How Are Palliative Care Cancer Populations Characterized in Randomized Controlled Trials? A Literature Review

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Journal of Pain and Symptom Management

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Review Article

How Are Palliative Care Cancer Populations Characterized in Randomized Controlled Trials? A Literature Review Katrin Ruth Sigurdardottir, MD, Line Oldervoll, PhD, Marianne Jensen Hjermstad, PhD, Stein Kaasa, MD, PhD, Anne Kari Knudsen, MD, PhD, Erik Torbjørn Løhre, MD, Jon H
avard Loge, MD, PhD, and Dagny Faksv
ag Haugen, MD, PhD European Palliative Care Research Centre (K.R.S., L.O., M.J.H., S.K., A.K.K., J.H.L., D.F.H.), Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim; Sunniva Centre for Palliative Care (K.R.S.), Haraldsplass Deaconess Hospital, Bergen; Regional Centre of Excellence for Palliative Care, Western Norway (K.R.S., D.F.H.), Haukeland University Hospital, Bergen; Røros Rehabilitation Centre (L.O.), Røros; Regional Centre for Excellence in Palliative Care, South Eastern Norway (M.J.H.), and National Resource Centre for Late Effects After Cancer Treatment (J.H.L.), Oslo University Hospital, Oslo; and Department of Oncology (S.K., A.K.K., E.T.L.), St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

Abstract Context. The difficulties in defining a palliative care patient accentuate the need to provide stringent descriptions of the patient population in palliative care research. Objectives. To conduct a systematic literature review with the aim of identifying which key variables have been used to describe adult palliative care cancer populations in randomized controlled trials (RCTs). Methods. The data sources used were MEDLINE (1950 to January 25, 2010) and Embase (1980 to January 25, 2010), limited to RCTs in adult cancer patients with incurable disease. Forty-three variables were systematically extracted from the eligible articles. Results. The review includes 336 articles reporting RCTs in palliative care cancer patients. Age (98%), gender (90%), cancer diagnosis (89%), performance status (45%), and survival (45%) were the most frequently reported variables. A large number of other variables were much less frequently reported. Conclusion. A substantial variation exists in how palliative care cancer populations are described in RCTs. Few variables are consistently registered and reported. There is a clear need to standardize the reporting. The results from this work will serve as the basis for an international Delphi process with the aim of

Address correspondence to: Katrin Ruth Sigurdardottir, MD, European Palliative Care Research Centre, Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Bevegelsessenteret Ó 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Etg 3 Øst, St. Olavs Hospital, N-7006 Trondheim, Norway. E-mail: [email protected] Accepted for publication: June 14, 2013.

0885-3924/$ - see front matter http://dx.doi.org/10.1016/j.jpainsymman.2013.06.005

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reaching consensus on a minimum set of descriptors to characterize a palliative care cancer population. J Pain Symptom Manage 2014;47:906e914. Ó 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Palliative care, literature review, randomized clinical trial, cancer, patient characteristic, generalizability, publication standard, basic data set

Introduction Balfour Mount introduced the term ‘‘palliative care’’ in 1973.1 Today, at least 37 English and 26 German definitions of palliative care have been identified.2 Most of the definitions agree about the holistic nature of the palliative care approach and the central objectives of ‘‘quality of life’’ and ‘‘relief of suffering.’’2,3 The definitions show much less agreement as to the target group, and whether a limited prognosis is a central patient characteristic.2 This may be illustrated by the two most frequently used definitions, the World Health Organization definitions of 19904 and 2002,5 respectively. The first describes the target population as ‘‘patients whose disease is not responsive to curative treatment,’’ whereas the second has extended the population to ‘‘patients and their families, facing the problems associated with life-threatening illness.’’ The difficulty in defining the target population for palliative care is getting more pronounced as more diagnostic groups are included and as the palliative care approach is implemented at an earlier stage in the disease trajectory. Indeed, palliative care patients are usually defined by the fact that they receive palliative care.6 This might serve a classification purpose on a pragmatic level, but it creates considerable problems for research purposes. Palliative care populations may differ extensively for age, diagnosis, symptom burden, functional status, and survival. Most patients admitted to palliative care programs in Europe are cancer patients,7 and the heterogeneity only within this diagnostic group is well documented. A large cross-sectional study performed by the European Association for Palliative Care Research Network in 20007 showed that the samples varied considerably for demographic characteristics, places of care, expected survival, type of analgesics, and treatment modalities.8,9 This

heterogeneity requires a thorough description of the study sample to be able to judge the external validity of results from clinical trials; that is, if the study results can be generalized to groups and settings beyond those in the trial.10 In recent years, palliative care has been increasingly expanded to include patients with advanced illness other than cancer. Other patient groups have been shown to have similar symptom burdens and palliative care needs to cancer patients11 and, therefore, to share some of their characteristics. However, increasing the spectrum of diagnoses also adds to the heterogeneity of the palliative care population. The need to reach international consensus on how to describe and classify a palliative care population has been recognized by several investigators.6,7,12e15 In a recent workshop on clinical priorities, barriers, and solutions in end-of-life care research across Europe, the challenge in describing and classifying the palliative care population was perceived as an important barrier to conducting high-quality research in end-of-life care.16 The lack of common descriptors makes it hard to get a clear picture of the populations and consequently to compare results across studies and apply the findings in clinical settings. At least one initiative has been taken to define a framework of variables to describe a palliative care population.12 The proposed checklist for reporting patient population and service characteristics in hospice and palliative care research has recently been revised.17 A limited number of demographic variables were proposed, including age, gender, socioeconomic indices, ethnicity, life-limiting illness, performance status, and days from referral until death. The list is limited, especially for disease-related variables, but it may be a starting point for establishing a common way for reporting study materials.

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The present work was part of a process that aimed to arrive at a more complete common set of descriptors for reporting population characteristics in palliative care research, with the ultimate aim to improve research quality. To obtain candidate variables for a planned Delphi process on patient descriptors, a literature review was performed. Because randomized controlled trials (RCTs) are considered the reference standard of clinical science,18 we assumed that peer-reviewed reports on RCTs in palliative care cancer patients would give the most comprehensive descriptions of the samples, compared with descriptive studies, and consequently the most relevant input to a forthcoming consensus process. The purpose of the present review was to identify which variables have been used to characterize adult palliative care cancer populations in RCTs.

Methods A systematic approach was used, which included the following three steps: 1) a systematic literature search, 2) selection of relevant articles from reading titles/abstracts, and 3) extraction of data from retrieved full-length articles.

