Published Ahead of Print on July 12, 2010 as 10.1200/JCO.2009.26.9381
Procarbazine-Free OEPA-COPDAC Chemotherapy in Boysand Standard OPPA-COPP in Girls Have ComparableEffectiveness in Pediatric Hodgkin’s Lymphoma: TheGPOH-HD-2002 StudyChristine Mauz-Ko¨rholz, Dirk Hasenclever, Wolfgang Do¨rffel, Kathrin Ruschke, Tanja Pelz, Antje Voigt,Martina Stiefel, Melanie Winkler, Constanze Vilser, Karin Dieckmann, Jonas Karle´n, Eva Bergstra¨sser, Alexander Fosså, Georg Mann, Michael Hummel, Wolfram Klapper, Harald Stein, Dirk Vordermark, Regine Kluge, and Dieter Ko¨rholz kum Berlin-Buch; Charite´-Berlin Univer- Franklin, Berlin; Campus Kiel, University Purpose
Vincristine, etoposide, prednisone, and doxorubicin (OEPA)– cyclophosphamide, vincristine, pred-
nisone, and dacarbazine (COPDAC) is derived from standard vincristine, procarbazine, prednisone, and doxorubicin (OPPA)– cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) chemotherapy by replacing procarbazine with etoposide and dacarbazine for a potentially less gonadotoxic regimen for boys with Hodgkin’s lymphoma (HL).
Patients and Methods
Five hundred seventy-three pediatric patients with classical HL were enrolled onto the German Society of Pediatric Oncology and Hematology–Hodgkin’s Disease (GPOH-HD) -2002 study between November 2002 and December 2005. Boys received two courses of OEPA and girls received two courses of OPPA for induction. Treatment group (TG) -2 (intermediate stages) and TG-3 (advanced stages) patients received further two or four cycles COPP (girls) or COPDAC (boys), respectively. After chemotherapy all patients received involved-field irradiation with 19.8 Gy, except for patients with early-stage disease (TG-1) in complete remission.
Five hundred seventy-three patients (287 males and 286 females) were less than 18 years old and
fulfilled all inclusion criteria; 195 patients (34.0%) were allocated to TG-1, 139 (24.3%) were allocated to TG-2, and 239 (41.7%) were allocated to TG-3. Toxicity of OEPA-COPDAC was tolerable overall. Hematotoxicity was more pronounced with OEPA than OPPA, whereas it was less pronounced with COPDAC compared with COPP. The median observation time was 58.6 months. Overall survival and event-free survival (EFS) rates (Ϯ SE) at 5 years were 97.4% Ϯ 0.7% and 89.0% Ϯ 1.4%, respectively. In TG-1, overall EFS was 92.0% Ϯ 2.0%. EFS of patients without irradiation (93.2% Ϯ 3.3%) was similar to that of irradiated patients (91.7% Ϯ 2.5%), confirming results of the previous GPOH-HD-95 study. In TG-2ϩ3, EFS did not significantly differ between boys and girls (90.2% Ϯ 2.3 v 84.7% Ϯ 2.7, respectively; P ϭ .12).
In TG-2ϩ3, results in boys and girls are superimposable. OPPA-COPP and OEPA-COPDAC seem to be Clinical Trials repository link available on exchangeable regimens in intermediate- and advanced-stage classical HL in pediatric patients.
J Clin Oncol 28. 2010 by American Society of Clinical Oncology are allocated to three treatment groups (TGs) INTRODUCTION
based on early- (TG-1), intermediate- (TG-2), and The German Society of Pediatric Oncology and advanced-stage (TG-3) disease. All patients start Hematology–Hodgkin’s Disease (GPOH-HD) -2002 with two intensive induction cycles of chemothe- study is the seventh in a series of treatment optimi- rapy (vincristine, procarbazine, prednisone, and zation studies for pediatric patients with Hodgkin’s doxorubicin [OPPA] or variants). In TG-2 and lymphoma (HL) started by Gu¨nther Schellong in TG-3, two or four consolidation cycles (cyclo- 1978.1-6 All seven studies evolved from a common phosphamide, vincristine, procarbazine, and pre- combined-modality treatment scheme. Patients dnisone [COPP] or variants) are given, respectively.
