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14-Day Variant of the Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, and Prednisone Regimen in Advanced-Stage Hodgkin’s Lymphoma: Results of a Pilot Study of the German Hodgkin’s Lymphoma Study Group

M. Sieber, H. Bredenfeld, A. Josting, T. Reineke, U. Rueffer, T. Koch, R. Naumann, F. Boissevain, P. Koch, P. Worst, M. Soekler, H. Eich, H.K. Müller-Hermelink, J. Franklin, U. Paulus, J. Wolf, A. Engert, V. Diehl

From the German Hodgkin’s Lymphoma Study Group, University of Cologne, Germany.

Address reprint requests to Markus Sieber, MD, Hodgkin-Studiensekretariat, Klinik I für Innere Medizin, Universität zu Köln, 50924 Köln, Germany; email: sieber{at}kkh-gummersbach.de.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 REFERENCES

 
Purpose: This multicenter pilot study assessed the feasibility and efficacy of a time-intensified bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimen given in 14-day intervals (BEACOPP-14) with granulocyte colony-stimulating factor (G-CSF) support in advanced Hodgkin’s lymphoma.

Patients and Methods: From July 1997 until March 2000, 94 patients with Hodgkin’s lymphoma stage IIB, III, and IV were scheduled to receive eight cycles of BEACOPP-14. Consolidation radiotherapy was administered to regions with initial bulky disease or residual tumor after chemotherapy.

Results: All patients were assessable for toxicity and treatment outcome. Eighty-six patients received the planned eight cycles of BEACOPP-14. Consolidation radiotherapy was given in 66 patients. Chemotherapy could generally be administered on schedule. Dose reductions varied among drugs but were generally low. Acute toxicity was moderate, with World Health Organization grade 3/4 leukopenia in 75%, thrombocytopenia in 23%, anemia in 65%, and infection in 12% of patients. A total of 88 patients (94%) achieved a complete remission. Four patients had progressive disease. At a median observation time of 34 months, five patients have relapsed, one patient developed a secondary non-Hodgkin’s lymphoma, and three deaths were documented. The overall survival and freedom from treatment failure rates at 34 months were 97% (95% confidence interval [CI], 93% to 100%) and 90% (95% CI, 84% to 97%), respectively.

Conclusion: Acceleration of the BEACOPP baseline regimen by shortening cycle duration with G-CSF support is feasible and effective with moderate acute toxicity. On the basis of these results, the German Hodgkin’s Lymphoma Study Group will compare the BEACOPP-14 regimen with BEACOPP-21 escalated in a prospective multicenter randomized trial.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 REFERENCES

 
THE ANTHRACYCLINE-containing chemotherapy regimens doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); mustargen, vincristine, procarbazine, and prednisone (MOPP) alternating with ABVD; hybrid MOPP/ABVD; or similar regimens have been considered standard treatment for advanced-stage Hodgkin’s lymphoma. However, approximately 20% of patients in advanced stages fail to achieve complete remission. In addition, one third of complete responders ultimately relapse, resulting in a long-term failure-free survival of 60% to 70%.^1–6

To improve the efficacy of chemotherapy for advanced Hodgkin’s lymphoma, the German Hodgkin’s Lymphoma Study Group (GHSG) introduced the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimen.⁷ In this regimen, dacarbazine and vinblastine were removed from the standard COPP/ABVD regimen, and etoposide was introduced. The BEACOPP regimen encompasses two main intensification principles: dose escalation of the putative most important drugs (cyclophosphamide, etoposide, and doxorubicin) and time intensification accomplished by shortening the respective chemotherapy cycles from 4 to 3 weeks. Accordingly, two different variants of BEACOPP were designed: BEACOPP in baseline dosage (BEACOPP-21 baseline) and BEACOPP in escalated dosage with granulocyte colony-stimulating factor (G-CSF) support (BEACOPP-21 escalated).

Within the randomized multicenter HD9 trial of the GHSG, it was demonstrated that the BEACOPP variants lead to a significantly lower progression rate and an improved failure-free and overall survival as compared with standard COPP/ABVD. As a result of this trial, BEACOPP-21 escalated was selected as standard chemotherapy for advanced stages in the GHSG follow-up trials HD12 and HD15.^8,9

An alternative approach to intensify therapy is to further shorten the cycle duration instead of dose escalation. Therefore, we designed a time-intensified variant of the BEACOPP regimen repeated every 14 days (BEACOPP-14). The backbone of this regimen is the BEACOPP-21 schedule in baseline dosage. In the multicenter pilot study reported here we show that BEACOPP-14 is both feasible and effective in a total of 94 patients with advanced Hodgkin’s lymphoma.

