Erythropoiesis Stimulating Factors (ESA)

PHASE OF CARE: Active antitumor treatment
 
APPLICATIONS: Elder care, palliative care

Societies in the United States and Europe continue to have different recommendations regarding the use of ESAs during cancer treatment; for QoL in palliative settings, the harmful effects of ESAs should be balanced against potential benefits. There is no evidence to support their use in managing cancer-related fatigue.

Greater than 90% of the studies were funded by pharmaceutical companies.

For patients receiving palliative care, there may be a role for ESAs in reducing transfusion use; there does not appear to be any role for ESAs in managing cancer-related fatigue.

STUDY PURPOSE: To review findings of 10 systematic reviews of clinical trials of erythropoietic-stimulating agents (ESAs) in the five-year period spanning 2004–2008.

TYPE OF STUDY: Systematic review

TOTAL REFERENCES RETRIEVED: 10

• FINAL NUMBER OF STUDIES INCLUDED = 10
• TOTAL PATIENTS INCLUDED IN REVIEW =  86,374
• SAMPLE RANGE ACROSS STUDIES: 1,949–21,378
• KEY SAMPLE CHARACTERISTICS: Inference that all patients included in reviews were patients with cancer, but report did not actually specify

PHASE OF CARE: Active treatment

10 reviews of effects of ESA treatment on symptoms and quality of life (QOL) were reviewed.

• (From authors) Overall evidence from studies seem to support  a symptom and QOL benefit from ESA treatment, which is unlikely to be due to chance alone.
• (From reviewer) Quality of studies presented in review, variability of instruments and ESAs used to measure variables of interest, missing data, and lack of description of sample populations in studies limits sufficient evidence for empirical benefit from ESA treatment in patients with cancer

• Focus of review was on patient-reported symptoms and QOL outcomes versus all risks (safety, survival, thrombosis) and benefits (transfusion use, hematologic response) of ESA use.
• Not all of the studies reviewed were placebo controlled or double blinded.
• Increased risk of placebo effect when outcome of interest is patient self-report.
• Many studies failed to report metrics needed for a more detailed analysis.
• Substantial loss of data and lack of documentation of how missing data were handled.
• Timing and conditions under which symptoms and QOL were measured were not described in many studies.

• Focus future studies on description of conditions for the safe use of ESAs.
• Determine empirically derived cutoff above which ESA therapy is contraindicated.
• Conduct detailed analysis of secondary data sources (meta-analysis).
• Need for inclusion of patient perspective of benefits and harms of ESA therapy.
• Development of patient education materials about relative risks and benefits of ESA use or lack thereof.

To evaluate the effectiveness of pharmacologic interventions used for fatigue in patients with cancer

Databases searched were PaPaS, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, Dissertation Abstracts International (DAI), metaRegister of Controlled Trials (mRCT) (January 2007–October 2009). Journals searched were British Journal of Cancer, Journal of Clinical Oncology, Journal of Pain and Symptom Management, and Journal of Palliative Medicine. The reference lists of all articles were checked for additional studies. Conference abstracts also were searched.

Search keywords were neoplasms, bone marrow transplantation, cancer, carcinoma, tumour, adenocarcinoma, leukemia, lymphoma, malignant, radiotherapy, fatigue, tired, weary, weariness, exhausted, lack or loss or lost energy or vigor, apathy or lassitude or lethargy, or feeling drained, sleepy, or sluggish.

Studies were included in the review if they

• Assessed drug therapy for the management of cancer-related fatigue (CRF) compared to placebo, usual care, or a nonpharmacologic intervention.
• Were randomized, controlled trials (single-blind and open-label were allowed).
• Included adult patients with a clinical diagnosis of cancer.

This review was an update of a previous review. The updated search retrieved 647 additional references. Of those, six additional studies met the inclusion criteria. The final sample of studies included was 31.

The review included 7,104 participants who received a drug intervention for CRF.

Psychostimulants

• Four trials examined methylphenidate, and one used dexamphetamine. These included 426 patients total.
• Evidence existed of a significant effect on fatigue with methylphenidate over placebo, and evidence supported the use of psychostimulants in the treatment of CRF.
• The standardized mean difference was positive, with a small effect and narrow confidence interval (CI) (total mean difference = –0.28; 95% CI [-0.48, -0.09]; Z = 2.83; p = 0.005).
• Fatigue was measured with the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) in all studies.

Erythropoietin and Darbepoetin

• Eleven studies were combined in total and demonstrated a positive effect. The weighted mean difference of studies using the FACT-F outcome measure in erythropoietin gave a score of 4.33, which was a clinically significant difference. The conclusion was limited to patients with anemia who were undergoing chemotherapy. Greater improvement was more likely in those with lower hemoglobin levels.
• In placebo-controlled trials of darbepoetin, the mean difference using the FACT-F score was -1.96, which was less than the minimally clinical significant difference.
• Combined analysis for both agents gave a mean difference score of 3.75, which was clinically significant. 
• Erythropoietin and darbepoetin cannot be recommended because of adverse events associated with these drugs.

Antidepressants/Paroxetine

• Two studies using paroxetine and a trial using sertraline were analyzed. Analysis showed no benefit for the treatment of CRF.

Progestational Steroids

• In studies that could be combined, no evidence existed to support continued use for the treatment of fatigue.
• The clinical significance of results of ibandronate were unclear.
• One study of etanercept during chemotherapy had statistically significant results, but the study had a small sample size and poor design. It was suggested that additional trials be conducted.
• One study of donepezil showed no benefit over placebo.

Four trials of methylphenidate provided evidence for use that was supportive but associated with a small effect size in a dose of 10–20 mg per day. Serious adverse events were minimal; however, clinicians need to review contraindications before prescribing. Additional large-scale trials were suggested using methylphenidate to further evaluate use in CRF. Erythropoietin and darbepoetin can no longer be recommended for CRF because of increased adverse events associated with these drugs. No current evidence exists to support the use of steroids.

• Reviewers found major limitations in the reporting of trials and multiple methods of measuring outcomes.
• Some outcomes in trials were not reported due to extensive missing data.
• These findings point to the need for improved research reporting to meet Consolidated Standards of Reporting Trials (CONSORT) guidelines and the benefit that could be derived from use of consistent methods of measuring outcomes.

To evaluate the safety and efficacy of darbepoetin alfa (DA) administration every three weeks at fixed doses with or without intravenous (IV) iron.

The study used 1:1:1:1 randomization to one of four groups, stratified by platinum versus nonplatinum. The primary endpoint was hemoglobin 11 g/dL or greater, with no iron deficiency. The secondary endpoint was incidence of transfusions and change in Functional Assessment of Cancer Therapy-Fatigue (FACT-F) score from baseline to end of study. DA was administered every three weeks, and dosages were reduced according to hemoglobin levels. Weekly, 400 µg of IV iron were given, and dosages were reduced as warranted based on ferritin levels. Patients were assigned to one of four groups with or without iron with DA at either 300 µg or 500 µg.

• The study included 128 patients (78 females, 40 males).
• Age ranged from 27 to 97 years. Mean ages for the four arms were 61.7, 54.5, 64.5, and 61.8 years.
• Patients had nonmyeloid malignancies.
• Hemoglobin 10 or less
• Patients had more than eight weeks of planned chemotherapy.

• Multisite
• North America and Europe (Romania and Russia)

FACT-F

DA at 300 µg and 500 µg given every three weeks demonstrated similar benefits, and added IV iron improved treatment response. There were larger increases in hemoglobin level, and increase in hemoglobin level occurred earlier. The proportions of patients with clinically significant increases in FACT-F score were 100% for the DA 300 µg group, 64% for the 500 µg DA group, 66% for those not receiving iron, and 100% for those receiving iron. No evidence existed of a statistically significant interaction between DA dose received and IV iron usage.

Fatigue and hemoglobin levels improved in patients with anemia receiving DA with and without iron.

