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Originally published as JCO Early Release 10.1200/JCO.2006.10.1386 on April 9 2007 © 2007 American Society of Clinical Oncology. Outcome of Patients Experiencing Progression or Relapse After Primary Treatment With Two Cycles of Chemotherapy and Radiotherapy for Early-Stage Favorable Hodgkin's Lymphoma
From the First Department of Internal Medicine, University Hospital Cologne; and German Hodgkin Study Group, Cologne, Germany Address reprint requests to Michal Sieniawski, MD, First Department of Internal Medicine, University Hospital Cologne, Kerpener Strasse 62, 50924 Cologne, Germany; e-mail: Michal.Sieniawski{at}ncl.ac.uk
Purpose To evaluate treatment outcome of patients with early-stage favorable Hodgkin's lymphoma (HL) who experience disease relapse after primary treatment with two cycles of chemotherapy followed by radiotherapy (RT).
Patients and Methods Of 1,129 patients with early-stage favorable HL enrolled onto the HD7/HD10/HD13 trials of the German Hodgkin Study Group, 42 patients were identified with treatment failure, of whom eight had primary progressive disease, seven had early relapse ( Results The median age was 41 years (range, 19 to 72 years); 24 patients were male, 15 patients had outfield relapse, 13 patients infield relapse, and nine patients outfield and infield relapse. At relapse, 24 patients were treated with conventional salvage chemotherapy, 14 patients were treated with high-dose chemotherapy followed by autologous stem-cell transplantation, and four patients were treated with RT alone. At 36 months median follow-up, freedom from second treatment failure (FF2F) and overall survival (OS) were 52% and 67%, respectively. According to the prognostic score for relapsed HL (duration of first remission, clinical stage, and anemia at relapse), patients with two or three poor prognostic features had a significantly worse outcome compared with patients with none or one of these factors (P < .05 for FF2F and OS). Conclusion Relapse after primary treatment with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine followed by RT is rare. In our analysis, results were influenced by a high treatment-related mortality rate. Additional studies are needed to define the optimal salvage therapy.
Depending on stage and risk factor profiles, up to 95% of patients with Hodgkin's lymphoma (HL) achieve complete remission after initial treatment.1-3 For early-stage favorable HL, extended-field radiotherapy (EF-RT) has been considered as standard treatment for more than two decades. However, EF-RT has been abandoned by most study groups due to the recognition of late effects such as heart failure, pulmonary dysfunction, and secondary malignancies.4,5 Instead, a brief chemotherapy course followed by involved-field radiotherapy (IF-RT) is considered as standard therapy for patients with early stage favorable HL. At relapse, patients with HL have various treatment options, including salvage RT, conventional chemotherapy, or high-dose chemotherapy (HDCT) followed by stem-cell transplantation (SCT). The choice of salvage therapy depends on several factors, including the type of first-line treatment and disease involvement at relapse. Conventional salvage chemotherapy is the treatment of choice for patients who experience relapse after initial EF-RT alone.6 Patients with isolated lymph node involvement and outfield relapse may be treated successfully with RT.7 In patients with more advanced disease, HDCT followed by autologous SCT (ASCT) has been shown to be superior to conventional salvage chemotherapy.8,9 Other options such as allogeneic stem-cell transplantation, nonmyeloablative conditioning with transplantation of allogeneic blood progenitor cells, and experimental strategies are being investigated in current trials. To predict the outcome of patients with relapsed HL, numerous scores have been evaluated. The common risk factors identified are age at relapse, duration of remission, anemia, and stage at relapse.10 Relapse rates for patients with early-stage favorable HL who were treated with two cycles of chemotherapy followed by IF-RT are very low. To our knowledge, there are no published data evaluating the optimal salvage therapy for these patients. We performed a retrospective analysis using the database of the German Hodgkin Study Group (GHSG) to investigate the outcome of patients relapsing after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by RT. A risk score was used to analyze the treatment outcome.
Patient Selection A total of 1,129 patients were treated in GHSG trials for first-line therapy in early-stage HL (trials HD7, HD10, and HD13) between 1994 and 2003. To be eligible for the trials, patients between 16 and 75 years old had to have histologically proven HL, clinical stage (CS) IA to IIB without risk factors (defined as large mediastinal mass, extranodal disease, elevated erythrocyte sedimentation rate, and involvement of  three lymph node areas). Patients had to have an adequate organ function as defined by a creatinine clearance more than 60 mL/min, serum aminotransferases less than 3x normal levels, bilirubin less than 2 mg/dL, left ventricular ejection fraction more than 0.45, forced expiratory volume in the first second or diffusion capacity of carbon monoxide more than 60% of predicted, WBC 3,500/mL, hemoglobin level 8 g/dL, and platelets 100,000/mL. In addition, a negative HIV test and absence of active infections were also required. All patients signed informed consent, on the basis of the institutional review board guidelines. The study design of HD7, HD10, and HD13 trials is listed in Table 1. Only patients who received two cycles of chemotherapy (ABVD) followed by RT were included in this analysis. As shown in Table 1, patients were assigned to the following groups: HD7, arm A; HD10, arms C and D; and HD13, arm A. Of the 316 patients treated on HD7, 12 patients (4%) experienced progressive disease/relapse. Of 599 patients on HD10, 29 patients (5%) experienced relapse, and of 214 patients on HD13, one patient (0.5%) experienced relapse.
