Multidisciplinary development of the Geriatric Core Dataset for clinical research in older patients with cancer: A French initiative with international survey.

BACKGROUND: To define a core set of geriatric data to be methodically collected in clinical cancer trials of older adults, enabling comparison across trials. PATIENTS AND METHODS: Following a consensus approach, a panel of 14 geriatricians from oncology clinics identified seven domains of importance in geriatric assessment. Based on the international recommendations, geriatricians selected the mostly commonly used tools/items for geriatric assessment by domain (January-October 2015). The Geriatric Core Dataset (G-CODE) was progressively developed according to RAND appropriateness ratings and feedback during three successive Delphi rounds (July-September 2016). The face validity of the G-CODE was assessed with two large panels of health professionals (55 national and 42 international experts) involved both in clinical practice and cancer trials (March-September 2017). RESULTS AND DISCUSSION: After the last Delphi round, the tools/items proposed for the G-CODE were the following: (1) social assessment: living alone or support requested to stay at home; (2) functional autonomy: Activities of Daily Living (ADL) questionnaire and short instrumental ADL questionnaire; (3) mobility: Timed Up and Go test; (4) nutrition: weight loss during the past 6 months and body mass index; (5) cognition: Mini-Cog test; (6) mood: mini-Geriatric Depression Scale and (7) comorbidity: updated Charlson Comorbidity Index. More than 70% of national experts (42 from 20 cities) and international experts (31 from 13 countries) participated. National and international surveys showed good acceptability of the G-CODE. Specific points discussed included age-year cut-off, threshold of each tool/item and information about social support, but no additional item was proposed. CONCLUSION: We achieved formal consensus on a set of geriatric data to be collected in cancer trials of older patients. The dissemination and prospective use of the G-CODE is needed to assess its utility.

Alterations in comprehensive geriatric assessment decrease survival of elderly patients with cancer.

INTRODUCTION: A comprehensive geriatric assessment (CGA) evaluating several domains of health is recommended for elderly patients with cancer. Effects of altered domains on the risk of death in this population need to be clarified. The aim of this study was to estimate the independent association of each CGA domain to overall survival (OS). METHOD: Patients included in the ONCODAGE cohort completed a CGA at baseline. Cox models (one per domain) estimated the hazard ratio (HR) of death for each CGA domain. Directed Acyclic Graphs (DAGs) selected specific sets of adjustment factors for each model. RESULTS: The analysis included 1264 patients (mean age: 78 years, women: 70%). Median follow-up was 5.2 years, and 446 patients died. Each altered domain had a detrimental effect on survival, sometimes dependent on gender, age, education or time from inclusion. Nutritional status had a time-varying effect, with higher mortality rates if altered only within the first 3 years of follow-up. In case of altered mobility, the risk of death was higher only for the youngest patients and, in case of altered autonomy, only for the youngest women. An altered neurological state led to higher mortality rates; this effect increased with the level of education. Patients with altered psychological status or more than four comorbidities at baseline had also higher mortality rates. CONCLUSIONS: Patients with an altered CGA domain have a higher risk of death than those without any alteration. The effect of some alterations is different in some subgroups or at a given time of the treatments.

ESMO Consensus Conference on malignant lymphoma: general perspectives and recommendations for the clinical management of the elderly patient with malignant lymphoma.

The European Society for Medical Oncology (ESMO) consensus conference on mature B cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (1) the elderly patient, (2) prognostic factors suitable for clinical use, and (3) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address clinically-relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the four questions assigned to their group. These recommendations were presented to the entire panel and a consensus was reached. This consensus, which was further developed in continuous post-meeting discussions, formed the basis of three manuscripts, each covering one of the three key areas identified. This manuscript presents the consensus recommendations regarding the clinical management of elderly patients diagnosed with malignant lymphoma. Four clinically-relevant topics identified by the panel were: 1) how to define patient fitness, 2) assessing quality of life, 3) diagnostic work-up and 4) clinical management of elderly patients with lymphoma. Each of these key topics is addressed in the context of five different lymphoma entities, namely: CLL, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma and diffuse large B-cell lymphoma. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript.

Modeling individual and relative accuracy of screening tools in geriatric oncology.

