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Salvage Therapy of Progressive and Recurrent Hodgkin’s Disease: Results From a Multicenter Study of the Pediatric DAL/GPOH-HD Study Group

From the Department of Pediatric Hematology and Oncology, University Children’s Hospital Münster, Münster; II. Children’s Hospital, HELIOS-Klinikum Berlin-Buch; University Children’s Hospital Kiel, Kiel; Division of Pediatric Hematology and Oncology, University Children’s Hospital Leipzig, Leipzig; Department of Pediatric Hematology and Oncology, University Children’s Hospital Tübingen, Tübingen; Department of Radiotherapy, Vivantes-Klinikum, Berlin-Moabit, Germany; St Anna Children’s Hospital, Vienna; Department of Radiotherapy and Radiobiology, University of Vienna, Vienna, Austria; and Department of Pediatric Hematology and Oncology, University Children’s Hospital Nijmegen, Nijmegen, the Netherlands

Address reprint requests to Günther Schellong, MD, Universitätsklinikum Münster, Kinderklinik, Pädiatrische Hämatologie und Onkologie, Albert-Schweitzer-Strasse 33, D-48129 Münster, Germany; e-mail: schellon{at}uni-muenster.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix Authors’ Disclosures of... REFERENCES

 
PURPOSE: To evaluate a salvage therapy (ST-HD-86) for patients with progressive and relapsed Hodgkin’s disease after primary treatment in the pediatric DAL/GPOH studies. The essential chemotherapeutic regimens were ifosfamide, etoposide, and prednisone (IEP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).

METHODS: One hundred seventy-six patients with progression (n = 51) or first relapse (n = 125) were enrolled by 67 centers. The median time from initial diagnosis to progression/relapse was 1.1 year (range, 0.1 to 15.3 years), and the patients’ median age was 14.7 years (range, 4.3 to 24.5 years). Salvage chemotherapy consisted of two to three cycles of IEP alternating with one to two cycles of ABVD supplemented in part by one to two cycles of cyclophosphamide, vincristine, procarbazine, and prednisone or lomustine (CCNU), etoposide, and prednimustine. Radiotherapy was given to involved areas using individualized doses. In the 1990s, additional high-dose chemotherapy with autologous stem-cell transplantation (SCT) was introduced for patients with unfavorable prognosis.

RESULTS: Disease-free survival (DFS) and overall survival (OS) after 10 years are 62% and 75%, respectively (SE, 4% each). Of 176 patients, 73 suffered second events. The risk-factor analysis revealed the time to progression/relapse as the strongest prognostic factor (P = .0001). Patients with progression have an inferior outcome (DFS, 41%; OS, 51%), whereas patients with late relapse (> 12 months after end of therapy) do well (DFS, 86%; OS, 90%), although none of them received SCT in second remission.

CONCLUSION: The result can be considered favorable. Whereas the salvage strategy for progressive disease has to be optimized further, it is possible to reduce intensity and avoid SCT in late relapses after Hodgkin’s disease in childhood/adolescence.

	INTRODUCTION

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Patients with Hodgkin’s disease (HD) have a substantial chance of cure even when primary therapy fails.¹ Thus far, however, a uniform strategy for a second-line treatment with the intent to cure (ie, salvage therapy) has been lacking. The backbone of all treatment approaches is chemotherapy, sometimes combined with radiotherapy. The protocols for salvage therapy usually consist of new drug combinations or at least contain some elements not included in primary therapy.^2-9 During the 1990s, high-dose therapy (HDT) with autologous hematopoietic stem-cell transplantation (SCT) steadily gained importance and has since been broadly utilized for intensification of salvage treatment in adult patients.^10-16 HDT has also been adopted for the treatment of pediatric patients with progressive and recurrent HD.^17-20 However, additional experience and discussion will be needed to arrive at generally applicable strategies.