Patients with progressive disease and relapse were analyzed retrospectively for toxicity, type of salvage therapy, overall response, and survival. Progressive disease was defined as the occurrence of new lesions or increase of at least one existing lesion by more than 25% during or within 3 months after therapy. Early relapse was defined as relapse after complete remission (CR) lasting 3 to 12 months. Late relapse was defined as relapse after CR lasting more than 12 months after the completion of the first-line treatment. Toxicity and adverse events were categorized according to the Common Toxicity Criteria of the WHO.
Response Assessment CR was defined as disappearance of all clinical and radiographic evidence of disease for at least 1 month. Partial remission (PR) was defined as a 50% or greater reduction of original measurable disease lasting at least 1 month. Any response less than PR was considered as treatment failure.
Prognostic Score
Statistical Analysis
Patient Characteristics A total of 42 patients who experienced relapse after two cycles of ABVD followed by RT were identified. The median age of the patients at progression was 41 years (range, 19 to 72 years); 24 (57%) patients were male. The patients had the following primary histology: mixed cellularity, n = 15 (36%); nodular sclerosis, n = 13 (31%); lymphocyte rich, n = 6 (14%); lymphocyte predominant, n = 6 (14%); lymphocyte depleted, n = 1 (2%); and HL unclassified, n = 1 (2%). At first diagnosis, seven patients (17%) were in CS I (Ann Arbor criteria) and 35 patients (83%) were in CS II. Ninety-five percent of the patients had involvement of the supradiaphragm and B symptoms were present in three patients (7%). With respect to first-line therapy, 13 patients (31%) were treated with two cycles of ABVD plus 30 Gy IF-RT, 12 patients (29%) were treated with two cycles of ABVD plus 30 Gy EF-RT, and 12 patients (29%) were treated with two cycles of ABVD plus 20 Gy IF-RT. Five patients (12%) were treated with two cycles of ABVD alone: these patients experienced disease progression before RT. Therefore, 37 patients (88%) received radiation therapy during first-line treatment.
Progressive disease was diagnosed in eight (19%) patients, early relapse (
Salvage Therapy and Response Conventional salvage chemotherapy was administered to 24 patients, and the treatment regimens included bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) escalated (11 patients) and baseline (five patients); cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine (COPP)/ABVD (four patients), ABVD (three patients), and gemcitabine monotherapy (one patient). Salvage therapy included HDCT followed by autologous bone marrow transplantation in 14 patients. Four patients were treated with RT alone and four patients were treated with combined-modality therapy. There were no significant differences in the type of salvage therapy regimen between the groups with progressive disease, early relapse (  12 months), and late relapse (> 12 months; Table 3).
The overall response rate was 86% (83% CR and 3% PR). Overall response rates were 93% with HDCT followed by ASCT, 91% with BEACOPP escalated, 80% with BEACOPP baseline, 50% with COPP/ABVD, and 100% with ABVD or RT alone (Table 4) .
Survival and Prognostic Factors With a median follow-up of 36 months, FF2F and OS were 52% and 67%, respectively (Fig 1A). According to our prognostic score for relapsed HL, the group of patients with no risk factors had FF2F and OS of 82% and 91%, respectively. Patients with one risk factor had a FF2F and OS of 56% and 75%, respectively. In contrast, FF2F and OS were both 14% for patients with two or more risk factors. These differences were significant: P < .05 (Figs 1B and 1C). When compared with a historical control group of patients registered in the GHSG database, patients treated with two cycles of ABVD plus RT had a poorer outcome than patients receiving RT alone as first-line therapy. At the same evaluation, this group of patients had better outcome than patients who experienced treatment failure after four cycles of chemotherapy for primary intermediate stages or eight cycles of chemotherapy for primary advanced stages (Figs 2A and 2B). Regarding the site of relapse, the FF2F was 67% for patients with both in- and outfield relapse, 61% for patients with infield relapse, and 26% for patients with outfield relapse. In contrast, the OS was 67% for patients with infield relapse and 60% for patients with outfield relapse as well as for patients with both in- and outfield relapse.