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Radiotherapy follows after completion of chemotherapy. The treat- equivalent to a cumulative oral procarbazine dose of 1,500 mg/m2 in ment results of the Deutschen Arbeitsgemeinschaft fu¨r Leuka¨miefor- the COPP cycle. The primary objective of this study was to show schung (DAL)/GPOH-HD trials have been generally excellent, with feasibility and effectiveness of OE*PA-COPDAC in boys compared event-free survival (EFS) rates of approximately 90% at 5 years in all TGs.1-7 However, the long-term outcome after 20 years truly reflectsthe HL treatment effects on morbidity and mortality.8,9 Thus, theconsecutive studies focused on reducing long-term toxicity. Without PATIENTS AND METHODS
compromising the treatment results, radiotherapy was reduced involume (from extended field to involved field) and in doses (from Patients and Study Design
36 to 20 Gy) to prevent growth impairment, lung dysfunction, From November 15, 2002 until December 31, 2005, the study recruited hypothyroidism, cardiac diseases, and secondary malignan- 660 consecutive patients with HL. The 97 trial sites in Germany, Austria, cies.10-13 The GPOH-HD-95 study established that radiotherapy Switzerland, Sweden, Netherlands, and Norway were committed to enroll all can be safely omitted in TG-1 patients achieving complete remis- pediatric patients with HL exclusively onto this study. Cross-check with the German Childhood Cancer Registry showed that approximately 98% of all Procarbazine is a major drug in both the OPPA and COPP German children up to 15 years old with HL were entered onto this study.26-28 regimens and is known to be gonadotoxic.14 Cumulative doses of Children and adolescents up to 18 years old with confirmed histology of procarbazine15,16 correlate with increasing rates of male infertility after either classical or lymphocyte-predominant HL (LPHL) were enrolled ontothe study. Main exclusion criteria were relapse of HL, HL as secondary malig- treatment. An attempt to eliminate procarbazine from OPPA and nancy, prior chemotherapy or radiotherapy (except corticosteroid prophase replacement of procarbazine by low-dose methotrexate in COPP led for large mediastinal mass), and simultaneous comorbidity rendering the to an unacceptable decrease in efficacy in the third study generation.3 protocol treatment unfeasible. The study protocol was approved by the Ethics Thus, procarbazine had to be substituted by an equipotent drug. In the Committee of the University of Leipzig and by the respective institutional fifth study generation, DAL-HD-90, boys received vincristine, etopo- review boards of the participating trial sites. Patients and/or their guardians side, prednisone, and doxorubicin (OEPA; procarbazine in OPPA replaced by a total etoposide dose of 500 mg/m2 within 4 consecutive The histopathologic diagnosis was based on biopsy of a lymph node or of another involved organ. Reference pathology was required including subtyp- days) to preserve fertility.5 With this regimen, the outcome in boys ing according to the WHO classification.29,30 was nearly comparable to that in girls. Fertility was preserved in Intravenous contrast-enhanced, cross-sectional imaging from the skull early-stage male patients. However, follicle-stimulating hormone base to the symphysis was required for staging. Investigation of the neck, (FSH) levels, which were used as a fertility surrogate marker, were still abdomen, and pelvis could be performed either by computed tomography elevated in males with intermediate- and advanced-stage disease (CT) or magnetic resonance imaging, whereas a chest CT was mandatory. In addition, abdominal ultrasonography had to be performed. All cross-sectional In the GPOH-HD-95 study, boys had significantly worse images were real-time reviewed centrally by the tumor board of the study.
