Older adult participation in cancer clinical trials: A systematic review of barriers and interventions.

Cancer is a disease of aging and, as the world's population ages, the number of older persons with cancer is increasing and will make up a growing share of the oncology population in virtually every country. Despite this, older patients remain vastly underrepresented in research that sets the standards for cancer treatments. Consequently, most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients, and effective strategies to improve clinical trial participation of older adults with cancer remain sparse. For this systematic review, the authors evaluated published studies regarding barriers to participation and interventions to improve participation of older adults in cancer trials. The quality of the available evidence was low and, despite a literature describing multifaceted barriers, only one intervention study aimed to increase enrollment of older adults in trials. The findings starkly amplify the paucity of evidence-based, effective strategies to improve participation of this underrepresented population in cancer trials. Within these limitations, the authors provide their opinion on how the current cancer research infrastructure must be modified to accommodate the needs of older patients. Several underused solutions are offered to expand clinical trials to include older adults with cancer. However, as currently constructed, these recommendations alone will not solve the evidence gap in geriatric oncology, and efforts are needed to meet older and frail adults where they are by expanding clinical trials designed specifically for this population and leveraging real-world data.

Making Decisions When No Further Diagnostic Testing is Available.

In this chapter, we illustrate how evidence about treatments' benefits and harms can be integrated to enable rational decision-making even under considerable clinical uncertainty.

Evidence and Decision-Making.

Today, every country struggles to provide adequate health care to its citizens. Globally, an average of $8.3 trillion or 10% of gross domestic product (GDP) is annually spent on health services. In 2019, the USA spent nearly 18% ($3.2 trillion) of its GDP on health care, projected to reach $6.2 trillion by 2028.

Making Decisions When no Further Diagnostic Testing is Available (Expected Regret Theory Threshold Model).

In Chap. 2 , we illustrated the application of the expected utility theory (EUT) to rational decision-making when no further diagnostic testing is available. In this chapter, we apply regret theory to the decision problems discussed in Chap. 2 .

Decision-Making When Diagnostic Testing is Available.

When a decision-maker has the option of diagnostic testing, they face a typical dilemma: (1) do not administer treatment and do not test, (2) test and decide to administer treatment based on the test result, and (3) administer treatment without testing. In this chapter, we will discuss the theory behind threshold modeling when diagnostic testing is available; we will illustrate the approach by presenting a case vignette.

Formulating Management Strategies Using Fast-and-Frugal Trees (A Decision Tool to Transform Clinical Practice Guidelines and Clinical Pathways into Decision Support at the Point of Care).

Clinical management is rarely based on the collection of one data item. Instead, it is typically characterized by the continuous collection and evaluation of clinical data (symptoms, signs, laboratory, imaging tests, etc.) to establish a platform for further management decisions.

Using Decision Curve Analysis to Evaluate Testing and/or Predictive Modeling.

In this chapter, we extend the threshold model to evaluate the value of diagnostic tests or predictive models over a range of all possible thresholds by using decision curve analysis (DCA). DCA has been developed within the expected utility theory (EUT) and expected regret theory (ERT) framework.

Hybrid and Dual-Processing Threshold Decision Models.

In the previous chapters, we presented various derivations of the threshold model based on the same disease outcomes. We assumed that a decision-maker would calculate the threshold based on either mortality or morbidity outcomes. Basinga and van den Ende derived the threshold by combining both mortality and morbidity outcomes.

Medical Decision-Making and Artificial Intelligence.

In this chapter, we discuss the potential role that artificial intelligence (AI) may have in medical decision-making, the pros and cons, and the limitations and biases that might be introduced when using these novel techniques. As computing becomes more powerful and models continue to grow increasingly more complex, the potential of AI to improve decision-making is increasingly promising. Within many medical fields, however, at the time of this writing (September 2023), the promise of AI is yet to translate into everyday reality. Here, we summarize the role of AI in medical decision-making (diagnosis, prognosis, and treatment).

Which Threshold Model?

As outlined in the Preface (and Chap. 1 and other chapters), this book espoused two fundamental views. The first view consists of the proposal that the threshold model represents a method to address the Sorites paradox, which is a consequence of a relationship between scientific evidence (that exists on a continuum of credibility) and decision-making (that is categorical, yes/no exercises).

The First 2 Years of Biosimilar Epoetin for Cancer and Chemotherapy-Induced Anemia in the U.S.: A Review from the Southern Network on Adverse Reactions.

