Salvage Radiotherapy in Patients With Relapsed and Refractory Hodgkin’s Lymphoma: A Retrospective Analysis From the German Hodgkin Lymphoma
http://www.100md.com
《临床肿瘤学》
the First Department of Internal Medicine and Clinic of Radiotherapy, University Hospital Cologne, and the German Hodgkin Lymphoma Study Group (GHSG), Cologne
Department of Radiotherapy, University Hospital Frankfurt, Frankfurt
the Clinic of Radiotherapy, City Hospital Krefeld, Krefeld, Germany.
ABSTRACT
PATIENTS AND METHODS: From 4,754 patients registered in the database of the German Hodgkin Study Group from 1988 to 1999, 624 patients were identified with progressive disease (n = 202), or with early (n = 170) or late (n = 252) relapsed HD. At first treatment failure, SRT alone was given to 100 patients. Patient characteristics were: median age, 36 years; progressive disease, 47%; early relapse, 23%; late relapse, 30%; and "B" symptoms, 14%. Eighty-five percent of the patients relapsed after cyclophosphamide, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP/ABVD) –like regimens; 8% after bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimens, 7% after first-line radiotherapy alone.
RESULTS: The volume irradiated was mantle field in 43% of patients, inverted-Y in 8%, total nodal irradiation in 12%, and involved-field in 37%. The median SRT dose was 40 Gy (range, 15 to 50 Gy). Seventy-seven patients achieved a complete remission and four patients achieved a partial remission. The 5-year freedom from treatment failure and overall survival (OS) rates were 28% and 51%, respectively. In multivariate analysis, significant prognostic factors for OS were B symptoms (P = .018) and stage at relapse (P = .014). For freedom from second failure (FF2F) Karnofsky performance status (P = .0001) was significant. In patients with limited stage at progression/relapse, duration of first remission was significant (P = .04) for FF2F.
CONCLUSION: SRT offers an effective treatment for selected subsets of patients with relapsed or refractory HD.
INTRODUCTION
Patients with relapsed HD have various treatment options including radiotherapy, conventional salvage chemotherapy, or high-dose chemotherapy (HDCT) followed by stem-cell transplantation (SCT).4 The majority of patients with relapsed or refractory disease fare poorly with conventional salvage chemotherapy regimens. During the last decade, numerous investigators have turned to the use of HDCT and SCT in an effort to improve the long-term results in these patients with relapsed or refractory HD. Two randomized studies performed by the British National Lymphoma Investigation (BNLI), the German Hodgkin Study Group (GHSG), and the European Group for Blood and Marrow Transplantation (EBMT) have shown superior outcome in relapsed patients treated with HDCT.5,6 More recently, new approaches such as sequential HDCT, tandem HDCT, allogeneic SCT, or nonmyeloablative conditioning with allogeneic blood progenitor-cell transplantation ("mini-transplants") have been investigated in relapsed and refractory HD.7-9
Salvage radiotherapy (SRT) provides an alternative treatment strategy for patients with localized disease in previously nonirradiated areas. However, published data are restricted to a number of very small series.10-15
The current study provides a detailed analysis of the largest reported experience of SRT for relapsed HD, as of publication. Patient characteristics, salvage modalities, and prognostic factors were evaluated at the time of relapse. We demonstrate that SRT may be a valid treatment option, particularly for patients without systemic "B" symptoms presenting with an isolated nodal relapse.
PATIENTS AND METHODS
Patients had been recruited into the GHSG trials of first-line therapy for early stages (HD4 and HD7), intermediate stages (HD5 and HD8), and advanced stages (HD6 and HD9) between 1988 and 1998.16-20
Patients in localized stages without risk factors received either extended-field (EF) radiotherapy (40 Gy EF or 30 Gy EF, with an additional 10 Gy involved-field [IF]) or two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by a dose of radiotherapy of 30 Gy EF with an additional 10 Gy IF. Localized stages with risk factors (intermediate stages) received four cycles of chemotherapy (cyclophosphamide, vincristine, procarbazine, and prednisone [COPP] plus ABVD or COPP plus doxorubicin, bleomycin, and vinblastine [ABV] plus ifosfamide, methotrexate, etoposide, and prednisone [IMEP]) and radiotherapy to the EF (30 Gy) with an additional 10 Gy for bulk or 30 Gy IF with 10 Gy to bulky disease. Patients in advanced stages received eight cycles of chemotherapy (COPP/ABVD or COPP/ABV/IMEP or bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP]) and localized radiotherapy to residual (40 Gy) and to initial bulky disease (30 Gy).
Patients with relapsed and primary progressive HD were retrospectively analyzed in the database of the GHSG. 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 determined as CR after first-line therapy, lasting 3 to 12 months. Late relapse was defined as CR, lasting more than 12 months after completion of induction treatment. A rebiopsy at the time of relapse was recommended. This analysis is based on data extracted from the database and patient files from September 1999 to January 2000. All patients who received salvage therapy at their progression or first relapse were analyzed.
Salvage Therapy
Data relating to salvage radiotherapy included field and size (ie, total nodal irradiation, mantle-field, EF, and IF radiation) and dose delivered.