Bone marrow biopsy was recommended in patients with a clinical stage greater 5-year disease-free survival rates than girls (0.86% v 0.93%, respec- than IIA. Suspected bone involvement was specifically imaged by bone scin- tively; P ϭ .005). This was probably related to procarbazine replace- tigraphy, CT bony window, magnetic resonance imaging, or conventional ment by etoposide in OEPA for boys. In addition, male sex has been an radiographs of the respective site(s). Fluorodeoxyglucose positron emission unfavorable prognostic factor in the adult setting and is considered tomography scanning of the whole body was optional and could be subject to unfavorable in the International Prognostic Score.17 Nevertheless, in GPOH-HD-2002, a procarbazine-free regimen Response assessment after two cycles had to be performed in all patients.
for boys was prioritized because of gonadotoxicity. This resulted in the A late response assessment was scheduled for patients in TG-2 after four cycles plan to escalate the etoposide dose in the OEPA regimen to optimize and for patients in TG-3 after six cycles of chemotherapy. Response assessmentimaging had to be performed according to the requirements for staging in all disease control. Etoposide administration was extended from 4 to 5 initially involved regions. After review of the response assessment, the central days (OE*PA), leading to a cumulative dose of 1,250 mg/m2 etoposide review board provided radiotherapy recommendations for all TG-2 and TG-3 in both cycles. This dose is below the critical dose of 2,000 mg/m2, patients, as well as for TG-1 patients who were not in complete remission.
above which an increased risk of secondary acute myeloid leukemia The definition of disease stages was adopted according to the Ann Arbor Conference classification. Patients were stratified into the following three TGs To eliminate oral procarbazine completely from treatment in according to disease stage: TG-1 (early stages: IA, IB, and IIA), TG-2 (interme- boys, procarbazine in COPP was replaced by intravenous (IV) dacar- diate stages: IE, IIB, IIAE, and IIIA), and TG-3 (advanced stages: IIBE, IIIAE,IIIB, IVA, IVB, and IVE; Fig 1).
bazine, resulting in the cyclophosphamide, vincristine, prednisone, Nodal involvement of a lymph node was defined if the node was greater and dacarbazine (COPDAC) regimen. Like procarbazine, dacarba- than 2 cm in largest diameter. The node was not involved if it was Յ 1 cm in zine acts as an alkylator and inhibits both DNA and RNA synthesis.
largest diameter and was considered questionably involved if the largest diam- Within the doxorubicin, bleomycin, vinblastine, and dacarbazine eter was between 1 and 2 cm. Involvement decision was then based on all (ABVD) regimen, dacarbazine has been studied extensively in HL, and further clinical evidence available. In the central review board, reference vol- it has been shown that male patients have a low probability of becom- umes were calculated from all involved nodal regions. The volume (V) was ing permanently azoospermic with this regimen.21,22 Earlier studies calculated with three dimensions (a, b, and c) of a node or conglomerate on single-drug administration with either dacarbazine23,24 or pro- approximating an ellipsoid as follows: volume ϭ (a ϫ b ϫ c)/2.
The response to chemotherapy after two, four, or six cycles was defined carbazine25 report similar objective response rates, suggesting as complete remission if the volume reduction was Ն 95% and Յ 2 mL of the equal effectiveness of dacarbazine 750 mg/m2 in ABVD compared initial volume. The response was defined as unconfirmed complete remission with procarbazine 1,800 mg/m2 in COPP. Thus, dacarbazine doses of if the volume reduction was Ն 75% or less than 2 mL, and partial remission 250 mg/m2 on days 1 to 3 in 30-minute infusions were considered (PR) was defined as 50% volume reduction.
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Time to event data were analyzed using the Kaplan-Meier method33 and the log-rank test.34 Overall survival was defined as time from registration untildeath from any cause. Progression-free survival (PFS) was defined as time from registration until the progression/relapse of disease or death from any cause, whichever occurred first. EFS was defined as time from registration until the occurrence of one of the following events: progression/relapse of disease, occurrence of a secondary malignancy, or death from any cause. The cutoff for data analysis was February 25, 2010.
GPOH-HD-2002 was originally planned as a 1-year feasibility study to pilot for a full randomized study comparing COPP and COPDAC. Start of this randomized study (European Network Group on Pediatric Hodgkin’s Lym- phoma [EuroNet-PHL] -C1 opened in 2007) was delayed because of a delay infunding and the foundation of a European study group (EuroNet-PHL). Thus, GPOH-HD-2002 over-recruited into a full study generation.