Step 1: Literature Search Searches were performed in MEDLINE and Embase via OvidSP on January 25, 2010. The MEDLINE search ranged from 1950 through the second week of January 2010 and used the search string (palliate$ or hospice$ or ‘‘terminal care’’).af. AND randomized controlled trial limit to (English language, ‘‘all adult (19 plus years)’’ and Cancer). The Embase search ranged from 1980 through the third week of January 2010 and used the search string (palliate$ or hospice$ or ‘‘terminal care’’).af. AND randomized controlled trial AND (Cancer.mp or Neoplasm/) limit to English language, and ‘‘adult <18 to 64 years> or aged <65þyears>’’. The search was first performed in the last week of 2008 and updated once in January 2010.

Step 2: Screening of Titles and Abstracts The titles and abstracts were screened for study design, population, interventions, and study end points. Inclusion criteria were RCTs in adult cancer patients with incurable disease.

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Exclusion criteria were study populations without malignancies, cancer populations with potentially curable malignancies, and mixed populations for diagnosis, treatment intention, or age. Studies also were excluded if the intervention given was neoadjuvant or adjuvant chemotherapy, or if the primary end point was survival or tumor response. References with no available abstract in MEDLINE or Embase also were excluded. All titles and abstracts were examined independently by two of the authors. In cases of doubt or disagreement, a third reader was consulted and agreement was reached.

Step 3: Extraction of Variables From Full-Text Articles Each eligible full-length article was read by two of the authors independently. In cases of disagreement about inclusion/exclusion, a third author was consulted and consensus was reached. Before reading the articles, a checklist of 43 items was developed, based on consensus among the readers about which variables to extract and how they should be recorded (Appendix I, available at jpsmjournal.com). The following information was recorded: author, publication year, country, journal, type of intervention, patient variables, sample size, and relevant comments. The patient variables were grouped into the following five domains: 1) demographic characteristics (age, gender, ethnicity, religion, education, and marital status), 2) social information (caregiver issues), 3) medical information (cancer diagnosis, extent of disease at inclusion, performance status, palliative anticancer therapy, expected survival, actual survival, cognitive function, current medication, hemoglobin value, albumin value, C-reactive protein value, weight, weight loss, body mass index, and assessment of general symptoms), 4) information about quality of life, and 5) information about the setting (outpatient/inpatient and study location). Citations were managed with Endnote X4. Data were analyzed with descriptive statistics with the use of SPSS version 18.0 (SPSS Inc., Chicago, IL).

Results Abstracts and Full-Text Articles The search in the two databases resulted in a total of 1358 citations (MEDLINE 849, Embase

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509); 999 after removal of duplicates. After the first screening, 545 abstracts were excluded, and 454 were included and examined in full text. After this examination, a further 118 studies were excluded, leaving a total of 336 studies (Appendix II, available at jpsmjournal.com) for the final analysis (Fig. 1), with a total sample size of 44,824 patients.

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the presence of metastases was reported in 36% of the studies. Expected survival was reported in 25% of the studies and actual survival in 45%. Information about physical performance was included in 45% of the RCTs. Karnofsky Performance Status was used in 47% of these reports,19 Eastern Cooperative Oncology Group Performance Status in 46%,20 and the Palliative Performance Scale in 3%.21 A general symptoms assessment (by use of scoring instruments) was reported in 25% of the RCTs. A huge variety of instruments was used. Cognitive function was evaluated in 16% of the studies. The Mini-Mental State Examination was the most commonly used instrument to evaluate cognitive function (55%).22 Body mass index was reported in five RCTs (1%) and weight/weight loss in 15% of the trials. C-reactive protein (2%), hemoglobin (11%), and albumin (8%) values were rarely reported.

Demographic Characteristics Age (98%) and gender (90%) were the only predefined categories in this domain that were regularly reported. Ethnicity was reported in 9%, marital status in 6%, education in 4%, and religion in 1% of the studies (Table 1).

Information on Social Issues Caregiver issues were defined to include variables related to the patient’s household and information about social networks. Only 2% of the reports gave information about this domain.

Quality-of-Life Information Medical Information

Quality of life was assessed by a number of different instruments/questionnaires and reported in 27% of the studies. The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire

Information about the cancer diagnosis was included in 89% of the studies; more detailed descriptions of the disease varied substantially between studies (Table 1). Information about

1358 records identified through the database searches

999 records after removal of duplicates

999 records screened

545 records excluded: Endpoint = 231 Study design = 126 Study population = 142 No abstract = 32 Intervention = 13 Other = 1

454 full-text articles assessed for eligibility

118 full-text articles excluded: Study population = 49 Study design = 33 Endpoint =32 Intervention = 2 Other = 2

336 studies included in the review

Fig. 1. Flow chart showing the selection of studies.

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Table 1 Percentage of Studies Reporting the Extracted Variables Extracted Variables

Percentage of Studies Reporting (%)

Demographic characteristics Age Gender Ethnicity Marital status Education Religion Social information/caregiver issues Information about caregiver issues or household/living with, more than marital status Information about social network/resources Medical information Cancer diagnosis Extent of disease at inclusion, advanced disease/cancer Extent of disease at inclusion, metastatic Extent of disease at inclusion, locally advanced Extent of disease at inclusion, palliative Extent of disease at inclusion, terminal Extent of disease at inclusion, not curable or not operable Extent of disease at inclusion, stage Performance status Palliative anticancer therapy terminated in the whole sample information Expected survival Actual survival Cognitive function Current medication (not anticancer or intervention medication) Hemoglobin Albumin C-reactive protein Other biometrics Weight and weight loss Body mass index General symptoms assessed Information about QoL QoL assessed Information about setting Outpatients/inpatients Location

98 90 9 6 4 1 2 2 89 37 36 12 12 9 31 12 45 23 25 45 16 16 11 8 2 23 15 1 25 27 41 56

QoL ¼ Quality of life.

was most frequently applied (31%),23 followed by the Functional Assessment of Cancer Therapy questionnaire24 (9%).

Treatment Setting Information Provision of care delivery was reported in 41% of the RCTs as follows: inpatients (45%), outpatients (34%), and a combination of the two (21%). Place of care delivery was reported in 56% of the studies as follows: palliative care unit (24%), department of oncology (13%), department of surgery (13%), hospice program (5%), department of internal medicine (3%), and multiple and other locations (42%).

Interventions The most common interventions were pharmacologic (not including tumor-directed

chemotherapy) in 40% of the studies, surgery (including stents) in 17%, radiotherapy in 14%, other interventions (nutrition, massage, complementary therapies, etc.) in 14%, chemotherapy in 6%, care delivery in 3%, and combinations of two or more of the above in 6%.

Discussion The aim of this review was to identify which variables have been used to characterize adult palliative care cancer populations in RCTs. The review includes 336 full-text articles reporting RCTs in adult palliative care cancer patients from 1950 to January 2010. The descriptions of the patient populations varied considerably across the studies. Age, gender,

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cancer diagnosis, performance status, and survival were the most frequently reported variables. A large number of other variables were much less frequently reported. The data confirm the lack of consensus on how to describe the population in studies reporting RCTs in palliative care cancer patients and show that just a few core variables are consistently registered and reported. The practice of evidence-based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research.18 Generally, the evidence base for palliative medicine is more limited than in many other areas of medicine.25 This fact may be the result of methodological, cultural, and structural barriers to research in palliative care.16,26 Consequently, for many years there has been a great need for new evidence from clinical trials to feed into clinical decision making as well as guideline development.25 In this respect, our present findings are disappointing. RCTs are considered the reference standard of clinical science18 and are commonly put at the top in the hierarchies of evidence.27 Even so, our results indicate an inconsistency in the reporting of sample characteristics that makes it almost impossible to extract useful evidence for clinical practice. We believe that this lack of reporting of eligibility criteria and population characteristics has substantially hampered the development of evidence-based palliative medicine. This situation presents an urgent need for consensus on common descriptors necessary and sufficient to describe the sample. The majority (89%) of the included RCTs reported on the cancer diagnosis. Information about advanced cancer or metastatic disease was given in approximately one-third of the studies. The cancer diagnosis and the pattern of metastases can be regarded as a minimum to describe a state of advanced cancer. Within oncology, the main breakthrough in classification happened when the tumor, node, metastasis (TNM) classification system was first published in 1953.28 This system guides individual anticancer treatment on the basis of evidence-based guidelines and is also important for prognostication. The TNM stage will decide inclusion into or exclusion from clinical trials in oncology, and there is broad consensus to include TNM staging when

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describing an oncology sample. However, only 12% of the studies included in this review reported on the stage of cancer. Several stakeholders both within palliative medicine and oncology strongly advocate the integration of palliative care services into standard oncology on the diagnosis of metastatic or advanced cancer, based on the systematic approach to symptom relief and enhanced quality of life for patients and caregivers, less use of emergency care services, and a timelier referral to specialist palliative care, which often takes place too late.29,30 However, this integration adds even more to the case-mix and highlights the need for using standardized descriptors. Many patient characteristics may influence the effect of interventions. This applies in particular to variables such as age, diagnosis, performance status, and expected survival. In the 336 studies covered by this review, only age, gender, and diagnosis were frequently reported, whereas performance status was included in less than 50% of the studies. Performance status is one of the most important patient characteristics, being a strong predictor for survival,31e33 symptom burden,34 and functional capacity, which is closely related to treatment tolerance.35 In our opinion, performance status should be reported in all clinical trials. The CONSORT (Consolidated Standards of Reporting Trials) Statement sets forth recommendations for investigators on how to report findings from RCTs.36 The framework consists of a 25-item checklist and a participant flow diagram. The checklist items focus on how the trial was designed, analyzed, and interpreted. A flow diagram displays the progress of all participants through the trial. However, equally as important as these factors are the recommendations for reporting accurate information about participant characteristics and eligibility criteria for the trial. The question is which variables are crucial to report to give a valid description of a palliative care population. The CONSORT Statement recommends to report the number and type of settings and to describe the care providers involved. Our results showed that place of care was reported in 56% of the studies and provision of care delivery in 41%. The diversity of palliative care services represents a main challenge when applying new knowledge in the field.7,37,38 The lack of reporting of basic descriptors

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such as type of setting and location further adds to this problem and makes it difficult to judge the external validity of a study.39 To our knowledge, this is the most comprehensive review to report on variables used to characterize adult palliative care cancer populations in RCTs to date. Two other, more limited reviews have been published, describing both cancer and noncancer populations. The systematic literature review by Van Mechelen et al.40 aimed to propose minimum characteristics to define a palliative care patient. The investigators systematically described six characteristics of the study populations in 60 included RCTs.40 Information on the following characteristics was extracted: diagnosis, disease progression, life expectancy, clinical settings, intervention, and outcome. The investigators conclude that there is a great diversity within palliative care populations. Their results are supported by a Dutch national questionnaire survey, also concluding that there is a lack of clear inclusion criteria in palliative care research.6 The investigators found a substantial difference in study populations on the basis of different inclusion criteria and point out the need for a common classification system to define whom to include in clinical studies.6 Currow et al.17 also conducted a literature review when refining their proposed discipline-specific checklist for reporting patient populations and service characteristics in hospice and palliative care research. Articles reviewed were empirically based studies in palliative care published in three leading palliative care journals in 2007. The most frequently reported subdomains in the 189 included studies were patient age, gender, and diagnosis, consistent with our findings. The investigators conclude that their results showed significant underreporting of information that is necessary to allow clinicians to assess the applicability of the study findings to their own patients. The present work was performed to explore which descriptors have been used to characterize palliative care cancer populations in RCTs. The inconsistencies found were greater than we had suspected. Further work is needed to reach international consensus on a set of core variables to be universally applied to describe the palliative care population. We believe that the proposed checklist by Currow

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et al.17 is a good starting point, but it is too limited for describing the samples in clinical research in necessary detail. In addition, the work needs to be internationally anchored. The findings from the present study will serve as basis for an international Delphi process to reach consensus on a set of core variables and how they should be recorded.

Limitations Limitations exist for the retrieval of all possible literature through electronic searching of bibliographic databases.41 However, to identify relevant palliative care literature the Boolean expression (palliat$ or hospice$ or ‘‘terminal care’’).af., often referred to as the ‘‘palliative search,’’ was used.42 These three terms achieved a specificity of 99.97% in a study that validated a palliative care electronic search filter.43 It is, therefore, widely accepted that these terms represent a robust strategy for the retrieval of palliative care literature.42 Our search terms did not include supportive care, which is a term variably defined, but focusing more on patients receiving disease-modifying treatment.3 However, not including this term might have led to some articles being missed. Our study has some other limitations. The number of retrieved articles would probably have been higher if we had searched more than two bibliographic databases; however, other databases add little to MEDLINE and Embase in terms of RCTs. Restriction to English language publications also may represent a source of bias, even if most medical research articles are published in English-language journals. Finally, our checklist of 43 variables was made by the research group before reading, and we are aware that some items might have been missed. We did not systematically record possible additional variables when extracting data from the retrieved articles. Inclusion criteria in the present study were RCTs in adult cancer patients with incurable disease. These criteria represent two additional limitations. The first is the restriction to cancer patients. A similar study should be performed in palliative care populations with noncancer diagnoses. The second limitation is the restriction to RCTs. In palliative care research, other research methods are extensively used, and including studies with different designs might have provided some articles with

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much better sample descriptions. In addition, other study designs might have elicited different descriptive variables than the ones used in RCTs. Despite these limitations, we believe that the results of our extensive review will serve as a useful basis for an international consensus process aimed at assembling a basic data set necessary and sufficient to describe a palliative care cancer population.

Conclusion Palliative care cancer populations are inconsistently and insufficiently described when reporting RCTs. There is an obvious need for a set of common descriptors, to be used primarily in research, but also in daily clinical practice and policy making. The use of a consensus-based basic data set would facilitate the transfer of research findings to the clinical setting and would allow comparisons across studies and settings, thereby increasing the evidence base in palliative care.

Disclosures and Acknowledgments This study was funded by the European Palliative Care Research Centre and Project PRISMA. PRISMA, Reflecting the Positive Diversities of European Priorities for Research and Measurement in End-of-Life Care, was funded by the European Commission’s Seventh Framework Programme (contract number: Health-F2-2008201655) with the overall aim to inform best practice and harmonize research in end-of-life care for cancer patients across Europe. There are no financial benefits or conflicts of interest that might bias this work. The authors thank Ingrid I. Riphagen for assistance with electronic database searches and constructive remarks on the manuscript.

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care,’’ ‘‘palliative care,’’ and ‘‘hospice care’’ in the published literature, dictionaries, and textbooks. Support Care Cancer 2013;21:659e685. 4. World Health Organization. Cancer pain relief and palliative care. Geneva: WHO, 1990. 5. World Health Organization. National cancer control programmes: Policies and managerial guidelines. Geneva: WHO, 2002. 6. Borgsteede SD, Deliens L, Francke AL, et al. Defining the patient population: one of the problems for palliative care research. Palliat Med 2006;20: 63e68. 7. Kaasa S, Torvik K, Cherny N, Hanks G, de Conno F. Patient demographics and centre description in European palliative care units. Palliat Med 2007;21:15e22. 8. Klepstad P, Kaasa S, Cherny N, Hanks G, de Conno F. Pain and pain treatments in European palliative care units. A cross sectional survey from the European Association for Palliative Care Research Network. Palliat Med 2005;19:477e484. 9. Laugsand EA, Kaasa S, de Conno F, Hanks G, Klepstad P. Intensity and treatment of symptoms in 3,030 palliative care patients: a cross-sectional survey of the EAPC Research Network. J Opioid Manag 2009;5:11e21. 10. Burchett H, Umoquit M, Dobrow M. How do we know when research from one setting can be useful in another? A review of external validity, applicability and transferability frameworks. J Health Serv Res Policy 2011;16:238e244. 11. Solano JP, Gomes B, Higginson IJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease and renal disease. J Pain Symptom Manage 2006;31: 58e69. 12. Currow DC, Wheeler JL, Glare PA, Kaasa S, Abernethy AP. A framework for generalizability in palliative care. J Pain Symptom Manage 2009;37: 373e386. 13. Boisvert M, Cohen SR. Opioid use in advanced malignant disease: why do different centers use vastly different doses? A plea for standardized reporting. J Pain Symptom Manage 1995;10:632e638. 14. Caraceni A, Cherny N, Fainsinger R, et al. Pain measurement tools and methods in clinical research in palliative care: recommendations of an Expert Working Group of the European Association of Palliative Care. J Pain Symptom Manage 2002;23: 239e255. 15. Kaasa S, Radbruch L. Palliative care research priorities and the way forward. Eur J Cancer 2008; 44:1175e1179. 16. Sigurdardottir KR, Haugen DF, van der Rijt CC, et al. Clinical priorities, barriers and solutions in end-of-life cancer care research across Europe. Report from a workshop. Eur J Cancer 2010;46: 1815e1822.

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17. Currow DC, Tieman JJ, Greene A, et al. Refining a checklist for reporting patient populations and service characteristics in hospice and palliative care research. J Pain Symptom Manage 2012;43: 902e910. 18. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn’t. BMJ 1996;312:71e72. 19. Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH. The use of nitrogen mustard in the palliative treatment of carcinoma. With particular reference to bronchogenic carcinoma. Cancer 1948;1:634e656. 20. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649e655. 21. Anderson F, Downing GM, Hill J, Casorso L, Lerch N. Palliative performance scale (PPS): a new tool. J Palliat Care 1996;12:5e11. 22. Folstein MF, Folstein SE, McHugh PR. ‘‘Minimental state’’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189e198. 23. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365e376. 24. Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 1993;11:570e579. 25. Kaasa S, Haugen DF. Cancer pain research: time to reset the strategy and the agenda. Palliat Med 2011;25:392e393. 26. Kaasa S, Hjermstad MJ, Loge JH. Methodological and structural challenges in palliative care research: how have we fared in the last decades? Palliat Med 2006;20:727e734.

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opinion: the integration of palliative care into standard oncology care. J Clin Oncol 2012;30:880e887. 31. Lau F, Cloutier-Fisher D, Kuziemsky C, et al. A systematic review of prognostic tools for estimating survival time in palliative care. J Palliat Care 2007;23:93e112. 32. Morita T, Tsunoda J, Inoue S, Chihara S. Validity of the palliative performance scale from a survival perspective. [letter]. J Pain Symptom Manage 1999; 18:2e3. 33. Yates JW, Chalmer B, McKegney FP. Evaluation of patients with advanced cancer using the Karnofsky performance status. Cancer 1980;45:2220e2224. 34. Seow H, Barbera L, Sutradhar R, et al. Trajectory of performance status and symptom scores for patients with cancer during the last six months of life. J Clin Oncol 2011;29:1151e1158. 35. Sweeney CJ, Zhu J, Sandler AB, et al. Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic nonsmall cell lung carcinoma. Cancer 2001;92:2639e2647. 36. Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann Intern Med 2010;152:726e732. 37. Centeno C, Clark D, Lynch T, et al. Facts and indicators on palliative care development in 52 countries of the WHO European region: results of an EAPC Task Force. Palliat Med 2007;21:463e471. 38. Clark D. From margins to centre: a review of the history of palliative care in cancer. Lancet Oncol 2007;8:430e438. 39. Juni P, Altman DG, Egger M. Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ 2001;323:42e46. 40. Van Mechelen W, Aertgeerts B, De Ceulaer K, et al. Defining the palliative care patient: a systematic review. Palliat Med 2012;27:197e208.

27. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000;342: 1887e1892.

41. Tieman JJ, Abernethy A, Currow DC. Not published, not indexed: issues in generating and finding hospice and palliative care literature. J Palliat Med 2010;13:669e675.

28. International Union Against Cancer. TNM history, evolution and milestones. 2010. Available from http://uicc.org. Accessed March 21, 2013.

42. Tieman J, Sladek R, Currow D. Changes in the quantity and level of evidence of palliative and hospice care literature: the last century. J Clin Oncol 2008;26:5679e5683.

29. Bruera E, Hui D. Integrating supportive and palliative care in the trajectory of cancer: establishing goals and models of care. J Clin Oncol 2010; 28:4013e4017. 30. Smith TJ, Temin S, Alesi ER, et al. American Society of Clinical Oncology provisional clinical

43. Sladek R, Tieman J, Fazekas BS, Abernethy AP, Currow DC. Development of a subject search filter to find information relevant to palliative care in the general medical literature. J Med Libr Assoc 2006;94:394e401.

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Appendix I Extraction of Variables From the Full-Text Articles Categories Author Year of publication Country Journal name Type of intervention in the randomized controlled trials

Sample size Comments about the study Patient variables Demographic characteristics Age Gender Ethnicity Marital status Education Religion Social information/caregiver issues Information about caregiver issues or household/ living with, more than marital status Information about social network Medical information Cancer diagnosis Extent of disease at inclusion e advanced disease/ cancer Extent of disease at inclusion, metastatic Extent of disease at inclusion, locally advanced Extent of disease at inclusion, palliative Extent of disease at inclusion, terminal Extent of disease at inclusion, not curable or not operable Extent of disease at inclusion, stage Performance status Performance status instrument used Palliative anticancer therapy terminated in the whole sample Expected survival Real survival Cognitive function Instrument used to measure cognitive function Current medication Hemoglobin Albumin C-reactive protein Other biometrics Weight and weight loss Body mass index Information on general symptoms Instrument used for assessment of general symptoms

Alternatives Name of the first author

0 ¼ Chemotherapy; 1 ¼ radiotherapy; 2 ¼ pharmacological; 3 ¼ surgery; 4 ¼ care delivery/ organization; 5 ¼ physiotherapy; 6 ¼ other; 7 ¼ two or more of the above Number at inclusion

0 0 0 0 0 0

¼ ¼ ¼ ¼ ¼ ¼

No No No No No No

information; information; information; information; information; information;

1 1 1 1 1 1

¼ ¼ ¼ ¼ ¼ ¼

specified information information information information information

0 ¼ No information; 1 ¼ information 0 ¼ No information; 1 ¼ information 0 ¼ No information; 1 ¼ specified 0 ¼ No information; 1 ¼ advanced cancer 0 0 0 0 0

¼ ¼ ¼ ¼ ¼

No No No No No

information; information; information; information; information;

1 1 1 1 1

¼ ¼ ¼ ¼ ¼

metastatic locally advanced palliative terminal not curable or not operable

0 ¼ No information; 1 ¼ stage given 0 ¼ No information; 1 ¼ inclusion criterion; 2 ¼ specified; 3 ¼ both 1 and 2 0 ¼ No information; 1 ¼ Karnofsky Performance Status Scale; 2 ¼ Palliative Performance Scale; 3 ¼ WHO/ ECOG Performance Status Scale; 4 ¼ other 0 ¼ No information; 1 ¼ yes; 2 ¼ no 0 ¼ No information; 1 ¼ inclusion criterion; 2 ¼ specified; 3 ¼ both 1 and 2 0 ¼ No information; 1 ¼ information 0 ¼ No information; 1 ¼ inclusion criterion; 2 ¼ specified instrument 0 ¼ None; 1 ¼ no instrument specified; 2 ¼ Mini-Mental State Examination; 3 ¼ other instrument specified 0 ¼ No information; 1 ¼ information 0 ¼ No information; 1 ¼ information 0 ¼ No information; 1 ¼ information 0 ¼ No information; 1 ¼ information 0 ¼ No information; 1 ¼ information 0 ¼ No information; 1 ¼ information 0 ¼ No information; 1 ¼ information 0 ¼ No information; 1 ¼ assessed, not reported; 2 ¼ assessed, partly reported; 3 ¼ assessed, completely reported 0 ¼ None; 1 ¼ Edmonton Symptom Assessment System; 2 ¼ Rotterdam Symptom Checklist; 3 ¼ other; 4 ¼ multiple (Continued)

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Appendix I Continued Categories Information on specific symptoms Information about QoL Information on QoL QoL information, instrument used

Information about setting Outpatients/inpatients Location

Alternatives 0 ¼ No information; 1 ¼ information 0 ¼ No information; 1 ¼ assessed, not reported; 2 ¼ assessed, partly reported; 3 ¼ assessed, completely reported 0 ¼ None; 1 ¼ European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire; 2 ¼ Functional Assessment of Cancer Therapy questionnaire; 3 ¼ Short Form-36/Short Form12; 4 ¼ other; 5 ¼ multiple 0 ¼ No information; 1 ¼ outpatients; 2 ¼ inpatients; 3 ¼ both 1 and 2 0 ¼ No information; 1 ¼ palliative care unit; 2 ¼ oncological department; 3 ¼ internal medicine department; 4 ¼ surgical department; 5 ¼ nursing home; 6 ¼ hospice; 7 ¼ primary care setting; 8 other location; 9 ¼ two/multiple locations

WHO ¼ World Health Organization; ECOG ¼ Eastern Cooperative Oncology Group; QoL ¼ quality of life.

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Appendix II References for the 336 Studies Included in the Analysis 1. Adam A, Ellul J, Watkinson AF, et al. Palliation of inoperable esophageal carcinoma: a prospective randomized trial of laser therapy and stent placement. Radiology 1997;202:344e348. 2. Agra Y, Sacristan A, Gonzalez M, et al. Efficacy of senna versus lactulose in terminal cancer patients treated with opioids. J Pain Symptom Manage 1998;15:1e7. 3. Agteresch HJ, Dagnelie PC, van der Gaast A, et al. Randomized clinical trial of adenosine 5’-triphosphate in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2000;92:321e328. 4. Ahles TA, Herndon JE, Small EJ, et al. Quality of life impact of three different doses of suramin in patients with metastatic hormone-refractory prostate carcinoma: results of Intergroup O159/Cancer and Leukemia Group B 9480. Cancer 2004;101:2202e2208. 5. Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. The TTS-Fentanyl Comparative Trial Group. J Pain Symptom Manage 1997; 13:254e261. 6. Ajani JA, Moiseyenko VM, Tjulandin S, et al. Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: the V-325 Study Group. J Clin Oncol 2007;25:3205e3209. 7. Alderson D, Wright PD. Laser recanalization versus endoscopic intubation in the palliation of malignant dysphagia. Br J Surg 1990;77:1151e1153. 8. Allard P, Lamontagne C, Bernard P, et al. How effective are supplementary doses of opioids for dyspnea in terminally ill cancer patients? A randomized continuous sequential clinical trial. J Pain Symptom Manage 1999;17: 256e265. 9. Amouzegar-Hashemi F, Behrouzi H, Kazemian A, et al. Single versus multiple fractions of palliative radiotherapy for bone metastases: a randomized clinical trial in Iranian patients. Curr Oncol 2008;15:36e39. 10. Anderson H, Hopwood P, Stephens RJ, et al. Gemcitabine plus best supportive care (BSC) vs. BSC in inoperable non-small cell lung cancer-a randomized trial with quality of life as the primary outcome. UK NSCLC Gemcitabine Group. Non-Small Cell Lung Cancer. Br J Cancer 2000;83:447e453. 11. Angelini G, Pasini AF, Ederle A, et al. Nd:YAG laser versus polidocanol injection for palliation of esophageal malignancy: a prospective, randomized study. Gastrointest Endosc 1991;37:607e610. 12. Angorn IB, Haffejee AA. Pulsion intubation v. restrosternal gastric bypass for palliation of unresectable carcinoma of the upper thoracic oesophagus. Br J Surg 1983;70:335e338. 13. Arican A, Icli F, Akbulut H, et al. The effect of two different doses of oral clodronate on pain in patients with bone metastases. Med Oncol 1999;16:204e210. 14. Artifon EL, Sakai P, Cunha JE, et al. Surgery or endoscopy for palliation of biliary obstruction due to metastatic pancreatic cancer. Am J Gastroenterol 2006;101:2031e2037. 15. Auret KA, Schug SA, Bremner AP, et al. A randomized, double-blind, placebo-controlled trial assessing the impact of dexamphetamine on fatigue in patients with advanced cancer. J Pain Symptom Manage 2009;37: 613e621. 16. Badzio A, Senkus-Konefka E, Jereczek-Fossa BA, et al. 20 Gy in five fractions versus 8 Gy in one fraction in palliative radiotherapy of bone metastases. A multicenter randomized study. Nowotwory 2003;53:261e264. 17. Baka S, Ashcroft L, Anderson H, et al. Randomized phase II study of two gemcitabine schedules for patients with impaired performance status and advanced non-small-cell lung cancer. J Clin Oncol 2005;23:2136e2144. 18. Bakitas M, Lyons KD, Hegel MT, et al. Effects of a palliative care intervention on clinical outcomes in patients with advanced cancer: the Project ENABLE II randomized controlled trial. JAMA 2009;302:741e749. 19. Barr H, Krasner N, Raouf A, et al. Prospective randomised trial of laser therapy only and laser therapy followed by endoscopic intubation for the palliation of malignant dysphagia. Gut 1990;31:252e258. 20. Beller E, Tattersall M, Lumley T, et al. Improved quality of life with megestrol acetate in patients with endocrine-insensitive advanced cancer: a randomised placebo-controlled trial. Australasian Megestrol Acetate Cooperative Study Group. Ann Oncol 1997;8:277e283. 21. Bergquist H, Wenger U, Johnsson E, et al. Stent insertion or endoluminal brachytherapy as palliation of patients with advanced cancer of the esophagus and gastroesophageal junction. Results of a randomized, controlled clinical trial. Dis Esophagus 2005;18:131e139.

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22. Bleehen NM, Girling DJ, Fayers PM, et al. Inoperable non-small-cell lung cancer (NSCLC): A Medical Research Council randomised trial of palliative radiotherapy with two fractions or ten fractions. Br J Cancer 1991;63:265e270. 23. Bleehen NM, Girling DJ, Machin D, et al. A Medical Research Council (MRC) randomised trial of palliative radiotherapy with two fractions or a single fraction in patients with inoperable non-small-cell lung cancer (NSCLC) and poor performance status. Br J Cancer 1992;65:934e941. 24. Booth S, Kelly MJ, Cox NP, et al. Does oxygen help dyspnea in patients with cancer? Am J Respir Crit Care Med 1996;153:1515e1518. 25. Bornman PC, Harries-Jones EP, Tobias R, et al. Prospective controlled trial of transhepatic biliary endoprosthesis versus bypass surgery for incurable carcinoma of head of pancreas. Lancet 1986;1:69e71. 26. Bower M, Stein R, Evans TR, et al. A double-blind study of the efficacy of metronidazole gel in the treatment of malodorous fungating tumours. Eur J Cancer 1992;28A:888e889. 27. Brown J, Thorpe H, Napp V, et al. Assessment of quality of life in the supportive care setting of the big lung trial in non-small-cell lung cancer. J Clin Oncol 2005;23:7417e7427. 28. Bruera E, Belzile M, Pituskin E, et al. Randomized, double-blind, cross-over trial comparing safety and efficacy of oral controlled-release oxycodone with controlled-release morphine in patients with cancer pain. J Clin Oncol 1998;16:3222e3229. 29. Bruera E, Belzile M, Neumann CM. Twice-daily versus once-daily morphine sulphate controlled-release suppositories for the treatment of cancer pain. A randomized controlled trial. Support Care Cancer 1999;7:280e283. 30. Bruera E, Belzile M, Neumann C, et al. A double-blind, crossover study of controlled-release metoclopramide and placebo for the chronic nausea and dyspepsia of advanced cancer. J Pain Symptom Manage 2000;19:427e435. 31. Bruera ED, MacEachern TJ, Spachynski KA, et al. Comparison of the efficacy, safety, and pharmacokinetics of controlled release and immediate release metoclopramide for the management of chronic nausea in patients with advanced cancer. Cancer 1994;74:3204e3211. 32. Bruera E, de Stoutz N, Velasco-Leiva A, et al. Effects of oxygen on dyspnoea in hypoxaemic terminal-cancer patients. Lancet 1993;342:13e14. 33. Bruera E, de Stoutz ND, Fainsinger RL, et al. Comparison of two different concentrations of hyaluronidase in patients receiving one-hour infusions of hypodermoclysis. J Pain Symptom Manage 1995;10:505e509. 34. Bruera E, Ernst S, Hagen N, et al. Effectiveness of megestrol acetate in patients with advanced cancer: a randomized, double-blind, crossover study. Cancer Prev Control 1998;2:74e78. 35. Bruera E, El Osta B, Valero V, et al. Donepezil for cancer fatigue: a double-blind, randomized, placebocontrolled trial. J Clin Oncol 2007;25:3475e3481. 36. Bruera E, Fainsinger R, Spachynski K, et al. Steady-state pharmacokinetic evaluation of a novel, controlledrelease morphine suppository and subcutaneous morphine in cancer pain. J Clin Pharmacol 1995;35:666e672. 37. Bruera E, Fainsinger R, Spachynski K, et al. Clinical efficacy and safety of a novel controlled-release morphine suppository and subcutaneous morphine in cancer pain: a randomized evaluation. J Clin Oncol 1995;13: 1520e1527. 38. Bruera E, Moyano JR, Sala R, et al. Dexamethasone in addition to metoclopramide for chronic nausea in patients with advanced cancer: a randomized controlled trial. J Pain Symptom Manage 2004;28:381e388. 39. Bruera E, Neumann CM, Pituskin E, et al. A randomized controlled trial of local injections of hyaluronidase versus placebo in cancer patients receiving subcutaneous hydration. Ann Oncol 1999;10:1255e1258. 40. Bruera E, Pituskin E, Calder K, et al. The addition of an audiocassette recording of a consultation to written recommendations for patients with advanced cancer: a randomized, controlled trial. Cancer 1999;86:2420e2425. 41. Bruera E, Palmer JL, Bosnjak S, et al. Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study. J Clin Oncol 2004;22:185e192. 42. Bruera E, Palmer JL, Pace E, et al. A randomized, controlled trial of physician postures when breaking bad news to cancer patients. Palliat Med 2007;21:501e505. 43. Bruera E, Roca E, Cedaro L, et al. Action of oral methylprednisolone in terminal cancer patients: a prospective randomized double-blind study. Cancer Treat Rep 1985;69:751e754. 44. Bruera E, Ripamonti C, Brennei C, et al. A randomized double-blind crossover trial of intravenous lidocaine in the treatment of neuropathic cancer pain. J Pain Symptom Manage 1992;7:138e140. 45. Bruera E, Sloan P, Mount B, et al. A randomized, double-blind, double-dummy, crossover trial comparing the safety and efficacy of oral sustained-release hydromorphone with immediate-release hydromorphone in patients with cancer pain. Canadian Palliative Care Clinical Trials Group. J Clin Oncol 1996;14:1713e1717.

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46. Bruera E, Sweeney C, Willey J, et al. A randomized controlled trial of supplemental oxygen versus air in cancer patients with dyspnea. Palliat Med 2003;17:659e663. 47. Bruera E, Strasser F, Palmer JL, et al. Effect of fish oil on appetite and other symptoms in patients with advanced cancer and anorexia/cachexia: a double-blind, placebo-controlled study. J Clin Oncol 2003;21:129e134. 48. Bruera E, Sala R, Rico MA, et al. Effects of parenteral hydration in terminally ill cancer patients: a preliminary study. J Clin Oncol 2005;23:2366e2371. 49. Bruera E, Sala R, Spruyt O, et al. Nebulized versus subcutaneous morphine for patients with cancer dyspnea: a preliminary study. J Pain Symptom Manage 2005;29:613e618. 50. Bruera E, Willey J, Cohen M, et al. Expressive writing in patients receiving palliative care: a feasibility study. J Palliat Med 2008;11:15e19. 51. Bruno MJ, Haverkort EB, Tijssen GP, et al. Placebo controlled trial of enteric coated pancreatin microsphere treatment in patients with unresectable cancer of the pancreatic head region. Gut 1998;42:92e96. 52. Caraceni A, Zecca E, Bonezzi C, et al. Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol 2004;22:2909e2917. 53. Carazzone A, Bonavina L, Segalin A, et al. Endoscopic palliation of oesophageal cancer: results of a prospective comparison of Nd:YAG laser and ethanol injection. Eur J Surg 1999;165:351e356. 54. Carter R, Smith JS, Anderson JR. Laser recanalization versus endoscopic intubation in the palliation of malignant dysphagia: a randomized prospective study. Br J Surg 1992;79:1167e1170. 55. Cassier PA, Chabaud S, Trillet-Lenoir V, et al. A phase-III trial of doxorubicin and docetaxel versus doxorubicin and paclitaxel in metastatic breast cancer: results of the ERASME 3 study. Breast Cancer Res Treat 2008;109: 343e350. 56. Cerchietti L, Navigante A, Sauri A. Hypodermoclysis for control of dehydration in terminal-stage cancer. Int J Palliat Nurs 2000;6:370e374. 57. Chan G, Barkun J, Barkun AN, et al. The role of ciprofloxacin in prolonging polyethylene biliary stent patency: a multicenter, double-blinded effectiveness study. J Gastrointest Surg 2005;9:481e488. 58. Charles MA, Reymond L, Israel F, et al. Relief of incident dyspnea in palliative cancer patients: a pilot, randomized, controlled trial comparing nebulized hydromorphone, systemic hydromorphone, and nebulized saline. J Pain Symptom Manage 2008;36:29e38. 59. Chen WC, Hou MC, Lin HC, et al. Feasibility and potential benefit of maintenance endoscopic variceal ligation in patients with unresectable hepatocellular carcinoma and acute esophageal variceal hemorrhage: a controlled trial. Gastrointest Endosc 2001;54:18e23. 60. Chibaudel B, Tournigand C, Artru P, et al. FOLFOX in patients with metastatic colorectal cancer and high alkaline phosphatase level: an exploratory cohort of the GERCOR OPTIMOX1 study. Ann Oncol 2009;20: 1383e1386. 61. Choi CH, Suit HD. Evaluation of rapid radiation treatment schedules utilizing two treatment sessions per day. Radiology 1975;116:703e707. 62. Christie JM, Simmonds M, Patt R, et al. Dose-titration, multicenter study of oral transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain. J Clin Oncol 1998;16:3238e3245. 63. Clark K, Currow DC, Agar M, et al. A pilot phase II randomized, cross-over, double-blinded, controlled efficacy study of octreotide versus hyoscine hydrobromide for control of noisy breathing at the end-of-life. J Pain Palliat Care Pharmacother 2008;22:131e138. 64. Clayton JM, Butow PN, Tattersall MH, et al. Randomized controlled trial of a prompt list to help advanced cancer patients and their caregivers to ask questions about prognosis and end-of-life care. J Clin Oncol 2007; 25:715e723. 65. Coluzzi PH, Schwartzberg L, Conroy JD, et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain 2001;91:123e130. 66. Conio M, Repici A, Battaglia G, et al. A randomized prospective comparison of self-expandable plastic stents and partially covered self-expandable metal stents in the palliation of malignant esophageal dysphagia. Am J Gastroenterol 2007;102:2667e2677. 67. Connor SR. Denial in terminal illness: to intervene or not to intervene. Hosp J 1992;8:1e15. 68. Corli O, Cozzolino A, Scaricabarozzi I. Nimesulide and diclofenac in the control of cancer-related pain. Comparison between oral and rectal administration. Drugs 1993;46(Suppl 1):152e155.