• No appropriate control group was used.
• Several anaphylactoid reactions to IV iron shed light on a safety issue.
• Efficacy results were pooled and summarized because no evidence was observed of a statistically significant interaction between DA and IV iron usage.

DA cannot be recommended at any dose for cancer-related fatigue.

To evaluate the effect of epoetin alfa on local disease-free survival (DFS) (primary endpoint), overall survival, and cancer treatment-related anemia and fatigue (secondary endpoint).

Patients were randomized to one of the following three groups:

• Radiation and epoetin alfa 10,0000 units subcutaneously (subq) if hemoglobin (Hgb) was less than 15 g/dL
• Radiation and epoetin alfa 4,000 units subq if Hgb was less than 12.5 g/dL
• Radiation alone.

• The study included 300 patients (232 men, 68 women); 111 completed the study.
• Age ranged from 35 to 88 years.
• Patients were diagnosed with squamous cell head and neck cancer, stages I to III.
• Patients had a Hgb level less than 15 g/dL.

• Multisite
• United Kingdom

The study was a phase III, randomized, controlled trial.

• Functional Assessment of Cancer Therapy-Anemia (FACT-An)
• FACT-Head and Neck

Hgb increased from baseline with epoetin alfa. Median duration of local DFS (primary endpoint) was not statistically significant (hazard ratio = 1.04). The groups did not differ significantly in terms of DFS, overall survival, tumor outcomes, or cancer-related anemia or fatigue.

The addition of epoetin alfa did not affect survival, tumor outcomes, anemia, or fatigue positively or negatively in the head and neck cancer population.

• The study had low accrual.
• The degree of diagnostic severity, combined with the effects of radiation, may have minimized the potential benefit of epoetin alfa.

Epoetin alfa cannot be recommended for the treatment of cancer-related fatigue in the head and neck cancer population.

To evaluate the effects of treatment with epoetin alfa on anemia-related, patient-reported outcomes in women with breast cancer receiving myelotoxic chemotherapy.

Women with a hemoglobin level of 12 g/dL or less were randomized 1:1 to receive epoetin alfa (10,000 IU three times weekly) or best standard care during chemotherapy.

• The study included 166 females (81 in the epoetin alfa group, 85 in the best supportive care group).
• Mean patient age ranged from 53.3 to 54.3 years (mean range 27–77). 
• Patients with breast cancer had a planned 12-week administration of chemotherapy.
• Stage IV was the most common stage.

• Multisite
• Outpatient
• Six European countries

The study was a randomized, controlled phase IIIb trial.

• Functional Assessment of Cancer Therapy-Anemia (FACT-An)
• Cancer Linear Analog Scale (CLAS) to assess patient-related outcomes

On the FACT-An nonfatigue subscale, change was significantly better (p = 0.008) in the epoetin alfa group than in the best supportive care group. CLAS assessment showed that energy, ability to perform activities of daily living, and overall quality of life were significantly better (p = 0.007). No difference existed between groups in tumor response of survival. A significant increase was noted in transfusions in the best supportive care group (p = 0.048).

Epoetin alfa was well tolerated. Early administration in the treatment course attenuated deterioration in anemia-related, patient-reported outcomes.

• No actual direct fatigue measurement was used. 
• A visual analog scale (VAS) was used for related measures, but no recognized definitive methods of measurement were used.

New U.S. Food and Drug Administration (FDA) guidelines exist for the administration of epoetin alfa.

To ensure that all cancer patients with fatigue were identified and treated promptly and effectively.  These guidelines included recommended standards of care for assessment and management of fatigue in children, adolescents, and adults with cancer.

The guidelines were evidence- and consensus-based. The guidelines were multidisciplinary, and all recommendations were category 2A unless otherwise stated.

The guidelines provided several algorithms for assessment and management based on age group, level of self-reported fatigue, and phase of treatment.

Screening

• All patients with cancer should be screened for the presence or absence of fatigue at regular intervals as a vital sign.
  • Age older than 12 years:  Screen on a 0-to-10 scale or as none, mild, moderate, or severe.
  • Age 7 to 12 years:   Use 1-to-5 scale (1 = no fatigue and 5 = worst).
  • Age 5 to 6 years:  Screen using “tired” or “not tired.”