Biosimilars are biologic drug products that are highly similar to reference products in analytic features, pharmacokinetics and pharmacodynamics, immunogenicity, safety, and efficacy. Biosimilar epoetin received Food and Drug Administration (FDA) approval in 2018. The manufacturer received an FDA nonapproval letter in 2017, despite receiving a favorable review by FDA's Oncologic Drugs Advisory Committee (ODAC) and an FDA nonapproval letter in 2015 for an earlier formulation. We discuss the 2018 FDA approval, the 2017 FDA ODAC Committee review, and the FDA complete response letters in 2015 and 2017; review concepts of litigation, naming, labeling, substitution, interchangeability, and pharmacovigilance; review European and U.S. oncology experiences with biosimilar epoetin; and review the safety of erythropoiesis-stimulating agents. In 2020, policy statements from AETNA, United Health Care, and Humana indicated that new epoetin oncology starts must be for biosimilar epoetin unless medical need for other epoetins is documented. Empirical studies report that as of 2012, reference epoetin use decreased from 40%-60% of all patients with cancer with chemotherapy-induced anemia to <5% of such patients because of safety concerns. Between 2018 and 2020, biosimilar epoetin use varied, increasing to 81% among one private insurer's patients covered by Medicare whose cancer care is administered with Oncology Analytics and to 41% with the same private insurer's patients with cancer covered by commercial health insurance and administered by the private insurer, to 0% in several Veterans Administration Hospitals, increasing to 100% in one large county hospital in California, and with yet-to-be-reported data from most oncology settings. We conclude that biosimilar epoetin appears to have overcome some barriers since 2015, although current uptake in the U.S. is variable. Pricing and safety considerations for all erythropoiesis-stimulating agents are primary determinants of biosimilar epoetin oncology uptake. IMPLICATIONS FOR PRACTICE: Few oncologists understand substitution and interchangeability of biosimilars with reference drugs. Epoetin biosimilar is new to the market, and physician and patient understanding is limited. The development of epoetin biosimilar is not familiar to oncologists.

Comparisons of commonly used front-line regimens on survival outcomes in patients aged 70 years and older with acute myeloid leukemia.

In older patients with acute myeloid leukemia, the more frequent presence of biologically inherent therapy-resistant disease and increased comorbidities translate to poor overall survival and therapeutic challenges. Optimal front-line therapies for older patients with acute myeloid leukemia remain controversial. We retrospectively evaluated survival outcomes in 980 elderly (≥70 years) acute myeloid leukemia patients from a single institution between 1995 and 2016. Four treatment categories were compared: high-intensity (daunorubicin/cytarabine or equivalent), hypomethylating agent, low-intensity (low-dose cytarabine or similar without hypomethylating agents), and supportive care therapy (including hydroxyurea). At a median follow up of 20.5 months, the median overall survival for the entire cohort was 7.1 months. Multivariate analysis identified secondary acute myeloid leukemia, poor-risk cytogenetics, performance status, front-line therapy, age, white blood cell count, platelet count, and hemoglobin level at diagnosis as having an impact on survival. High-intensity therapy was used in 360 patients (36.7%), hypomethylating agent in 255 (26.0%), low-intensity therapy in 91 (9.3%), and supportive care in 274 (28.0%). Pairwise comparisons between hypomethylating agent therapy and the three other treatment groups demonstrated statistically significant superior median overall survival with hypomethylating agent [14.4 months) vs high-intensity therapy 10.8 months, hazard ratio 1.35, 95% confidence interval (CI): 1.10-1.65; P =0.004], low-intensity therapy (5.9 months, hazard ratio 2.01, 95%CI: 1.53-2.62; P<0.0001), and supportive care (2.1 months, hazard ratio 2.94, 95%CI: 2.39-3.61; P<0.0001). Our results indicate a significant survival benefit with hypomethylating agents compared to high-intensity, low-intensity, or supportive care. Additionally, high-intensity chemotherapy resulted in superior overall outcomes compared to low-intensity therapy and supportive care. Results from this study highlight the need for novel therapeutic approaches besides utilization of intensive chemotherapy in this specific aged population.

Unprocessed Red Meat and Processed Meat Consumption: Dietary Guideline Recommendations From the Nutritional Recommendations (NutriRECS) Consortium.

