Abstract Background Systemic anticancer therapy (SACT) is a collective term to describe the growing number of differing therapies used in malignancy to achieve palliation. Improving symptoms, quality of life (QOL) and where possible quantity of life are the goals of these treatments. Sources of data A comprehensive literature review was undertaken using Medline, Embase and the Cochrane database. Areas of agreement The use of palliative SACT can lead to increases in symptom control, QOL and survival. The breadth of treatable cancers has increased along with the number of therapeutic options. Areas of controversy The increasing use of SACT in the last weeks of life and the lack of consistency about the terms Supportive Care/Best Supportive Care in the trial setting. Growing points Integration between oncology and other palliative services leads to better outcomes. Areas timely for developing research Improved prognostication tools to elucidate which patients will benefit from SACT. chemotherapy, systemic anticancer therapy, palliation, supportive care Introduction The role of palliative chemotherapy in improving both quality and quantity of life in people diagnosed with an incurable malignancy is continuing to evolve. The advent of newer agents such as tyrosine kinase inhibitors, monoclonal antibodies and immunotherapies which along with palliative chemotherapy are collectively termed systemic anticancer therapy (SACT) has seen a surge in the number of patients treated. This article aims to review the role of SACT in disease palliation through review of published data and guidance. Methods A comprehensive literature search of all published reviews and studies between 2000 and 2017 using the terms ‘palliative’, ‘chemotherapy’, systemic anticancer therapy’, ‘supportive care’ and ‘Quality of life’ using Medline, Embase and Cochrane database was undertaken. Abstracts were reviewed by the two authors and full articles were identified and reviewed. Those whereby interventions included radiotherapy as a concurrent palliative option or those whereby they were testing tools to identify quality of life scales were excluded. Haematological systemic therapies and paediatric studies were also excluded. Where the impact of palliative chemotherapy on Quality of Life (QOL) was the aim of the study or review were included. Additionally a ‘snowball’ approach was undertaken whereby any reference not identified as part of the primary search but included in the reviewed article was obtained where deemed relevant and agreed by the authors. Results The goals of chemotherapy in disease palliation The goal of palliative chemotherapy is to assist patients in living both longer and better.1 Systemic anticancer therapies, such as palliative chemotherapy, may decrease disease burden through cancer cell kill thereby improving symptom control, changing the natural course of disease and in some situations prolong life. These gains are reliant on the chosen therapy achieving the required amount of cell kill to afford these benefits and are at the expense of a variety of potential toxicities and time invested in undertaking treatment. Because neither benefit nor toxicity is guaranteed there is clearly an element of uncertainty with SACT; the risk of having more side effects than symptom relief is real. Traditional intravenous chemotherapies can predictably cause patients to feel less well within the first two weeks of administration, before any advantage of treatment is seen. When the SACT is effective this can result in a brief decline in QOL due to toxic effects1; when the response is less than hoped it can decrease overall symptom control and shorten life.2 As of result of these uncertainties, there clearly needs to be careful consideration and communication between the patient and the oncologist regarding the risk/benefit ratio for that specific patient before embarking on SACT. The American Society of Clinical Oncology (ASCO) provide guidelines which describe a number of essential requirements to palliation in cancer.3 An emphasis on exploring patient’s understanding of illness, prognosis and clarification of treatment goals with the pursuit of assisted decision making in addition to addressing both the patient and carers symptom, psychological and care needs is fundamental to these guidelines and good shared decision making.3 Clinicians and patients perspectives on value Good quality shared decision making relies on an understanding of what is valued by a patient and their caregivers. This is individual, personal and not always predictable. People who have been diagnosed with a terminal illness may value small chances of benefit more highly than the staff who administer the treatment. A British study of attitudes to chemotherapy found that patients would accept a toxic treatment for a 1% chance of cure, 10% chance of symptom