12 april 2011: Aan onderstaand artikel de originele studie toegevoegd. Gepubliceerd in The Lancet in 2009. Medicijnen tegen bloedarmoede (ESA's) verbeteren bloedarmoede maar verhogen de kans op eerder overlijden aan de kanker.

Onderaan het artikel het nieuwste abstract. Klik hier voor volledige studierapport dat u op kunt vragen of inzien bij The Lancet.

27 november 2009: Medscape en The Lancet

ESA's - Epo gerelateerde medicijnen ter verbetering van bloedarmoede doen de sterfte significant toenemen bij patiënten met kanker, bevestigt een meta-analyse van gerandomiseerde studies. De studie werd gepubliceerd in The Lancet in mei 2009.
De onderzoekers analyseerden gegevens van 13.933 kankerpatiënten in 53 studies en vonden dat ESA's het relatieve risico voor sterfte met 17% verhogen. Bij kankerpatiënten die enige vorm van chemotherapie ondergingen (10.441 patiënten in 38 trials), vonden ze dat ESA's het relatieve risico verhoogde met 10%.
"De stijging van de mortaliteit is zeer zorgwekkend," zegt J. Evan Sadler, MD, PhD, uit Washington University in St. Louis, Missouri, en merkt op dat deze producten moeten worden gebruikt met "de nodige voorzichtigheid."
Maar een andere deskundige, Samuel Zilver, MD, PhD, FACP, van de Universiteit van Michigan in Ann Arbor, suggereert dat er "geen nieuwe reden tot bezorgdheid is."
De veiligheid van deze geneesmiddelen bij patiënten met kanker zijn al uitvoerig besproken door de regelgevende autoriteiten in de Verenigde Staten en Europa, en beide hebben hun gebruik beperkt in deze patiëntenpopulatie. In de Verenigde Staten wordt bij deze medicijnen ook een black-box waarschuwing gegeven waaruit blijkt dat zij het risico op overlijden bij patiënten met kanker kunnen verhogen. De beperkingen zijn al in lijn met deze nieuwe gegevens.
De nieuwe individuele patiënt data meta-analyse geeft een nog duidelijker beeld van het risico op sterfte met deze middelen, waaruit echter wel een groter effect van de behandeling en een grotere statistische significantie werd gezien dan eerder in de literatuur op basis van meta-analyses was gemeld aldus de onderzoeksleidster. . "Ik ben er nu meer van overtuigd dat het ongunstige effect ook echt is, 'zei ze.
"Het verhoogde risico van overlijden in verband met de behandeling met deze geneesmiddelen moet worden afgewogen tegen de voordelen ervan," concluderen Dr Bohlius en collega's .
Over de voordelen van ESE's die worden gebruikt voor de behandeling van anemie (bloedarmoede) bij patiënten met kanker, zegt Dr Bohlius dat ze overtuigd is van het bewijs uit de literatuur dat deze producten de noodzaak verminderen van bloedtransfusies. Maar ze is ere minder van overtuigd van het bewijs dat zij de kwaliteit van leven en vermoeidheid verminderen, omdat sommige studies positief zijn en andere resultaten zijn minder goed, en er kan nu geen eenduidige effectiviteit worden aangetoond.
"In de klinische praktijk moet het verhoogd risico op overlijden en trombo-embolische voorvallen worden afgewogen tegen de voordelen van de behandeling met ESA's, rekening houdend met de klinische omstandigheden van elke patiënt en voorkeuren", schrijven de onderzoekers.

