1 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig; 2 Clinic I for Internal Medicine, University of Cologne, Cologne; 3 Clinic for Haematology and Internal Oncology, Carl-Thiem Hospital, Cottbus; 4 Clinic for Internal Medicine, Georg-August University, Goettingen; 5 Department of Oncology and Haematology, University Hospital HamburgEppendorf, Hamburg; 6 Department of Internal Medicine II, Friedrich-Schiller University, Jena; 7 Clinic I for Internal Medicine, University of Saarland, Homburg, Germany
Received 18 December 2002; accepted 17 February 2003
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Abstract |
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There is evidence that intensified variants of the classical 3-weekly CHOP-21 chemotherapy [cyclophosphamide (C), doxorubicin (H), vincristine (O), prednisone (P)] may improve treatment outcome in aggressive lymphoma. Three variants using either an addition of etoposide (CHOEP-21: 100 mg/m2 on days 13), the shortening to 2-week intervals using recombinant human granulocyte colony-stimulating factor (rhG-CSF; CHOP-14) or both (CHOEP-14) are currently compared with CHOP-21 in the NHL-B trial of the German High-Grade Non-Hodgkins Lymphoma Study Group (DSHNHL). To enable more extensive testing of these schemes we here characterise their practicability regarding schedule adherence, acute haematotoxicity and need for supportive treatment.
Patients and methods:
The trial included patients with normal lactate dehydrogenase (LDH) aged ≤60 years (NHL-B1) and patients aged 6175 years (NHL-B2). The data are taken from an interim analysis. Data from 959 patients (CHOP-21: 232; CHOP-14: 238; CHOEP-21: 244; CHOEP-14: 245) from 162 institutions with a total of 5331 therapy cycles were evaluated.
Results:
The dose adherence in the NHL-B1 trial was excellent. The median relative dose (RD; i.e. actually given compared to planned dose) exceeds 98% for the myelosuppressive drugs in all four regimens. Only ≤5% of patients received a relative dose <80% (RD <80). The median treatment duration could be shortened as scheduled for both CHOP-14 by 36 days and CHOEP-14 by 35 days. The dose adherence in the NHL-B2 trial was excellent for CHOP-21 and CHOP-14 for the myelosuppressive drugs (median RD ≥98%, RD <80 ≤15%). Addition of etoposide, however, was accompanied by more dose erosion (median RD ≥97%, RD <80 ≤17% for CHOEP-21 and ≤27% for CHOEP-14). The median treatment duration could be shortened by 34 days with CHOP-14 compared with CHOP-21. Less treatment shortening was feasible for CHOEP-14 compared with CHOP-21 (median of 29 days). CHOP-14 and CHOP-21 were similar regarding toxicity profile, rate of infection, use of antibiotics, rate of transfusions and hospitalisation. CHOEP schemes were associated with a higher rate of infections, more transfusion requirements, more antibiotic use and longer hospitalisation than the CHOP schemes, particularly in patients aged >60 years. Haematopoietic recovery was age- and treatment-related.
Conclusions:
CHOP-14 with the addition of rhG-CSF is safe and practicable in a large multicentre setting in patients aged 1875 years. Despite shorter treatment intervals it can be delivered at the same dose as the classical 3-weekly CHOP with a comparable toxicity profile. The addition of etoposide is feasible and safe for patients ≤60 years old in both the CHOEP-21 and CHOEP-14 schemes. For patients >60 years of age the addition of etoposide is associated with marked dose erosion due to increased toxicity. In this age group CHOEP should be used with caution.
Key words: aggressive lymphomas, CHOP regimen, clinical study, relative dose toxicity
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Introduction |
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In 1993 the German High-Grade Non-Hodgkins Lymphoma Study Group (DSHNHL) decided to investigate in a large multicentre randomised phase III trial whether specific intensifications of the classical 3-weekly CHOP scheme could improve long-term treatment outcome. Two methods of intensification were considered. One was the addition of a presumably potent cytotoxic substance to the CHOP scheme without modifying dosing and timing of the other components. The drug selected was etoposide, because of data indicating a relevant activity in aggressive lymphoma. Furthermore, a phase II trial had previously shown feasibility of the CHOEP scheme (CHOP plus etoposide 100 mg/m2 on days 13) in a multicentre setting and suggested promising tumour control in previously untreated patients [9].
