Original Article
High-Dose Daunorubicin in Older Patients with Acute Myeloid Leukemia
N Engl J Med 2009; 361:1235-1248September 24, 2009
- Abstract
Background
A complete remission is essential for prolonging survival in patients with acute myeloid leukemia (AML). Daunorubicin is a cornerstone of the induction regimen, but the optimal dose is unknown. In older patients, it is usual to give daunorubicin at a dose of 45 to 50 mg per square meter of body-surface area.
Methods
Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square meter by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square meter (411 patients) or at an escalated dose of 90 mg per square meter (402 patients); this treatment was followed by a second cycle of cytarabine at a dose of 1000 mg per square meter every 12 hours for 6 days. The primary end point was event-free survival.
Results
The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P=0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P=0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%).
Conclusions
In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects. (Current Controlled Trials number, ISRCTN77039377; and Netherlands National Trial Register number, NTR212.)
Media in This Article
Figure 1
Effect of Remission-Induction Chemotherapy with an Escalated Dose of Daunorubicin versus a Conventional Dose on Event-free Survival and Overall Survival in Patients 60 years of Age or Older with Acute Myeloid Leukemia.Table 1
Characteristics of Patients, Induction and Consolidation Treatments, and Effects of Treatment.Article Activity
- Article
Most patients with acute myeloid leukemia (AML) are 60 years of age or older, and in this age group, the outcome of treatment is unfavorable. Among these older patients, a combination of daunorubicin plus cytarabine induces a complete remission in 40 to 50% of cases. It is standard practice to treat patients with daunorubicin at doses of 45 to 50 mg per square meter of body-surface area for 3 days, plus cytarabine at a dose of 100 to 200 mg per square meter for 7 to 10 days.1-11 However, the optimal dose of daunorubicin is unknown.
Maximizing the rate of complete remission among patients with AML is a prerequisite for improving survival and quality of life,12-14 but maintaining the remission is equally important. We investigated whether an escalation of the dose of daunorubicin is feasible and beneficial in patients 60 years of age or older who have AML or high-risk refractory anemia. We compared the conventional dose of daunorubicin (45 mg per square meter for 3 days) with an escalated dose of 90 mg per square meter for 3 days (each given in combination with cytarabine) in the first induction cycle of the treatment of AML.
Methods
Study Design and Chemotherapy
Previously untreated patients, 60 years of age or older, with a cytologically confirmed diagnosis of AML and at least 20% myeloblasts in the bone marrow or with refractory anemia with excess blasts and an international prognostic score15 of 1.5 or higher (on a scale of 0 to 3.0, with higher scores indicating a poorer prognosis) and a World Health Organization (WHO) performance status score of 2 or less (on a scale of 0 to 5, with lower numbers indicating better performance status) were eligible for inclusion in the study. The exclusion criteria can be found in the Supplementary Appendix, available with the full text of this article at NEJM.org.
Eligible patients were randomly assigned to receive daunorubicin at a dose of 45 mg per square meter (conventional-dose group) or at a dose of 90 mg per square meter (escalated-dose group) — both administered intravenously over the course of 3 hours on days 1 to 3 of the first cycle of induction treatment — plus cytarabine at a dose of 200 mg per square meter, administered by continuous infusion for 7 days. In the second cycle of treatment, both groups received cytarabine at a dose of 1000 mg per square meter twice daily, given intravenously over the course of 6 hours on days 1 through 6. Patients who were in complete remission after the second cycle and who had an HLA-matched donor could undergo allogeneic stem-cell transplantation. Alternatively, they could be randomly assigned to receive either three cycles of treatment with gemtuzumab ozogamicin at a dose of 6.0 mg per square meter or no further maintenance treatment.
The study was designed by the Leukemia Working Group of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group, the data were gathered at the data center of HOVON, and the statisticians in that group conducted the analysis. The study was approved by the ethics committee at each participating institution and was conducted in accordance with the Declaration of Helsinki. All patients gave written informed consent.