Causes of Death Seven patients (17%) died as a result of disease progression of HL and six patients (14%) as a result of treatment-related toxicities (two patients developed pneumonia: one patient had been treated with BEACOPP escalated and another had been treated with ABVD). Three patients had invasive fungal infection (one patient had received HDCT followed by ASCT, one patient had received BEACOPP baseline, and one patient had received COPP/ABVD). One patient treated with HDCT followed by ASCT died as a result of sepsis. Among the patients who died from treatment-related toxicities, two patients received prior EF-RT and four patients received IF-RT.
The following findings emerge from this analysis. Relapse of HL after first-line treatment with two cycles of chemotherapy followed by RT is rare. The outcome of patients experiencing relapse after two cycles of chemotherapy followed by RT is inferior compared with that of patients with relapse after EF-RT alone. However, the prognosis is superior compared with patients experiencing relapse after four and eight cycles of polychemotherapy. Treatment results are compromised by a high treatment-related mortality rate. The prognostic score developed for relapsed HL can be used to predict the outcome of patients. Although the long-term outcome of early-stage favorable HL is excellent, 10% to 30% of patients will experience a relapse, depending on the treatment regimens.11-13 Patients treated with a combined-modality regimen have a lower relapse rate compared with patients treated with RT alone.14 In the present analysis, 3.7% of patients experienced relapse after combined-modality treatment with two cycles of ABVD followed by RT. Rueffer et al6 reported a relapse rate of 19% in patients treated with RT alone.
Among 42 assessable patients, 19% had progressive disease, 17% had early relapse ( The type of salvage therapy varies from high-dose regimens followed by ASCT through conventional salvage chemotherapy to salvage RT. Compared with early-stage favorable HL treated with RT alone, more patients in our analysis were treated with HDCT followed by ASCT.6 The reason for this difference might be that, at present, HDCT with ASCT is considered as standard treatment after primary chemotherapy. The overall response after salvage therapy for all patients in our analysis was 86% and is comparable with the results reported for salvage treatment of patients with early-stage favorable HL receiving RT alone as first-line treatment.16,17,19 We did not observe any significant differences between the various treatment groups except for patients treated with COPP/ABVD. These results should be interpreted cautiously because of the small numbers of patients and retrospective data. Since the introduction of MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), ABVD, or alternating MOPP/ABVD, the outcome of patients experiencing relapse with early-stage favorable HL pretreated with RT has been improved. Others have reported a 10-year FF2F of 60% to 70% and a 10-year OS of 80% to 90%.13,17,20 In our study, the 5-year FF2F of patients experiencing relapse after two cycles of ABVD plus RT was 52%; the 5-year OS was 67% in the same group. This finding suggests that the ability of patients experiencing relapse to respond to salvage therapy after a brief chemotherapy course with two cycles ABVD followed by RT is compromised compared with patients receiving RT alone as first-line treatment.13,17,20 In contrast, the outcome of patients reported in our study was better when compared with a historical control group of patients registered in the GHSG database who experienced treatment failure after four cycles of chemotherapy for primary intermediate stages or eight cycles for primary advanced stages (Figs 2A and 2B). The mortality rate among patients with relapse of early-stage favorable HL varies between 18% and 28%.16,17,21 In this study of 42 assessable patients, 13 patients (31%) died. The treatment-related mortality rate of salvage therapy was 14% and has to be considered as high when compared with other reports. None of the salvage regimens used was associated with an excessively high rate of toxicity-related deaths. With the use of a previously developed prognostic score for patients with relapsed HL, we were able to distinguish patients with high, intermediate, and low risk for disease progression after salvage therapy. In conclusion, relapse after first-line treatment with two cycles ABVD followed by RT is rare. The outcome of these patients is compromised when compared with patients receiving RT alone and is significantly better than that of patients treated with four or eight cycles of chemotherapy at first diagnosis. Additional studies are needed to define the optimal treatment (ie, HDCT v standard chemotherapy) with regard to high efficacy and a low treatment-related mortality rate.
The authors indicated no potential conflicts of interest.