This article has been corrected. The original version (PDF) is appended to this article as a Supplement. Description: Dietary guideline recommendations require consideration of the certainty in the evidence, the magnitude of potential benefits and harms, and explicit consideration of people's values and preferences. A set of recommendations on red meat and processed meat consumption was developed on the basis of 5 de novo systematic reviews that considered all of these issues. Methods: The recommendations were developed by using the Nutritional Recommendations (NutriRECS) guideline development process, which includes rigorous systematic review methodology, and GRADE methods to rate the certainty of evidence for each outcome and to move from evidence to recommendations. A panel of 14 members, including 3 community members, from 7 countries voted on the final recommendations. Strict criteria limited the conflicts of interest among panel members. Considerations of environmental impact or animal welfare did not bear on the recommendations. Four systematic reviews addressed the health effects associated with red meat and processed meat consumption, and 1 systematic review addressed people's health-related values and preferences regarding meat consumption. Recommendations: The panel suggests that adults continue current unprocessed red meat consumption (weak recommendation, low-certainty evidence). Similarly, the panel suggests adults continue current processed meat consumption (weak recommendation, low-certainty evidence). Primary Funding Source: None. (PROSPERO 2017: CRD42017074074; PROSPERO 2018: CRD42018088854).

Progress in evidence-based medicine: a quarter century on.

In response to limitations in the understanding and use of published evidence, evidence-based medicine (EBM) began as a movement in the early 1990s. EBM's initial focus was on educating clinicians in the understanding and use of published literature to optimise clinical care, including the science of systematic reviews. EBM progressed to recognise limitations of evidence alone, and has increasingly stressed the need to combine critical appraisal of the evidence with patient's values and preferences through shared decision making. In another progress, EBM incorporated and further developed the science of producing trustworthy clinical practice guidelines pioneered by investigators in the 1980s. EBM's enduring contributions to clinical medicine include placing the practice of medicine on a solid scientific basis, the development of more sophisticated hierarchies of evidence, the recognition of the crucial role of patient values and preferences in clinical decision making, and the development of the methodology for generating trustworthy recommendations.

Bisphosphonates for Patients Diagnosed With Multiple Myeloma.

Clinical Question: Among patients with multiple myeloma, is bisphosphonate therapy associated with lower rates of mortality, vertebral fractures, nonvertebral fractures, and skeletal-related events compared with placebo or no treatment? Bottom Line: Among patients with myeloma, bisphosphonates were associated with lower rates of pathological fractures and skeletal-related events compared with placebo or no treatment. Direct meta-analysis showed no association between bisphosphonates and mortality. In network meta-analysis, zoledronate was associated with lower risk of mortality compared with placebo or no treatment.

Monte Carlo decision curve analysis using aggregate data.

BACKGROUND: Decision curve analysis (DCA) is an increasingly used method for evaluating diagnostic tests and predictive models, but its application requires individual patient data. The Monte Carlo (MC) method can be used to simulate probabilities and outcomes of individual patients and offers an attractive option for application of DCA. MATERIALS AND METHODS: We constructed a MC decision model to simulate individual probabilities of outcomes of interest. These probabilities were contrasted against the threshold probability at which a decision-maker is indifferent between key management strategies: treat all, treat none or use predictive model to guide treatment. We compared the results of DCA with MC simulated data against the results of DCA based on actual individual patient data for three decision models published in the literature: (i) statins for primary prevention of cardiovascular disease, (ii) hospice referral for terminally ill patients and (iii) prostate cancer surgery. RESULTS: The results of MC DCA and patient data DCA were identical. To the extent that patient data DCA were used to inform decisions about statin use, referral to hospice or prostate surgery, the results indicate that MC DCA could have also been used. As long as the aggregate parameters on distribution of the probability of outcomes and treatment effects are accurately described in the published reports, the MC DCA will generate indistinguishable results from individual patient data DCA. CONCLUSIONS: We provide a simple, easy-to-use model, which can facilitate wider use of DCA and better evaluation of diagnostic tests and predictive models that rely only on aggregate data reported in the literature.

Bisphosphonates in multiple myeloma: an updated network meta-analysis.