Fig 1. Study design of the German Society of Pediatric Oncology and Hematology–
Hodgkin’s Disease (GPOH-HD) 2002 study for male patients. Girls were similarlytreated with standard two cycles of vincristine, procarbazine, prednisone, anddoxorubicin instead of vincristine, etoposide, prednisone, and doxorubicin (OE*PA) Patient Characteristics
and cyclophosphamide, vincristine, procarbazine, and prednisone instead of cyclo-phosphamide, vincristine, prednisone, and dacarbazine (COPDAC) in treatment From November 2002 until December 2005, 660 consecutive group (TG) 2ϩ3. CR, complete remission; RT, radiotherapy.
patients were enrolled onto the study. Thirty patients had to be ex-cluded. The diagnosis was revised by reference pathology in fivepatients, and five patients had comorbidities (immunodeficiency syn-dromes, n ϭ 2; cardiac diseases, n ϭ 2; and secondary HL, n ϭ 1). Ten All patients received two induction cycles, OPPA for girls and OE*PA for patients were older than age 18 years at diagnosis, eight patients were boys. In addition, patients with intermediate- or advanced-stage disease re-ceived two or four cycles, respectively, of COPP (girls) or COPDAC (boys).
referred for consultation only or from nonparticipating trial sites, and OPPA cycles consisted of vincristine 1.5 mg/m2 IV on days 1, 8, and 15; two patients had prior chemotherapy. Furthermore, 57 patients with procarbazine 100 mg/m2 orally (PO) on days 1 to 15; prednisone 60 mg/m2 PO LPHL were excluded from this analysis. The demographics and clini- on days 1 to 15; and doxorubicin 40 mg/m2 IV on days 1 and 15. OE*PA cycles cal characteristics of 573 study patients with classical HL (287 boys and were identical to OPPA except that etoposide 125 mg/m2 IV on days 2 through 286 girls; mean age, 14 years; range, 2.8 to 18 years) are listed in Table 6 replaced procarbazine. COPP chemotherapy contained cyclophosphamide 1. Five hundred sixty-seven (99%) of 573 study patients had central 500 mg/m2 IV on days 1 and 8; vincristine 1.5 mg/m2 IV on days 1 and 8; review of staging. In nine patients (1.4%), the TG was assigned by local procarbazine 100 mg/m2 PO on days 1 to 15, and prednisone 40 mg/m2 PO ondays 1 to 15. COPDAC cycles were identical to COPP except that dacarbazine staging and differed from central review. Fifteen patients (2.6%) had 250 mg/m2 IV on days 1 to 3 replaced procarbazine (Fig 1). Chemotherapy- individual chemotherapy modifications. Analysis is based on the TG related toxicity had to be graded and documented for each given cycle as treated. The proportions of patients in TG-1, TG-2, and TG-3 according to National Cancer Institute Common Toxicity Criteria (NCI- were 34.0%, 24.3%, and 41.7%, respectively. Three hundred seventy-eight patients (183 boys and 195 girls) were classified as After chemotherapy, modified involved-field radiotherapy was delivered having intermediate- or advanced-stage disease (TG-2ϩ3; Table 1).
