Erythropoietin for patients with malignant disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To investigate the use of recombinant human erythropoietin to prevent or alleviate anaemia in patients with malignant disease regarding to haematologic response, red blood cell transfusion need, changes of quality of life, tumor response and overall survival.
Background
Anaemia, defined as a deficiency in the concentration of haemoglobin‐containing red blood cells, is a widely prevalent complication among cancer patients. According to the type of neoplasia, the prevalence of anaemia varies from 10 to 40% (Abels 1992; Monnerat 1999). Patients with haematological malignancies frequently experience anaemia. At the time of diagnosis, 30‐40% of patients with non‐Hodgkin´s lymphoma (NHL) or Hodgkin´s lymphoma (HD) and up to 70% of patients with multiple myeloma are anaemic, the figures are even higher in myelodysplastic syndromes (Greenberg 1994; Garton 1995; Coiffier 1999). The extent of anaemia is influenced by the type of the cytostatic treatment. It is known that the proportion of anaemic patients after chemotherapy or combined radiochemotherapy rises up to 50‐60% (Reed 1994; Mittelman 1997; Dalton 1998; Ludwig 1998b; Harrison 2001). The National Cancer Institute and others have agreed to use the following classification for anaemia based on haemoglobin (Hb) values: Grade 0, within normal limits (WNL), haemoglobin values are 12.0‐16.0 g/dL for women and 14.0‐18.0 g/dL for men; Grade 1, mild (Hb 10 g/dL to normal limits); Grade 2, moderate (Hb 8.0 to 10.0 g/dL); Grade 3, serious/severe (Hb 6.5 to 7.9 g/dL); Grade 4, life threatening (Hb less than 6.5 g/dL) (Groopman 1999).
The pathophysiology of tumor anaemia is multi‐factorial. In advanced stages of haematological malignancies bone marrow involvement with malignant cells often leads to progressive anaemia. After exclusion of other causes, e.g. iron or vitamin deficiencies, occult bleeding, autoimmune haemolysis or pure red blood cell aplasia, anaemia can be related to "anaemia of chronic disorders". It is characterized by a close interaction between the tumor cell population and the immune system, leading to the activation of macrophages and increased expression of various cytokines, especially Interferon‐g, Interleukin‐1 and tumor necrosis factor. This is followed by an insufficient endogenous erythropoietin synthesis, suppressed differentiation of erythroid precursor cells in the bone marrow and alterations of the iron metabolism (Johnson 1990; Spivak 1994a; Beguin 1995; Nowrousian 1996; Ludwig 1998). The anaemia of chronic disorders, or chronic tumor anaemia is the most common type in patients with malignant disease, though it is often aggravated by chemo‐ or radiotherapy. Especially platinum‐based chemotherapy regimens may deminish the endogenous erythropoietin production by damaging renal tubular cells (Wood 1995).
Manifestation and severity of anaemia vary considerably among individual patients. Mild to moderate anaemia can cause typical symptoms including headache, palpitations, tachycardia and shortness of breath. Chronic anaemia may result in severe organ damage affecting the cardiovascular system, immune system, lungs, kidneys, muscles and the central nervous system (Erslev 1991; Nissenson 1992; Bergström 1993; Wintrobe 1993; Ludwig 1999). In addition to the physical symptoms, the subjective impact of cancer‐related anaemia on quality of life, mental health and social activities may be substantial (Leitgeb 1994; Cella 1998; Thomas 1998; Brandberg 2000). Another aspect of anaemia in patients with malignant disease is the effect on the tumor itself. For malignant diseases like HD, CLL, cervix carcinoma and cancer of the head and neck, anaemia is known to be an independent prognostic factor (Hockel 1993; Nordsmark 1996; Hasenclever 1998). There is growing evidence that anaemia, with the consequence of increased tumor hypoxia, might result in a poorer response to radio‐ or chemotherapy. Severe symptoms of anaemia may also necessitate dose reduction or delay of chemotherapy. All these factors may lead to a higher tumor burden and a decreased overall survival (Grau 1998; Knocke 1999; Glaser 2001). Thus, strategies to diminish cancer‐related anaemia should alleviate symptoms, improve quality of life and might extend survival time.