The second method of intensification, so far not investigated in a large-scale trial, was the shortening of the time intervals of the CHOP regimens. In rapidly growing tumours shortening treatment intervals should considerably impair tumour regrowth between the treatment cycles. To obtain an idea of the potential magnitude of this effect we performed biomathematical model calculations applying a model used for designing an intensified regimen for advanced stage Hodgkins disease [1012]. This model predicted that shortening treatment intervals from 3 weeks to 2 weeks should lead to an improvement in long-term treatment outcome (i.e. time-to-treatment failure, TTF) in the order of ≥10%. Such a difference was considered to be clinically relevant and detectable in a sufficiently large phase III trial. To support recovery of granulocytes it was decided to include recombinant human granulocyte colony-stimulating factor (rhG-CSF) in the 2-week regimens from days 4 to 13.
In 1993 the DSHNHL activated the multicentre randomised phase III trial called NHL-B (Figure 1). Four treatment options were compared in a 2 x 2 factorial design. CHOP chemotherapy was planned to be given in 21-day intervals without rhG-CSF (CHOP-21) or in 14-day intervals with the addition of rhG-CSF (CHOP-14). Two further treatment arms resulted from the addition of etoposide (CHOEP-21 and CHOEP-14). The trial was formally split into two trials as two different groups of patients were enrolled. One trial (NHL-B1) included patients ≤60 years of age with a low-risk profile [lactate dehydrogenase (LDH) below the upper normal value). The second trial (NHL-B2) included patients between 61 and 75 years of age irrespective of the risk profile. Patients ≤60 years of age with an elevated LDH value were included in a different trial of the study group (NHL-A), comparing conventional CHOEP-21 with a strategy including high-dose chemotherapy and autologous bone marrow transplantation [13].
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It is the objective of this report to describe in detail the practicability of the four CHOP variants by analysing how well the intended schedules could be applied, to what extent dose erosion occurred and what spectrum of dose-limiting toxicities occurred. As the NHL-B trial was conducted in a multicentre setting with a broad spectrum of participating institutions this analysis should provide important information for wider use of the new schemes.
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Patients and methods |
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Patients aged 1860 years were only included if the pretreatment LDH value had not exceeded the upper normal value of the local laboratory (NHL-B1 trial). Patients aged between 61 and 75 years were included irrespective of LDH values (NHL-B2 trial). Exclusion criteria were presence of a second tumour, previous chemo/radiotherapy, severe concomitant disease or organ dysfunction, bone marrow involvement with >25% lymphoma cells, HIV infection, initial white blood cell (WBC) count <3 x 103/mm3, initial platelet level <100 x 103/mm3, a World Health Organisation (WHO) performance status of 4 and reduced patient compliance. The protocol was approved by the local ethics review committees responsible for the participating centres. The staging procedure involved the following mandatory examinations: clinical examination, laboratory investigations, chest X-ray, abdomen sonography, CT of chest and abdomen, bone marrow biopsy. Written informed consent was requested.
A 2 x 2 factorial study design was implemented for both the NHL-B1 and NHL-B2 trials. In Figure 1 both are shown together. The primary end point of the trial is time-to-treatment failure (TTF) which is defined as time elapsed from the first day of treatment to progression, failure to achieve a complete response/unconfirmed complete response (CR/CRu) at termination of protocol treatment, initiation of an alternative treatment, relapse or death, whichever comes first. The trial was set up to detect a 30% reduction of the hazard rate of the primary end point separately in the groups of patients aged 1860 years and 6175 years. We planned to randomise a minimum of 700 eligible patients into each of the two trials.