to initially involved regions. Treated areas were smaller than classical involvedfields because upper and lower neck; supraclavicular region; upper, mid, andlower mediastinal; and upper and lower para-aortic regions were distin- Treatment Results and Toxicity
guished. Lateral field borders for mediastinal or para-aortic regions were based Median follow-up time was 58.6 months. Fifteen patients died, on tumor extension after chemotherapy. Standard recommended radiother- and 10 deaths were related to HL progression or relapse. Two deaths apy dose was 19.8 Gy (1.8-Gy fractions). In regions with less than 75% volume were toxic deaths (intracranial hemorrhage after lysis of sinus venous reduction, a boost to approximately 30 Gy was administered, and residual thrombosis after the first OEPA cycle and allergic shock and renal masses greater than 100 mL were boosted to approximately 35 Gy. Stage IV failure after the second COPDAC cycle). Three patients died of other lung disease was irradiated only if lung nodules were still detectable after twocycles of chemotherapy. Lung and liver radiation dose varied from 12 to 15 Gy causes (one patient with relapse of ovarian carcinoma surgically re- (1- to 1.2-Gy fractions). Radiotherapy was omitted in TG-1 patients in com- moved before HL, one girl with secondary myelodysplastic syndrome/ An interim analysis of the first 70 patients receiving COPDAC suggested Second malignancies occurred in 10 girls; in three of these pa- a trend toward 5-year EFS of less than 90%, although toxicity was low. There- tients the tumors were considered unrelated to HL treatment (one fore, the study committee decided to increase the dacarbazine dose from three ovarian teratoma, one ovarian carcinoma, and one retrothyroidal to four doses of 250 mg/m2. This amendment was activated August 3, 2005 and fibrosarcoma) because the tumors occurred during or soon after treat- was implemented in 20 boys only. Concomitantly, 12 trial sites started aseparate vinblastine, etoposide, cyclophosphamide, vincristine, prednisone, ment. The remaining seven tumors occurred after full therapy, includ- and doxorubicin (VECOPA) pilot study recruiting nine TG-2ϩ3 boys with ing radiotherapy (five thyroid carcinomas, one nasopharyngeal classical HL until the end of GPOH-HD-2002.
carcinoma, and one secondary AML). In one boy, secondary T-cellacute lymphocytic leukemia occurred. The median latency period for Statistical Methods
a second malignancy was 48.1 months (range, 2.7 to 63.3 months).
Here, we report on all patients with classical HL. Patients with LPHL have been excluded for this report because LPHL is now generally considered a Overall, the probability estimates of overall survival, PFS, and separate disease entity,30 and some LPHL patients have been treated with EFS at 5 years were 97.4% Ϯ 0.7%, 90.7% Ϯ 1.2%, and 89.0% Ϯ 1.4%, respectively (Fig 2). The probabilities of PFS and EFS in TG-1, TG-2, 2010 by American Society of Clinical Oncology Information downloaded from and provided by KLINIKUM KROELLWITZ on July 30, 2010 from Copyright 2010 by the American Society of Clinical Oncology. All rights reserved. Mauz-Ko¨rholz et al
Table 1. Demographics and Clinical Characteristics of Eligible Study Patients and OS, PFS, and EFS
Abbreviations: OS, overall survival; PFS, progression-free survival; EFS, event-free survival; NA, not applicable; TG, treatment group; RT, radiotherapy.
ءExcluding one early toxic death and six patients with missing RT documentation.
and TG-3 patients at 5 years were 92.7% Ϯ 1.9% and 92.0% Ϯ 2.0%, tively (Fig 3; Table 1). Five-year PFS and EFS rates did not differ 93.4% Ϯ 2.1% and 88.3% Ϯ 2.9%, and 87.4% Ϯ 2.2% and 86.9% Ϯ significantly between boys and girls (PFS: 90.2% Ϯ 1.8% and 91.1% Ϯ 2.3%, respectively (P ϭ .066/P ϭ .15). The PFS and EFS probabilities 1.7%, respectively; P ϭ .93; EFS: 90.2% Ϯ 1.8% and 87.7% Ϯ 2.0%, in TG-2ϩ3 patients were 89.6% Ϯ 1.6% and 87.7% Ϯ 1.8%, respec- respectively; P ϭ .38; Table 1).
In 62 TG-1 patients (31.8% of all TG-1 patients), radiotherapy was omitted after completion of chemotherapy because of excellent Fig 2. Overall survival (OS), progression-free survival (PFS), and event-free
survival (EFS) for all patients in the German Society of Pediatric Oncology andHematology–Hodgkin’s Disease 2002 study. Kaplan-Meier curves for OS, PFS, Fig 3. Event-free survival (EFS) according to treatment groups (TGs). Kaplan-
and EFS are presented for all study patients (N ϭ 573). Median observation time Meier curves of EFS are presented for the following three stratification groups: was 58.6 months. Five-year rate estimates are provided. For OS, events include TG1 (early stages), TG2 (intermediate stages), and TG3 (advanced stages). Death, only death; for PFS, events include death and progression/relapse; and for EFS, relapse/progression, and secondary malignancy counted as events. Median events include death, progression/relapse, and second malignancies. The treat- observation time was 58.6 months. Five-year rate estimates are provided. There ment results were at or around the target rate of 90%.
is only a statistically nonsignificant trend between the treatment groups.