Staging Procedures
Before SRT, the extent of disease was assessed by chest x-ray, abdominal ultrasound, computed tomography, and bone marrow biopsy. After the end of the salvage radiotherapy, all sites of initial disease were reassessed by adequate methods.
Response Definition
CR was defined as disappearance of all clinical and radiographic evidence of disease for at least 1 month. Partial response (PR) was defined as a greater than 50% reduction in the product of the largest diameter and its perpendicular of measurable disease, lasting at least 1 month. Any response less than PR was considered treatment failure.
Statistics
Freedom from second treatment failure (FF2F) was measured from the date of entry into the salvage protocol until progression, relapse, or death from any cause. Overall survival (OS) was measured from the date of entry into the salvage protocol until death from any cause. Demographics and disease characteristics were summarized using descriptive statistics. OS and FF2F rates were estimated according to the method of Kaplan and Meier.21
The following factors documented at relapse were analyzed for their prognostic influence: age, B symptoms, stage, duration of response, and Karnofsky performance status. The significance was tested by multivariate Cox regression analysis for each of the outcome variables (FF2F and OS),22 and candidate factors were examined by stepwise procedures. Removal and entry levels of significance were .1 and .05, respectively. No adjustment was made for multiple comparisons, and all P values were two-sided. All statistical analyses were performed using SPSS 6.1 (SPSS Inc, Chicago, IL).
RESULTS
At first diagnosis, 7% of patients had early-stage, 31% intermediate-stage, and 62% advanced-stage HD. B symptoms were present in 56% of patients. Seven percent of patients were treated with radiotherapy alone (4% received 40 Gy to EF, and 3% received 30 Gy to EF and an additional 10 Gy IF), 85% of patients were treated with COPP/ABVD-like regimens (in addition, 17% of patients received 30 Gy EF, 38% received 30 Gy to bulk and 40 Gy to rest of tumor, 2% received 30 Gy IF plus 10 Gy to bulk), 5% of patients were treated with BEACOPP baseline (4% of patients received additional radiotherapy: 30 Gy to bulk and 40 Gy for rest of tumor). Three percent of patients were treated with BEACOPP escalated. In summary, 68% of patients received radiation therapy (RT) in the initial treatment approach.
Stage at progression/relapse by Ann Arbor criteria was I in 44%, II in 43%, III in 11%, and IV in 2%. Exact locations of relapses in regard to primary disease sites are partly discussed elsewhere.16 Briefly, 44 patients had progression on the same anatomic sites as first diagnosis, and three patients developed out-field disease progression after primary radiation. Regarding relapses, 32 patients relapsed in out-field anatomic sites and 21 patients had in-field relapse. Regarding the duration of the first remission, 47% of patients had primary progressive disease, 23% had early relapse, and 30% late relapse. Fourteen percent of patients had B symptoms, and 12% had a Karnofsky performance score of less than 90% at the time of progression/relapse (Table 1).
Salvage Radiotherapy at Progression or Relapse
Salvage radiotherapy as second-line treatment included mantle-field radiation in 42% of patients, inverted-Y field in 8% of patients, total nodal irradiation or subtotal nodal irradiation in 12% of patients, and involved-field radiotherapy in 37% of patients. One patient received an undefined type of radiotherapy. The median dose of radiotherapy delivered was 40 Gy (range, 15 to 50 Gy). Details are listed in Table 2.
Forty-four patients were not irradiated at first-line therapy and 35 patients received SRT to previously not-irradiated sites.
Response After Salvage Radiotherapy
After salvage radiotherapy, 77% of patients achieved CR as listed in Table 3. Sixty-eight of these patients (88%) had stage I/II disease, and nine patients (12%) had stage III/IV disease at the time of progression/relapse. Four patients (4%) achieved partial remission; three of these had stage I/II disease and one patient had stage III/IV disease at the time of progression/relapse. A total of 19 patients (19%) failed to respond. Sixteen of these 19 patients had stage I/II disease, and three had stage III/IV patients.
Survival and Prognostic Factors
With a median observation time of 52 months, the actuarial 5-year FF2F and OS were 28% and 51%, respectively (Fig 1).
The results of the univariate and multivariate analysis are listed in Table 4. In multivariate analysis, Karnofsky performance status was found to be a significant predictor for FF2F (P = .0001; Fig 2).
B symptoms (P = .018 in univariate v P < .0001 in multivariate analysis) and stage at progression/relapse (P = .014 v P = .019) were significant for OS. OS for patients with and without B symptoms was 8% and 57%, respectively (Fig 3). Regarding stage of disease at progression/relapse, OS for patients with stage I disease was 68%, for stage II disease, 42%, and for stage III/IV disease, 27% (Fig 4).
Survival and Prognostic Factors for Patients With Limited-Stage Progressions/Relapses
Because of the fact that stage of disease at progression/relapse was identified as a prognostic factor for OS, we analyzed subsequent patients with limited stage progressions/relapses. After a median observation time of 52 months, the actuarial 5-year FF2F and OS were 22% and 55%, respectively (Fig 5). For FF2F, the univariate analysis identified duration of first remission (P = .007), B symptoms (P = .008), and Karnofsky index (P = .02) as predictive factors. Duration of first remission (P = .04) was also statistically significant in the multivariate analysis (Fig 6). For OS, Karnofsky index (P = .0009), B symptoms (P < .0001), and duration of response (P = .04) were significant predictors in the univariate analysis, but no factor was significant in the multivariate analysis.