The CHOP scheme was defined as cyclophosphamide [750 mg/m2 intravenously (i.v.)], doxorubicin (50 mg/m2 i.v.), vincristine (2 mg i.v.) all given on day 1 and prednisone (100 mg/day per os) given on days 15. In the CHOEP regimen the same dosage is used for cyclophosphamide, doxorubicin, vincristine and prednisone. Etoposide was given in a dose of 100 mg/m2 i.v. on days 13. All patients were planned to receive six cycles of chemotherapy. In case of progression of the disease during treatment or in case of insufficient response (no change/minor response) at the time of interim restaging after three cycles of chemotherapy, switching to a salvage therapy was recommended. Planned treatment was continued without any dose reduction if the WBC count was >2.5 x 103/mm3 and if platelets were >80 x 103/mm3 on day 1 of the next intended cycle. In case these threshold values were not exceeded, physicians were advised to wait and control the WBC count and platelets up to 1 week and give full dose treatment as soon as the criteria were met. A dose reduction of 25% for cyclophosphamide, doxorubicin and etoposide was recommended if the WBC count and platelet recovery took >1 week. A 50% reduction for these drugs was recommended if the recovery was delayed by >2 weeks. Support by rhG-CSF was scheduled in the 2-weekly regimens (CHOP-14 and CHOEP-14) from days 4 to 13 (10 day duration) at a dose of 300 µg/day and 480 µg/day for patients <75 kg and ≥75 kg body weight, respectively. rhG-CSF was not recommended for the 3-weekly schemes.
After completion of six cycles of chemotherapy, local radiotherapy with 36 Gy was planned for all patients with initial bulky disease or conglomerate tumours (largest diameter ≥7.5 cm) and was recommended for extranodal tumours.
Trial and data management
A total of 1500 eligible patients from 162 centres were randomised into the two trials until June 2000 (NHL-B1: 762; NHL-B2: 738). Of these patients, 39% were treated in university hospitals, 59% in regional hospitals and 2% by private oncological practitioners in Germany and Switzerland (see Acknowledgements).
All data were submitted on case report forms and checked by a physician and data manager. According to standard operating procedures they checked the data for completeness and consistency and initiated queries back to the treating physicians if necessary. Queries were initiated for 16% of all case report forms. Cleared data were entered into an Oracle 8 (Oracle Corp., Redwood Shores, CA, USA) database via a data entry process with additional checks for consistency. No routine on-site monitoring or source data verification was undertaken.
For the subsequent analysis the following data were used on a per cycle basis: date of cycle start, total dose of each drug given, days of rhG-CSF, number of erythrocyte and platelet transfusions, application and duration of antibiotics, number of days with fever, total number of days of hospitalisation, WBC count, platelet counts, haemoglobin, and occurrence of acute toxicities according to WHO grades [18].
For each patient entering into the analysis a panel (consisting of a physician, statistician and data manager) assessed whether the treatment was given according to protocol. In case of deviation the panel identified the time of and classified the reasons for early treatment termination [tumour-related, excessive toxicity, major protocol violation, patient withdrawal, concomitant disease or other (e.g. accidents)]. For each patient who died the cause of death was retrieved whenever possible.
Patient characteristics
This analysis is based on data obtained in the interim analysis in 2000. At this time point 959 patients had complete information on treatment and treatment outcome. Patient characteristics are listed in Table 1. Due to the different inclusion criteria the risk profile of the two age groups differs. However, with regard to blood counts before the first treatment cycle no differences were observed.
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Blood count measurements for WBC, platelets and haemoglobin were requested. The treatment protocol recommended two measurements per week, but to account for the multicentre setting no strict rules were imposed to comply with this recommendation. In fact a median number of three blood counts were documented per cycle and treatment arm. In total 17 015 blood counts were documented. To obtain a population description of the blood count time courses over the planned six-cycle treatments aggregate figures were generated with time scales according to protocol treatment (e.g. day 1 of cycle 3 is day 29 in 2-weekly schemes and day 43 in 3-weekly schemes). Thus in these plots data observed on day 15 or later in the CHOP-14 and CHOEP-14 cycles are not considered, and likewise data obtained later than day 21 in the CHOP-21 and CHOEP-21 cycles are not considered. Hence, a total of 15 638 values were entered into generation of the aggregate figures (see below). Using this procedure the median number of measurements obtained for each day was 35 (range 191). To describe the observed data we used boxplots with the upper and lower limits describing the 25% and 75% percentiles.
To estimate the independent impact of age and treatment arms on the treatment-related mortality we performed a multivariate analysis using a logistic regression model. To compare protocol adherence between university hospitals and regional hospitals with regard to the supportive treatments and frequency of side-effects we used t-test statistics and chi-square test statistics on a significance level of 0.05.