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response (58 of 62 patients). PFS and EFS rates in patients who did not NCI-CTC grade 3 or 4 leukopenia, neutropenia, anemia, and throm- receive radiotherapy (both 93.2% Ϯ 3.3%) were similar (P ϭ .88 and bocytopenia were recorded in 70.5%, 81.5%, 11.9%, and 2.8% of P ϭ .74, respectively) to those in patients who received radiotherapy patients receiving OE*PA compared with 52.4%, 57.1%, 9.9%, and (92.8% Ϯ 2.3% and 91.7% Ϯ 2.5%, respectively). PFS and EFS rates in 0.7% of patients receiving OPPA. Rates of leukopenia and neutrope- prepubertal patients (Ͻ 13 years old) tended to be more favorable nia with OE*PA were significantly higher compared with OPPA (P ϭ .085 and P ϭ .036, respectively) than in postpubertal patients (P Ͻ .001; Table 2). NCI-CTC grade 3 or 4 infections were infrequent, (Ͼ 13 years old; Table 1). PFS and EFS rates in TG-2ϩ3 patients did and there were no early deaths as a result of infection.
not differ by sex or chemotherapy (90.2% Ϯ 2.3% and 90.2% Ϯ 2.3%, In COPDAC cycles, NCI-CTC grade 3 or 4 hematotoxicity rates respectively, for boys [OE*PA-COPDAC] and 89.1% Ϯ 2.2% and were significantly lower compared with the COPP cycles. Leukopenia, 84.7% Ϯ 2.7%, respectively, for girls [OPPA-COPP]; P ϭ .49 and neutropenia, anemia, and thrombocytopenia were recorded in P ϭ .12, respectively; Figs 4A and 4B; Table 1).
13.1%, 22.7%, 6.9%, and 3.4% of patients, respectively, receiving In all chemotherapy blocks (OPPA/OE*PA and COPP/COPDAC COPDAC. NCI-CTC grade 3 or 4 infections were rare (0.8% and 0% in TG-2 and TG-3), more than 90% of all patients received more than with COPDAC and COPP, respectively). Interestingly, NCI-CTC 90% of their target doses of all single drugs, except for vincristine in grade Ն 2 sensory and motor neurotoxicity rates were significantly COPP/COPDAC in TG-3, where only 89.4% of patients received lower with COPDAC compared with those recorded for COPP (2.3% v 7.0% and 1.7% v 10.0%, respectively; P Ͻ .005; Table 2).
In the OE*PA regimen, hematotoxicity was the most common Adherence to central review radiotherapy recommendations was recorded adverse reaction greater than NCI-CTC grade 2. Maximum verified by documentation forms and physicians’ reports in 522 of 573patients, excluding progression before end of radiotherapy (n ϭ11) or toxic death (n ϭ 1). Radiotherapy with 19.8 Gy was recom-mended in 426 of 522 patients, no radiotherapy was recommended in 62 of 522 patients, and boost radiotherapy was recommended in34 of 522 patients. Treatment differed from these recommendations DISCUSSION
In 2002, the GPOH-HD study group changed the chemotherapy for male pediatric patients with HL for two reasons. First, in DAL-HD-905 TG2+3 5-yr PFS Girls/OPPA-COPP89.1%, 22/195 events and GPOH-HD-95,6 results for boys were slightly inferior to resultsfor girls. Therefore, we increased the dose of etoposide in OE*PA by 25%. Second, although fertility data in TG-1 had improved after the change from OPPA to OEPA in DAL-HD-90, elevated follicle-stimulating hormone levels in TG-2ϩ3 patients suggested a persistent fertility problem probably as a result of procarbazine in COPP. There-fore, procarbazine in COPP was replaced by dacarbazine, creating the novel regimen COPDAC. Dacarbazine is an alkylator like procarba-zine, has been extensively used in the ABVD regimen, and seems to be less gonadotoxic. The overall treatment results in 573 patients withclassical HL confirm the good results of the preceding DAL-HD-90 In GPOH-HD-95, TG-1 patients achieving a complete remission after OPPA or OEPA chemotherapy did not require radiotherapy.