Risk Classification and Clinical Characteristics
Patients were classified into prognostic categories on the basis of the karyotype of the leukemic cells (for details, see the Supplementary Appendix). Favorable risk was defined by the presence of abnormalities in core-binding factors; very unfavorable risk, by the presence of a monosomal karyotype16; and unfavorable risk, by the presence of complex cytogenetic abnormalities (at least three unrelated cytogenetic abnormalities), monosomies or partial deletions of chromosome 5 or 7 (del(5q), del(7q), -5, -7), abnormalities of the long arm of chromosome 3 (q21;q26), t(6;9)(p23;q34), t(9;22)(q34;q11.2), or abnormalities involving the long arm of chromosome 11 (11q23)17 unless the criteria for a monosomal karyotype were fulfilled. Any other cytogenetic abnormalities, as well as AML without cytogenetic abnormalities or with loss of an X or Y chromosome as the only abnormality, were considered to indicate an intermediate risk. Leukemia that developed after chemotherapy or radiation therapy or after a myelodysplastic syndrome was classified as secondary AML. Hepatomegaly and splenomegaly as assessed on physical examination, WHO performance status, extramedullary disease, and white-cell count were recorded at the time of diagnosis (Table 1Table 1
Characteristics of Patients, Induction and Consolidation Treatments, and Effects of Treatment.).Criteria for Response and End Points
The definitions of complete response, disease-free survival, and relapse have been described previously.11 Event-free survival refers to the interval from randomization to the date of the evaluation of response after the last induction cycle if complete remission had not been achieved by that time, the date of death, or the date of relapse. Overall survival was measured from randomization. Early death refers to death within 30 days after randomization. Time to hematopoietic recovery was measured from the first day of chemotherapy to the time when the neutrophil count reached 0.5×109 per liter and the platelet count reached 50×109 per liter.
Statistical Analysis
Event-free survival was the primary end point. Randomized assignments to study groups were balanced with the use of a biased-coin minimization procedure, with the bias dependent on the average imbalance between the numbers of patients already assigned to each group overall, within the participating hospital and within the diagnostic subgroup (AML or refractory anemia) of the new patient. The expected complete-remission rate in the conventional-treatment group was 45% and the expected 1-year rate of event-free survival in that group was 22%. With enrollment of 800 patients and an additional follow-up of 1 year after enrollment of the last patient before the final analysis was performed, we estimated that for the analysis of event-free survival, the number of events would be 765, and the study would have 87% power to show an improvement in event-free survival in the escalated-dose group corresponding to a hazard ratio of 0.80 (an increase in the 1-year event-free survival rate from 22% to 30%), at a two-sided significance level of 5% with the use of a log-rank test. All analyses were performed according to the intention-to-treat principle, irrespective of patients' compliance with the protocol, but 15 patients who were ineligible were excluded (6 in the conventional-treatment group and 9 in the escalated-dose group). The reasons for ineligibility included a diagnosis of acute promyelocytic leukemia (six patients), previously treated AML (one), no AML (four), refractory anemia with an international prognostic score of less than 1.5 (one), a history of malignant lymphoma (one), concurrent liver cancer (one), and no provision of informed consent (one). In addition, one eligible patient in the conventional-treatment group, who withdrew after randomization but before the start of treatment, was excluded. To avoid a selection bias in the outcome estimates due to selective reporting, all 33 patients from four hospitals (13 patients in the conventional-treatment group and 20 in the escalated-dose group) were excluded because the appropriate treatment and evaluation forms for more than 25% of the patients at each of these hospitals had not been received.
The effect of treatment group and covariates on the complete-remission rate was analyzed with the use of logistic regression, and the survival end points were analyzed with the use of Cox regression. These analyses were performed with and without adjustment for covariates. The possible heterogeneity of the treatment effects in subgroups was explored in post hoc analyses by estimation of the odds ratios for complete remission and the hazard ratios for survival end points for each subgroup, together with 95% confidence intervals, and performing tests for interaction. Subgroups defined according to age (three groups of similar size: 60 to 65, 66 to 70, and >70 years of age), cytogenetic risk category (favorable, intermediate, unfavorable, or very unfavorable), WHO performance status (0, or 1 or 2), primary AML or secondary AML (the latter after chemotherapy or radiation therapy or after a myelodysplastic syndrome), presence or absence of extramedullary disease, white-cell count (<20×109 per liter or ≥20×109 per liter), presence or absence of splenomegaly and of hepatomegaly, and sex were considered. The power of these tests of interaction was limited, since the trial was not designed to test for interactions. A competing-risk analysis was performed to calculate the cumulative competing risks of lack of a complete remission during the treatment period, relapse after complete remission, and death during complete remission.