relief, or the chance to prolong life by only 12 months.4 Their physicians and nurses however would require a 50% chance of cure, 75% chance of symptom relief and 24–60 months added survival to want to proceed with chemotherapy.4 Their willingness to undergo aggressive treatment with major adverse effects for a small chance of benefit, when their physicians or nurses would not, is mirrored in studies outside the United Kingdom (UK).5–7 Whilst the study comparing views of healthcare professionals and patients is quite old, a more recent study looking at patient and physician preferences for chemotherapy similarly showed that patients were more likely to chose to have chemotherapy with only a modest survival benefits compared to doctors.8 Furthermore those patients prepared to undergo experimental therapies in the form of early phase clinical trials have reported that they would accept mortality rates of 10% alongside no degree of certainty of benefit.7 Evidence suggests patients’ value honesty in their decision-making process highly. In a study of 126 terminally ill pts, 98% said they wanted their oncologist to be realistic and truthful. Honest explanation of potential benefits and risks of palliative interventions clearly facilitates good decision making, however patients also desire honesty about prognosis and survival.9 That said there is evidence that, despite having been given a palliative diagnosis, patients can have unrealistic beliefs regarding the efficacy of treatment. The reasons for this can be multifactorial including doctors not wanting to remove hope, and patients not being able to understand or accept a terminal prognosis.10 In this context it is understandable how clinicians may feel pressured by patients and their families to prescribe SACT even when they believe that there may be little benefit. Whilst oncologists have been found to be fairly accurate in estimating whether a patient is likely to die within a 12 month period, their ability to make more detailed predictions on prognosis and survival is less accurate.11 The accuracy of prognostic estimation by oncologists is reported to be as low as 20–35%.2,12 A recent meta-analysis found that cancer physicians consistently over estimated prognosis by at least 30%.12 Current UK guidelines advise against SACT within 30 days of death, whilst American guidelines recommend avoidance within 2 weeks of death.13,14 There is evidence that those patients receiving treatment near the end of life are more frequently admitted to hospital, less likely to die at home and less likely to enter hospice care.2,15,16 Despite these recommendations reports suggest increasing numbers of patients receive ongoing administration of SACT near the end of life.16 American patients receiving chemotherapy within the last 2 weeks of life increased from 13.7% in 1993 to 18.5% by 199 6.17 Between 2000 and 2003 43% of lung cancer patients were given chemotherapy within the last month of life and 20% within the last 2 weeks of life.18 Furthermore, a 2007 retrospective Swedish study found 23% of patients received chemotherapy within the last month of life.2 One of the strongest indicators of a patient being close to their terminal phase is performance status (PS), a measure of functional capability.19 SACT is not usually recommended for those patients with poor PS.11,12 There are however occasions where both short predicted prognosis and poor performance status may not deter patient or cancer physician from SACT.20 The use of SACT may be acceptable in chemotherapy naïve patients with highly chemo-sensitive patients such as small cell lung cancer where response rates and symptom improvement rates are predictably up to 90% are an example of this.21 It is accepted practice to give this patient group SACT even when PS is poor and predicted prognosis may be very short. Whilst a very high chance of benefit may clearly tip the decision point in favour of intervention, it is not clear how low a chance of response is acceptable to proceed with SACT. ASCO consensus group were unable to decide on a minimal benefit for which chemotherapy was indicated, only that some benefit must be demonstrable and acknowledged that there are groups of patients for whom there is no evidence that chemotherapy is of any clinical benefit and that treating this patient group was ‘wasteful and unnecessary’.3 Quantifying the benefit of systemic anticancer therapy Traditionally SACT providing benefits in terms of improved survival and QOL has been limited to certain cancer groups. Data confirming benefit of traditional palliative chemotherapy in breast, colorectal, lung and pancreatic cancer have existed for many years.22–25 Other cancer groups, such as melanoma and renal cell carcinoma have traditionally been regarded as relatively chemo-resistant and treatment options have been limited. However