Focused Evaluation of Fatigue

• A focused history and assessment of contributing factors should be performed when screening indicates moderate to severe fatigue.
  • Age older than 12 years:  score of 4 to 10
  • Age 7 to 12 years:  score of 3 to 5
  • Age 5 to 6 years:  “tired”
• Focused history should
  • Rule out recurrence or progression of cancer
  • Include a review of systems
  • Include an in depth fatigue history, including onset and patterns, associated/alleviating factors, and interference with function.
• Assessment of treatable contributing factors, such as
  • Other related symptoms
  • Anemia
  • Sleep disturbance
  • Medication and side effects
  • Comorbidities
  • Activity and fitness level.

Management and Interventions

• Active Treatment
  • Education and counseling regarding known patterns of fatigue and reassurance that treatment-related fatigue is not necessarily indicative of progression of disease.
  • General management strategies to include self-monitoring, energy conservation techniques, and use of distraction
  • Nonpharmacologic interventions to include activity enhancement, physically based therapies (such as massage), psychosocial interventions, nutritional consultation, and cognitive behavioral therapy for sleep
  • Pharmacologic interventions to include consider psychostimulants, treatment of anemia as indicated, and consideration of mediation for sleep
• Posttreatment
  • Education and counseling about known fatigue patterns and self-monitoring of fatigue levels
  • General management and nonpharmacological and pharmacological interventions as for active treatment above
• End of Life
  • Education and counseling about known fatigue patterns and as an expected end of life symptom
  • General strategies as per active treatment and post treatment
  • Nonpharmacologic interventions to include activity enhancement, psychosocial interventions, and nutrition consultation
  • Pharmacologic interventions as per active and post treatment

Within activity enhancement information, the guideline cites several synthesized reviews regarding the use of exercise and concludes that

• Improvement in fatigue was not noted with all diagnoses.
• It is reasonable to encourage all patients to engage in a moderate level of physical activity during and after cancer treatment.
• Referral to exercise specialists or physical therapy should be triggered by
  • Patients with comorbid conditions, such as chronic obstructive pulmonary disease or cardiac disease
  • Recent major surgery
  • Specific functional or anatomical deficits
  • Substantial deconditioning.
• Exercise should be used with caution in patients with
  • Bone metastases
  • Immunosuppression or neutropenia
  • Thrombocytopenia
  • Anemia
  • Fever or active infection
  • Limitations due to other illnesses.

Because fatigue is a subjective experience, it was recommended that assessment should use patient self-reports and other sources of data.

Several barriers were identified related to effective treatment for fatigue.  Due to barriers, it was stated that screening for fatigue needs to be emphasized.  Rescreening was emphasized because fatigue may exist beyond the period of active treatment.

Factors identified as potential causative agents that should be specifically assessed were outlined.  These factors were pain, emotional distress, sleep disturbance, anemia, nutrition, activity level, medication side effects, and other comorbidities.

It was noted that fatigue often occurs as part of a symptom cluster, often with sleep disturbance, emotional distress, or pain, so that assessment of these problems and institution of effective treatment is essential.

The importance of comprehensive assessment, including review of all current medications and noncancer comorbidities, was identified.  For example, it was noted that there can be thyroid dysfunction after radiation therapy for various cancers or use of biological and that hypogonadism can be associated with fatigue.

• The majority of studies regarding the impact of exercise on fatigue were performed in patients with limited types of cancer, and findings may not be applicable to all types of patients.  In addition, the timing and amount of exercise for various groups are not clear.  There are also few longitudinal studies examining fatigue in long-term disease-free survivors, although fatigue can be a long-term or late effect.
• Although the guideline was structured according to phase of treatment, recommended interventions did not vary according to phase of treatment.  There were minimal differences in recommended content of education and counseling.
• There was little evidence regarding effective management of fatigue in end of life care.
• There was no discussion of prevention related to fatigue.