression in the terminal phase. reluctance to discuss end of life issues [33–35]. Interestingly, Given the prevalence of symptoms, potential for treat- our data show that 48% (23/48) of patients in this review ment toxicity, and poor OS, prospective quality of life data had documented uncontrolled pain and 31% (15/48) had could aid decision making in the STS population. Given the uncontrolled dyspnoea at the time of a BSC decision. Most potential for PC to improve quality of life and survival in had already been referred to a PC team by this point. patients with advanced cancer, these data support the need This may indicate inadequate access to PC services despite for early PC referral in patients with metastatic STS. The lack referral, or that a rapid escalation in “difficult to control” of prospective studies into this important area indicates the pain/dyspnoea is a predictive factor for the terminal phase need for further research. in STS patients. The authors recognise these data are from a single UK References cancer center. Results will be indicative of the STS units individual practice as well as UK health policy which limits [1] S. Sinha and A. H. S. Peach, “Diagnosis and management of generalisation nationally or globally. 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Guillou et al., “Predictive value of active PC network and its government has recently invested grade for metastasis development in the main histologic types in PC resources and end of life care [25, 42]. of adult soft tissue sarcomas: a study of 1240 patients from the The studies retrospective design is also a potential source French Federation of Cancer Centers sarcoma group,” Cancer, of major bias: the symptom data are based on clinician vol. 91, no. 10, pp. 1914–1926, 2001. Sarcoma 7 [5] M. F. Brennan, K. Alektiar, and R. Maki, “Soft tissue sarcoma,” [23] N. Penel, M. V. Glabbeke, S. Mathoulin-Pelissier et al., in Cancer: Principles and Practice of Oncology,V.DeVitaJr.,S. “Performance status is the most powerful risk factor for early Hellamn, and S. Rosenberg, Eds., pp. 1741–1794, Lippincott death among patients with advanced soft tissue sarcoma,” Williams & Wilkins, Philadelphia, Pa, USA, 6th edition, 2008. British Journal of Cancer, vol. 104, no. 10, pp. 1544–1550, 2011. [6] L. 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