For a long time blood transfusion has been the conventional treatment of severe cancer‐related anaemia, often administered on subjective consideration rather than objective data. The literature reports a critical degree of anaemia as haemoglobin level below 8g/dl, while mild‐to‐moderate anaemia (haemoglobin level 8‐11g/dl) mainly has been left untreated (Henry 1992; Glaspy 1997a; Koeller 1998; Cella 1999). Although homologous blood transfusion is the fastest method to alleviate symptoms, short and long term risks exist. Potential complications associated with blood transfusion are transmission of infectious diseases, transfusion reactions, alloimmunisation, over transfusion and immune modulation with possible adverse effects on tumor growth (Landers 1996; Williamson 1999). The development of intensified anti‐neoplastic therapies comes along with an increased use of blood transfusion necessitating oncologists to consider carefully the advantages and disadvantages of this treatment.
RECOMBINANT HUMAN ERYTHROPOIETIN AS A TREATMENT OPTION FOR CANCER‐RELATED ANAEMIA
Human erythropoietin is an acidic glycoprotein hormone. In adults, 90% of the hormone is synthesized in the kidney and 10% in the liver (Koury 1988; Koury 1991). The plasma erythropoietin is constant on an individual level within a range from 9 to 26 mU/ml due to the basal erythropoietin production with tissue hypoxia being the most important trigger for increased synthesis. The effects of erythropoietin in the bone marrow are mediated by a specific surface receptor mainly located on erythroid progenitor and precursor cells (Cazzola 1989; D´Andrea 1989; Spivak 1994b). Two major functions of erythropoietin are described, the stimulation of progenitor cell proliferation and the maintenance of their viability (Koury 1990). Two forms of recombinant human erythropoietin (rHuEpo), Epoetin alfa and Epoetin beta, are available for the treatment of anaemia, both with similar clinical efficacy (Storring 1998). Epoetin was first approved for the treatment of anaemia in chronic kidney failure. In 1990, Epoetin was introduced in cancer therapy regimen of patients with multiple myeloma in a pilot study showing haematologic response rates of 85% and an improved performance status (Ludwig 1990). Over the last decade a large number of trials on Epoetin in cancer patients has been undertaken, showing Epoetin to be a safe drug. Only small numbers of cancer patients with adverse effects such as hypertension, headaches and thrombotic events that can be conclusively attributed to Epoetin treatment have been reported (Beguin 1998). Concerning the effectiveness at increasing haemoglobin levels, large, prospective, community‐based trials suggest no difference between a single dose of 40000 U per week or three times 10000 U per week of subcutaneous application (Glaspy 1997b; Demetri 1998; Gabrilove 2001). Of current interest is the question if Epoetin can cause a relevant and permanent rise in haemoglobin with the consequence of reduced blood transfusion requirements in patients with malignant disease. Several evidence‐based guidelines have been published so far, two publications, containing mainly non‐randomized trials, one concentrating on the effectiveness of Epoetin in the myelodysplastic syndromes, the other one on Epoetin treatment of end‐stage renal disease and cancer (Hellström‐L 1995; Marsh 1999). Another practice guideline, assessing the efficacy of Epoetin in the treatment of patients with solid tumors receiving chemotherapy provides evidence for reduced transfusion requirements. The results on changes in quality of life may be questionable, as only one trial assessing quality of life was evaluated. Data from the updated version of July 2000 is not yet available (Quirt 1997). Most comprehensive data provides a systematic review recently published by the Agency for Health Care Research and Quality (Aronson 2001). Although this report provides evidence for Epoetin to significantly increase haemoglobin levels in anaemic cancer patients and reduce blood transfusion requirements, the critical question whether Epoetin is able to influence tumor response and to prolong survival time, has not been answered yet. There is still a number of large randomized trials to be published or on active status recruiting patients, therefore the authors of the AHRQ‐report are involved in the current work to provide updated evidence on recombinant human erythropoietin for patients with malignant disease.