BACKGROUND: Bisphosphonates are specific inhibitors of osteoclastic activity and are used in the treatment of patients with multiple myeloma (MM). While bisphosphonates are shown to be effective in reducing vertebral fractures and pain, their role in improving overall survival (OS) remains unclear. This is an update of a Cochrane review first published in 2002 and previously updated in 2010 and 2012. OBJECTIVES: To assess the evidence related to benefits and harms associated with use of various types of bisphosphonates (aminobisphosphonates versus non-aminobisphosphonates) in the management of patients with MM. Our primary objective was to determine whether adding bisphosphonates to standard therapy in MM improves OS and progression-free survival (PFS), and decreases skeletal-related morbidity. Our secondary objectives were to determine the effects of bisphosphonates on pain, quality of life, incidence of hypercalcemia, incidence of bisphosphonate-related gastrointestinal toxicities, osteonecrosis of jaw (ONJ) and hypocalcemia. SEARCH METHODS: We searched MEDLINE, Embase (September 2011 to July 2017) and the CENTRAL (2017, Issue 7) to identify all randomized controlled trial (RCT) in MM up to July 2017 using a combination of text and MeSH terms. SELECTION CRITERIA: Any randomized controlled trial (RCT) comparing bisphosphonates versus placebo/no treatment/bisphosphonates and observational studies or case reports examining bisphosphonate-related ONJ in patients with MM were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors extracted the data. Data were pooled and reported as hazard ratio (HR) or risk ratio (RR) using a random-effects model. We used meta-regression to explore statistical heterogeneity. Network meta-analysis using Bayesian approach was conducted. MAIN RESULTS: In this update, we included four new studies (601 participants), resulting in a total of 24 included studies.Twenty RCTs compared bisphosphonates with either placebo or no treatment and four RCTs involved another bisphosphonate as a comparator. The 24 included RCTs enrolled 7293 participants. Pooled results showed that there was moderate-quality evidence of a reduction in mortality with on OS from 41% to 31%, but the confidence interval is consistent with a larger reduction and small increase in mortality compared with placebo or no treatment (HR 0.90, 95% CI 0.76 to 1.07; 14 studies; 2706 participants). There was substantial heterogeneity among the included RCTs (I2 = 65%) for OS. To explain this heterogeneity we performed a meta-regression assessing the relationship between bisphosphonate potency and improvement in OS, which found an OS benefit with zoledronate but limited evidence of an effect on PFS. This provided a further rationale for performing a network meta-analyses of the various types of bisphosphonates that were not compared head-to-head in RCTs. Results from network meta-analyses showed evidence of a benefit for OS with zoledronate compared with etidronate (HR 0.56, 95% CI 0.29 to 0.87) and placebo (HR 0.67, 95% CI 0.46 to 0.91). However, there was no evidence for a difference between zoledronate and other bisphosphonates.The effect of bisphosphonates on disease progression (PFS) is uncertain. Based on the HR of 0.75 (95% CI 0.57 to 1.00; seven studies; 908 participants), 47% participants would experience disease progression without treatment compared with between 30% and 47% with bisphosphonates (low-quality evidence). There is probably a similar risk of non-vertebral fractures between treatment groups (RR 1.03, 95% CI 0.68 to 1.56; six studies; 1389 participants; moderate-quality evidence). Pooled analysis demonstrated evidence for a difference favoring bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; seven studies; 1116 participants; moderate-quality evidence) and skeletal-related events (SREs) (RR 0.74, 95% CI 0.63 to 0.88; 10 studies; 2141 participants; moderate-quality evidence). The evidence for less pain with bisphosphonates was of very low quality (RR 0.75, 95% CI 0.60 to 0.95; eight studies; 1281 participants).Bisphosphonates may increase ONJ compared with placebo but the confidence interval is very wide (RR 4.61, 95% CI 0.99 to 21.35; P = 0.05; six studies; 1284 participants; low-quality evidence). The results from the network meta-analysis did not show any evidence for a difference in the incidence of ONJ (eight RCTs, 3746 participants) between bisphosphonates. Data from nine observational studies (1400 participants) reported an incidence of 5% to 51% with combination of pamidronate and zoledronate, 3% to 11% with zoledronate alone, and 0% to 18% with pamidronate alone.The pooled results showed no evidence for a difference in increase in frequency of gastrointestinal symptoms with the use of bisphosphonates compared with placebo or no treatment (RR 1.23, 95% CI 0.95 to 1.59; seven studies; 1829 participants; low-quality evidence).The pooled results showed no evidence for a difference in increase in frequency of hypocalcemia with the use of bisphosphonates compared with placebo or no treatment (RR 2.19, 95% CI 0.49 to 9.74; three studies; 1090 participants; low-quality evidence). The results from network meta-analysis did not show any evidence for differences in the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used. AUTHORS' CONCLUSIONS: Use of bisphosphonates in participants with MM reduces pathological vertebral fractures, SREs and pain. Bisphosphonates were associated with an increased risk of developing ONJ. For every 1000 participants treated with bisphosphonates, about one patient will suffer from the ONJ. We found no evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) or non-aminobisphosphonate (etidronate or clodronate) for any outcome. However, zoledronate was found to be better than placebo and first-generation bisposphonate (etidronate) in pooled direct and indirect analyses for improving OS and other outcomes such as vertebral fractures. Direct head-to-head trials of the second-generation bisphosphonates are needed to settle the issue if zoledronate is truly the most efficacious bisphosphonate currently used in practice.

When to perform hepatic resection for intermediate-stage hepatocellular carcinoma.

UNLABELLED: Transcatheter arterial chemoembolization (TACE) is the first-line therapy recommended for patients with intermediate hepatocellular carcinoma (HCC). However, in clinical practice, these patients are often referred to surgical teams to be evaluated for hepatectomy. After making a treatment decision (e.g., TACE or surgery), physicians may discover that the alternative treatment would have been preferable, which may bring a sense of regret. Under this premise, it is postulated that the optimal decision will be the one associated with the least amount of regret. Regret-based decision curve analysis (Regret-DCA) was performed on a Cox's regression model developed on 247 patients with cirrhosis resected for intermediate HCC. Physician preferences on surgery versus TACE were elicited in terms of regret; threshold probabilities (Pt) were calculated to identify the probability of survival for which physicians are uncertain of whether or not to perform a surgery. A survey among surgeons and hepatologists regarding three hypothetical clinical cases of intermediate HCC was performed to assess treatment preference domains. The 3- and 5-year overall survival rates after hepatectomy were 48.7% and 33.8%, respectively. Child-Pugh score, tumor number, and esophageal varices were independent predictors of survival (P<0.05). Regret-DCA showed that for physicians with Pt values of 3-year survival between 35% and 70%, the optimal strategy is to rely on the prediction model; for physicians with Pt<35%, surgery should be offered to all patients; and for Pt values>70%, the least regretful strategy is to perform TACE on all patients. The survey showed a significant separation among physicians' preferences, indicating that surgeons and hepatologists can uniformly act according to the regret threshold model. CONCLUSION: Regret theory provides a new perspective for treatment-related decisions applicable to the setting of intermediate HCC.

NCCN Guidelines Insights: Multiple Myeloma, Version 3.2016.

These NCCN Guidelines Insights highlight the important updates/changes specific to the 2016 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include updated recommendations to the overall management of multiple myeloma from diagnosis and staging to new treatment options.