BACKGROUND: Classification probabilities reflect to what degree a screening test represents the true disease state and include true positive (TPF) and false positive fractions (FPF). With two tests, one can compare TPF and FPF using relative probabilities which offer advantages in terms of interpretation and statistical modeling. Our objective was to highlight how individual and relative TPF and FPF can be easily estimated and compared within a regression modeling framework. This allows the modeling of tests' accuracy while adjusting for multiple covariates, and thus provides valuable information in addition to the crude TPF and FPF. We illustrate our purpose with the G8 and VES-13 screening tests aimed at identifying elderly cancer patients in need for a comprehensive geriatric assessment (CGA). METHODS: Prospective cohort with a paired design. TPF and FPF of each test, as well as relative TPF and FPF were modeled using log-linear models. RESULTS: G8 detected patients in need for CGA better than VES-13 at the expense of misclassifying a large number of normal patients. Both tests had better TPF with older age and poorer performance status (PS), and for all cancer subtypes compared with prostate cancer. Effect of age and PS on TPF was more pronounced with VES-13. Age affected FPF, but not differentially. CONCLUSIONS: Regression modeling helps provide a thorough assessment of the accuracy of diagnostic tests and should be used more frequently. In the context of screening, we encourage the use of G8 as failing to identify patients in need of a CGA might be more problematic than over-detection. Moreover, although we identified variables associated with the sensitivity of these tests, this association was less pronounced for the G8.

Predictive factors of depressive symptoms of elderly patients with cancer receiving first-line chemotherapy.

BACKGROUND: Depression is the most common psychiatric disorder in geriatrics and oncology. For elderly cancer patients, it has a significant impact on quality of life, morbidity, and mortality. Nevertheless, depression is under-diagnosed and under-treated. Cancer management is key in improving the quality of care in this population. We aim to identify sociodemographic, clinical, and treatment-related factors of depression in elderly patients during chemotherapy, thus allowing early detection of patients in need of specific treatment. Further, we investigate whether chemotherapy efficacy and safety are associated with depression. PATIENTS AND METHODS: A prospective multicenter cohort composed of incident cases of cancer diagnosed in patients 70 years and older, receiving first-line chemotherapy. Depressive symptoms were measured by the Geriatric Depression Scale at baseline and after four chemotherapy cycles. Associations between depressive symptoms during chemotherapy and patients' clinical and treatment characteristics were identified by logistic regression. RESULTS: Among 344 patients measured for depression before chemotherapy, 260 had a second assessment at the fourth treatment cycle. At baseline, 45.4% were depressed, and 44.6% were depressed after the fourth cycle. Independent factors of depression were depressive symptoms at baseline (odds ratio (OR) = 6.7, p < 0.001), malnutrition (OR = 5.1, p = 0.014), and risk of malnutrition (OR = 1.6, p = 0.014). After controlling for missing data, effective chemotherapy was associated with a lower risk of depression (OR = 0.4, p = 0.018). CONCLUSION: We highlight the role of depressive symptoms and nutritional status at baseline, on the occurrence of depressive symptoms during chemotherapy. These factors should be taken into account in any pre-treatment consultation and appropriate nutritional and psychiatric preventative measures established. Copyright © 2016 John Wiley & Sons, Ltd.

[Comprehensive geriatric assessment (CGA) in elderly with cancer: For whom?]. / Évaluation gériatrique en oncologie : pour quels patients ?

Scientific societies recommend the implementation of a comprehensive geriatric assessment (CGA) in cancer patients aged 70 and older. The EGA is an interdisciplinary multidimensional diagnostic process seeking to assess the frail older person in order to develop a coordinated plan of treatment and long-term follow-up. Identification of comorbidities and age-induced physiological changes that may increase the risk of anticancer treatment toxicities is essential to better assess the risk-benefit ratio in elderly cancer patients. The systematic implementation of a CGA for each patient is difficult to perform in daily practice. Therefore, it is recommended to screen vulnerable patients who will benefit from a complete CGA. Our work presents the vulnerability screening tools validated by at least two independent studies in a cancer elderly population setting. Among seven screening tools, the G8 and the VES13 are the most effective, and have been validated specifically in older population with cancer. The G8 is recommended by scientific societies and the French National Cancer Institute (INCa) because of its easy implementation in daily clinical practice, its high sensitivity and fair specificity. Although studies are underway to improve its performance, the G8 is currently the simplest tool to routinely identify older cancer patients who should have a complete assessment in geriatric oncology.

[How to identify frailty in older patients with cancer? Available tools]. / Comment identifier les personnes âgées fragiles ? Outils à disposition.