TG2+3 5-yr EFS Girls/OPPA-COPP84.7%, 29/195 events This applies to approximately 30% of the patients. GPOH-HD-2002confirms this important result. Patients in TG-1 who did and did not receive radiotherapy both had excellent results.
The alternative chemotherapy OE*PA-COPDAC regimen for boys is feasible even in a broad multicenter setting. More than 90% of Fig 4. (A) Progression-free survival (PFS) and (B) event-free survival (EFS) by
the target dose was given to approximately 90% of the patients for all sex/chemotherapy in treatment group (TG) 2ϩ3. Kaplan-Meier curves of PFS andEFS are presented for boys (treated with vincristine, etoposide, prednisone, and drugs administered. The hematotoxicity after OE*PA is more pro- doxorubicin [OEPA]– cyclophosphamide, vincristine, prednisone, and dacarbazine nounced than with OPPA. However, COPDAC is less hematotoxic [COPDAC]) and girls (treated with vincristine, procarbazine, prednisone, and doxoru- bicin [OPPA]– cyclophosphamide, vincristine, procarbazine, and prednisone [COPP])in TG2 (intermediate stages) and TG3 (advanced stages). Median observation time In intermediate- and advanced-stage disease (TG-2ϩ3), PFS was 58.6 months. Five-year rate estimates are provided. Death and relapse/ curves for girls treated with standard OPPA-COPP and boys treated progression counted as events in PFS. Death, relapse/progression, and secondary with OE*PA-COPDAC are superimposable. This holds true also malignancy counted as events in EFS. There was no statistically significant differ-ence in PFS or EFS between sex or chemotherapy.
when considering TG-2 and TG-3 separately (data not shown). The 2010 by American Society of Clinical Oncology Information downloaded from and provided by KLINIKUM KROELLWITZ on July 30, 2010 from Copyright 2010 by the American Society of Clinical Oncology. All rights reserved. Mauz-Ko¨rholz et al
Table 2. Toxicities of Chemotherapy Cycles in the GPOH-HD-2002 Study
Abbreviations: GPOH-HD, German Society of Pediatric Oncology and Hematology–Hodgkin’s Disease; NCI-CTC, National Cancer Institute Common Toxicity Criteria; OEPA, vincristine, etoposide, prednisone, and doxorubicin; OPPA, vincristine, procarbazine, prednisone, and doxorubicin; COPDAC, cyclophosphamide, vincristine,prednisone, and dacarbazine; COPP, cyclophosphamide, vincristine, procarbazine, and prednisone; NS, not significant; NA, not applicable.
present study constitutes no randomized comparison because treat- AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
ment was stratified by sex. However, the comparison is probably only OF INTEREST
conservatively biased because results of boys tended to be slightlyinferior in previous studies. In addition, male sex is a known prognos-tic factor in the adult International Prognostic Score.17 Thus, we The author(s) indicated no potential conflicts of interest.