The role of iron in the management of chemotherapy-induced anemia in cancer patients receiving erythropoiesis-stimulating agents.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are commonly used to treat chemotherapy-induced anemia (CIA). However, about half of patients do not benefit. OBJECTIVES: To evaluate the benefits and harms related to the use of iron as a supplement to ESA and iron alone compared with ESA alone in the management of CIA. SEARCH METHODS: We searched for relevant trials from the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 1 January 2016), MEDLINE (1950 to February 2016), and www.clinicaltrials.gov without using any language limits. SELECTION CRITERIA: All randomized controlled trials (RCTs) comparing 'iron plus ESA' or 'iron alone' versus 'ESA alone' in people with CIA were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included eight RCTs (12 comparisons) comparing ESA plus iron versus ESA alone enrolling 2087 participants. We did not find any trial comparing iron alone versus ESAs alone in people with CIA. None of the included RCTs reported overall survival. There was a beneficial effect of iron supplementation to ESAs compared with ESAs alone on hematopoietic response (risk ratio (RR) 1.17, 95% confidence interval (CI) 1.09 to 1.26; P < 0.0001; 1712 participants; 11 comparisons; high-quality evidence). Assuming a baseline risk of 35% to 80% for hematopoietic response without iron supplementation, between seven and 16 patients should be treated to achieve hematopoietic response in one patient. In subgroup analyses, RCTs that used intravenous (IV) iron favored ESAs and iron (RR 1.20 (95% CI 1.10 to 1.31); P < 0.00001; 1321 participants; eight comparisons), whereas we found no evidence for a difference in hematopoietic response in RCTs using oral iron (RR 1.04 (95% CI 0.87 to 1.24); P = 0.68; 391 participants; three comparisons). There was no evidence for a difference between the subgroups of IV and oral iron (P = 0.16). There was no evidence for a difference between the subgroups of types of iron (P = 0.31) and types of ESAs (P = 0.16) for hematopoietic response.The iron supplementation to ESAs might be beneficial as fewer participants treated with iron supplementation required red blood cell (RBC) transfusions compared to the number of participants treated with ESAs alone (RR 0.74 (95% CI 0.60 to 0.92); P = 0.007; 1719 participants; 11 comparisons; moderate-quality evidence). Assuming a baseline risk of 7% to 40% for RBC transfusion without iron supplementation, between 10 and 57 patients should be treated to avoid RBC transfusion in one patient.We found no evidence for a difference in the median time to hematopoietic response with addition of iron to ESAs (hazard ratio (HR) 0.93 (95% CI 0.67 to 1.28); P = 0.65; 1042 participants; seven comparisons; low-quality evidence). In subgroup analyses, RCTs in which dextran (HR 0.95 (95% CI 0.36 to 2.52); P = 0.92; 340 participants; three comparisons), sucrose iron (HR 1.15 (95% CI 0.60 to 2.21); P = 0.67; 102 participants; one comparison) and sulfate iron (HR 1.24 (95% CI 0.99 to 1.56); P = 0.06; 55 participants; one comparison) were used showed no evidence for difference between iron supplementation versus ESAs alone compared with RCTs in which gluconate (HR 0.78 (95% CI 0.65 to 0.94); P = 0.01; 464 participants; two comparisons) was used for median time to hematopoietic response (P = 0.02). There was no evidence for a difference between the subgroups of route of iron administration (P = 0.13) and types of ESAs (P = 0.46) for median time to hematopoietic response.Our results indicated that there could be improvement in the hemoglobin (Hb) levels with addition of iron to ESAs (mean difference (MD) 0.48 (95% CI 0.10 to 0.86); P = 0.01; 827 participants; seven comparisons; low-quality evidence). In RCTs in which IV iron was used there was evidence for a difference (MD 0.84 (95% CI 0.21 to 1.46); P = 0.009; 436 participants; four comparisons) compared with oral iron (MD 0.07 (95% CI -0.19 to 0.34); P = 0.59; 391 participants; three comparisons) for mean change in Hb level (P = 0.03). RCTs in which dextran (MD 1.55 (95% CI 0.62 to 2.47); P = 0.001; 102 participants; two comparisons) was used showed evidence for a difference with iron supplementation versus ESAs alone compared with RCTs in which gluconate (MD 0.54 (95% CI -0.15 to 1.22); P = 0.12; 334 participants; two comparisons) and sulfate iron (MD 0.07 (95% CI -0.19 to 0.34); P = 0.59; 391 participants; three comparisons) were used for mean change in Hb level (P = 0.007). RCTs in which epoetin was used showed evidence for a difference with iron supplementation versus ESAs alone (MD 0.77 (95% CI 0.25 to 1.29); P = 0.004; 337 participants; five comparisons) compared with darbepoetin use (MD 0.10 (95% CI -0.13 to 0.33); P = 0.38; 490 participants; two comparisons) for mean change in Hb level (P = 0.02).We found no evidence for a difference in quality of life with addition of iron to ESAs (standardized mean difference 0.01 (95% CI -0.10 to 0.12); P = 0.88; 1124 participants; three RCTs; high-quality evidence).We found no evidence for a difference in risk of grade III-IV thromboembolic events (RR 0.95 (95% CI 0.54 to 1.65); P = 0.85; 783 participants; three RCTs; moderate-quality evidence). The incidence of treatment-related mortality (TRM) was 0% (997 participants; four comparisons; high-quality evidence).Other common adverse events included vomiting, asthenia, and leukopenia, and were similar in both arms.Overall the risk of bias across outcomes was high to low. Since the included RCTs had shorter follow-up duration (up to 20 weeks), the long-term effects of iron supplementation are unknown. Our main reasons for downgrading the quality of evidence were inconsistency across the included studies and imprecision of results. AUTHORS' CONCLUSIONS: Our systematic review shows that addition of iron to ESAs offers superior hematopoietic response, reduces the risk of RBC transfusions, and improves Hb levels, and appears to be well tolerated. None of the included RCTs reported overall survival. We found no evidence for a difference in quality of life with iron supplementation.