Management of cancer in the elderly needs more attention than in younger patients mainly because of comorbidities and geriatric syndromes. Each frailty encountered will facilitate adverse events and complications which are more frequent and more severe in the elderly and have to be anticipated to control for the risk of organ failure and dependencies. Fortunately, tools which have been developed and validated by geriatricians, are available to the oncologists and their validity has been demonstrated in oncology. Yet, they are quite time-consuming and consequently available for a minority of patients. Furthermore, it appears that some of the older patients can be proposed standard therapy and do not need the intervention of geriatricians. This is the reason why screening tools have been developed and validated among which the G8 questionnaire appears to be one of the best. This approach is beginning to be implemented in the daily routine in France and abroad but their appropriate use according to cancer types and treatment intensity should be further improved for the benefit of our patients.

Approach to therapy of diffuse large B-cell lymphoma in the elderly: the International Society of Geriatric Oncology (SIOG) expert position commentary.

Diffuse large B-cell lymphoma (DLBCL) is a treatable and potentially curable malignancy that is increasing in prevalence in the elderly. Until recently, older patients with this malignancy were under-represented on clinical treatment trials, so optimal therapeutic approaches for these patients were generally extrapolated from the treatment of younger patients with this disorder. Because of heightened toxicity concerns, older patients were sometimes given reduced dose therapy, potentially negatively impacting outcome. Geriatric considerations including functional status and comorbidities often were not accounted for in treatment decisions. Because of these issues as well as the lack of treatment guidelines for the elderly population, the International Society of Geriatric Oncology convened an expert panel to review DLBCL treatment in the elderly and develop consensus guidelines for therapeutic approaches in this patient population. The following treatment guidelines address initial DLBCL therapy, in both limited and advanced stage disease, as well as approaches to the relapsed and refractory patient.

p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells.

The p62/SQSTM1 adapter protein has an important role in the regulation of several key signaling pathways and helps transport ubiquitinated proteins to the autophagosomes and proteasome for degradation. Here, we investigate the regulation and roles of p62/SQSTM1 during acute myeloid leukemia (AML) cell maturation into granulocytes. Levels of p62/SQSTM1 mRNA and protein were both significantly increased during all-trans retinoic acid (ATRA)-induced differentiation of AML cells through a mechanism that depends on NF-κB activation. We show that this response constitutes a survival mechanism that prolongs the life span of mature AML cells and mitigates the effects of accumulation of aggregated proteins that occurs during granulocytic differentiation. Interestingly, ATRA-induced p62/SQSTM1 upregulation was impaired in maturation-resistant AML cells but was reactivated when differentiation was restored in these cells. Primary blast cells of AML patients and CD34(+) progenitors exhibited significantly lower p62/SQSTM1 mRNA levels than did mature granulocytes from healthy donors. Our results demonstrate that p62/SQSTM1 expression is upregulated in mature compared with immature myeloid cells and reveal a pro-survival function of the NF-κB/SQSTM1 signaling axis during granulocytic differentiation of AML cells. These findings may help our understanding of neutrophil/granulocyte development and will guide the development of novel therapeutic strategies for refractory and relapsed AML patients with previous exposure to ATRA.

Oxidative stress-induced p53 activity is enhanced by a redox-sensitive TP53INP1 SUMOylation.

Tumor Protein p53-Induced Nuclear Protein 1 (TP53INP1) is a tumor suppressor that modulates the p53 response to stress. TP53INP1 is one of the key mediators of p53 antioxidant function by promoting the p53 transcriptional activity on its target genes. TP53INP1 expression is deregulated in many types of cancers including pancreatic ductal adenocarcinoma in which its decrease occurs early during the preneoplastic development. In this work, we report that redox-dependent induction of p53 transcriptional activity is enhanced by the oxidative stress-induced SUMOylation of TP53INP1 at lysine 113. This SUMOylation is mediated by PIAS3 and CBX4, two SUMO ligases especially related to the p53 activation upon DNA damage. Importantly, this modification is reversed by three SUMO1-specific proteases SENP1, 2 and 6. Moreover, TP53INP1 SUMOylation induces its binding to p53 in the nucleus under oxidative stress conditions. TP53INP1 mutation at lysine 113 prevents the pro-apoptotic, antiproliferative and antioxidant effects of TP53INP1 by impairing the p53 response on its target genes p21, Bax and PUMA. We conclude that TP53INP1 SUMOylation is essential for the regulation of p53 activity induced by oxidative stress.