	PATIENTS AND METHODS

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Eligibility and Staging
Patients between the ages of 15 and 75 years with biopsy-proven Hodgkin’s lymphoma entered onto this study. Patients with stage IIB disease and massive mediastinal involvement and/or extranodal involvement and all patients with stage III and IV disease were eligible. Massive mediastinal involvement was defined as a tumor one third or more of the maximum intrathoracic diameter as determined on a posterior-anterior chest radiograph. Stage of disease was defined according to the Ann Arbor Conference classification.¹⁰

Patients with impaired heart, lung, liver, or kidney function, previous malignant disease, and patients known to be positive for human immunodeficiency virus were excluded. Minimal hematologic requirements were WBC more than 3,000/µL and platelet count more than 100,000/µL. All participating patients gave written informed consent.

Routine staging studies included medical history; physical examination; chest radiography; computed tomography of the chest, abdomen, and pelvis; bone marrow biopsy; isotopic bone scan; complete blood cell count; and serum chemistry. In addition, lung function test and echocardiography were routinely performed before treatment.

Statistical Methods
Freedom from treatment failure (FFTF) was defined as the time from the beginning of treatment to occurrence of one of the following events: death from any cause, progressive disease, no complete remission at the end of treatment, or relapse. Survival (SV) was defined as the time from beginning of treatment to death, whether disease-related or not. FFTF and SV were estimated by the method of Kaplan and Meier.¹¹

Administrative Information
From July 1997 until March 2000, 99 patients were registered from 32 participating centers in Germany (Appendix 1). Five registrants were excluded from the study because review of histology by a pathology review panel resulted in a change of diagnosis from Hodgkin’s lymphoma to non-Hodgkin’s lymphoma. Thus, 94 patients were enrolled and are available for this analysis.

Pathology Review Panel
Histologic diagnosis was made initially by local pathologists, who were asked to send paraffin block biopsy samples to a central pathology review panel involving six leading German lymphoma experts (Appendix 2). The pathology review panel reclassified all received biopsy samples. However, registration to the trial occurred based on the initial diagnosis. Patients with a review diagnosis other than Hodgkin’s lymphoma were excluded from analysis. In the absence of a review diagnosis, the initial diagnosis of Hodgkin’s lymphoma was deemed sufficient for eligibility.

Chemotherapy
Patients were scheduled to receive eight cycles of the BEACOPP-14 regimen. Table 1 lists the dose and schedule of drugs. As compared with the standard BEACOPP-21 baseline regimen, treatment intervals were shortened to 14 days. G-CSF (filgrastim 300 µg for patients < 75 kg body weight or 480 µg for patients 75 kg body weight) was applied subcutaneously once daily from days 8 to 13. The application of prednisone was restricted to the first 7 days, but the dose was increased to 80 mg/m². Cycles were repeated on day 15 if the leukocyte count was more than 2,500/µL and the platelet count was more than 80,000/µL. Dose reduction was performed according to the following guideline: No dose reduction was carried out if delay of leukocyte or platelet recovery occurred in less than 1 week. Twenty-five percent dose reduction of cyclophosphamide, doxorubicin, etoposide, and procarbazine was carried out if there was a 1- to 2-week delay in recovery, and 50% dose reduction of these drugs was carried out if the delay in recovery exceeded 2 weeks.

Response Assessment and Follow-Up
The success of treatment was determined by restaging immediately after four cycles and after eight cycles of chemotherapy. If radiotherapy was given, a final restaging was performed 4 to 8 weeks after the end of irradiation. Restaging consisted of a control and careful documentation of all initial disease manifestations by adequate clinical methods including a physical examination, complete blood cell count, blood chemistry, and computed tomography of the chest, abdomen, and pelvis. A bone marrow biopsy or isotopic bone scan was performed if the initial examination revealed a disease manifestation. Complete remission was defined as the disappearance of all disease manifestations. Partial remission was defined as a reduction in all disease manifestations by at least 50% compared with the initial involvement.