Conception and design: Michal Sieniawski, Volker Diehl, Andreas Josting Administrative support: Thomas Schober, Hiltrud Nisters-Backes, Andreas Josting Provision of study materials or patients: Lucia Nogova, Thomas Schober, Hiltrud Nisters-Backes Collection and assembly of data: Michal Sieniawski, Lucia Nogova, Hiltrud Nisters-Backes, Andreas Josting Data analysis and interpretation: Michal Sieniawski, Jeremy Franklin, Jan-Peter Glossmann Manuscript writing: Michal Sieniawski, Andreas Josting Final approval of manuscript: Volker Diehl, Andreas Josting
published online ahead of print at www.jco.org on April 9, 2007. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Diehl V, Franklin J, Pfreundschuh M, et al: Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med 348: 2386-2395, 2003 2. Connors JM, Klimo P, Adams G, et al: Treatment of advanced Hodgkin's disease with chemotherapy: Comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD—A report from the National Cancer Institute of Canada clinical trials group. J Clin Oncol 15: 1638-1645, 1997[Abstract] 3. Canellos GP, Anderson JR, Propert KJ, et al: Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327: 1478-1484, 1992[Abstract] 4. Bonadonna G, Bonfante V, Viviani S, et al: ABVD plus subtotal nodal versus involved-field radiotherapy in early stage Hodgkin's disease: Long-term results. J Clin Oncol 22: 2835-2841, 2004 5. Press OW, LeBlanc M, Lichter AS, et al: Phase III randomized intergroup trial of subtotal lymphoid irradiation versus doxorubicin, vinblastine, and subtotal lymphoid irradiation for stage IA to IIA Hodgkin's disease. J Clin Oncol 19: 4238-4244, 2001 6. Rueffer JU, Ballova V, Glossmann J, et al: BEACOPP and COPP/ABVD as salvage treatment after primary extended field radiation therapy of early stage Hodgkin's disease: Results of the German Hodgkin Study Group. Leuk Lymphoma 46: 1561-1567, 2005[CrossRef][Medline] 7. Josting A, Nogova L, Franklin J, et al: Salvage radiotherapy in patients with relapsed and refractory Hodgkin's lymphoma: A retrospective analysis from the German Hodgkin Lymphoma Study Group. J Clin Oncol 23: 1522-1529, 2005 8. Linch DC, Winfield D, Goldstone AH, et al: Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: Results of a BNLI randomised trial. Lancet 341: 1051-1054, 1993[CrossRef][Medline] 9. Schmitz N, Pfistner B, Sextro M, et al: Aggressive conventional chemotherapy compared with high dose chemotherapy with autologous haemopoietic stem cell transplantation for relapsed chemosensitive Hodgkin's disease: A randomised trial. Lancet 359: 2065-2071, 2002[CrossRef][Medline] 10. Josting A, Franklin J, May M, et al: New prognostic score based on treatment outcome of patients with relapsed Hodgkin's lymphoma registered in the database of the German Hodgkin's lymphoma study group. J Clin Oncol 20: 221-230, 2002 11. Carde J, Noordijk E, Hagenbeek A, et al: Superiority of EBVP chemotherapy in combination with involved field irradiation over subtotal nodal irradiation in favorable clinical stage I-II Hodgkin's disease: The EORTC-GPMC H7F randomized trial. Proc Amer Soc Clin Oncol 16: 13a, 1997 (abstr 44) 12. Hartsell WF, Sarin P, Recine DC, et al: Long-term results of curative irradiation in pathologically staged IA and IIA Hodgkin disease. Radiology 186: 565-568, 1993 13. Zinzani PL, Barbieri E, Gherlinzoni F, et al: Radiotherapy in early stage Hodgkin's disease. Leuk Lymphoma 13: 285-289, 1994[Medline] 14. Koontz BF, Kirkpatrick JP, Clough RW, et al: Combined-modality therapy versus radiotherapy alone for treatment of early stage Hodgkin's disease: Cure balanced against complications. J Clin Oncol 24: 605-611, 2006 15. Santoro A, Viviani S, Villarreal CJ, et al: Salvage chemotherapy in Hodgkin's disease irradiation failures: Superiority of doxorubicin-containing regimens over MOPP. Cancer Treat Rep 70: 343-348, 1986[Medline] 16. Zijlstra JM, Dressel AJ, Mens JW, et al: Radiation therapy in early stage Hodgkin's disease: Long-term results and adverse effects. Hematol J 3: 179-184, 2002[CrossRef][Medline] 17. Amini RM, Glimelius B, Gustavsson A, et al: A population-based study of the outcome for patients with first relapse of Hodgkin's lymphoma. Eur J Haematol 68: 225-232, 2002[CrossRef][Medline] 18. Zapatero A, Lopez MA, Cerezo L, et al: Stage I-III Hodgkin's disease: Outcome and pattern of failure following treatment with radiation therapy and chemotherapy in a modern era. Hematology 7: 43-50, 2002[CrossRef][Medline] 19. Roach M III, Brophy N, Cox R, et al: Prognostic factors for patients relapsing after radiotherapy for early stage Hodgkin's disease. J Clin Oncol 8: 623-629, 1990[Abstract] 20. Olver IN, Wolf MM, Cruickshank D, et al: Nitrogen mustard, vincristine, procarbazine, and prednisolone for relapse after radiation in Hodgkin's disease: An analysis of long-term follow-up. Cancer 62: 233-239, 1988[CrossRef][Medline] 21. Enrici RM, Osti MF, Zurlo A, et al: Long-term results of 60 patients with pathologic stage I & IIA Hodgkin's disease treated with exclusive mantle radiation therapy. Eur J Haematol 63: 126-133, 1999[Medline] Submitted November 28, 2006; accepted February 23, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