the landscape of palliative therapies has changed dramatically over recent years with the arrival of what has been called ‘personalized medicine’. This term has been used to describe therapies that are directed to a specific cancer or genomic subgroup of cancer types, such as brca positive ovarian cancer (which is targeted by parp inhibitors such as olaparip) and include oral tyrosine kinase therapies, antibody therapies and immune check point inhibitors which have heralded a change in both the expected likelihood of benefit, and toxicity profiles. These therapeutic interventions, which are perhaps better described as tumour specific therapies rather than ‘personalized medicine’, along with palliative chemotherapy, are collectively termed SACT. These newer treatment options have differing toxicity profiles and expected responses compared to traditional palliative chemotherapy, but they still carrying significant risks of side effects. Renal cell carcinoma, a disease which does not respond to traditional chemotherapy can now be treated with oral targeted tyrosine kinase inhibitors and more recently with immune check point inhibitors. This has resulted in second and third line therapeutic options and predicted median survivals of around 28 months26 for patients who previously had little that could be realistically offered in terms of palliative options. Table 1 is a non-exhaustive representation of expected benefits from current first line SACT regimens for the four most common cancers presenting in the UK, these cancers account for 53% of cancer incidence.27 The QOL data includes health related questionnaires (HRQ) which assess quality of life through a range of measures including disease specific symptoms, for example breathless. Table 1 Expected benefits from first line SACT for breast, prostate, lung and colorectal cancer Disease type Trial intervention Efficacy QOL data Breast cancer ER positive Breast cancer Epirubicin vs fluorouracil, epirubicin and cyclophosphamide28 RR – 48% vs 55% OS – 16 vs 18 mo QOL increased in epirubicin arm HER 2 positive Breast Cancer Trastuzumab and Docetaxel +/− Pertuzumab29 RR – 80% vs 69% PFS – 19 vs 12 mo OS – 56.5 vs 40.8 mo Median time to deterioration in HRQOL (TOI-PFB) 18.4 vs 18.3 weeks = ns Prostate cancer Castrate Resistant Enzalutamide vs placebo30 OS – 32.4 vs 30.2 mo RR – 59% vs 5% Median time to QOL deterioration 11.3 vs 5.6 mo Lung cancer Adenocarcinoma – no actionable mutation Cisplatin/Pemetrexed +/– maintenance pemetrexed31 OS – 13.9 vs 11.0 mo ORR – 28.2 vs 30.6% Hospitalizations due to study drugs 8.4% vs 3.3% EQ-5D scores – no significantly different32 Adenocarcinoma – activating EGFR mutation Erlotinib vs platinum based doublet33 PFS – 13.7 vs 4.6 mo OS – 22.8 vs 27.2 mo ORR – 83 vs 36% Total FACT-L –OR 6.69 favouring Erlotinib TOI – OR 8.07 favouring Erlotinib LCS – OR -7.54 favouring Erlotinib Adenocarcinoma – ALK rearrangement Crizotinib vs Cisplatin or Carboplatin and Pemetrexed34 ORR – 74 vs 45% PFS – 10.9 vs 7 mo QLQ-LC13, QLQ-C30 and EQ-5D all favour Crizotinib NSCLC – High PD-L1 expression Pembrolizumab vs platinum doublet35 PFS – 10.3 vs 6 mo ORR – 45% vs 28% HRQOL improved in 40% pts having Pembrolizumab vs 26.5% for chemo36 Colorectal cancer Mutated RAS colorectal cancer 5-Fluorouracil and Leucovorin +/− Oxaliplatin37 PFS – 9.0 vs 6.2 mo ORR – 50.7 vs 22.3% OS – 16.2 vs 14.7 mo No significant difference in median survival Time to deterioration in Global Health Status longer with combination treatment Wild type RAS colorectal cancer Irinotecan, 5-fluorouracil and Leucovorin +/− Cetuximab20 PFS – 9.9 vs 8.7 ORR – 59.3% vs 43.2% OS – 24.9 vs 21.0 mo Global Health Status/QOL no significant38 Key mOS = median Overall Survival PFS = Progression Free Survival OR = Odds Ratio ER = Oestrogen Receptor ORR = Overall Response Rate Mo = Months Ns = not significant QOL = Quality of Life (HRQOL, EQ-5D, FACT-L, TOI, LCS, QLQ-LC13, EQ-5D, HRQOL are all QOL scoring tools) Disease type Trial intervention Efficacy QOL data Breast cancer ER positive Breast cancer Epirubicin vs fluorouracil, epirubicin and cyclophosphamide28 RR – 48% vs 55% OS – 16 vs 18 mo QOL increased in epirubicin arm HER 2 positive Breast Cancer Trastuzumab and Docetaxel +/− Pertuzumab29 RR – 80% vs 69% PFS – 19 vs 12 mo OS – 56.5 vs 40.8 mo Median time to deterioration in HRQOL (TOI-PFB) 18.4 vs 18.3 weeks = ns Prostate cancer Castrate Resistant Enzalutamide vs placebo30 OS – 32.4 vs 30.2 mo RR – 59% vs 5% Median time to QOL deterioration 11.3 vs 5.6 mo Lung cancer Adenocarcinoma – no actionable mutation Cisplatin/Pemetrexed +/– maintenance pemetrexed31 OS – 13.9 vs 11.0 mo ORR – 28.2 vs 30.6% Hospitalizations due to study drugs 8.4% vs 3.3% EQ-5D scores – no significantly different32 Adenocarcinoma – activating EGFR mutation Erlotinib vs platinum based doublet33 PFS – 13.7 vs 