Follow-up examinations including medical history and physical examination, complete blood cell count and blood chemistry, chest x-ray, and abdominal ultrasound were performed within the first 2 years in 3-month intervals, at years 3 and 4 in 4-month intervals, and from year 5 in 6-month intervals.

	RESULTS

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Patient Characteristics
Table 2 lists the characteristics of the 94 assessable patients. The median age of patients was 31 years (range, 17 to 63 years). Twenty-two patients had stage IIB disease with massive mediastinal involvement and/or extranodal involvement. Forty patients had stage III, and 32 patients stage IV disease. B-symptoms were present in 78 patients (83%). Overall, 29 patients (31%) had massive mediastinal involvement, and 22 patients (23%) had extranodal involvement (excluding the stage IV patients).

Administration of Therapy
Of 94 patients, 86 patients (91%) received the planned eight cycles of BEACOPP-14. Overall, eight patients received fewer cycles: three patients received only seven cycles, two patients received six cycles, one patient received four cycles, one patient received two cycles, and one patient received only one cycle. The reasons for early termination of chemotherapy were excessive toxicity (n = 3), patient’s wish (n = 1), progressive disease (n = 1), or unknown (n = 1). In the first seven cycles of chemotherapy, 77% of cycles were given within 16 days and 94% of cycles were given within 22 days. Table 3 lists the percentage of patients with a substantial reduction in doses of drugs. The amounts of the dose reductions varied among drugs but were, in general, low. The most frequent reductions were carried out for vincristine and bleomycin, with 24% and 18% of patients receiving less than 80% of the planned dosage.

Toxicity
As shown in Table 4, acute hematologic toxicity of the BEACOPP-14 regimen was moderate. With BEACOPP-14, 74% of patients had at least one World Health Organization (WHO) grade 3 or 4 leukopenia and 23% of patients had at least one grade 3 or 4 thrombocytopenia. WHO grade 3 or 4 anemia occurred in 65% of patients, and RBC transfusions were given in 29% of all chemotherapy cycles. Severe infections were observed in 12% of patients, and one patient (male, 56 years of age) died because of a septic complication in a leukopenic episode during the seventh cycle of BEACOPP-14.

Treatment Outcome
Eighty-eight patients (94%) achieved a complete remission, and only four patients had progressive disease (Table 6). With a median follow-up of 34 months, five relapses were reported. One patient developed a secondary high-grade non-Hodgkin’s lymphoma. Overall, three patients died. Of these three patients, one patient (a 56-year-old male) died of septicemia during the seventh cycle of BEACOPP-14. The other two patients (a 43-year-old male and a 52-year-old male) had progressive disease and died because of toxic events (sudden heart death and septic death) during aggressive salvage therapy. Figure 1 shows FFTF and SV for the 94 patients included in this analysis. The estimated FFTF was 90% (95% confidence interval [CI], 84% to 97%) and the estimated SV was 97% (95% CI, 93% to 100%) at the median observation time of 34 months.

View larger version (16K): [in this window] [in a new window]   Fig 1. Freedom from treatment failure (FFTF; 11 events) and survival (SV; three events) of 94 patients treated with BEACOPP-14. Median observation time 34 months.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 REFERENCES

Theoretical background for treatment intensification of established chemotherapy regimens by increasing the dose, by shortening intervals between cycles, or both was first introduced by Skipper.¹³ The Skipper model postulated that the time course of the tumor volume during treatment depends on the tumor regrowth during treatment intervals and the chemosensitivity of tumor cells at each treatment. As an extension of these considerations, Hasenclever et al^14,15 developed a statistical model that was based on tumor growth kinetics and chemotherapy effects, which was fitted to the data of 706 patients treated with COPP/ABVD-like regimens. The model was used to simulate the effects of various treatment strategies with dose escalation and schedule changes. It was predicted that shortening cycle intervals from 4 to 3 weeks would lead to a small benefit in 5-year tumor control rates (about 3%). Moderate average dose escalation of standard chemotherapy (30%) should result in a benefit of 10% to 15% in 5-year tumor control.^14,15 On the basis of these theoretical assumptions, the GHSG designed the first variant of the BEACOPP regimen in 1991 and initiated a series of clinical studies.