Objectives
To investigate the use of recombinant human erythropoietin to prevent or alleviate anaemia in patients with malignant disease regarding to haematologic response, red blood cell transfusion need, changes of quality of life, tumor response and overall survival.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials with or without blinding using recombinant human erythropoietin for the treatment of anaemia in patients with malignant disease. Placebo control as opposed to "no treatment" was not an inclusion criterion but was taken into consideration as a matter of quality. Trials in which patients were allocated by a quasi‐random method, for example date of birth or day of month were excluded as we considered this study design to be of poor quality leading to unreliable results. The minimum sample size for inclusion were at least 10 similarly treated evaluable patients in each study arm or relevant stratum. There was no restriction on language.
Types of participants
Only participants diagnosed with malignant disease, using clinical and histological/cytological criteria were included regardless of type or stage of the disease, previous therapy or not. All study participants had to be anaemic or at risk for anaemia from chemotherapy and/or radiotherapy or the underlying malignant disease. Patients of every age were included.
Types of interventions
The use of recombinant human erythropoietin to prevent or reduce anaemia in cancer patients, given singly or concomitantly with chemotherapy, radiotherapy or combination therapy. Epoetin alfa or Epoetin beta administered subcutaneously or intravenously in a dose of at least 300U/kg body weight per week, given for at least four weeks. Dose adaption of Epoetin in case of haematologic response or no response was allowed. Studies on new erythropoiesis stimulating substances like NESP, Darbepoetin were not considered for this review. Concomitant supportive treatments, e.g. G‐CSF or iron supplementation, had to be given equally in all study arms. Trials on high‐dose myeloablative chemotherapy regimens followed by bone marrow or peripheral blood stem cell transplantation were excluded as well as trials using Epoetin for short‐term preoperative treatment to correct anaemia or to support collection of autologous blood prior to cancer surgery.
Included trials addressed one or more of the following comparisons of interest:
1) Epoetin versus placebo or no treatment.
2) Epoetin and RBC transfusion as necessary versus RBC transfusion as necessary
alone or with placebo.
3) Epoetin plus conventional‐dose cancer therapy (non‐myeloablative chemotherapy
and/or radiotherapy) versus identical therapy alone or with placebo.
4) Epoetin and RBC transfusion as necessary plus conventional‐dose cancer therapy
versus RBC transfusion as necessary plus identical therapy alone or with placebo.
Types of outcome measures
1) Primary outcome measures:
-
Haematologic response:
a) for interventional studies only: measured as a binary outcome (proportion of patients with an increase in Haemoglobin level of 2g/dl or more, or increase in Haematocrit of 6% points or more)
b) measured as continous data (change in Haemoglobin level from baseline after 6‐12 weeks)
-
Number of patients transfused
-
Number of Red Blood Cell units transfused
-
Overall survival
2) Secondary outcome measures:
-
Tumor response (complete response)
-
Changes of quality of life including cancer‐related fatigue
-
Incidence of adverse events
-
Predictors of response to Epoetin
Search methods for identification of studies
Relevant trials in any language were identified through:
1) Electronic searches
electronic searching of the Cochrane Controlled Trials Register (CENTRAL/CCTR), MEDLINE (1985‐2001), Cancer Lit (1985‐2001), EMBASE (1985‐2001), Medikat (1985‐2001), Russmed Articles (1988‐2001), SOMED (1985‐2001), Toxline (1985‐2001), BIOSIS Previews (1985‐2001), LILACS (1986‐2001)
electronic searching of the conference proceedings of the American Society of Clinical Oncology (1997‐2001), European Society of Medical Oncology (1995‐2001), American Society of Hematology (1998‐2001)
databases of ongoing trials:
Current Controlled Trials Register: http://www.controlled‐trials.com
European Organisation for Research and Treatment of Cancer (EORTC): http://www.eortc.be
United Kingdom Co‐ordinating Committee on Cancer Research (UKCCCR): http://www.ctu.mrc.ac.uk/ukcccr/
UK National Research Register of all NHS‐funded research: http://www.doh.gov.uk/research/nrr.htm
National Cancer Institute, America: http://cancertrials.nci.nih.gov/researchers/index.html
National Cancer Institute, Canada: http://www.ctg.queensu.ca/ctg_home.htm
National Health and Medical Research Council of Australia: http://www.ctc.usyd.edu.au/
For a full search strategy see end of this section.
2) Hand searching
Citations from identified trials and relevant review articles
Hand searching of the conference proceedings of the American Society of Clinical Oncology (1989‐1996), European Society of Medical Oncology (1989‐1994), American Society of Hematology (1989‐1997)
3) Contact
• Groups or individuals who may have done randomized trials in recombinant human erythropoietin and cancer
• Pharmaceutical companies who manufacture recombinant human Erythropoietin (Amgen, Hoffmann‐LaRoche, Janssen‐Cilag)
ad 1) electronic searches:
The following search strategy was used to search MEDLINE
#1 an updated version of the Cochrane randomisation filter (Dickersin 1994)
#2 explode "Erythropoietin"/ all subheadings
#3 explode "Erythropoietin‐Recombinant"/ all subheadings
#4 explode "Epoetin‐Alfa"/ all subheadings
#5 erythropoietin*
#6 Epoetin*
#7 Epogen*
#8 procrit*
#9 eprex*
#10 marogen*
#11 recormon*
#12 erypo*
#13 epo
#14 rhuepo*
#15 r‐huepo*
#16 rhu‐epo*
#17 recomb* near epo*
#18 explode "Anemia"/ diet‐therapy, drug‐therapy, therapy
#19 anemi* near canc*
#20 anaemi* near canc*
#21 (#2 or #3 or #4 or #5 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20)
#22 explode "Neoplasms"/ all subheadings
#23 explode "Carcinoma"/ all subheadings
#24 explode "Chemotherapy‐Adjuvant"/ all subheadings
#25 carcinom*
#26 neoplas*
#27 sarcom*
#28 solid* next tumor*
#29 malign*
#30 antineoplas* next agent*
#31 antineoplas* next therap*
#32 chemotherap*
#33 radiotherap*
#34 explode "Hematologic‐Neoplasms"/ all subheadings
#35 explode "Leukemia"/ all subheadings
#36 explode "Multiple‐Myeloma"/ all subheadings
#37 explode "Lymphoma"/ all subheadings
#38 hemato* near malign*
#39 haemato* near malign*
#40 hemato* near neoplas*
#41 haemato* near neoplas
#42 leu?em*
#43 leu?aem*
#44 myelom*
#45 lymphom*
#46 plasm?cytom*
#47 plasm?zytom*
#48 Hodgkin*
#49 non‐hodgkin*
#50 nonhodgkin*
#51 immuno?ytom*
#52 myelodysplas* next syndrom*
#53 (#22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #49 or #50 or #51 or #52)
#54 (#1 and #21 and #52)
This search strategy was adapted for the databases as outlined.
Data collection and analysis
TRIALS SELECTION
Titles and abstracts of studies identified from the above sources were screened independently by two reviewers (SL, JB) for the eligibility criteria stated previously. If this could not be done satisfactorily from the title and abstract, a full text version was obtained for assessment. Studies that seemed to meet the inclusion criteria by this screening were assessed for eligibility with an eligibility form containing following questions:
Q1. Is the study described as randomized?
Q2. Did the participants in the study have a previously treated or untreated malignant
disease?
Q3. Were the participants anaemic or at risk for anaemia from chemotherapy and/or
radiotherapy or their malignant disease?
Q4. Was one group given Epoetin alpha or Epoetin beta subcutaneously or
intravenously in a dose of at least 300U /kg /week for at least four weeks?
Q5. Did the control group receive the same care (e.g. chemotherapy and supportive
therapies) with or without placebo?
Q6. Did the study document haematologic response or
did the study document number of patients or red blood cell units transfused or
did the study document quality of life?
To be eligible, studies had to meet all of the criteria stated above. If there was insufficient information to judge eligibility, the first author of the report was contacted for clarification. Any disagreements between the reviewers were resolved by discussion. Duplicate reports were identified and data were extracted from the most recent publication. Full text versions of all eligible studies were obtained for quality assessment and data extraction.
QUALITY ASSESSMENT
Two reviewers (SL, JB) independently assessed the full text articles eligible for the review on quality. To obtain unpublished data all first authors of the included trials were contacted. Any discordances were discussed with the rest of the group until consensus was obtained. Because of the problematic use of quality summary scores (Schulz 1995; Jüni 1999), we used a Quality assessment form designed for the topic of this review (source used: Verhagen 1998; Jüni 2001), containing the following questions:
1. Was allocation truly random?
2. Was the treatment allocation concealed?
3. Were the patients characteristics at baseline similar in all groups?
4. Was the treatment allocation masked from the participants?
5. Was the treatment allocation masked from the clinicians?
6. Were the number of withdrawals, drop outs and lost to follow‐up in each group
stated?
7. Did the analysis include an intention‐to‐treat analysis?
Summarized Quality
The studies were classified in four categories of quality:
A: all of the criteria met: low risk of bias
B: all criteria of question 1‐3 met, one or more criteria of question 4‐7 not met: moderate
risk of bias
C: question 1 met, one or both criteria of questions 2 and 3 not met: high risk of bias
D: criteria of question 1 not met: unacceptable risk of bias, study will be excluded
unclear : for any criterion that is unclear we will contact the first author of the study.
The summarized quality classification was used to describe the study quality, but not to perform a sensitivity analysis. Instead, sensitivity analysis was based on the individual quality criteria.
DATA EXTRACTION
Data extraction for the review was independently performed by two reviewers (SL, JB) using a standardized data extraction form, including at least following items:
General information: title, authors, source, contact address, year of publication, duplicate publications, setting, funding.
Trial characteristics: design, method of randomization, concealment of allocation, blinding of patients and clinicians will be extracted with the validity form.
Patients: sampling, exclusion criteria, sample size, baseline characteristics, similarity of groups at baseline, diagnostic criteria, withdrawals, losses to follow up.
Interventions: placebo use, dose, dosing regimen, duration, route, RBC transfusion, co‐medications with dose, route and timing.
Outcomes: outcomes as specified above.
To obtain data that were not reported we contacted the first author of the particular publication. Disagreements arising at any stage were resolved by discussion and consensus.
DATA ANALYSIS
A random effect model will be assumed in all meta‐analyses. For binary data, the relative risk will be used as measure of treatment effect and the Mantel‐Haenszel Method will be used for pooling. The estimated overall relative risk and a range of plausible values for the baseline‐risk will be used to estimate numbers needed to treat (NNT) and numbers needed to harm (NNH), respectively. For continuous data, weighted mean differences (WMD) will be calculated if the outcome was measured on the same scale in all trials; otherwise the standardised mean difference (SMD) will be calculated. Time to event data, e.g. overall survival, will be calculated as hazard ratios (HR) based on individual patient data (IPD). If IPD are not available HR will be calculated from published reports, using methods described in Parmar et al (Parmar 1998). The p‐value of the homogeneity test will only be used to describe the extent of heterogeneity inherent in a meta‐analysis. Potential causes of heterogeneity will be explored by performing sensitivity and sub‐group analyses (see below) using meta‐regression. In meta‐analyses with at least four trials, a funnel plot will be generated and a linear regression test22 will be performed to examine the likely presence of bias in meta‐analysis. A p‐value less than 0.1 will be considered significant for the linear regression test. Analyses will be performed using the latest version of the Cochrane statistical package, Meta View 4.1.; the STATA software package will be used for additional analyses, which cannot be done with MetaView 4.1.
SENSITIVITY ANALYSIS and SUBGROUP ANALYSIS
Sensitivity analysis and subgroup analysis will be performed on following factors if appropriate:
-
Different quality of studies
-
Peer reviewed publications versus abstract publications
-
Haemoglobin at study entry ( Haemoglobin level <10g/dl versus 10‐12g/dl versus >12g/dl)
-
Haematological malignancies versus solid tumours
-
Platinum‐based chemotherapy versus non‐platinum containing chemotherapy
-
G‐CSF support
-
Age
-
Iron supplementation