Subsequent Treatment
Fifteen patients received HDCT with SCT, 27 patients were treated with conventional therapy (Dexa-BEAM–like therapy [n = 17], BEACOPP [n = 3], cyclophosphamide, etoposide, vindesine, and dexamethasone [CEVD; n = 1], cyclophosphamide, vincristine, procarbazine, and prednisone [COPP; n = 1], lomustine, etoposide, prednimustine [CEP; n = 1], mechlorethamine, vincristine, procarbazine, prednisone/epirubicin, bleomycin, vinblastine, prednisone [MOPP/EBVP; n = 1], IMEP [n = 1], ifosfamide, etoposide/vincristine, procarbazine, prednisone, doxorubicin [IE/OPPA; n = 1], epirubicin, bleomycin, vincristine, etoposide, procarbazine, prednisone [EBOEPP; n = 1]), three patients were treated with radiation again, and 16 patients received palliative therapy.
Treatment Toxicity
Because of the fact that the patients with SRT were not enrolled onto clinical trials, we had little data on acute hematologic toxicity. However, data on other types of toxicities were available: six patients developed pulmonary toxicity (three patients had mycotic pneumonia, one patient had Pneumocystis carinii pneumonia, one patient developed pneumonitis, and one patient was diagnosed with pneumonitis). Three patients developed cardiovascular toxicities (two patients had myocardial infarctions and one patient had stroke). We registered no cases of acute myeloid leukemia or myelodysplastic syndrome after SRT.
DISCUSSION
Despite the good results of first-line therapy for HD, salvage treatment has remained unsatisfactory. Current treatment strategies include conventional second-line chemotherapy, high-dose chemotherapy with autologous SCT, and salvage radiotherapy. One important issue of salvage treatment is to determine the optimal balance between potential curative therapy and possible side effects. Thus, it is necessary to identify the appropriate subset of patients for each type of salvage treatment.
There are relatively few instances in which radiotherapy would be considered the treatment of choice for relapsed HD because it is generally assumed that recurrence indicates disseminated disease. However, salvage radiotherapy offers an effective treatment option for a subset of selected HD patients.
Wirth et al10 reported on the experience of salvage radiotherapy in 51 patients with relapsed or refractory HD after initial chemotherapy treatment. They reported that 5-year failure-free survival (FFS) and OS rates following salvage radiotherapy were 26% and 57%, respectively. B symptoms were found prognostically significant for both FF2F and OS, and extranodal involvement was shown as a significant predictor of FFS. Patients in whom both factors were absent had a favorable outcome. The estimated 5-year FFS and OS for patients with supradiaphragmatic disease, no B symptoms, and no extranodal involvement were 36% and 75%, respectively.
Leigh et al11 analyzed 28 patients with advanced HD who were treated with salvage radiotherapy after failing to respond to intensive combination chemotherapy in previously unirradiated nodal and/or pulmonary sites. They reported actuarial 5-year relapse-free survival (RFS) and OS rates of 40% and 63%, respectively. Patients’ initial response to chemotherapy was predictive for 5-year RFS after salvage radiotherapy. Patients with an initial complete response to chemotherapy had a significantly longer actuarial RFS than those patients with an initial partial response (P = .02).
Pezner et al12 presented a study on 10 patients who received salvage radiotherapy. Their reported 5-year RFS and OS rates were 30% and 60%, respectively, for all patients. Predictive factors correlating with OS and RFS were the disease-free interval (DFI) after the end of initial treatment. For patients with a DFI of fewer than 12 months, the 5-year RFS and OS rates were 0% and 20%, respectively. For patients with a DFI of more than 12 months, the 5-year RFS and OS rates were 60% and 100%, respectively.
Brada et al13 performed a study in 44 patients who relapsed after chemotherapy and were treated with salvage radiotherapy. They reported a 5-year progression-free survival rate of 38%. Age (> 40 years) and progression-free interval (≤ 1 year) were identified as adverse independent prognostic factors.
However, the published studies were based on small groups of patients, making the identification of relevant prognostic factors for SRT difficult.
The present study is the largest analysis of patients with relapsed Hodgkin’s disease treated with SRT. Our 5-year freedom from treatment failure and OS were 28% and 51%, respectively. Our data proved B symptoms and stage at the time of relapse/disease progression to be significant prognostic factors for OS. OS for patients without B symptoms was 57%, compared with 8% for patients with B symptoms. Patients with isolated nodal relapse (stage I/II) at the time of progression/relapse showed a favorable prognosis compared with patients with advanced disease.10,23 OS for patients with stage I disease was 68%, for stage II disease was 42%, and for stage III/IV disease was 27%. Thus, patients with localized disease at the time of progression/relapse without B symptoms seem to be the most suitable candidates for salvage radiotherapy. Other study groups10,13 described the site of relapse as a predictive feature for OS.