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92. Falk SJ, Girling DJ, White RJ, et al. Immediate versus delayed palliative thoracic radiotherapy in patients with unresectable locally advanced non-small cell lung cancer and minimal thoracic symptoms: randomised controlled trial. BMJ 2002;325:465. 93. Farooqi JI, Hameed K, Khan IU, et al. Efficacy of intrahepatic absolute alcohol in unresectable hepatocellular carcinoma. J Coll Physicians Surg Pak 2001;11:383e386. 94. Fentiman IS, Ruben RD, Hayward JL. Control of pleural effusions in patients with breast cancer. A randomized trial. Cancer 1983;52:737e739. 95. Fentiman IS, Rubens RD, Hayward JL. A comparison of intracavitary talc and tetracycline for the control of pleural effusions secondary to breast cancer. Eur J Cancer Clin Oncol 1986;22:1079e1081. 96. Finn JW, Walsh TD, MacDonald N, et al. Placebo-blinded study of morphine sulfate sustained-release tablets and immediate-release morphine sulfate solution in outpatients with chronic pain due to advanced cancer. J Clin Oncol 1993;11:967e972. 97. Fiori E, Lamazza A, Volpino P, et al. Palliative management of malignant antro-pyloric strictures. Gastroenterostomy vs. endoscopic stenting. A randomized prospective trial. Anticancer Res 2004;24:269e271. 98. Fiori E, Lamazza A, De Cesare A, et al. Palliative management of malignant rectosigmoidal obstruction. Colostomy vs. endoscopic stenting. A randomized prospective trial. Anticancer Res 2004;24:265e268. 99. Fisch MJ, Loehrer PJ, Kristeller J, et al. Fluoxetine versus placebo in advanced cancer outpatients: a doubleblinded trial of the Hoosier Oncology Group. J Clin Oncol 2003;21:1937e1943. 100. Flock P. Pilot study to determine the effectiveness of diamorphine gel to control pressure ulcer pain. J Pain Symptom Manage 2003;25:547e554. 101. Focan C, Levi F, Kreutz F, et al. Continuous delivery of venous 5-fluorouracil and arterial 5fluorodeoxyuridine for hepatic metastases from colorectal cancer: feasibility and tolerance in a randomized phase II trial comparing flat versus chronomodulated infusion. Anticancer Drugs 1999;10:385e392. 102. Foro Arnalot P, Fontanals AV, Galceran JC, et al. Randomized clinical trial with two palliative radiotherapy regimens in painful bone metastases: 30 Gy in 10 fractions compared with 8 Gy in single fraction. Radiother Oncol 2008;89:150e155. 103. Fuchs KH, Freys SM, Schaube H, et al. Randomized comparison of endoscopic palliation of malignant esophageal stenoses. Surg Endosc 1991;5:63e67. 104. Gaze MN, Kelly CG, Kerr GR, et al. Pain relief and quality of life following radiotherapy for bone metastases: a randomised trial of two fractionation schedules. Radiother Oncol 1997;45:109e116. 105. Gessner U, Koeberle D, Thuerlimann B, et al. Economic analysis of terminal care for patients with malignant osteolytic bone disease and pain treated with pamidronate. Support Care Cancer 2000;8:115e122. 106. Glimelius B, Hoffman K, Olafsdottir M, et al. Quality of life during cytostatic therapy for advanced symptomatic colorectal carcinoma: a randomized comparison of two regimens. Eur J Cancer Clin Oncol 1989;25:829e835. 107. Glimelius B, Hoffman K, Graf W, et al. Quality of life during chemotherapy in patients with symptomatic advanced colorectal cancer. The Nordic Gastrointestinal Tumor Adjuvant Therapy Group. Cancer 1994;73: 556e562. 108. Glover D, Lipton A, Keller A, et al. Intravenous pamidronate disodium treatment of bone metastases in patients with breast cancer. A dose-seeking study. Cancer 1994;74:2949e2955. 109. Goodman A, Davies CW. Efficacy of short-term versus long-term chest tube drainage following talc slurry pleurodesis in patients with malignant pleural effusions: a randomised trial. Lung Cancer 2006;54:51e55. 110. Groth G, Gatzemeier U, Haussingen K, et al. Intrapleural palliative treatment of malignant pleural effusions with mitoxantrone versus placebo (pleural tube alone). Ann Oncol 1991;2:213e215. 111. Han SH, de Klerk JM, Tan S, et al. The PLACORHEN study: a double-blind, placebo-controlled, randomized radionuclide study with (186)Re-etidronate in hormone-resistant prostate cancer patients with painful bone metastases. J Nucl Med 2002;43:1150e1156. 112. Hanks GW, Hanna M, Finlay I, et al. Efficacy and pharmacokinetics of a new controlled-release morphine sulfate 200-mg tablet. J Pain Symptom Manage 1995;10:6e12. 113. Hansen MJ, Enright RD, Baskin TW, et al. A palliative care intervention in forgiveness therapy for elderly terminally ill cancer patients. J Palliat Care 2009;25:51e60. 114. Hardy J, Ling J, Mansi J, et al. Pitfalls in placebo-controlled trials in palliative care: dexamethasone for the palliation of malignant bowel obstruction. Palliat Med 1998;12:437e442. 115. Harris JT, Suresh Kumar K, Rajagopal MR. Intravenous morphine for rapid control of severe cancer pain. Palliat Med 2003;17:248e256.

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