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Results |
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Figure 2D, F and H provides detailed insight into dose erosion for patients >60 years of age. With regard to the median RD the four regimens reached values >96% of the planned dose. However, the schemes containing etoposide led to a considerable dose erosion of cyclophosphamide and doxorubicin compared with the CHOP schemes. In the CHOP-21 scheme only 7% of the patients received a relative dose of cyclophospamide <80% while in the CHOEP-14 and CHOEP-21 schemes these were 24% and 15%, respectively. Comparing Figure 2G and H shows an important age-dependent dose erosion with regard to etoposide. While only 5% of the younger patients received <80% of the planned etoposide dose, this increased to 17% for CHOEP-21 and 27% for CHOEP-14 in elderly patients.
Deviations from the planned dose of vincristine primarily occurred in the late therapy cycles. Eighty-three per cent of patients ≤60 years of age received full vincristine dose in cycle 6, while this number diminished to 75% for the elderly patients.
rhG-CSF was given regularly in the 2-week schemes. Ninety-five to 100% of the patients received rhG-CSF in the first five cycles of the 2-week regimens in both age groups. In cycle 6, 91% of the patients in the CHOP-14 arm and 94% in the CHOEP-14 arm received rhG-CSF. In the 3-week treatment arms rhG-CSF was not recommended. Among patients ≤60 years of age 6% received rhG-CSF in cycle 5 in the CHOP-21 arm and 15% in the CHOEP-21 arm. For patients >60 years of age 5% received rhG-CSF in cycle 5 in the CHOP-21 arm and 24% in the CHOEP-21 arm. In the 2-week treatment regimens the duration of rhG-CSF reached a median of 10 days.
Haematotoxicity and supportive measures
Figures 3, 4 and 5 describe the time courses of leucocytes, thrombocytes and haemoglobin over the entire treatment period for the four different treatment arms. Figure 3 shows the periodic pattern for leucocytes. In the 3-week schemes the nadir counts occur on days 1012 of the cycle and on days 810 in the 2-week schemes. Nadir leucocyte counts of successive cycles reached similar values providing no evidence for cumulative toxicity in any treatment arm. In the 2-week schemes a two-peak pattern is observed under rhG-CSF. Immediately after the start of rhG-CSF (i.e. following day 4 in each cycle) a transient increase in WBC count was followed by the nadir; a second overshoot occurred on days 1214. Nadir counts are generally higher than in 3-weekly CHOP. Furthermore, the second overshoot shows a remarkable variation, which is indicated by the increasing size of the boxes in the aggregated boxplots. Generally lower leucocyte nadir counts were observed in the older age group.
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Figure 5 shows the time courses for haemoglobin concentrations. There is cumulative toxicity which differs between the treatment arms. It is minor for the CHOP-21 regimen and most prominent for the CHOEP-14 regimen. It should be noted that these data are biased by red blood cell (RBC) transfusions in later cycles. Table 3 summarises toxicities and toxicity-related supportive measures. Generally, the haematological toxicities and the incidence of infections and mucositis are elevated in patients >60 years of age. Platelet transfusions reached 1% per cycle in the CHOP-14 arm in the elderly patients. Platelet transfusions were more frequent in patients >60 years of age and in etoposide-containing regimens. Furthermore, patients aged >60 years receiving CHOEP-14 required RBC transfusion in 32% of the cycles. Rate of infections and mucositis in patients aged >60 years was between 02% (CHOP-schemes) and 27% in etoposide-containing schemes. Table 3 also gives the average duration of hospitalisation. Generally the elderly age group required one to three extra days of hospitalisation per cycle compared with the patients aged ≤60 years. The etoposide-containing regimens required on average about 13 days more hospitalisation than the CHOP regimens.
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A logistic regression model was applied to model the probability of treatment-related mortality. Age >60 years was the most prominent adverse prognostic factor (P = 0.0001). Compared with CHOP-21 only CHOEP-14 was associated with a significant risk increase (P = 0.02).
In a median observation time of 34 months 14 secondary cancers have been observed so far. There was no association with treatment arms.