Hematologic recovery after the first cycle was analyzed actuarially and was compared between the groups with the use of a log-rank test. In these analyses, recovery before the start of the next cycle was counted as an event, whereas data were censored at the time of a patient's death or at the start of the next treatment if the patient had not yet recovered at that time. All reported P values are two-sided and have not been adjusted for multiple testing.
Results
Patients
From October 27, 2000, through June 9, 2006, a total of 813 eligible patients who could be evaluated were randomly assigned to a treatment group — 411 to the conventional-dose group and 402 to the escalated-dose group. The median follow-up period for patients who were still alive at the date of last contact (148 patients) was 40 months. Table 1 shows the demographic characteristics of the patients. The median age was 67 years (range 60 to 83); 26% of the patients were 71 years of age or older. There were no significant differences between the two groups with respect to clinical and hematologic features at baseline except for a higher prevalence of extramedullary disease in the conventional-dose group (P=0.006).
Cytogenetic Risk
Of the 813 patients who were randomly assigned to a study group, 102 had a very unfavorable (monosomal) karyotype. These patients had a low rate of complete remission (34%), a 2-year rate of disease-free survival after complete remission of 3%, and a 2-year rate of overall survival of only 4%. Patients with an unfavorable karyotype but no monosomal karyotype (79 patients) had a complete-remission rate of 56% and 2-year rates of disease-free survival and overall survival of 27% and 19%, respectively. The 33 patients with abnormalities in core-binding factors had a complete-remission rate of 82% and 2-year rates of disease-free survival and overall survival of 47% and 60%, respectively.
Treatment, Response, and Outcome
Of 813 patients, 803 received treatment in the first induction cycle, and 583 (72%) received treatment in the second induction cycle; the proportions of patients who received treatment were similar for the two study groups (Table 1). Ten patients (five in each group) did not receive the assigned study treatment owing to deterioration of their condition or early death. Patients assigned to the escalated-dose group had a significantly higher complete-remission rate than patients in the conventional-dose group (64% vs. 54%, P=0.002) (Table 2Table 2
Treatment Outcome According to Treatment Group and Clinical and Hematologic Factors.). There were more complete remissions after the first induction cycle in the escalated-dose group than in the conventional-dose group (52% vs. 35%, P<0.001) (Table 1). Of the patients in whom complete remission was achieved, 25% received treatment with gemtuzumab ozogamicin, 11% received an allograft, and 4% received chemotherapy or underwent autologous transplantation as consolidation treatment (Table 1). In the conventional-dose group, 149 patients had a relapse, and 340 died, of whom 24 were in complete remission. Of those who died while in complete remission, 3 died after the first cycle, 16 after the second cycle, 1 after receiving an allograft, and 4 after receiving other therapies. In the escalated-dose group, 158 patients had a relapse and 325 died, including 46 who were in complete remission. Of these 46 deaths, 4 occurred after the first cycle, 28 after the second cycle, 7 after receipt of an allograft, and 7 after other treatments (Table 1, and Table 1 in the Supplementary Appendix). There were no significant differences between the two groups in event-free survival (P=0.12) (Figure 1Figure 1
Effect of Remission-Induction Chemotherapy with an Escalated Dose of Daunorubicin versus a Conventional Dose on Event-free Survival and Overall Survival in Patients 60 years of Age or Older with Acute Myeloid Leukemia.), disease-free survival (P=0.77), or overall survival (P=0.16) (Figure 1). The cumulative 2-year probabilities for the competing risks of relapse after complete remission and of death during complete remission in the conventional-dose group as compared with the escalated-dose group were 61% versus 54% for relapse and 10% versus 16% for death.Prognostic Factors
Table 2 shows the probabilities of complete remission and the actuarial 2-year probabilities of disease-free survival, event-free survival, and overall survival according to treatment group and characteristics of patients, along with the results of univariate and multivariate analyses. Cytogenetic risk category, age, white-cell count, presence or absence of splenomegaly, presence or absence of extramedullary disease, WHO performance status, and primary or secondary AML were all significantly associated with the rate of complete remission (Table 2); cytogenetic risk category and age were associated with disease-free survival; and cytogenetic risk category, age, white-cell count, WHO performance status, primary or secondary AML, and presence or absence of splenomegaly were associated with event-free and overall survival. After adjustment for these factors, the difference in the complete-remission rate between the conventional-dose group and the escalated-dose group remained significant (P=0.003), whereas there were no significant differences in event-free survival, overall survival, or disease-free survival.
Exploratory Analyses of Subgroups
Exploratory post hoc analyses (Table 3Table 3
Effect of Treatment with a Conventional Dose versus an Escalated Dose of Daunorubicin on Outcome, According to Age, Performance Status, and Cytogenetic Risk Category.) showed that patients who were 60 to 65 years of age had the greatest benefit from an escalated dose of daunorubicin with respect to the complete-remission rate (51% in the conventional-dose group vs. 73% in the escalated-dose group), the 2-year rate of event-free survival (14% vs. 29%), and the 2-year rate of overall survival (23% vs. 38%) (Figure 1). Tests for an interaction between age and treatment were significant with respect to complete remission, event-free survival, and overall survival. Tests for an interaction between cytogenetic risk category and treatment were not significant except with respect to disease-free survival (Table 3), but in the subgroup with abnormalities in core-binding factors, the escalated dose was associated with an increased rate of complete remission and with reduced hazard ratios for disease progression or death (Table 3 and Figure 1). None of the tests for interaction with respect to the other factors were significant.Adverse Events
The two groups were compared with respect to adverse events associated with the first induction cycle. There were no significant differences between the two groups in 30-day mortality (12% in the conventional-dose group and 11% in the escalated-dose group), the number of nights spent in the hospital, and the time to recovery of neutrophil or platelet counts (Table 4Table 4
Adverse Events during and after the First Cycle of Remission Induction.). There were also no significant differences with respect to the rate of death during induction or the incidence of serious adverse events after the first two cycles overall. In the escalated-dose group, as compared with the conventional-dose group, there were more infections of grade 2 to 4, slightly more platelet transfusions were given, and the time to the beginning of the second cycle was, on average, 3 days longer. The difference in the time to the second cycle probably reflects the higher rate of complete remission after the first cycle in the escalated-dose group; among patients with no response, the second cycle was frequently started as soon as possible because hematologic recovery was not expected. There was no significant difference in the rate of grade 2 to 4 (i.e., moderate, severe, or life-threatening) side effects between the two groups (74% in the conventional-dose group and 80% in the escalated-dose group, P=0.08).Discussion
There is evidence that in the fit elderly, the outcome after intensive chemotherapy to induce a remission is superior to that with a wait-and-watch approach or dose-attenuated cytoreductive treatment.12-14 Our results make a case for intensified initial treatment in older patients. Induction treatment with twice the usual dose of daunorubicin (90 mg per square meter on each of 3 days, all administered in the first induction cycle) was not associated with an increase in serious side effects or with an increase in early mortality or a decrease in overall survival. The escalated-dose regimen did not prolong marrow suppression, a finding that suggests that the customary dose of daunorubicin is too low. Moreover, not only was the rate of complete remission higher with the escalated dose than with the conventional dose but also remissions were achieved earlier, with a higher rate of remission after the first cycle with the escalated dose than with the conventional dose (52% vs. 35%). The increase in the rate of remissions was independent of the cytogenetic risk category; however, it was particularly apparent in the subgroup of patients who were 60 to 65 years of age. Notwithstanding the increased rate of complete remission with the higher dose of daunorubicin, there was no improvement in overall survival or event-free survival. In the escalated-treatment group, as compared with the conventional-dose group, more patients died while they were in complete remission after the second induction cycle or after further consolidation treatment, suggesting that there may be some cumulative toxic effects after successive therapies, but there was no significant difference between the two groups in disease-free survival after complete remission (Table 2).