In the first pilot study, the BEACOPP regimen was tested in a baseline dose variant that proved to be effective and feasible with moderate hematologic toxicity.⁷ In a subsequent multicenter dose escalation study, the doses of cyclophosphamide, etoposide, and doxorubicin were then escalated with hematologic growth factor (G-CSF) support to 192%, 200%, and 140% of the baseline variant dose, respectively.¹⁶

In the subsequent three-arm multicenter HD9 trial, the GHSG standard COPP/ABVD was compared with the two variants of the BEACOPP regimen (baseline and escalated-dose variant). Eight cycles of each regimen were given, followed by local irradiation to bulky disease or residual tumors.¹⁷ The final analysis of this trial based on the data of 1,195 patients showed significant differences in progression rate and in FFTF at 5 years among the treatment arms, with BEACOPP escalated better than baseline BEACOPP, which was in turn better than standard COPP/ABVD. In addition, the BEACOPP escalated regimen produced a significantly superior overall survival compared with that of COPP/ABVD and showed a trend toward superior overall survival compared with that of BEACOPP baseline.⁹ The toxicity of BEACOPP baseline was equal to that of COPP/ABVD, whereas the acute hematologic toxicity for the BEACOPP escalated was more pronounced. However, there was no difference in life-threatening toxicity or toxicity-related deaths. The number of patients with secondary acute leukemia or myelodysplastic syndrome is increased with BEACOPP escalated. However, the overall incidence of secondary malignancies including non-Hodgkin’s lymphoma and solid tumors is not higher in the BEACOPP-escalated arm (2.6%) compared with that in the BEACOPP baseline regimen (2.6%) or COPP/ABVD (3.4%).

On the basis of the excellent treatment results with BEACOPP escalated within the HD9 trial and the assumption that a substantial proportion of patients might be overtreated, the ongoing HD12 trial aimed at reducing acute and long-term toxicity by testing the strategy of administering four cycles of BEACOPP escalated followed by four cycles of BEACOPP baseline.

Despite the consideration of the Hasenclever-Loeffler^14,15 model of a relatively small benefit in tumor control rates, shortening of chemotherapy cycle intervals is an attractive method to intensify treatment without reaching critical absolute doses of drugs. Therefore, we designed the BEACOPP 14-day variant in baseline dosage with the aim of decreasing toxicity compared with BEACOPP escalated while maintaining treatment results. When toxicity and treatment outcome for BEACOPP-14 in this pilot study are compared with the data of the HD9 trial, it seems that treatment outcome compares favorably with BEACOPP escalated, whereas acute toxicity compares favorably with BEACOPP baseline. As detailed in Table 7, the rates of leukopenia and thrombocytopenia were comparable to those observed with BEACOPP baseline in 21-day intervals.⁹ However, anemia was more frequent with BEACOPP-14, and the rate of grade 3 or 4 anemia was comparable with the rate reported with escalated BEACOPP. Interestingly, the rate of severe infections was lower for BEACOPP-14 than for the 21-day variants of BEACOPP. To date, no acute leukemia or myelodysplastic syndrome has been observed with BEACOPP-14. However, the median follow-up of 34 months is too short to determine the late consequences of this time-intensified treatment regimen.

At Stanford University (Stanford, CA), the Stanford V regimen was developed including doxorubicin, vinblastine, mustard, bleomycin, vincristine, etoposide, and prednisone. This regimen is given weekly for a total of 12 weeks. Treatment is followed by consolidative radiotherapy to sites of initial bulky disease. The results of 142 patients were encouraging, with an estimated 5-year freedom from progression of 89% and an overall survival rate of 96%.¹⁸ However, treatment results have to be confirmed in a larger randomized trial. At present, a North American Intergroup trial is comparing Stanford V and ABVD in advanced-stage Hodgkin’s lymphoma in a prospective randomized trial. It is notable that another etoposide-containing regimen, chlorambucil, vinblastine, procarbazine, prednisolone, etoposide, vincristine, and doxorubicin called ChlVPP/EVA hybrid, developed by investigators from the United Kingdom, produced almost identical response rates to those reported for BEACOPP and Stanford V.¹⁹ ChlVPP/EVA was also combined with radiotherapy to initial bulky disease or sites of residual radiographic abnormality in 58% of patients.