Vanuit het gezichtspunt van een arts is een van de grootste problemen met het gebruik van deze middelen dat er geen manier is om vooraf te voorspellen of de ESA's bij een individuele patient wel of niet aan zal slaan. zegt Dr Bohlius.
Er is ook geen manier om degenen bij wie het risico voor de dood wordt verhoogd met het gebruik van ESA's te identificeren, voegt ze eraan toe. Geen van de factoren die het onderzoeksteam geanalyseerd hebben waren voorspellend - noch de hemoglobine-niveaus bij aanvang, noch de target hemoglobine niveaus, noch de geplande doses van ESA. "Maar er kan iets anders zijn, iets dat niet is gemeten, of iets dat we nog niet weten," voegt ze eraan toe.
"De patiënten die reageren op de ESA-behandeling zijn degenen die een betere overleving laten zien, 'zei ze, maar dit kan niet worden gerelateerd aan de behandeling. Het kan zijn dat deze de "gezondere" kanker patiënten zijn; degenen met de meest ernstige bloedarmoede zijn waarschijnlijk degenen die de meest agressieve vormen van kanker hebben en zijn degenen die de meeste kans hebben om te sterven.
Gevraagd naar het mechanisme waarmee ESA's het risico verhogen op mortaliteit, zegt senior auteur Andreas Engert, MD, van de Cochrane hematologische maligniteiten Group van de Universiteit van Keulen in Duitsland, dat de meest waarschijnlijke verklaring is een toename van trombo-embolische voorvallen.

Er zijn verschillende andere hypothesen uit te leggen hoe ESA's het risico op sterfte verhogen bij patiënten met kanker. Een richt zich op erytropoëtine-receptoren op tumoren die de tumorgroei zouden stimuleren, Sommige studies hebben deze receptoren aangetoond, terwijl andere nog niet daarop werden gemeten, zegt Dr Bohlius.
Nader onderzoek is nodig om te verduidelijken hoe ESA's precies werken en degenen te vinden die de meeste kans hebben om te profiteren van deze middelen zegt ze.
Dr Bohlius meldt dat ze honoraria en reiskosten heeft ontvangen van Amgen, en sommige van haar coauthors verklaren relaties met farmaceutische bedrijven te hebben, zoals beschreven in de The
Lancet. 2009; 373:1532-1542.

ESAs Increase Mortality in Cancer Patients, Meta-Analysis Confirms

Zosia Chustecka

April 30, 2009 — The huge meta-analysis of individual patient data that confirmed an increased mortality in cancer patients treated with erythropoiesis-stimulating agents (ESAs) has been published in the May 2 issue of the Lancet.

The researchers analyzed individual data for 13,933 cancer patients participating in 53 trials, and found that ESAs increased the relative risk for mortality by 17%. When they considered only cancer patients who were undergoing chemotherapy (10,441 patients in 38 trials), they found that ESAs increased the relative risk by 10%.

These results were first presented at the 2008 annual meeting of the American Society of Hematology (ASCO), and were reported by Medscape Oncology at the time.

"The increase in mortality is very worrisome," J. Evan Sadler, MD, PhD, from Washington University in St. Louis, Missouri, commented at the time, noting that these products should be used with "appropriate caution."

These new data will reignite concerns over the use of ESAs in cancer patients, Dr. Sadler said. But another expert, Samuel Silver, MD, PhD, FACP, from the University of Michigan in Ann Arbor, suggested that there was "no new cause for concern."

The safety of these drugs in cancer patients has already been extensively discussed by regulatory authorities in both the United States and Europe, and both have restricted their use in this patient population. In the United States, these products also carry a black-box warning stating that they can increase the risk for death in cancer patients. The restrictions are already in line with these new data, Dr. Silver said, adding that he does not anticipate any further regulatory moves in the near future.

New Data Back Regulatory Moves

Lead author of the meta-analysis, Julia Bohlius, MD, from the Institute of Social and Preventive Medicine at the University of Bern in Switzerland, said that the US Food and Drug Administration was right in restricting the use of these products in cancer patients, and that her team's results — which were not available at the time the regulatory moves were made — "back this decision." The individual patient data meta-analysis provides a clearer picture of the risk for mortality with these agents, showing a larger treatment effect and greater statistical significance than had been reported previously in literature-based meta-analyses, she said. In addition, the team was able, for the first time, to separate on-study mortality from overall survival. "I am more convinced now that the adverse effect is real," she said.

"The increased risk of death associated with treatment with these drugs should be balanced against their benefits," Dr. Bohlius and colleagues conclude in their paper.

On the benefits of ESAs, which are used to treat anemia in cancer patients, Dr. Bohlius told Medscape Oncology that she is convinced by the evidence from the literature that these products reduce the need for blood transfusions. However, she is less convinced by the evidence that they improve quality of life and reduce fatigue, because some studies are positive and others are less so, and there might be a publication bias here.