Karnofsky performance status in our analysis was a predictive factor for FF2F. This is in line with previous reports from our group demonstrating that the Karnofsky performance status at the time of disease progression/relapse in patients with primary progressive and relapsed HD is an important predictive factor correlated with outcome after salvage chemotherapy.24,25
Because of a result of multivariate analysis for OS we subsequently analyzed patients with limited-stage progressions/relapses. After a median observation time of 52 months, the actuarial 5-year freedom from treatment failure and OS rates were 22% and 55%, respectively. In multivariate analysis, duration of first remission was identified as a predictive factor for FF2F.
MacMillan et al14 analyzed 11 patients treated with radiotherapy for relapse at a localized site. All 11 patients achieved a CR, and the overall and cause-specific survival for these patients was 100% at 5 years and 90% at 10 years. Five patients had no further relapse.
Uematsu et al15 performed a study in 28 patients with Hodgkin’s disease who had relapses in nodal sites after combination chemotherapy alone. The patients were treated with wide-field, high-dose RT, with or without additional chemotherapy with curative intent. The 7-year actuarial freedom from relapse and survival rates for the patients re-treated with chemotherapy and RT were 93% and 85%, respectively, as compared with 36% and 36% for patients re-treated with RT alone. There was a significant difference for freedom from relapse and survival rates favoring patients re-treated with both chemotherapy and RT. However, patient numbers and characteristics differed substantially between these two groups.
The published data demonstrate the important role of radiation therapy in patients with limited-stage relapses, and indicate that radiation may play a key role in the management of recurrent Hodgkin’s disease when combined with systemic management. However, there are no data as of publication that would prospectively analyze the best therapy option for patients with limited-stage progressions/relapses.
We admit that based on the data presented, it is not a convincing argument to say that the reason certain groups of patients do well (those patients with no B symptoms and nodal relapse or stage I/II at relapse) with salvage RT is as a result of the RT. The prognostic factor analysis for these factors is only significant for OS, which obviously is impacted by treatment subsequent to salvage RT.
Concerning the subsequent treatment in our study, we have shown that patients who relapsed after SRT can be successfully treated with high-dose chemotherapy with SCT or with conventional chemotherapy. Thus, SRT by first relapse represents a potential treatment option for suitable patients, and still allows a subsequent treatment possibility by new relapse. The comparison of our results with those of alternative salvage therapy programs is difficult, as patient groups usually differ in several predictive factors.26
Incorporating radiotherapy in salvage therapy programs seems to be feasible, but the exact efficacy of salvage radiotherapy should be investigated in prospective clinical investigations, using the same selection criteria for all patients with progressive or relapsed HD.
Authors’ Disclosures of Potential Conflicts of Interest
NOTES
Supported by a grant from the Bundesministerium für Forschung und Technologie (BMFT) and by a grant from the Deutsche Krebshilfe.
A.J. and L.N. contributed equally to this work.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. 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 327:1478-1483, 1992
2. Carde P, 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)
3. 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
4. Canellos GP: Treatment of relapsed Hodgkin’s disease: Strategies and prognostic factors. Ann Oncol 9:S91-S98, 1998 (suppl 5)
5. 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 randomized trial. Lancet 341:1051-1054, 1993
6. 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 randomized trial. Lancet 359:2065-2071, 2002
7. Josting A, Rudolph C, Mapara M, et al: Cologne high-dose sequential chemotherapy in relapsed and refractory Hodgkin lymphoma: Results of a large multicenter study of the German Hodgkin Lymphoma Study Group (GHSG). Ann Oncol 16:116-123, 2005
8. Brice P, Divine M, Simon D, et al: Feasibility of tandem autologous stem-cell transplantation (ASCT) in induction failure or very unfavorable (UF) relapse from Hodgkin’s disease (HD): SFGM/GELA Study Group. Ann Oncol 10:1485-1488, 1999
9. Khouri IF, Keating M, Korbling M, et al: Transplant-lite: Induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 16:2817-2824, 1998
10. Wirth A, Corry J, Laidlaw C, et al: Salvage radiotherapy for Hodgkin’s disease following chemotherapy failure. Int J Radiat Oncol Biol Phys 39:599-607, 1997
11. Leigh BR, Fox KA, Mack CF, et al: Radiation therapy salvage of Hodgkin’s disease following chemotherapy failure. Int J Radiat Oncol Biol Phys 27:855-862, 1993
12. Pezner RD, Lipsett JA, Vora N, et al: Radical radiotherapy as salvage treatment for relapse of Hodgkin’s disease initially treated by chemotherapy alone: Prognostic significance of the disease-free interval. Int J Radiat Oncol Biol Phys 30:965-970, 1994
13. Brada M, Eeles R, Ashley S, et al: Salvage radiotherapy in recurrent Hodgkin’s disease. Ann Oncol 3:131-135, 1992
14. MacMillan CH, Besell EM: The effectiveness of radiotherapy for localized relapse in patients with Hodgkin’s disease (IIB-IVB) who obtained a complete response with chemotherapy alone as initial treatment. Clin Oncol (R Coll Radiol) 6:147-150, 1994
15. Uematsu M, Tarbell NJ, Silver B, et al: Wide-field radiation therapy with or without chemotherapy for patients with Hodgkin disease in relapse after initial combination chemotherapy. Cancer 72:207-212, 1993
16. Dühmke E, Franklin J, Pfreundschuh M, et al: Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin’s disease: Long-term results of a randomized trial of radiotherapy alone. J Clin Oncol 19:2905-2914, 2001
17. Sieber M, Franklin J, Tesch H, et al: Two cycles of ABVD plus extended field radiotherapy is superior to radiotherapy alone in early stage Hodgkin’s disease: Results of the German Hodgkin’s Lymphoma Study Group (GHSG) trial HD7. Blood 100:341, 2002 (supp 1)
18. Sieber M, Tesch H, Pfistner B, et al: Rapidly alternating COPP/ABV/IMEP is not superior to conventional alternating COPP/ABVD in combination with extended-field radiotherapy in intermediate-stage Hodgkin’s lymphoma: Final results of the German Hodgkin’s Lymphoma Study Group trial HD5. J Clin Oncol 20:476-484, 2002
19. Engert A, Schiller P, Josting A, et al: Involved field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin’s lymphoma: Results of the HD8 trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 21:3601-3608, 2003
20. Diehl V, Franklin J, Hasenclever D, et al: BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin’s lymphoma: Interim report from a trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 16:3810-3821, 1998
21. Kaplan EL, Meier P: Nonparametric estimation from incomplete observation. J Am Stat Assoc 53:457-481, 1958
22. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin’s disease: . International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med 339:1506-1514, 1998
23. Roach M, Kapp DS, Rosenberg SA, et al: Radiotherapy With Curative Intent: An Option in Selected Patients Relapsing for Advanced Hodgkin’s Disease. J Clin Oncol 5:550-555, 1987
24. Josting A, Rueffer U, Franklin J, et al: Prognostic factors and treatment outcome in primary progressive Hodgkin’s lymphoma: A report from the German Hodgkin’s Lymphoma Study Group (GHSG). Blood 96:1280-1286, 2000
25. Josting A, Franklin J, May M, et al: New prognostic score based on treatment of patients with relapsed Hodgkin lymphoma registered in the database of the German Hodgkin Lymphoma Study Group (GHSG). J Clin Oncol 20:221-230, 2002
26. Desch CE, Lasala MR, Smith TJ, et al: The optimal timing of autologous bone marrow transplantation in Hodgkin’s disease patients after a chemotherapy relapse. J Clin Oncol 10:200-209, 1992(Andreas Josting, Lucia No)
Department of Radiotherapy, University Hospital Frankfurt, Frankfurt
the Clinic of Radiotherapy, City Hospital Krefeld, Krefeld, Germany.
ABSTRACT
PATIENTS AND METHODS: From 4,754 patients registered in the database of the German Hodgkin Study Group from 1988 to 1999, 624 patients were identified with progressive disease (n = 202), or with early (n = 170) or late (n = 252) relapsed HD. At first treatment failure, SRT alone was given to 100 patients. Patient characteristics were: median age, 36 years; progressive disease, 47%; early relapse, 23%; late relapse, 30%; and "B" symptoms, 14%. Eighty-five percent of the patients relapsed after cyclophosphamide, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP/ABVD) –like regimens; 8% after bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimens, 7% after first-line radiotherapy alone.
RESULTS: The volume irradiated was mantle field in 43% of patients, inverted-Y in 8%, total nodal irradiation in 12%, and involved-field in 37%. The median SRT dose was 40 Gy (range, 15 to 50 Gy). Seventy-seven patients achieved a complete remission and four patients achieved a partial remission. The 5-year freedom from treatment failure and overall survival (OS) rates were 28% and 51%, respectively. In multivariate analysis, significant prognostic factors for OS were B symptoms (P = .018) and stage at relapse (P = .014). For freedom from second failure (FF2F) Karnofsky performance status (P = .0001) was significant. In patients with limited stage at progression/relapse, duration of first remission was significant (P = .04) for FF2F.
CONCLUSION: SRT offers an effective treatment for selected subsets of patients with relapsed or refractory HD.
INTRODUCTION
Patients with relapsed HD have various treatment options including radiotherapy, conventional salvage chemotherapy, or high-dose chemotherapy (HDCT) followed by stem-cell transplantation (SCT).4 The majority of patients with relapsed or refractory disease fare poorly with conventional salvage chemotherapy regimens. During the last decade, numerous investigators have turned to the use of HDCT and SCT in an effort to improve the long-term results in these patients with relapsed or refractory HD. Two randomized studies performed by the British National Lymphoma Investigation (BNLI), the German Hodgkin Study Group (GHSG), and the European Group for Blood and Marrow Transplantation (EBMT) have shown superior outcome in relapsed patients treated with HDCT.5,6 More recently, new approaches such as sequential HDCT, tandem HDCT, allogeneic SCT, or nonmyeloablative conditioning with allogeneic blood progenitor-cell transplantation ("mini-transplants") have been investigated in relapsed and refractory HD.7-9
Salvage radiotherapy (SRT) provides an alternative treatment strategy for patients with localized disease in previously nonirradiated areas. However, published data are restricted to a number of very small series.10-15
The current study provides a detailed analysis of the largest reported experience of SRT for relapsed HD, as of publication. Patient characteristics, salvage modalities, and prognostic factors were evaluated at the time of relapse. We demonstrate that SRT may be a valid treatment option, particularly for patients without systemic "B" symptoms presenting with an isolated nodal relapse.
PATIENTS AND METHODS
Patients had been recruited into the GHSG trials of first-line therapy for early stages (HD4 and HD7), intermediate stages (HD5 and HD8), and advanced stages (HD6 and HD9) between 1988 and 1998.16-20
Patients in localized stages without risk factors received either extended-field (EF) radiotherapy (40 Gy EF or 30 Gy EF, with an additional 10 Gy involved-field [IF]) or two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by a dose of radiotherapy of 30 Gy EF with an additional 10 Gy IF. Localized stages with risk factors (intermediate stages) received four cycles of chemotherapy (cyclophosphamide, vincristine, procarbazine, and prednisone [COPP] plus ABVD or COPP plus doxorubicin, bleomycin, and vinblastine [ABV] plus ifosfamide, methotrexate, etoposide, and prednisone [IMEP]) and radiotherapy to the EF (30 Gy) with an additional 10 Gy for bulk or 30 Gy IF with 10 Gy to bulky disease. Patients in advanced stages received eight cycles of chemotherapy (COPP/ABVD or COPP/ABV/IMEP or bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP]) and localized radiotherapy to residual (40 Gy) and to initial bulky disease (30 Gy).
Patients with relapsed and primary progressive HD were retrospectively analyzed in the database of the GHSG. 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 determined as CR after first-line therapy, lasting 3 to 12 months. Late relapse was defined as CR, lasting more than 12 months after completion of induction treatment. A rebiopsy at the time of relapse was recommended. This analysis is based on data extracted from the database and patient files from September 1999 to January 2000. All patients who received salvage therapy at their progression or first relapse were analyzed.
Salvage Therapy
Data relating to salvage radiotherapy included field and size (ie, total nodal irradiation, mantle-field, EF, and IF radiation) and dose delivered.
Staging Procedures
Before SRT, the extent of disease was assessed by chest x-ray, abdominal ultrasound, computed tomography, and bone marrow biopsy. After the end of the salvage radiotherapy, all sites of initial disease were reassessed by adequate methods.
Response Definition
CR was defined as disappearance of all clinical and radiographic evidence of disease for at least 1 month. Partial response (PR) was defined as a greater than 50% reduction in the product of the largest diameter and its perpendicular of measurable disease, lasting at least 1 month. Any response less than PR was considered treatment failure.
Statistics
Freedom from second treatment failure (FF2F) was measured from the date of entry into the salvage protocol until progression, relapse, or death from any cause. Overall survival (OS) was measured from the date of entry into the salvage protocol until death from any cause. Demographics and disease characteristics were summarized using descriptive statistics. OS and FF2F rates were estimated according to the method of Kaplan and Meier.21
The following factors documented at relapse were analyzed for their prognostic influence: age, B symptoms, stage, duration of response, and Karnofsky performance status. The significance was tested by multivariate Cox regression analysis for each of the outcome variables (FF2F and OS),22 and candidate factors were examined by stepwise procedures. Removal and entry levels of significance were .1 and .05, respectively. No adjustment was made for multiple comparisons, and all P values were two-sided. All statistical analyses were performed using SPSS 6.1 (SPSS Inc, Chicago, IL).
RESULTS
At first diagnosis, 7% of patients had early-stage, 31% intermediate-stage, and 62% advanced-stage HD. B symptoms were present in 56% of patients. Seven percent of patients were treated with radiotherapy alone (4% received 40 Gy to EF, and 3% received 30 Gy to EF and an additional 10 Gy IF), 85% of patients were treated with COPP/ABVD-like regimens (in addition, 17% of patients received 30 Gy EF, 38% received 30 Gy to bulk and 40 Gy to rest of tumor, 2% received 30 Gy IF plus 10 Gy to bulk), 5% of patients were treated with BEACOPP baseline (4% of patients received additional radiotherapy: 30 Gy to bulk and 40 Gy for rest of tumor). Three percent of patients were treated with BEACOPP escalated. In summary, 68% of patients received radiation therapy (RT) in the initial treatment approach.
Stage at progression/relapse by Ann Arbor criteria was I in 44%, II in 43%, III in 11%, and IV in 2%. Exact locations of relapses in regard to primary disease sites are partly discussed elsewhere.16 Briefly, 44 patients had progression on the same anatomic sites as first diagnosis, and three patients developed out-field disease progression after primary radiation. Regarding relapses, 32 patients relapsed in out-field anatomic sites and 21 patients had in-field relapse. Regarding the duration of the first remission, 47% of patients had primary progressive disease, 23% had early relapse, and 30% late relapse. Fourteen percent of patients had B symptoms, and 12% had a Karnofsky performance score of less than 90% at the time of progression/relapse (Table 1).
Salvage Radiotherapy at Progression or Relapse
Salvage radiotherapy as second-line treatment included mantle-field radiation in 42% of patients, inverted-Y field in 8% of patients, total nodal irradiation or subtotal nodal irradiation in 12% of patients, and involved-field radiotherapy in 37% of patients. One patient received an undefined type of radiotherapy. The median dose of radiotherapy delivered was 40 Gy (range, 15 to 50 Gy). Details are listed in Table 2.
Forty-four patients were not irradiated at first-line therapy and 35 patients received SRT to previously not-irradiated sites.
Response After Salvage Radiotherapy
After salvage radiotherapy, 77% of patients achieved CR as listed in Table 3. Sixty-eight of these patients (88%) had stage I/II disease, and nine patients (12%) had stage III/IV disease at the time of progression/relapse. Four patients (4%) achieved partial remission; three of these had stage I/II disease and one patient had stage III/IV disease at the time of progression/relapse. A total of 19 patients (19%) failed to respond. Sixteen of these 19 patients had stage I/II disease, and three had stage III/IV patients.
Survival and Prognostic Factors
With a median observation time of 52 months, the actuarial 5-year FF2F and OS were 28% and 51%, respectively (Fig 1).
The results of the univariate and multivariate analysis are listed in Table 4. In multivariate analysis, Karnofsky performance status was found to be a significant predictor for FF2F (P = .0001; Fig 2).
B symptoms (P = .018 in univariate v P < .0001 in multivariate analysis) and stage at progression/relapse (P = .014 v P = .019) were significant for OS. OS for patients with and without B symptoms was 8% and 57%, respectively (Fig 3). Regarding stage of disease at progression/relapse, OS for patients with stage I disease was 68%, for stage II disease, 42%, and for stage III/IV disease, 27% (Fig 4).
Survival and Prognostic Factors for Patients With Limited-Stage Progressions/Relapses
Because of the fact that stage of disease at progression/relapse was identified as a prognostic factor for OS, we analyzed subsequent patients with limited stage progressions/relapses. After a median observation time of 52 months, the actuarial 5-year FF2F and OS were 22% and 55%, respectively (Fig 5). For FF2F, the univariate analysis identified duration of first remission (P = .007), B symptoms (P = .008), and Karnofsky index (P = .02) as predictive factors. Duration of first remission (P = .04) was also statistically significant in the multivariate analysis (Fig 6). For OS, Karnofsky index (P = .0009), B symptoms (P < .0001), and duration of response (P = .04) were significant predictors in the univariate analysis, but no factor was significant in the multivariate analysis.
Subsequent Treatment
Fifteen patients received HDCT with SCT, 27 patients were treated with conventional therapy (Dexa-BEAM–like therapy [n = 17], BEACOPP [n = 3], cyclophosphamide, etoposide, vindesine, and dexamethasone [CEVD; n = 1], cyclophosphamide, vincristine, procarbazine, and prednisone [COPP; n = 1], lomustine, etoposide, prednimustine [CEP; n = 1], mechlorethamine, vincristine, procarbazine, prednisone/epirubicin, bleomycin, vinblastine, prednisone [MOPP/EBVP; n = 1], IMEP [n = 1], ifosfamide, etoposide/vincristine, procarbazine, prednisone, doxorubicin [IE/OPPA; n = 1], epirubicin, bleomycin, vincristine, etoposide, procarbazine, prednisone [EBOEPP; n = 1]), three patients were treated with radiation again, and 16 patients received palliative therapy.
Treatment Toxicity
Because of the fact that the patients with SRT were not enrolled onto clinical trials, we had little data on acute hematologic toxicity. However, data on other types of toxicities were available: six patients developed pulmonary toxicity (three patients had mycotic pneumonia, one patient had Pneumocystis carinii pneumonia, one patient developed pneumonitis, and one patient was diagnosed with pneumonitis). Three patients developed cardiovascular toxicities (two patients had myocardial infarctions and one patient had stroke). We registered no cases of acute myeloid leukemia or myelodysplastic syndrome after SRT.
DISCUSSION
Despite the good results of first-line therapy for HD, salvage treatment has remained unsatisfactory. Current treatment strategies include conventional second-line chemotherapy, high-dose chemotherapy with autologous SCT, and salvage radiotherapy. One important issue of salvage treatment is to determine the optimal balance between potential curative therapy and possible side effects. Thus, it is necessary to identify the appropriate subset of patients for each type of salvage treatment.
There are relatively few instances in which radiotherapy would be considered the treatment of choice for relapsed HD because it is generally assumed that recurrence indicates disseminated disease. However, salvage radiotherapy offers an effective treatment option for a subset of selected HD patients.
Wirth et al10 reported on the experience of salvage radiotherapy in 51 patients with relapsed or refractory HD after initial chemotherapy treatment. They reported that 5-year failure-free survival (FFS) and OS rates following salvage radiotherapy were 26% and 57%, respectively. B symptoms were found prognostically significant for both FF2F and OS, and extranodal involvement was shown as a significant predictor of FFS. Patients in whom both factors were absent had a favorable outcome. The estimated 5-year FFS and OS for patients with supradiaphragmatic disease, no B symptoms, and no extranodal involvement were 36% and 75%, respectively.