4.6 mo OS – 22.8 vs 27.2 mo ORR – 83 vs 36% Total FACT-L –OR 6.69 favouring Erlotinib TOI – OR 8.07 favouring Erlotinib LCS – OR -7.54 favouring Erlotinib Adenocarcinoma – ALK rearrangement Crizotinib vs Cisplatin or Carboplatin and Pemetrexed34 ORR – 74 vs 45% PFS – 10.9 vs 7 mo QLQ-LC13, QLQ-C30 and EQ-5D all favour Crizotinib NSCLC – High PD-L1 expression Pembrolizumab vs platinum doublet35 PFS – 10.3 vs 6 mo ORR – 45% vs 28% HRQOL improved in 40% pts having Pembrolizumab vs 26.5% for chemo36 Colorectal cancer Mutated RAS colorectal cancer 5-Fluorouracil and Leucovorin +/− Oxaliplatin37 PFS – 9.0 vs 6.2 mo ORR – 50.7 vs 22.3% OS – 16.2 vs 14.7 mo No significant difference in median survival Time to deterioration in Global Health Status longer with combination treatment Wild type RAS colorectal cancer Irinotecan, 5-fluorouracil and Leucovorin +/− Cetuximab20 PFS – 9.9 vs 8.7 ORR – 59.3% vs 43.2% OS – 24.9 vs 21.0 mo Global Health Status/QOL no significant38 Key mOS = median Overall Survival PFS = Progression Free Survival OR = Odds Ratio ER = Oestrogen Receptor ORR = Overall Response Rate Mo = Months Ns = not significant QOL = Quality of Life (HRQOL, EQ-5D, FACT-L, TOI, LCS, QLQ-LC13, EQ-5D, HRQOL are all QOL scoring tools) In addition to a changing landscape of systemic anticancer therapies, there have been real advances in supportive drugs available to reduce chemotherapy side effects. The arrival of 5-HT3 antagonists has transformed emetic experiences; the advent of granulocyte-colony stimulating factor has reduced the risk of febrile neutropenia and the modernization of chemotherapy support services such as dedicated triage lines and acute oncology services has improved the patient experience.39 However despite new regimens, supportive therapies and associated care delivery many of which have undoubtedly improved the patient outcomes, these schedules remain palliative, with fewer than 50% of newer drugs improving survival by more than 3 months.40 Aids to decision making Giving patients sufficient information to make an informed decision on which interventions will allow them the chance to maximize good palliation, taking into account their values requires shared decision making between oncologist, patient and carers. Research has shown that information sharing on the survival benefit of palliative chemotherapy is vague or non-existent in ~70% of oncology patient interactions and that prognosis is only discussed 39% of the time.41,42 However, it has also shown that patients want this information in order to participate fully in decision-making.22 Furthermore, patients that have a more accurate understanding of their cancer trajectory when discussing treatment goals are more likely to favour supportive therapies rather than aggressive ones.22 This suggests that more accurate estimations of survival may serve to avoid SACT in the last weeks of life. The European Association for Palliative Care have identified different factors that correlate with actual patient survival and include PS, signs or symptoms of cancer-anorexia-cachexia syndrome, delirium, dyspnoea and biological factors such as leucocytosis, lymphocytopenia and C-reactive protein.19 A number of palliative prognostic scoring systems have been produced to predict survival, the common features between these scores include PS, laboratory values and location of disease.43–51 In addition patient and care provider support tools to enhance communication within consultations can improve the quality of decisions made. These include tables of suggested prompts or questions to enhance decision making in the initial consultation between patient and cancer physician, and flow charts emphasising the balance between effective palliation and side effects may also assist ongoing effective decision making once SACT has been initiated.9,52 An integrated approach to palliative treatment The World Health Organization (WHO) defines palliative care as ‘as an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual’.53 Whilst it may be clear from the point of diagnosis, or when relapse occurs, that treatment is palliative in nature, patient understanding of the treatment aims in this situation can be variable. One study looking at the expectations of the outcomes of treatment for women undergoing second or third line chemotherapy for ovarian cancer found that 42% believed that treatment would have a moderately high to high probability of curing their disease.54 The historical perception, particularly in trials where the gain for patients from chemotherapy was uncertain, has been a choice between SACT and supportive care (SC)/best supportive care (BSC). Although WHO has been clear that this should mean randomizing between SACT and palliative care the interpretation of SC/BSC in the trial setting has been variable, raising concerns about the validity of such comparisons. A systemic literature review between 1980 and 2012 demonstrated that there is significant variation in how SC/BSC are interpreted.55 This may potentially lead to patients not receiving some palliative interventions including routine holistic assessments, transfusions, radiotherapy and access to palliative care specialists. Access to these types of therapies should be regarded as a critical element of SC/BSC and in their absence may well have contributed to poorer QOL and survival outcomes in patients receiving SC/BSC as opposed to SACT. A randomized study comparing standard oncology care versus standard oncology care plus early palliative care intervention in patients with metastatic non-small cell lung cancer demonstrated improved mood, QOL scores and less aggressive end of life care for those patients randomized to the integrated oncology/palliative care arm. Furthermore, those randomized to the palliative care arm had a 2.7 month improvement in their overall survival. Precisely why this survival benefit was seen remains unclear but may reflect a combination of both improved symptom control and cessation of potentially harmful chemotherapy at a stage where the risk of harm has begun to outweigh the benefit.56 ASCO recommended that patients with advanced cancer should receive access to palliative care services at an early stage of the disease course, in addition to any active oncological treatment.57 However many providers in the USA will only fund this when it has been agreed that the patient is in the last 6 months of life. Referral to hospice and palliative care services may potentially limit subsequent access to some oncological and therapeutic interventions due to current palliative care funding provision by healthcare providers such as Medicare and Medicaid. In the UK there is a combination of both statutory and third sector providers delivering a range of palliative care services which are free at the point of contact. This means that access is potentially easier but there remains anxiety and confusion amongst both clinicians and patients about referring patients to palliative care and hospice services. In a survey of medical oncologists and midlevel providers at a cancer centre the term palliative care was found to be regarded as a barrier to referral, clinicians preferring the term ‘supportive care’ as they believed the term palliative care was more likely to cause distress and a reduction in hope for patients and their families.58 Confusion regarding the precise meaning of the terms ‘palliative care’ was also reported in a study by Hui et al. the resulting recommendation being for ‘palliative care’ and ‘hospice care’ to sit within a framework of Supportive Care.59 Historically therapeutic modalities used to treat this patient group, particularly as their cancer progresses, have been applied in a binary fashion, i.e. either ‘active treatment’ or ‘palliative care/BSC/SC’. This has been exacerbated by a lack of clarity from clinicians about what the latter three terms actually mean. There is increasing evidence that a more multidisciplinary team approach to the management of this patient population can result in an improved outcome clinically, and potentially at a reduced cost.60 There is an argument that we move away from regarding BSC as withdrawal of oncological interventions in the last months of life and move to an integrated multispecialty approach with input from specialist palliative care, primary care providers as well as social, psychological and spiritual service providers in addition to oncological treatment at all stages of the patients journey where indicated.13 In this way we move away from a binary treatment approach to a more holistic, patient focused approach more in keeping with the WHO definition of palliative care. Further emerging themes In addition to the increasing speed and variety of new therapies available for disease palliation, the rapidly changing environment both culturally and socially, affect changes that are difficult for clinicians, patients and carers to keep apace. As well as textbooks, word of mouth and the media increasingly patients and their families access the internet and social media for information.61 The plethora of information freely available via reputable third sector websites (cancer specific charities, forums and patient advisory groups) can support the patient and caregiver in their decision making, improve confidence in the advice they are given by healthcare professionals and offer support through a variety of mechanisms. Social media and non-specialist websites can potentially offer all of these advantages to service users, but carries with it risks of inaccuracies and frank misinformation which could conversely potentially adversely affect patients’ health as a consequence of patients altering medication regimes or failing to follow clinical advice based on information accessed.62 It can be difficult for non-specialists to separate, anecdote, opinion and fact and it can be equally challenging for clinical teams to support families in processing the information they receive. However despite these potential challenges patients and oncologists report that this ‘information seeking’ behaviour does not affect the patient–physician relationship.61 What does the future look like The aspirations of future palliative treatment of this patient group should have its foundations on effective communication centred on honesty about the likely prognosis, benefits and toxicities of any intervention and what the patient values the most in this context. This is reliant on adequate and accurate information being available to both patient and health professionals. Clinical research incorporating QOL measures is now already the norm, as shown in Table 1. However research incorporating QOL measures that include not only physical aspects of disease, but also psychological, social and sexual function remains uncommon. A study looking at QOL at the end of life by assessing caregiver’s ratings of patients’ physical and mental distress in the last week of life for those patients with a predicted survival of <6 months found those patients receiving chemotherapy did not have an improved survival, they also found no improvement in their quality of death (QOD).63 A randomized study of early palliative care involvement in a cancer centre versus usual care utilized a number of QOL measures. This study found improved QOL, improved QOD and improved patient satisfaction; despite this there was no improvement in spiritual wellbeing.64 An alternative route is to prospectively evaluate those QOL factors which are most important to the patients. A schedule for evaluation of individual QOL has been devised that evaluates what the patient feels dictates QOL. This involves the patient identifying their five most important QOL factors which are then measured prospectively within the clinical trial.65 It is also important that research data are aligned with real-life clinical practice. A process of continual validation of patient and clinical experience is vital to ensure the applicability of advice and information given to patients and their caregivers. Programmes of assessing and benchmarking patient experiences and outcomes through quality indicators which include response rates, survival, patient feedback, end of life experience and emotional wellbeing are increasingly being encouraged through international initiatives and adopted within cancer centres.14,66 In addition more accurate tools to support patient specific prognostication would support discussions regarding appropriateness of SACT. Delivering quality information, symptom control, goal and value led palliative interventions requires interdisciplinary team working. Early intervention with specialized palliative care teams improves the chances of this being successful. This can improve QOL, increase physical and mental wellbeing outcomes for caregivers, improves timely access to hospice care and in some studies has been suggested to improve survival.16,56,57 Whilst early intervention has been suggested to constitute palliative care interaction within 8 weeks of diagnosis of an incurable cancer ASCO do not specify timelines for this intervention but do recommend interdisciplinary palliative care management for all patients with advanced disease alongside standard oncology care.56 Conclusion The landscape of therapeutic options for cancer palliation has dramatically changed over recent years resulting in more treatment options, higher response rates, improvement in survival and changing toxicity profiles. However evidence also suggests that, despite guidelines to the contrary, increasing numibers of patients are receiving SACT in the last weeks of life. There appears to remain a disconnect between patient and doctor understanding and expectations of treatment outcomes. These factors make an emphasis on communication, honesty and frank discussion on benefits versus risks perhaps even more important than in the past. However, tools to support prognostication by clinicians is an area of significant importance for further research to aid decision making for clinicians, patients and their carers. There is also increasing evidence that a multidisciplinary approach to cancer palliation which includes palliative and hospice care from the start is of benefit however this remains aspirational in many parts of the world. Conflict of interest statement The authors have no potential conflicts of interest. Author Biography Dr C.M. 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British Medical Bulletin – Oxford University Press
Published: Mar 1, 2018
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