IGHV gene features and MYD88 L265P mutation separate the three marginal zone lymphoma entities and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas.

To clarify the relationships between marginal zone lymphomas (MZLs) and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas (WM/LPLs), immunoglobulin heavy chain variable gene (IGHV) features were analyzed and the occurrence of MYD88 L265P mutations was identified in a series of 123 patients: 53 MZLs from the spleen (SMZLs), 11 from lymph nodes (NMZLs), 28 mucosa-associated lymphatic tissue (MALT) lymphomas and 31 WM/LPLs. SMZLs were characterized by overrepresentation of IGHV1-2 gene rearrangements with a canonical motif, without selection pressure and with long CDR3 segments. NMZLs had increased frequencies of IGHV3 genes. The IGHV gene was unmutated in most cases, often with long CDR3 segments. MALT lymphomas were usually associated with a mutated IGHV gene, but with the absence of selection pressure. WM/LPLs were associated with an IGHV3-23 overrepresentation and high IGHV mutation rate, with features of selection pressure and short CDR3 segments. MYD88 L265P mutations were almost restricted exclusively to WM/LPL patients. Taken all diagnoses together, all patients with MYD88 L265P mutations had an immunoglobulin M peak and almost all patients except one had bone marrow infiltration. These results demonstrate that the history of antigen exposure of the four entities studied was different and MYD88 L265P was specifically associated with WM/LPLs. WM/LPL may thus be functionally associated with constitutive nuclear factor-κB activation.

Rituximab induction immunotherapy for first-line low-tumor-burden follicular lymphoma: survival analyses with 7-year follow-up.

BACKGROUND: The purpose of this study was to report long-term results of rituximab induction monotherapy in patients with low-tumor-burden follicular lymphoma (LTBFL). PATIENTS AND METHODS: Of 49 first-line LTBFL patients who received weekly doses of rituximab (375 mg/m(2)), 46 have been followed with a long-term analysis of clinical and molecular responses. RESULTS: Best clinical response (at any staging within a year following treatment) was 80%, 24 (52%) patients had complete or unconfirmed complete response, 13 (28%) had partial response and 9 (20%) had stable or progressive disease. Of 31 patients having a positive bcl2-JH rearrangement, 15 (48%) became negative following treatment. After 83.9 months of follow-up (95% confidence interval 6.4-92.8 months), the median progression-free survival is 23.5 months and overall survival (OS) is 91.7%. Five patients died (one progression, one myelodysplasia, one diffuse large B-cell lymphoma and two solid tumors). Seven patients (15%) are progression-free including five who are bcl2 informative. No unexpected long-term adverse event has been observed. CONCLUSION: A significant proportion of patients remain progression-free 7 years after a single 4-dose rituximab treatment in first-line LTBFL. The 7-year overall survivalOS is very high in this selected population of patients.

Therapeutic strategies in elderly and very elderly patients.

Management of the elderly with lymphoma needs specific attention. This means supplementary evaluation as regards to younger patients. The objective is to identify specific weaknesses of the patients and thus to foresee potential unexpected toxicities which may endanger patients' outcome. With this information, the hematologist will be able to propose an optimized treatment strategy i.e. with an adapted efficacy/toxicity ratio. These general principles are consensual but it remains to determine what the practical content of this approach is. Recent results suggest some specific tools for the pre-treatment evaluation. Some specific indexes have been proposed to categorize patients but the ultimate approach remains to be outlined. Finally, while geriatric intervention has demonstrated its capacity to improve survival in the general elderly population, no such demonstration has been made in cancer patients including lymphoma.

Screening older cancer patients: first evaluation of the G-8 geriatric screening tool.

BACKGROUND: Development of a geriatric screening tool is necessary to identify elderly cancer patients who would benefit from comprehensive geriatric assessment (CGA). We develop and evaluate the G-8 screening tool against various reference tests. PATIENTS AND METHODS: Analyses were based on 364 cancer patients aged>70 years scheduled to receive first-line chemotherapy included in a multicenter prospective study. The G-8 consists of seven items from the Mini Nutritional Assessment (MNA) questionnaire and age. Our primary reference test is based on a set of seven CGA scales: Activities Daily Living (ADL), Instrumental ADL, MNA, Mini-Mental State Exam, Geriatric Depression Scale, Cumulative Illness Rating Scale-Geriatrics, and Timed Get Up and Go. We considered the presence of at least one questionnaire with an impaired score as an abnormal reference exam. Additional reference exams are also discussed. RESULTS: The prevalence of being at risk varied from 60% to 94% according to the various definitions of the reference test. When considering the primary reference test, a cut-off value of 14 for the G-8 tool provided a good sensitivity estimate (85%) without deteriorating the specificity excessively (65%). CONCLUSION: The G-8 shows good screening properties for identifying elderly cancer patients who could benefit from CGA.

Anthracycline cardiotoxicity in the elderly cancer patient: a SIOG expert position paper.

BACKGROUND: Comorbidities and risk factors likely to complicate treatment are common in elderly cancer patients. Anthracyclines remain the cornerstone of first-line therapy for non-Hodgkin's lymphoma (NHL) and metastatic and early breast cancer but can cause congestive heart failure. Elderly patients are at increased risk of this event and measures to reduce it should be considered. METHODS: A committee of experts in breast cancer and NHL met under the auspices of the International Society for Geriatric Oncology to review the literature and make recommendations, based on level of evidence, for the assessment, treatment and monitoring of elderly patients requiring anthracyclines. RESULTS AND RECOMMENDATIONS: Use of anthracycline-based chemotherapy illustrates many of the dilemmas facing elderly cancer patients. Age in itself should not prevent access to potentially curative treatment or treatment that prolongs life or improves its quality. The risk of cardiotoxicity with conventional anthracyclines is increased by the following factors: an existing or history of heart failure or cardiac dysfunction; hypertension, diabetes and coronary artery disease; older age (independent of comorbidities and performance status); prior treatment with anthracyclines; higher cumulative dose of anthracyclines and short infusion duration. The fact that cumulative and irreversible cardiotoxicity is likely to be greater in this population than among younger patients calls for effective pretreatment screening for risk factors, rigorous monitoring of cardiac function and early intervention. Use of liposomal anthracycline formulations, prolonging the infusion time for conventional anthracyclines and cardioprotective measures should be considered. However, when treatment is being given with curative intent, care should be taken to ensure reduced cardiotoxicity is not achieved at the expense of efficacy.

Questionnaires and instruments for a multidimensional assessment of the older cancer patient: what clinicians need to know?

Due to the ageing of the population in the Western world, a significant increase in the number of older patients diagnosed with neoplastic diseases is observed. Hence, there is an emerging need for tools to efficiently evaluate older patients' functional and global status. These tools can allow treating oncologists to better select patients, to propose treatment modifications, implement supportive measures and develop interventions to decrease the risk of toxicity and in general better tailor the treatment plan on an individual level. Currently significant uncertainty exists about the optimal tools and strategy for geriatric assessment, but on the other hand there is more than enough evidence that (some form of) geriatric assessment detects many previously unrecognised problems, and allows directed intervention which can improve outcome and compliance of proposed treatments. In the present paper, we discuss the most commonly used and studied tools for the assessment of functional status of older cancer patients.

VAV2 regulates epidermal growth factor receptor endocytosis and degradation.

Vav proteins are guanine nucleotide exchange factors for Rho GTPases that regulate cell adhesion, motility, spreading and proliferation in response to growth factor signalling. In this work, we show that Vav2 expression delayed epidermal growth factor receptor (EGFR) internalization and degradation, and enhanced EGFR, ERK and Akt phosphorylations. This effect of Vav2 on EGFR degradation is dependent on its guanine nucleotide exchange function. Knockdown of Vav2 in HeLa cells enhanced EGFR degradation and reduced cell proliferation. epidermal growth factor stimulation led to co-localization of Vav2 with EGFR and Rab5 in endosomes. We further show that the effect of Vav2 on EGFR stability is modulated by its interaction with two endosome-associated proteins and require RhoA function. Thus, in this work, we report for the first time that Vav2 can regulate growth factors receptor signalling by slowing receptor internalization and degradation through its interaction with endosome-associated proteins.

Heat shock protein 27 confers resistance to androgen ablation and chemotherapy in prostate cancer cells through eIF4E.

One strategy to improve therapies in advanced prostate cancer (PC) involves targeting genes that are activated by androgen withdrawal to delay the emergence of the androgen-independent (AI) phenotype. Heat shock protein 27 (Hsp27) expression becomes highly upregulated in PC cells after androgen withdrawal or chemotherapy, in which it functions as a cytoprotective chaperone to confer broad-spectrum treatment resistance. The purpose of this study is to elucidate anti-apoptotic pathways regulated by Hsp27 that are activated during PC progression. Using two-hybrid experiment, we found that Hsp27 was having a major role in the protein translational initiation process. Furthermore, using complementary DNA (cDNA) microarray analysis, 4E binding protein 1 was identified as being proportionately and highly regulated by Hsp27. These data led us to analyze the protein synthesis initiation pathway, which is a prerequisite for cell growth and proliferation. Using northern and western blot analysis, we found that Hsp27 downregulation decreased eukaryotic translation initiation factor 4E (eIF4E) expression at the protein, but not mRNA, level. The cytoprotection afforded by Hsp27 overexpression was attenuated by eIF4E knockdown using specific eIF4E short interfering RNA (siRNA). Co-immunoprecipitation and co-immunofluorescence confirmed that Hsp27 colocalizes and interacts directly with eIF4E. Hsp27-eIF4E interaction decreases eIF4E ubiquitination and proteasomal degradation. By chaperoning eIF4E, Hsp27 seems to protect the protein synthesis initiation process to enhance cell survival during cell stress induced by castration or chemotherapy. Forced overexpression of eIF4E induces resistance to androgen-withdrawal and paclitaxel treatment in the prostate LNCaP cells in vitro. These findings identify Hsp27 as a modulator of eIF4E and establish a potential mechanism for the eIF4E-regulated apoptosis after androgen ablation and chemotherapy. Targeting Hsp27-eIF4E interaction may serve as a therapeutic target in advanced PC.

CIP4 is a new ArgBP2 interacting protein that modulates the ArgBP2 mediated control of WAVE1 phosphorylation and cancer cell migration.

ArgBP2 is a multi-adapter protein involved in signal transduction associated to the cytoskeleton and was shown to regulate the migration and adhesion of pancreatic cancer cells thereby modulating their tumorigenicity. Here we describe the interaction of ArgBP2 with CIP4, a new associated protein identified by yeast two-hybrid. We found that both proteins modulated their reciprocal tyrosine phosphorylation catalyzed by the non-receptor tyrosine kinase c-Abl. We observed that, like ArgBP2, CIP4 directly interacted with WAVE1 and could enhance its phosphorylation by c-Abl. ArgBP2 and CIP4 acted synergistically to increase WAVE1 tyrosine phosphorylation. Finally, we could show that CIP4 was dispensable for the ArgBP2 induced blockade of cell migration whereas its overexpression was deleterious for this important function of ArgBP2.

Modeling of treatment response to erythropoiesis-stimulating agents as a function of center- and patient-related variables: results from the Anemia Cancer Treatment (ACT) study.

BACKGROUND: In anemic cancer patients treated with erythropoiesis-stimulating agent (ESA), (i) to examine the proportion of variance in hemoglobin (Hb) outcomes attributable to patients versus center, country, and region and (ii) to develop predictive models of treatment response. METHODS: Retrospective study with a minimum of three visits at 1-month intervals. Three hundred and seven centers in 13 European countries contributed 2192 anemic ESA-treated cancer patients. Treatment response criteria included: Hb increase > or =1 g/dl, Hb increase > or =1 g/dl within 8 weeks, hematopoietic response (Hb increase > or =2 g/dl or Hb > or = 12 g/dl), Hb increase > or =2 g/dl, and Hb between 12 and 13 g/dl. RESULTS: Hb increased from 9.54 +/- 0.95 g/dl (baseline) to 10.88 +/- 1.49 g/dl (visit 3). Hb change from visits 1 to 2 (index of relative immediacy of response to ESA) averaged 0.81 +/- 1.17 g/dl. The proportion of variance in Hb outcomes attributable to center was 11.8%-34.3%, country 2.9%-20.7%, and region 0.0%-7.6%. Immediacy of response to ESA was the most prevalent predictor of treatment response, followed by diagnosis of hematological malignancy and age <70 years. CONCLUSIONS: . Hb outcomes are determined significantly by the treating center and less so by country or region. The remaining majority variance was attributable to patient-related factors. Immediacy of response to ESA is the single most important predictor of treatment. When used according to guidelines, ESAs are effective in managing anemia in cancer patients and improving treatment outcomes.