When daunorubicin was first introduced, it was administered at a dose of 30 mg per square meter, since early experience indicated that induction therapy with 60 mg per square meter for 3 days was not feasible in older persons.18 Subsequently, a dose of 45 to 50 mg per square meter became widely accepted. Virtually all major cooperative groups have adopted this dose as the standard dose for treating AML in patients 55 to 60 years of age or older.4-11 A dose of 60 mg per square meter has not been evaluated in direct comparisons.19 Prospectively evaluated regimens of mitoxantrone–etoposide9 or combinations of cytarabine with either idarubicin (12 mg per square meter) or mitoxantrone (12 mg per square meter)10 did not appear to be superior to a regimen of 45 to 50 mg of daunorubicin per square meter plus cytarabine. Furthermore, in another study, treatment with daunorubicin at a dose of 50 mg per square meter for 3 days during each of two successive induction cycles of daunorubicin–cytarabine, with a total dose of daunorubicin of 300 mg per square meter, conferred no more benefit than a dose of 35 mg of daunorubicin per square meter, with a total dose after two successive induction cycles of 210 mg per square meter.20 This lack of a benefit of 300 mg per square meter administered over two cycles suggests that the advantage of the dose level of 90 mg per square meter (and a total dose of 270 mg per square meter) given in a single cycle, as reported here, is probably due to the higher peak exposure levels of the intensified dose of daunorubicin, not an increase in the cumulative dose.
In our study, as in previous studies, younger age,4,6,9,21,22 better performance status,6,21-23 primary rather than secondary leukemia,6,9,21 more favorable cytogenetic risk group,4,6,17,19,21,23 and absence of splenomegaly and of extramedullary disease were independently associated with a higher rate of complete response. A monosomal karyotype distinguished patients with particularly low rates of complete remission, overall survival, and event-free survival, findings that are similar to those from a large series of patients with AML who were younger than 60 years of age.16 Furthermore, the 33 patients with cytogenetic abnormalities in core-binding factors17,21,23-25 (67% of whom were 65 years of age or older) had the best outcome, irrespective of age; however, this subgroup was small. In accordance with findings in other studies, older age,6,9,21,22,24,26 reduced performance status,6,9,21,22,26 presence of splenomegaly,21 increased white-cell count,6,9,21,26 and an unfavorable cytogenetic risk category6,9,21-24,26 were associated with decreased overall and event-free survival.
In our study, it is apparent that the subgroup of patients who were 60 to 65 years of age benefited the most from intensified doses of daunorubicin. In this subgroup, the rate of complete remission among patients who received the escalated dose, as compared with those who received the conventional dose, was 73% versus 51%; this subgroup, as compared with all other cytogenetic subgroups, also had the highest rates of overall survival (Table 3 and Figure 1). Patients in the escalated-dose group with a core-binding–factor karyotype also had a survival advantage. Although these differences could be due to chance findings in post hoc analyses, the data and the strong interaction effects between treatment and age with respect to complete remission, event-free survival, and overall survival support a true and consistent effect in favor of the escalated dose of daunorubicin in patients who are 60 to 65 years of age. This outcome is of clinical interest, since our results suggest that high-dose daunorubicin could be an alternative therapy to high-dose cytarabine (up to 3000 mg per square meter), which is an effective treatment for AML in patients younger than 60 years of age but is far too toxic in patients 60 years of age or older.27
Supported by the Dutch Cancer Society Queen Wilhelmina Foundation.
No potential conflict of interest relevant to this article was reported.
This article (10.1056/NEJMoa0901409) was updated on March 24, 2010, at NEJM.org.
We thank the local and central data managers for collecting patient data, in particular Petra Cornelisse, Ine Meulendijks, Anneke Ammerlaan, Silvia Verelst, and Christel van Hooije (Dutch-Belgian Hemato-Oncology Cooperative Group Data Center), Bettina Adamo and Brigitte Fuellgraf (German AML Study Group), and Christina Biaggi (Swiss Group for Clinical Cancer Research), and Yvette van Norden for statistical assistance.
Source Information
From Erasmus University Medical Center, Rotterdam (B.L., P.S., M.J.-L.); the Department of Hematology, Free University Medical Center, Amsterdam (G.J.O.); the HOVON Data Center and Department of Trials and Statistics, Erasmus University Medical Center, Rotterdam (W.P.); University Medical Center, Maastricht (H.C.S.); Amsterdam University Medical Center, Amsterdam (B.J.B.); University Medical Center, Groningen (E.V.); Isala Hospital, Zwolle (M.M.K.); and University Medical Center, Utrecht (L.F.V.) — all in the Netherlands; Hôpital Mont Godinne, Yvoir (C.G.); Hôpital St. Luc, Brussels (A.F.); and University Hospital Gasthuisberg, Leuven (J.M., G.V.) — all in Belgium; University Hospital, Bonn (M.L.-T.); the Department of Internal Medicine III, University-Hospital, Mainz (J.B.); and the Department of Internal Medicine III, University of Ulm, Ulm (H.D.) — all in Germany; and University Hospital, Basel (A.G.); and Inselspital, Bern (T.P.) — both in Switzerland.
Address reprint requests to Dr. Löwenberg at Erasmus University Medical Center, Department of Hematology (L413), P.O. Box 2040, 3000 CA Rotterdam, the Netherlands, or at b.lowenberg@erasmusmc.nl.
Appendix
The following institutes and investigators of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology, the German AML Study Group, and the Swiss Group for Clinical Cancer Research participated in the study: Belgium — Brussels, St. Luc, A. Ferrant; Haine, St. Paul Jolimont, A. Delannoy; Leuven, Gasthuisberg, J. Maertens, G. Verhoef; Roeselare, Heilig Hart, H. Demuynck; Yvoir, Mont Godinne, A. Bosly, C. Graux; Antwerp, Ziekenhuis Netwerk, D.A. Breems, P. Zachee. Germany — Frankfurt am Main, Nordwest, E. Jaeger; Mainz, Gutenberg, J. Beck, T. Fischer; Bonn, Universität Bonn, M. von Lilienfeld-Toal, A. Glasmacher; Hamburg, Altona Hospital, H.J. Salwender; Hamburg, University Hospital Saarland, F. Hartmann; Munich, Klinikum Technischen Universität München, K. Goetze; Stuttgart, Buerger Hospital, W. Grimminger; Ulm, University Hospital Ulm, H. Döhner. Switzerland — Aarau, Kantonsspital, M. Bargetzi, M. Wernli; Basel, University Hospital, A. Gratwohl; Bern, Inselspital, M.F. Fey, T. Pabst; Geneva, Cantonal University, B. Chapuis; Lausanne, Centre Hospitalier Universitaire Vaudois, A. Herr; Lucerne, Kantonsspital, W.A. Wuillemin; Zurich, University Hospital, E. Jacky, U. Schans. The Netherlands — Amersfoort, Meander, S. Wittebol; Amsterdam, Academic Medical Center, J. Van Der Lelie, B.J. Biemond; Amsterdam, Hospital Onze Lieve Vrouwen Gasthuis, B. De Valk; Amsterdam, Free University Medical Center, G.J. Ossenkoppele, P.C. Huijgens; The Hague, Leyenburg, P.W. Wijermans; Dordrecht, Albert Schweitzer Hospital, M.D. Levin; Enschede, Medisch Spectrum Twente, M.R. Schaafsma; Groningen, University Medical Center, S.M.G.J. Daenen, E. Vellenga; Heerlen, Atrium, P.J. Voogt; Maastricht, University Hospital, H.C. Schouten; Nieuwegein, Antonius, D.H. Biesma; Rotterdam, Erasmus University Medical Center, P. Sonneveld, J. Zijlmans, M. Jongen-Lavrencic, G.E. De Greef, B. Löwenberg; Utrecht, University Hospital Utrecht, L.F. Verdonck, J. Kuball; Zwolle, Isala Hospital, M. van Marwijk Kooy. United Kingdom — Hampshire, Basingstoke, A. Milne; Birmingham, Heartlands Hospital, D.W. Milligan; Canterbury, Eastham Hospital, C. Pocock; Cardiff, University of Wales, A.K. Burnett; Gillingham, Medway Hospital, M. Aldouri; Manchester, Christie Hospital, M. Dennis.
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