Centre effect
No significant differences could be detected with regard to toxicity-related mortality comparing university hospitals and regional hospitals (P = 0.280). Furthermore, no differences with regard to rate of infection (P = 0.991), use of platelet (P = 0.740) and RBC transfusion (P = 0.450) were seen between these institutions. We found, however, that hospitalisation for regional hospitals lasted 1 day longer and that they had a more extensive use of antibiotics (P <0.001).
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Discussion |
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Our data confirm that the CHOP-21 standard regimen is characterised by a moderate degree of haematopoietic toxicities and can be applied very closely to the intended dose and time schedule. Leucocytopenia of World Health Organization (WHO) grade 4 occurred in only 7% of all cycles in patients ≤60 years of age and in 44% of all cycles in older patients. Most therapy cycles (96%) were given without administration of rhG-CSF. Severe thrombocytopenia (WHO grade 4) and platelet transfusions were rare events (both <1% of all cycles). The time course of leucocytes and platelets during the therapy cycles showed that within 3 weeks sufficient recovery was achieved on average. Over six consecutive therapy cycles no exhaustion of the haematopoietic recovery dynamics could be noticed.
The three intensified CHOP variants were designed to achieve moderate intensification under the constraint of maintaining multicentre practicability with a conventional multicycle chemotherapy. Our data clearly show that the CHOP regimen can be given every 2 weeks for six cycles with no increased toxicity compared with the 3-weekly CHOP standard regimen. The total drug doses delivered were comparable for CHOP-14 and CHOP-21 while the total treatment duration could be shortened by 36 days in patients aged ≤60 years and by 34 days in elderly patients. Grade 4 leucocytopenia in patients aged >60 years was considerably less frequent in CHOP-14 compared with CHOP-21 treatment arms (24% versus 44%; P <0.001). This effect is likely due to rhG-CSF administration. The rates of infections, the transfusion needs and the use of antibiotics were similar for both regimens. Haematopoietic recovery was possible for granulopoiesis and thrombocytopoiesis without cumulative toxicity after CHOP-14 in all age groups. We observed a slow decline in haemoglobin levels that led to a slight increase in RBC transfusions (10% versus 12% of all cycles in patients >60 years).
Remarkably, the mean duration of hospitalisation per cycle was 1 day shorter following CHOP-14 compared with CHOP-21 in elderly patients (4 versus 5 days; P = 0.005). Hence the data provide evidence that the toxicity profile of CHOP-14 (with rhG-CSF) and CHOP-21 (without rhG-CSF) is almost identical and a marked shortening of the treatment period is possible. We therefore conclude that six cycles of CHOP-14 is safe and feasible in a multicentre setting for all age groups between 18 and 75 years.
Based on the available interim analyses on treatment efficiency mentioned above the German study group decided in 2000 to consider six cycles of 2-weekly CHOP with addition of rhG-CSF as the reference treatment for its future trials in all patients aged >60 years. A trial is presently ongoing for patients aged 6180 years comparing six versus eight cycles of CHOP-14 in a 2 x 2 factorial study design with or without the addition of anti-CD20 antibody (RICOVER60 trial). So far this ongoing trial supports the conclusion that CHOP-14 is a safe and feasible regimen.
As expected, the addition of etoposide to the CHOP regimen led to more haematological toxicities. Leucocytopenia, thrombocytopenia and anaemia were more pronounced in the CHOEP schemes compared with the CHOP schemes. Recovery was age dependent. In patients ≤60 years of age recovery of leucocytopenia and thrombocytopenia occurred regularly to pre-treatment levels permitting the continuation with either CHOEP-21 or CHOEP-14.
Considering also the data on the rates of infections, antibiotic use, transfusion requirements, hospitalisation and particularly fatal treatment-related toxicities, we conclude that CHOEP-21 and CHOEP-14 are feasible and safe schemes in a multicentre setting in the age group ≤60 years.
Based on the available interim analyses on treatment efficiency mentioned above, the German study group decided in 2000 to consider CHOEP as the reference treatment for its future trials in all patients aged ≤60 years. A trial is presently ongoing for these patients with low and lowintermediate International Prognostic Index comparing six cycles of CHOEP-21 with six cycles of a dose-escalated variant of CHOEP-21. Furthermore, the study group opted to use CHOEP-21 as the standard treatment in the ongoing Mabthera Intergroup trial (MINT trial) investigating the role of anti-CD20 antibodies in CHOP-like treatments in patients ≤60 years of age, a population not covered by the recent GELA trial [19]. So far our ongoing trials support our conclusion that CHOEP is a safe and feasible regimen in the age group <60 years.