consider OE*PA-COPDAC a safe treatment alternative to OPPA-COPP. Currently, a randomized study comparing OE*PA-COPPwith OE*PA-COPDAC with concomitant fertility testing (EuroNet- AUTHOR CONTRIBUTIONS
Interestingly, second malignancies within the present study oc- Conception and design: Christine Mauz-Ko¨rholz, Wolfgang Do¨rffel,
curred predominantly in girls (10 of 11 second malignancies), so our conclusion is even stronger when looking at EFS. Five of 10 secondary Administrative support: Alexander Fosså
cancers in females were thyroid cancers, which have a female prepon- Provision of study materials or patients: Christine Mauz-Ko¨rholz, Jonas
Karle´n, Eva Bergstra¨sser, Alexander Fosså, Georg Mann, Michael
derance in non– cancer survivors as well,36 and four of the five thyroid Hummel, Wolfram Klapper, Harald Stein, Regine Kluge, Dieter Ko¨rholz cancers were microcarcinomas. Because diagnostic means for thyroid Collection and assembly of data: Christine Mauz-Ko¨rholz, Tanja Pelz,
carcinoma have rapidly improved over time, microcarcinomas may Antje Voigt, Martina Stiefel, Melanie Winkler, Constanze Vilser, Michael Because fertility assessment was not an objective of GPOH-HD- Data analysis and interpretation: Christine Mauz-Ko¨rholz, Dirk
2002, fertility data were not prospectively collected. Although procar- Hasenclever, Kathrin Ruschke, Dirk Vordermark, Regine Kluge, bazine is generally considered more gonadotoxic than dacarbazine, Viviani et al22 reported on a relevant proportion of male patients being Manuscript writing: Christine Mauz-Ko¨rholz, Dirk Hasenclever,
diagnosed as already infertile before the start of HL treatment. Thus, Wolfgang Do¨rffel, Karin Dieckmann, Alexander Fosså, DirkVordermark, Dieter Ko¨rholz the hypothesis still requires proof of whether the elimination of pro- Final approval of manuscript: Christine Mauz-Ko¨rholz, Dirk
carbazine leads to preservation of male fertility in intermediate- and Hasenclever, Wolfgang Do¨rffel, Kathrin Ruschke, Tanja Pelz, Antje advanced-stage disease. This question is currently under investigation Voigt, Martina Stiefel, Melanie Winkler, Constanze Vilser, Karin in the prospective EuroNet-PHL-C1 trial.35 In conclusion, OPPA- Dieckmann, Jonas Karle´n, Eva Bergstra¨sser, Alexander Fosså, Georg COPP and OE*PA-COPDAC seem to be exchangeable regimens in Mann, Michael Hummel, Wolfram Klapper, Harald Stein, Dirk intermediate- and advanced-stage HL in pediatric patients.
Vordermark, Regine Kluge, Dieter Ko¨rholz splenectomy—A report of the cooperative therapy center trial DAL-HD-90 —The German-Austrian Pe- REFERENCES
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The authors thank the trial participants in the respective Pediatric Oncology, Hemato-Oncology, Diagnostic Radiology, and Radiotherapy Departments in Germany (Aachen, Augsburg, Bayreuth, Berlin-Charite´, Berlin-Buch, Bielefeld, Bonn, Braunschweig, Bremen, Chemnitz,Cottbus, Datteln, Detmold, Dortmund, Dresden, Du¨sseldorf, Erfurt, Erlangen, Essen, Frankfurt/Main, Freiburg, Giessen, Go¨ttingen, Greifswald,Halle/Saale, Hamburg, Hameln, Hamm, Hannover, Heidelberg, Heilbronn, Herdecke, Homburg/Saar, Idar-Oberstein, Jena, Karlsruhe, Kassel,Kiel, Koblenz, Ko¨ln-Uni, Ko¨ln-Sta¨dtische Kliniken, Krefeld, Leipzig, Ludwigshafen, Magdeburg, Mainz, Mannheim, Marburg, Minden,Mu¨nchen-Harlaching, Mu¨nchen-Haunersches Kinderspital, Mu¨nchen-Schwabing, Mu¨nster, Nu¨rnberg, Oldenburg, Olpe, Osnabru¨ck, Pots-dam, Regensburg, Rostock, Saarbru¨cken, Schwerin, Siegen, St Augustin, Stuttgart, Trier, Tu¨bingen, Ulm, Vechta, Wolfsburg, Wu¨rzburg,Wuppertal), Austria (Graz, Innsbruck, Klagenfurt, Leoben, Linz, Salzburg, Vienna), the Netherlands (Amsterdam, Nijmegen), Norway (Trond-heim), Sweden (Lund, Linko¨ping, Stockholm, Uppsala), and Switzerland (Basel, Bern, Lausanne, Luzern, St Gallen, Zu¨rich).
2010 by American Society of Clinical Oncology Information downloaded from and provided by KLINIKUM KROELLWITZ on July 30, 2010 from Copyright 2010 by the American Society of Clinical Oncology. All rights reserved.


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