Published reports on salvage therapy in pediatric patients with progressive and relapsed HD have been limited thus far to comparatively small series,^21,22 because cure rates of front-line therapy are high in the young age group. In 1986, we initiated a prospective nonrandomized salvage-therapy study (ST-HD-86) in conjunction with the German-Austrian pediatric HD trials. Because of favorable interim results,²³ this study was continued with slight modifications until 2003. The salvage-therapy project was based on consecutive multicenter trials for optimizing primary therapy of HD in children and adolescents conducted since 1978 and approved by the German Association for Childhood Leukemia Research and Treatment (Deutsche Arbeitsgemeinschaft für Leukämieforschung und Behandlung im Kindesalter [DAL]) and later by the Society of Pediatric Oncology and Hematology (Gesellschaft für Pädiatrische Onkologie und Hämatologie [GPOH]).^24-28

	METHODS

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Primary Therapy
The regimens for primary treatment in studies HD-78 to HD-95 as a rule combined chemotherapy and radiation.^24-28 Patients were stratified to three treatment groups (TGs) according to stage of disease: TG1 (early stages), two cycles of chemotherapy were given; TG2 and TG3 (intermediate and advanced stages), four and six to eight cycles, respectively. The first two cycles (ie, also the total chemotherapy in TG1) comprised the drug combinations vincristine, prednisone, procarbazine, doxorubicin (OPPA), OEPA (ie, etoposide instead of procarbazine for the boys in studies HD-90 and HD-95), or OPA (ie, without procarbazine and etoposide). The additional cycles consisted of cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) or COMP (ie, methotrexate replacing procarbazine). Chemotherapy was followed by radiotherapy applied as extended-field irradiation with doses of up to 36 to 40 Gy in the first trial and later as involved-field irradiation of 20 to 35 Gy. In the HD-95 trial, for the first time in the DAL/GPOH HD studies, an attempt was made to abandon radiotherapy in those patients who achieved complete remission by the end of chemotherapy.²⁸

Salvage Therapy
ST-HD-86 salvage therapy, like primary therapy, consisted of combined-modality treatment. Patients were started on chemotherapy containing the new combination of ifosfamide, etoposide, and prednisone (IEP; Table 1) and the established doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen.²⁹ During the initial study phase, all patients received a total of six chemotherapy cycles: two series of three combinations, including COPP²⁷ as the third combination when not given for primary therapy (in trial HD-85 and in TG1 of the other trials); the three elements IEP, ABVD, and COPP were alternated twice.²³ For patients who had been treated with COPP already, this combination was replaced by lomustine (CCNU), etoposide, and prednimustine (CEP, Table 2). ³⁰ During the second phase of the study, from 1992 onward, the total number of cycles was reduced to three to five depending on the patients’ individual pretreatment and response situation (Table 2). For patients with slow response, the centers were free to add another one to two cycles at their discretion.

HDT with subsequent autologous SCT after first recurrence was not provided initially, but some years into the study we began to use this method of intensification as an option in second remission for high-risk patients (ie, after progression under primary therapy and after early relapse), to be used at the discretion of the participating centers. Standardized methods of HDT and SCT did not exist yet. Salvage chemotherapy was cut short in some of the patients before HDT/SCT, and some also received no radiotherapy. If the study therapy failed and a patient developed a second progression/relapse, additional chemotherapeutic approaches were applied in the following salvage treatment including HDT with SCT, but strategies for a second salvage therapy are not a main topic of this report, although they may have an impact on definitive survival.

The therapy protocol was reviewed and approved by the local ethics committee on the basis of the Helsinki Declaration. Informed consent was given by patients and/or parents/legal representatives.

Statistical Methods
Probabilities of overall survival (OS), disease-free survival (DFS), event-free survival (EFS), and cumulative incidence were calculated according to the Kaplan-Meier method³¹ using SAS software (SAS Institute, Cary, NC). The calculations of the survival estimates refer to the day of diagnosis of first recurrence (progression, relapse) and those of the cumulative incidences of secondary malignancies (SMs) to the first day of front-line therapy. Patients alive were censored at the day of the last follow-up information. For OS, death of any cause was considered as an event. DFS was calculated with respect to disease progression under therapy and relapse, whereas for EFS, death as the first event after initiation of salvage therapy and diagnosis of an SM were also included. The SE was calculated according to Greenwood’s equation. Between-group differences were analyzed by using the log-rank test.³² The risk-factor analyses (univariate and multivariate) were performed by use of the stepwise regression model of Cox.³³ The cutoff date for the analyses was March 1, 2004.

	RESULTS

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Patients
From July 1986 through March 2003 a total of 176 patients (110 male, 66 female) were enrolled onto the study (51 with progression during initial therapy and 125 with a first relapse of HD) from 67 departments in Germany, Austria, the Netherlands, Sweden, and Switzerland. They had been treated originally according to the multicenter DAL studies HD-78, HD-82, HD-85, HD-87, and HD-90 or the GPOH study HD-95. The distribution within the three initial TGs was: TG1 (early stages), 32%; TG2 (intermediate stages), 28%; and TG3 (advanced stages), 40%. Characteristics of the cohort at first diagnosis (frequencies of B symptoms, histologic subtype nodular sclerosis type 2 according to Bennett,³⁴ and extralymphatic involvement) are listed in Table 3 (risk-factor analyses). Two thirds of the 176 patients had their primary therapy in the two most recent trials, HD-90 and HD-95. The median age of the patients was 13.3 years (range, 1.9 to 17.9 years) at first diagnosis and 14.7 years (range, 4.3 to 24.5 years) at diagnosis of progression/relapse. The median interval between initiation of primary therapy and recurrence was 1.1 years (range, 0.1 to 15.3 years), that is, in nearly half of the 176 patients the treatment failures were diagnosed during the first year. Forty-four patients primarily treated in our trials who received a different salvage therapy (eg, in departments for adults) during the respective period (1986 to 2003) were not included in this evaluation.

Group One. Progression of the disease during treatment or until 3 months after completion of therapy: 51 patients, corresponding to 29% of the total group.

Group Two. Early relapse diagnosed between 3 and 12 months after completion of therapy: 57 patients, corresponding to 32% of the total group.

Group Three. Late relapse diagnosed 12 months from the end of therapy: 68 patients, corresponding to 39% of the total group.

The three prognostic risk groups among the patients of the original TGs and their prevalences are TG1 (n = 56): progression, 9 (16%); early relapse, 17 (30%); late relapse, 30 (54%); TG2 (n = 49): progression, 8 (16%); early relapse, 20 (41%); late relapse, 21 (43%); and TG3 (n = 71); progression, 34 (48%); early relapse, 20 (28%); late relapse, 17 (24%). Thus, patients with primary localized stages tended to develop more late relapses, and patients with advanced stages tended to develop more progressions.

Treatment
The median amount of salvage chemotherapy given to the 176 patients was five cycles (range, one to 10 cycles). Six percent of the patients received three cycles, 24% received four cycles, 27% received five cycles, and 26% received six cycles. Thus, as many as 85% of all patients were treated with the scheduled three to six cycles. In 6% of the patients, only one to two cycles could be given, mostly because of further recurrence of HD, death, or initiation of HDT/SCT. In 9% of the patients, seven to 10 cycles were applied, because their response was slow or incomplete. The distribution in the patients of the three initial TGs does not differ significantly (Table 4).

Toxicity
The acute toxicity profile of the chemotherapy was generally comparable with that of similar regimens, which is true for the widely spread protocols ABVD, COPP, and CCNU, etoposide, and prednimustine, as well as for the novel IEP schedule. Detailed documentation of 146 IEP cycles in 70 patients revealed nadir values corresponding to World Health Organization grades 3 and 4 for white blood cell count after 28% of the cycles, for platelets after 4% of the cycles, and for hemoglobin after 2.5% of the cycles. Grade 3 infections were observed in 4% of the cycles and grade 3 neurotoxicity in only 0.8% of the cycles.

Outcome
The median follow-up time of the entire cohort, including deaths, from diagnosis of first recurrence is 5.0 years (range, 0.2 to 17.1 years). Seventy-three of the 176 patients suffered a second event (Table 5) after a median time of 1.1 year (range, 0.1 to 16.2 years): 61 progressions/relapses, four deaths as second events, and eight SMs (four of them with a fatal result). A total of 44 patients died after a median of 1.7 years (range, 0.2 to 16.2 years).

Figure 1 presents the life-table curves of OS, DFS, and EFS for the total group of 176 patients. The probabilities after 10 years are 75% (OS), 62% (DFS), and 57% (EFS), with an SE of 4% each.

View larger version (15K): [in this window] [in a new window]   Fig 1. Probabilities of overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) of the total group of 176 patients treated with salvage therapy ST-HD-86 until 10 years of follow-up after diagnosis of first recurrence. prog., progressions; rel., relapses.

Figures 2 and 3 show the life-table curves of DFS and OS, respectively, for the three above-defined prognostic groups. The probabilities of DFS and OS after 10 years for late relapse are 86% (SE, 5%) and 90% (SE, 4%), for early relapse, 55% (SE, 7%) and 78% (SE, 6%), and for progression, 41% (SE, 7%) and 51% (SE, 8%), respectively. The comparison of the survival estimates between the prognostic groups (Table 6) reveals significant risk ratios (RRs) of DFS for progression versus early relapse (P = .03), progression versus late relapse (P = .0001), and early relapse versus late relapse (P = .0006) and significant RRs of OS for progression versus early relapse (P = .0005) and progression versus late relapse (P = .0001) but not early relapse versus late relapse.

View larger version (16K): [in this window] [in a new window]   Fig 2. Probabilities of disease-free survival (DFS) for the three prognostic groups until 10 years of follow-up. LREL, late relapses; EREL, early relapses; PROG, progressions.

View larger version (14K): [in this window] [in a new window]   Fig 3. Probabilities of overall survival (OS) for the three prognostic groups until 10 years of follow-up. LREL, late relapses; EREL, early relapses; PROG, progressions.

Risk-Factor Analysis
To assess the prognostic impact of other factors besides time until recurrence, we performed univariate and multivariate risk-factor analyses, mainly looking at features of primary disease and first-line therapy. Table 3 shows the results of the univariate analyses of eight parameters based on a follow-up of 10 years (separately for DFS und OS). With both survival estimates, the time until recurrence of HD was proven to be the strongest prognostic factor (P = .0001). Patients with primary progressive disease had the worst outcome. The cut points in the time until recurrence after first-line therapy that mark a considerable improvement of prognosis are 3 months with regard to OS and 12 months with regard to DFS. Additional significant parameters with both DFS and OS are extralymphatic involvement at primary diagnosis (stages IV, E), TG at first-line treatment (better outcome after TG1 than after TG2 and TG3), and type of chemotherapy (with v without etoposide/procarbazine). It is remarkable that the results after etoposide-containing primary therapy (ie, after OEPA/COPP) are not inferior to those after OPPA/COPP. A significantly better outcome was achieved in patients pretreated without procarbazine and etoposide (ie, after the combinations OPA/COMP). The stepwise multivariate analysis, looking at the combined parameters, revealed that the time until recurrence of HD strongly dominates over all other parameters. At a level of 5%, only one additional risk factor each is additionally significant for DFS and OS: mode of primary chemotherapy for DFS (ie, patients after primary therapy without procarbazine and etoposide do better [RR, 1.6; P = .02]) and sex for OS (ie, girls have a lower survival rate than boys [RR, 1.95; P = .03]).

	DISCUSSION

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The main purpose of this study was to evaluate the impact of an effective salvage therapy (ST-HD-86) for patients with progression or first relapse of HD who were treated primarily in childhood or adolescence. We report results with this protocol in a group of 176 patients with first recurrence from the DAL/GPOH therapy studies HD-78 through HD-95. To our knowledge, equally large groups of originally pediatric patients who underwent a fairly uniform treatment for progression or first relapse of HD have not been published thus far. Despite a generally low incidence of treatment failures with modern therapeutic strategies for pediatric HD, our cohort included the relatively large number of 176 patients, because accrual time extended over 17 years and participating centers have remained motivated by positive interim results.²³ The protocol ST-HD-86 consisted of conventional chemotherapy in combination with radiotherapy to the involved areas. All patients received the cytotoxic combinations IEP and ABVD in an alternating mode. Those two schemes are the essential elements of our salvage protocol, notwithstanding the additional use of some other combinations in a part of the patients depending on his or her individual situation (see Salvage Therapy). From our observation of the individual patients we concluded that it was the IEP regimen in particular, applied according to a specific schedule (5 days, continuous infusion of ifosfamide), that was responsible for the remarkable efficacy of the entire strategy. In our opinion, the systematic use of radiotherapy to the involved regions also contributed considerably to the outcome; however, for definitive proof, a randomized setting would be required.

Treatment results of the 176 patients reported here (ie, probabilities of 10-year EFS, DFS, and OS of 57%, 62%, and 75% [SE, 4% for all]) compare quite favorably to other series of pediatric and adult patients with recurrent HD.^11,17,22,39 Within the total group, several subgroups with a markedly better or poorer prognosis than the average patient could be distinguished. The results of our statistical analyses indicate, in agreement with those of other authors,^11,35,36 that the length of the interval between primary therapy and manifestation of treatment failure was the strongest prognostic factor by far. The highly significant differences prompted us to allocate our patients to three prognostic groups: primary progressive disease (worst prognosis), early relapse (intermediate), and late relapse (favorable prognosis).

Multivariate analysis shows that the remaining risk factors under evaluation recede behind the time until progression/relapse. Looking at the parameter combination, there is just one other significant variable each with DFS and OS: primary chemotherapy without procarbazine and etoposide predicts relatively favorably for DFS (RR, 1.6; P = .02), and female sex predicts relatively unfavorably for OS (RR, 1.95; P = .03).

The contribution of HDT with SCT to the overall outcome result in this study is rather small: 30% of all patients (53 of 176) and 23% of the surviving patients (30 of 132) had received this type of intensification during salvage therapy (ie, in 102 [77%] of 132 surviving patients, the favorable outcome was obtained only by use of the salvage treatment ST-HD-86 described here without HDT/SCT). However, we have to stress that it was not a primary purpose of this trial to evaluate the efficacy of HDT and SCT in patients with primary pediatric HD with recurrences. Our somewhat conflicting outcome results after SCT, which suggest a significant survival benefit for patients who received a transplant after second or later recurrences but no benefit for those who received a transplant after the first recurrence, are difficult to compare with published studies, because patient characteristics, risk factors, and especially first-line therapy are different.

Two randomized studies comparing HDT followed by SCT with conventional salvage chemotherapy in adult patients with relapsed HD indicated a superior outcome for patients who received an autograft.^11,13 In the more recent study, a significant superiority of SCT in terms of freedom from treatment failure, but not in terms of OS, was found.¹¹ Randomized trials analyzing the impact of HDT/SCT in pediatric patients with recurrent HD have not been performed. Several studies indicated a benefit from HDT for children and adolescents with recurrent HD,^17-19,40 but the optimal time point for SCT still has to be determined. In a recently published British study, the outcome of children receiving SCT for progression/relapse was compared retrospectively with a group of patients treated with conventional chemotherapy. Although the authors found no survival advantage for patients who received a transplant, there seemed to be a benefit of HDT for patients with primary refractory disease.³⁸

Consequently, from the literature as well as from the data presented here, it seems to be likely that, for the coming years, conventional salvage strategies will keep a fundamental position in the therapy of patients with relapsed HD primarily treated with pediatric protocols. However, to improve the outcome results in the patients of the high-risk groups, additional assessing of the role of HDT/SCT within the entire salvage concept is necessary.

Looking at the possibilities for future improvement of treatment results, patients with primary progression pose the greatest challenge, because their group (progression), representing only 29% of all our patients, contributes 48% of all later recurrences and 59% of all deaths. Moreover, in half of the patients who died as a result of the disease, the fatal outcome occurred within 12 months after initiating salvage therapy, which means that there is only limited time available for intensified or novel therapeutic measures to influence the course of the disease.

By contrast, the situation is completely different in the late-relapse group, which represents 39% of the total group but contributes only 15% of both later recurrences and deaths. Considering the long-term survival rate of 90%, future efforts directed to this group should be aimed at treatment reduction rather than intensification. We want to emphasize that none of the 68 patients with late relapses in the study presented here received HDT with SCT in second remission, and only six did so later after second or additional recurrences.

The outcome of the patients with early relapse (32% of all patients, 38% of later recurrences, and 27% of deaths) is between progression and late relapse: DFS (55%) is only slightly higher than in progression, whereas the OS of 78% is not significantly different from the favorable result in late relapse. A possible benefit from HDT might become evident by this difference between DFS and OS. Thus, the indication for an intensified treatment strategy for patients in this particular group is to be tailored especially well to the individual course (ie, therapy has to be adapted according to treatment response).

In the GPOH HD-2002 pilot study and the HD-2003 protocol allocation of patients whose first-line therapy failed will take into account the following parameters: time until recurrence, TG stratification during first-line therapy, and response to salvage therapy. Based on this information, risk groups will be defined. For chemotherapy-sensitive patients with primary disease progression and early relapses, HDT with SCT will be offered at an early time point. In primary refractory patients or relapse after HDT/SCT, new approaches such as allogeneic SCT after reduced intensity conditioning will be considered.²⁰ The lower relapse rate, however, has to be balanced carefully against the higher treatment-related mortality compared to patients receiving autologous SCT.

	Appendix

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Participating Children’s Hospitals at Universities/Medical Schools (together with their radiotherapy partners). Germany: Aachen, Berlin, Bonn, Dresden, Düsseldorf, Erfurt, Erlangen, Essen, Frankfurt/Main, Freiburg, Gießen, Göttingen, Greifswald, Halle, Hamburg, Hannover, Heidelberg, Homburg/Saar, Jena, Kiel, Köln, Leipzig, Lübeck, Magdeburg, Mainz, Marburg, München (Kinderklinik München-Schwabing, von Haunersches Kinderspital, München), Münster, Rostock, Tübingen, and Ulm; Austria: Graz and Innsbruck; Sweden: Lund, Stockholm, and Umea; Switzerland: Zürich; the Netherlands: Nijmegen.

Children’s Hospitals and Departments (together with their radiotherapy partners). Germany: II. Kinderklinik, Helios-Klinikum Berlin-Buch, Kinderkrankenhaus Bethel-Bielefeld, Städtische Kinderklinik Braunschweig, Prof-Hess-Kinderklinik Bremen, Allgemeines Krankenhaus Celle, Bezirkskrankenhaus Chemnitz, Landkrankenhaus Coburg, Carl-Thiem-Klinikum Cottbus, Kreiskrankenhaus Detmold, Städtische Kinderklinik Dortmund, Städtische Kinderklinik Karlsruhe, Städtische Kinderklinik Kassel, Städtische Kinderklinik Köln, Städtische Kinderklinik Krefeld, Kinderklinik Minden, Städt. Krankenhaus München-Harlaching, Friedrich-Ebert-Krankenhaus Neumünster, Städtische Kinderklinik Nürnberg, Kinderhospital Osnabrück, Marienhospital Osnabrück, Bezirkskrankenhaus Schwerin, Johanniter-Kinderklinik St Augustin, and Olgahospital Stuttgart; Austria: Landeskrankenhaus Feldkirch and St-Anna-Kinderspital Wien; Switzerland: Kantonsspital Aarau.

	Authors’ Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix Authors’ Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank the colleagues and data managers of the participating departments for their cooperation and acknowledge gratefully the help of Angelika Görgen and Gabriele Braun-Munzinger in preparing the manuscript.

	NOTES

 
Supported by Deutsche Leukämieforschungs-Hilfe-Dachverband, Bonn, and Kinderkrebshilfe Münster, Germany.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted December 2, 2004; accepted May 11, 2005.

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