In contrast, we recommend that the CHOEP schemes should be used with caution in patients >60 years of age. Regarding practicability we observed a substantial dose and schedule erosion, particularly for CHOEP-14. Regarding safety an increased risk of treatment-related mortality has to be taken into account.
Clearly the toxicity and feasibility data presented in this analysis have to be balanced against the treatment outcome data. The forthcoming final analysis of the NHL-B trial will provide further clarification about whether and which of the intensified CHOP regimens are superior to classical CHOP-21 with regard to tumour control and long-term outcome. Clearly large gains in outcome may encourage us to accept larger risks regarding acute toxicities and vice versa. In view of the increased aggressiveness of these schemes late sequelae such as the rate of secondary leukaemias or myelodysplastic syndromes need to be carefully monitored in the future. However, due to short follow-up the data presently available are too immature and incomplete.
An interesting observation is the large variance of WBC counts under rhG-CSF. We believe this is largely due to non-standardised intervals between rhG-CSF application and time of blood sampling. As rhG-CSF concentrations rise and fall quickly the phenomenon of bone marrow release and of demargination of leucocytes attached to the arterial walls may play a crucial role. The clinical implication is that measurements of WBC following rhG-CSF injection are somewhat invalidated and more reliable data may be obtained by measurements immediately before the daily rhG-CSF injection [20]. The time courses of WBC count under rhG-CSF observed by Crawford et al. [21] could in general be confirmed, showing a first peak on days 4 and 5 and a second peak after the nadir. We anticipate that new G-CSF molecules with a different pharmacokinetic make-up may lead to a smoothing of the variant WBC time courses [2224].
An interesting extension of this analysis is concerned with the predictibility of haematotoxicity based on parameters available before the start of treatment. This may help to adjust individual treatment intensity in patients [25, 26]. A more detailed analysis is forthcoming.
As a consequence of the increased haematotoxicity, clearly more haematosupportive treatment (rhG-CSF and transfusions) was required during intensified CHOP variants. A median number of 10 rhG-CSF injections per cycle were given in the 2-weekly regimen. This is a considerable cost factor. At present, it is not clear whether this rhG-CSF schedule is optimal regarding cost-effectiveness. The number of G-CSF injections might be reduced without jeopardising the safety of the 2-weekly schedules. Efforts to identify rhG-CSF administration schedules that potentially are more cost-effective have been initiated using computer-based modelling of granulopoiesis [27]. In the presently ongoing RICOVER60 trial for elderly patients we use CHOP-14 with a 7-day rhG-CSF schedule from day 6 to 12.
In summary, we conclude that CHOP-14 is a safe and feasible regimen for all age groups with toxicity profiles and need for supportive treatment similar to CHOP-21 while permitting a more rapid dose delivery. CHOEP-21 and CHOEP-14 are also safe and feasible regimens for patients ≤60 years of age. CHOEP variants should be used with caution in age groups >60 years.
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Acknowledgements |
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Reference pathology: Prof. Feller (chairman), Lübeck; Prof. Hansmann, Frankfurt/Main; Prof. Müller-Hermelink, Würzburg; Prof. Parwaresch, Kiel; Prof. Stein, Berlin. Reference radiotherapy: K. Schnabel, Ch. Rübe, T. P. Nguyen, Homburg/Saar. Study group centre Homburg/Saar. Secretary: W. Beck, V. Barnsdorf. Clinicians: L. Truemper, R. Schmits, M. Pfreundschuh. Data centre Leipzig. Documentation: B. Mann, A. L. Martín Montáñez, A. Schöler, U. Schönwiese. Database: B. Wicklein, M. Kunert, R. Speer. Biometry: M. Kloess, D. Hasenclever, M. Loeffler. Writing committee: A. Wunderlich, M. Kloess, M. Loeffler. We acknowledge valuable comments from Christoph Engel and Dirk Hasenclever (Leipzig).
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Footnotes |
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References |
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