According to the treatment strategy of the GHSG for advanced stages in this pilot study, consolidating radiotherapy was given to initial bulky disease or residual tumor remaining after chemotherapy. Overall, 70% of patients in this study received radiotherapy. The percentage of patients who have received radiotherapy was approximately identical to the rates within BEACOPP-21 baseline and escalated (66% in each treatment arm). However, the importance of radiotherapy after intensive chemotherapy in advanced stages has recently been questioned. A meta-analysis conducted by the International Database on Hodgkin’s Disease Overview Study Group showed that the addition of radiotherapy did not improve long-term treatment outcome if an adequate number of chemotherapy cycles were given.²⁰ In the H89 trial of the Groupe d’Etude des Lymphomes de l’Adulte, patients in CR or good partial remission after six cycles of a doxorubicin-containing chemotherapy regimen were randomly assigned to receive two more cycles chemotherapy or (sub)total nodal irradiation as consolidation treatments. There was no advantage for radiotherapy consolidation in this trial.²¹ However, in the above-mentioned ongoing HD12 trial of the GHSG, the patients undergo a second random assignment for radiotherapy to initial bulky and/or residual disease versus no further treatment. This trial will help to determine whether consolidating radiotherapy after BEACOPP chemotherapy will be required in most patients.

In conclusion, in this pilot study of the GHSG, intensification of BEACOPP-21 baseline by additional shortening of cycle duration (from 3 to 2 weeks) with G-CSF support is feasible, safe, and proven to be effective. On the basis of these study data, the GHSG will initiate a large, randomized, multicenter trial comparing BEACOPP-21 escalated with BEACOPP-14. End points for this trial will include FFTF, overall survival, toxicity, and quality of life.

	APPENDIX 1

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 REFERENCES

 
Participating centers (all in Germany) are listed according to recruitment: R. Naumann, Universitäts-Klinik, Dresden; F. Boissevain, Medizinische Klinik, Nürnberg; P. Koch, Universitäts-Klinik, Münster; Heinz, Universitäts-Klinik, Freiburg; M. Sieber, H. Bredenfeld, Universitäts-Klinik, Köln; P. Worst, Klinikum Mannheim, Mannheim; M. Söckler, Universitäts-Klinik, Tübingen; Sandherr, Medizinische Klinik Rechts der Isar, München; Lindemann, Marienhospital, Hagen; Schmitt, Universitäts-Klinik, Homburg; Wodzynski, Universitäts-Klinik, Regensburg; Schwartz, Universitäts-Klinik B. Franklin, Berlin; Bartels, Städtisches Krankenhaus Süd, Lübeck; Schliesser, Praxis für Hämatologie, Gießen; J. Karow, Krankenhaus, Düren; Reschke, Städtisches Krankenhaus, Oldenburg; Wiedemann, Heidelberg Universitäts-Klinik, Heidelberg; Fischer, Städtisches Klinikum, Karlsruhe; Seyfarth, Städtisches Krankenhaus, Kiel; Unbehaun, Universitätsklinik, Ulm; Nielsen, Städtisches Krankenhaus, Hildesheim; Hörnlein, Robert-Bosch-Krankenhaus, Stuttgart; Kämpfe, Kreiskrankenhaus, Lüdenscheid; Gmelin, Bürgerhospital, Stuttgart; Harms, Kreiskrankenhaus, Aurich; Trommer, Heinrich Braun Krankenhaus, Zwickau; Assmann, Katharinen Hospital, Stuttgart; Kohl, Krankenhaus Maria Hilf, Mönchengladbach; Appenrodt, Städtisches Krankenhaus, Nettetal; Fischbach, Dr Horst Schmidt Krankenhaus, Wiesbaden, Germany.

	APPENDIX 2

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 REFERENCES

 
The pathology review panel included H.K. Müller-Hermelink, Würzburg; H. Stein, Berlin; A.C. Feller, Lübeck; M.L. Hansmann, Frankfurt; M.R. Parwaresch, Kiel; and P. Möller, Ulm, Germany.

	NOTES

 
Supported in part by a grant from the Deutsche Krebshilfe, Bonn, Germany.

The study protocol has been positively voted by the ethical commission of the University of Cologne, Germany (Date July 15, 1997, Protocol No. 9769).

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 REFERENCES

 
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Submitted June 5, 2002; accepted February 10, 2003.

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