Leigh et al11 analyzed 28 patients with advanced HD who were treated with salvage radiotherapy after failing to respond to intensive combination chemotherapy in previously unirradiated nodal and/or pulmonary sites. They reported actuarial 5-year relapse-free survival (RFS) and OS rates of 40% and 63%, respectively. Patients’ initial response to chemotherapy was predictive for 5-year RFS after salvage radiotherapy. Patients with an initial complete response to chemotherapy had a significantly longer actuarial RFS than those patients with an initial partial response (P = .02).
Pezner et al12 presented a study on 10 patients who received salvage radiotherapy. Their reported 5-year RFS and OS rates were 30% and 60%, respectively, for all patients. Predictive factors correlating with OS and RFS were the disease-free interval (DFI) after the end of initial treatment. For patients with a DFI of fewer than 12 months, the 5-year RFS and OS rates were 0% and 20%, respectively. For patients with a DFI of more than 12 months, the 5-year RFS and OS rates were 60% and 100%, respectively.
Brada et al13 performed a study in 44 patients who relapsed after chemotherapy and were treated with salvage radiotherapy. They reported a 5-year progression-free survival rate of 38%. Age (> 40 years) and progression-free interval (≤ 1 year) were identified as adverse independent prognostic factors.
However, the published studies were based on small groups of patients, making the identification of relevant prognostic factors for SRT difficult.
The present study is the largest analysis of patients with relapsed Hodgkin’s disease treated with SRT. Our 5-year freedom from treatment failure and OS were 28% and 51%, respectively. Our data proved B symptoms and stage at the time of relapse/disease progression to be significant prognostic factors for OS. OS for patients without B symptoms was 57%, compared with 8% for patients with B symptoms. Patients with isolated nodal relapse (stage I/II) at the time of progression/relapse showed a favorable prognosis compared with patients with advanced disease.10,23 OS for patients with stage I disease was 68%, for stage II disease was 42%, and for stage III/IV disease was 27%. Thus, patients with localized disease at the time of progression/relapse without B symptoms seem to be the most suitable candidates for salvage radiotherapy. Other study groups10,13 described the site of relapse as a predictive feature for OS.
Karnofsky performance status in our analysis was a predictive factor for FF2F. This is in line with previous reports from our group demonstrating that the Karnofsky performance status at the time of disease progression/relapse in patients with primary progressive and relapsed HD is an important predictive factor correlated with outcome after salvage chemotherapy.24,25
Because of a result of multivariate analysis for OS we subsequently analyzed patients with limited-stage progressions/relapses. After a median observation time of 52 months, the actuarial 5-year freedom from treatment failure and OS rates were 22% and 55%, respectively. In multivariate analysis, duration of first remission was identified as a predictive factor for FF2F.
MacMillan et al14 analyzed 11 patients treated with radiotherapy for relapse at a localized site. All 11 patients achieved a CR, and the overall and cause-specific survival for these patients was 100% at 5 years and 90% at 10 years. Five patients had no further relapse.
Uematsu et al15 performed a study in 28 patients with Hodgkin’s disease who had relapses in nodal sites after combination chemotherapy alone. The patients were treated with wide-field, high-dose RT, with or without additional chemotherapy with curative intent. The 7-year actuarial freedom from relapse and survival rates for the patients re-treated with chemotherapy and RT were 93% and 85%, respectively, as compared with 36% and 36% for patients re-treated with RT alone. There was a significant difference for freedom from relapse and survival rates favoring patients re-treated with both chemotherapy and RT. However, patient numbers and characteristics differed substantially between these two groups.
The published data demonstrate the important role of radiation therapy in patients with limited-stage relapses, and indicate that radiation may play a key role in the management of recurrent Hodgkin’s disease when combined with systemic management. However, there are no data as of publication that would prospectively analyze the best therapy option for patients with limited-stage progressions/relapses.
We admit that based on the data presented, it is not a convincing argument to say that the reason certain groups of patients do well (those patients with no B symptoms and nodal relapse or stage I/II at relapse) with salvage RT is as a result of the RT. The prognostic factor analysis for these factors is only significant for OS, which obviously is impacted by treatment subsequent to salvage RT.
Concerning the subsequent treatment in our study, we have shown that patients who relapsed after SRT can be successfully treated with high-dose chemotherapy with SCT or with conventional chemotherapy. Thus, SRT by first relapse represents a potential treatment option for suitable patients, and still allows a subsequent treatment possibility by new relapse. The comparison of our results with those of alternative salvage therapy programs is difficult, as patient groups usually differ in several predictive factors.26
Incorporating radiotherapy in salvage therapy programs seems to be feasible, but the exact efficacy of salvage radiotherapy should be investigated in prospective clinical investigations, using the same selection criteria for all patients with progressive or relapsed HD.
Authors’ Disclosures of Potential Conflicts of Interest
NOTES
Supported by a grant from the Bundesministerium für Forschung und Technologie (BMFT) and by a grant from the Deutsche Krebshilfe.
A.J. and L.N. contributed equally to this work.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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