"In clinical practice, the increased risk of death and thromboembolic events should be balanced against the benefits of treatment with ESAs, taking into account each patient's clinical circumstances and preferences," the researchers write.

No Way of Identifying Patients

From a physician's point of view, one of the most perplexing issues with the use of these agents is that there is no way of identifying which cancer patients are most likely to benefit — only about 50% to 60% respond to treatment with ESAs with an increase in red blood cell count, Dr. Bohlius noted.

There is also no way to identify those in whom the risk for death is increased with the use of ESAs, she added. None of the factors that the team analyzed were predictive — not hemoglobin levels at baseline, target hemoglobin levels, or the planned doses of ESA. "But there may be something else, something that wasn't measured, or something that we don't know about yet," she added.

"The patients who respond to ESA treatment are the ones who show better survival," she said, but this might not be related to the treatment. It might be that these are the "healthier" cancer patients; the ones with the most severe anemia are likely the ones who have the most aggressive cancers and are the ones who are the most likely to die.

When asked about the mechanism by which ESAs raise the risk for mortality, senior author Andreas Engert, MD, from the Cochrane Haematological Malignancies Group at the University of Cologne in Germany, said he felt the most likely explanation was an increase in thromboembolic events.

"Increasing evidence suggests that ESAs might cause thromboembolic and cardiovascular events, independent of hemoglobin concentrations," the researchers write in the paper. In their analysis, patients with previous thromboembolic events seemed to be protected, and they speculate that this might be because they had received prophylactic anticoagulation treatment.

There are several other hypotheses explaining how ESAs increase the risk for mortality in cancer patients. One focuses on erythropoietin receptors on tumors, hypothesizing that ESAs act on these receptors and stimulate tumor growth, as previously reported by Medscape Oncology. Some studies have shown such receptors, whereas others haven't, Dr. Bohlius said.

Further study is needed to elucidate how ESAs exert this adverse effect, and to find some clinical or molecular factor that identifies patients who are most likely to be harmed and those who are most likely to benefit from these agents, she said.

Dr. Bohlius reported receiving honoraria and travel grants from Amgen, and some of her coauthors declare relationships with pharmaceutical companies, as detailed in the paper.

Lancet. 2009;373:1532-1542.

Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials

The Lancet, Volume 373, Issue 9674, Pages 1532 - 1542, 2 May 2009

doi:10.1016/S0140-6736(09)60502-X

Cite or Link Using DOI

Editors' note: Erythropoeisis stimulating agents have been shown to be beneficial in anaemia and are widely used. There has, however, been considerable disquiet about the possible adverse events associated with these treatments. This paper reports an individual patient data meta-analysis of public and pharmaceutical industry trials of epoetins in cancer patients. It quantifies the risk of death with epoetin treatments and provides much needed information to help assess the value of these treatments.

Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials

Julia Bohlius MD a, Kurt Schmidlin DMD a, Corinne Brillant MSc b, Guido Schwarzer PhD c, Sven Trelle MD a d, Jerome Seidenfeld PhD e, Marcel Zwahlen PhD a d, Prof Michael Clarke DPhil f g, Olaf Weingart MD b, Sabine Kluge MA b, Margaret Piper PhD h, Dirk Rades MD i, David P Steensma MD j, Prof Benjamin Djulbegovic k l, Prof Martin F Fey MD m, Isabelle Ray-Coquard MD n, Prof Mitchell Machtay MD o, Prof Volker Moebus MD p, Prof Gillian Thomas MD q, Prof Michael Untch MD r, Prof Martin Schumacher PhD c, Prof Matthias Egger MD a, Prof Andreas Engert MD b

Summary

Background

Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer.

Methods

Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups.

Findings

Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio 1·17, 95% CI 1·06—1·30) and worsened overall survival (1·06, 1·00—1·12), with little heterogeneity between trials (I2 0%, p=0·87 for mortality during the active study period, and I2 7·1%, p=0·33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1·10 (0·98—1·24), and 1·04 (0·97—1·11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0·42).

Interpretation

Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits.