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Prognostic factors and treatment outcome in patients with primary progressive and relapsed Hodgkin's disease
Annals of Oncology 13 (Supplement 1): 112–116, 2002 DOI: 10.1093/annonc/mdf624
Symposium article
Prognostic factors and treatment outcome in patients with primary progressive and relapsed Hodgkin’s disease A. Josting1*, A. Engert1, V. Diehl1 & G. P. Canellos2 1
Department of Internal Medicine I, University Hospital Cologne, Germany, and the German Hodgkin Lymphoma Study Group (GHSG); Department of Adult Oncology, Dana Faber Cancer Institute, Boston, MA, USA
2
Introduction Depending on stage and risk factor profile, up to 95% of patients with Hodgkin’s disease (HD) at first presentation reach complete remission (CR; disappearance of all detectable clinical and radiographic evidence of disease) after standard treatment [1]. Depending on their initial treatment, those patients relapsing have different treatment options, including radiotherapy for localized disease in previously non-irradiated areas, conventional salvage chemotherapy, or high-dose chemotherapy (CT) followed by autologous stem cell transplantation (autoSCT) [2, 3]. Conventional CT is the treatment of choice for patients relapsing after initial radiotherapy for early stage HD. The survival of these patients is at least equal compared with advanced-stage patients initially treated with CT [4]. In contrast, patients with relapsed HD after primary CT generally have a poorer prognosis. The therapeutic options include salvage radiotherapy, salvage CT, and high-dose CT with autoSCT. More recently, new approaches such as sequential highdose CT, tandem high-dose CT, allogeneic (allo) SCT, or nonmyeloablative conditioning with allogeneic blood progenitor cell transplantation (‘mini-transplants’) have been investigated in relapsed HD [4–6]. Since more aggressive approaches are associated with increased toxicity, an accurate pretreatment prognostic assessment of patients is required to help selection of the most appropriate therapeutic regimen.
Prognostic factors in patients relapsing after primary radiotherapy Primary radiotherapy is now used less often in the treatment of localized HD. It has been replaced by combined modality therapy, where various numbers of cycles of combined CT are given prior to lower dose radiotherapy, which is limited to the involved field rather than being extensive, as in the past. Combined modality therapy has reduced the relapse rate to <10%
*Correspondence to: Dr A. Josting, Department of Internal Medicine I, University Hospital Cologne, Joseph-Stelmann-Str. 9, D-50924 Cologne, Germany. Tel: +49-221-478-3745; Fax: +49-221-478-3577; E-mail: [email protected] © 2002 European Society for Medical Oncology
in patients presenting with clinical stage I/IIA. In the future, CT alone may replace combined modality treatment. Currently, this is the subject of a number of prospective controlled trials. The general relapse rate following primary radiotherapy averages between 30 and 35% [7–9]. With more intense staging procedures, including laparotomy and splenectomy, the proportion of those relapsing seems to be lower (20–25%) [10, 11]. The majority of relapses occur within 3 years of radiotherapy, although late relapse after 4 years or more have been noted to occur in the range of 5–7% [8, 9]. This small fraction of late recurrence is noteworthy, since this is generally a more favorable prognostic group when treated with systemic therapy. In fact, their overall survival (OS) is not different from those patients who never relapse [8, 9]. The majority of patients in relapse following radiotherapy are treated with systemic combination CT, often with the inclusion of involved-field radiotherapy if a nodal site was previously unirradiated. The general patterns of recurrence, especially after extensive radiation such as subtotal nodal irradiation, is more often in unirradiated visceral sites with 30–40% of relapses in stage III/IV [10, 11]. The long-term survival of patients ranges significantly according to the pattern of relapse. Three major prognostic factors for response to second-line therapy include age (>40 or 50 years), stage at relapse and the type of therapy used for the treatment of relapse, i.e. CT alone or CT and radiation (Table 1). In some serious mixed cellularity or lymphoid-depleted history were also negative prognostic factors. Second-line therapy for radiation relapse has been quite successful in most series with long-term follow-up, demonstrating a 10-year relapse-free survival of 60% (Table 1). The overall salvage of unirradiated nodal-only relapse is superior to symptomatic disseminated recurrence [7, 10]. Royal Marsden Hospital series indicated that age, histology and nodal versus extranodal relapse determined the sucess of second-line treatment. In that series, the relapse-free survival at 10 years was 63%; however, nodal recurrence had a 10-year survival rate of 74% compared with 51% for those with an extranodal relapse [7]. With relatively small numbers, the Stanford series suggested that combined modality therapy has a better 10-year progression-free rate than CT alone (62% versus 37%),
113 Table 1. Prognostic factors: salvage after relapse from radiotherapy (multivariate analysis) Series
Significant factors
10-year survival from relapse (%)
Royal Marsden (473 patients) [7]
Age (>40 years), unfavorable histology, extranodal relapse
63
Stanford (109 patients) [10]
Age (>50 years), stage II, IIIA/B or IV, treatment (CMT versus CT)
57
Harvard Joint Center (138 patients) [11]
Unfavorable histology
62
CMT, combined modality treatment; CT, chemotherapy.
especially in patients with more advanced stages at relapse (stages IIA–IV) [10]. Isolated stage IA relapse has a markedly high salvage rate (∼90%) as opposed to patients in stage IIIB and IV, where the long term salvage rate is ∼30%. Differences between types of salvage therapy—mainly CT alone versus combined modality—have not been corrected for the patterns of relapse. It is understandable that nodal relapses might be better treated with combined modality therapy as opposed to disseminated IIIB or IV recurrences, where the addition of radiotherapy might not be an advantage. Patients with a bulky mediastinal mass treated with radiation therapy alone have at least a 50% recurrence rate, compared with patients without mediastinal bulk, who have much more favorable freedom from progression. However, it is noteworthy that in most series the OS is similar, attesting to the potential value of systemic CT alone in the setting of relapse at this bulky site. The second-line combination CT used initially was the classical MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) or its variant MVPP (with vinblastine instead of vincristine) [12–14]. A high rate of CR was achieved in the range of 70–85%. There were, however, some secondary leukemias resulting from the alkylating agents contained in these regimens [14, 15]. The introduction of ABVD (doxurubicin, bleomycin, vinblastine, dacarbazine) as a primary systemic treatment for newly diagnosed advanced disease or disease in relapse from primary radiation demonstrated equivalence to MOPP. ABVD is associated with fewer secondary leukemias, resulting in its widespread use [1]. In the Milan series, a historical comparison of doxurubicin-containing regimens suggested that they were superior to MOPP in the setting of radiation relapse [16]. In most series, CT regimens have not been compared prospectively in the setting of relapse from primary radiation therapy. Although ABVD has generally replaced MOPP as the salvage CT of choice, some caution is indicated in patients with prior extensive thoracic irradiation requiring special attention to cardiac and pulmonary function. Patients who relapse from second-line therapy are often candidates for high-dose CT with stem-cell support. The salvage of relapsing patients is likely to get better than the 60% level with the potential for earlier diagnosis with
more sensitive diagnostic techniques such as PET scans. In addition, for those who fail conventional-dose salvage CT, high-dose therapy can still result in long-term disease-free survival in a further 30–50%.
Prognostic factors in patients relapsing after primary CT It was first noted in 1979 that the length of remission after first-line CT had a marked effect on the ability of patients to respond to subsequent salvage treatment [17]. In 1992 the National Cancer Institute (NCI) updated their experience with the long-term follow-up of patients who relapsed after polychemotherapy [18]. Derived primarily from investigations involving failures after MOPP and MOPP variants, the conclusions are relevant to other CT programs. On this basis, CT failures can be divided into three subgroups: • Primary progressive HD (∼10% of all cases), i.e. patients who never achieved a CR • Early relapses within 12 months of CR (∼15% of all cases) • Late relapses after CR lasting >12 months (∼15% of all cases) Using conventional CT for patients with primary progressive disease, virtually no patient survives >8 years. In contrast, the projected 20-year survival for patients with early relapse or late relapse was 11 and 22%, respectively [18].
Primary progressive HD Patients with primary progressive HD, defined as progression during induction treatment or within 90 days after the end of treatment, have a particularly poor prognosis. Treatment of patients with primary progressive HD has consisted of salvage CT, radiotherapy, and high-dose CT with autoSCT. Conventional salvage regimens have given disappointing results in the vast majority of patients: response to salvage treatment is low and the duration of response is often short. The 8-year OS ranges between 0 and 8%. Freedom from treatment failure (FFTF) in second remission is 0% at 4–8 years in small series reported [18, 19]. Extensive disease often limits the use of radiotherapy. The German Hodgkin’s Lymphoma Study Group (GHSG) retrospectively analyzed 206 patients with progressive disease to determine outcome after salvage therapy and identify prognostic factors [20]. The 5-year freedom from second failure (FF2F) and OS for all patients was 17 and 26%, respectively. As reported from transplant centers, the 5-year FF2F and OS for patients treated with high-dose CT was 42 and 48%, respectively, but only 33% of all patients received high-dose CT. A high proportion of those patients will rapidly succumb to progressive disease. Life-threatening severe toxicity upon salvage treatment occurred in 11% of patients. Insufficient stem-cell harvest, poor performance status and older age also contributed to ineligibility for high-dose CT. In a multivariate
114 analysis, Karnofsky performance score at progress (P <0.0001), age (Cox regression P = 0.019) and attainment of a temporary remission to first-line CT (P = 0.0003) were significant prognostic factors for survival. Patients with none of these risk factors had a 5-year OS of 55%, compared with 0% for patients with all three of these unfavorable prognostic factors (Table 2). In conclusion, high-dose CT is an effective treatment for a proportion of patients with primary progressive HD. Owing to the poor outcome of HD patients with progressive disease, future trials must aim to identify patients at very high risk for induction failure and to modify at primary treatment in this group to avoid progressive disease.
Early and late relapsed HD The overall prognosis is worse for patients relapsing after first-line CT when treated with conventional CT. At present, high-dose CT followed by autoSCT is the treatment of choice for patients with relapsed HD after first-line polychemotherapy. Two randomized studies performed by the British National Lymphoma Investigation (BNLI) and the GHSG/European Bone-Marrow Transplant Registry (EBMT) (HDR-1) have shown improved outcome in patients with relapsed HD treated with high-dose CT [21, 22]. Although the results reported with high-dose CT in patients with late relapse have been superior to those reported in most series of conventional CT, the use of high-dose CT in late relapses had been an area of controversy. Patients with late relapse have satisfactory second CR rates when treated with conventional CT, with OS ranging from 40 to 55%. However, the HDR-1 trial of the GHSG showed improved FFTF after high-dose CT compared with conventional CT in patients with late relapse. Therefore, high-dose CT should be considered as standard treatment for all patients with previous CT, including those with late relapse. Although these results indicate the superiority of high-dose CT compared with conventional CT in patients with relapsed HD, a proportion of patients with early relapse will develop recurTable 2. Predicted OS by prognostic factor distribution in patients with primary progressive HD Age (years)
Temporary remission
Karnofsky performance score
Percentage of patients
Predicted OS at 36 months
≤50
Yes
≥90
49
55
<90
15
23
≤50
No
≥90
16
25
<90
6
3
>50
Yes
≥90
5
34
<90
4
7
>50
No
≥90
3
8
<90
2
0
rent disease after high-dose CT. On the other hand, a considerable number of low risk patients might be overtreated with high-dose CT. Thus, an effective assessment of prognostic factors, evaluable at the time of relapse, is required to guide the physician in selecting the most appropriate therapeutic regimen and to evaluate new experimental approaches in very high-risk relapses. Many prognostic factors have been described for patients relapsing after first-line CT. These include age, sex, histology, relapse sites, stage at relapse, B symptoms, performance status and extranodal relapse. The impact of these factors is difficult to assess because of confounding factors such as small number of patients and inclusion of primary progressive HD. In addition, multivariate analyses were not performed systematically. Lohri et al. [23] observed a favorable outcome for patients with favorable risk factors such as no stage IV at diagnosis, absence of B symptoms at relapse and initial remission duration of >12 months. The 5-year failure-free survival was 82% for those lacking all three (n = 22) and 17% for those in whom one or more risk factor was present (n = 49). Fermé et al. [24] analyzed 100 patients with relapsed or refractory HD who were treated with salvage therapy prior to high-dose therapy. By univariate analysis, patients with a long initial remission (<12 months), untreated relapse and good performance status showed improved OS. Reece et al. [25] reported an analysis on 58 patients treated with high-dose CT and autoSCT at the same institution. Four prognostic subgroups were identified according to the presence of the following parameters at relapse: B symtoms, extranodal disease and initial remission duration of <12 months. Patients with no risk factor had a 3-year progression-free survival of 100%, compared with 81% in patients with one factor, 40% in those with two factors and 0% in patients with all three factors. Brice et al. [26] performed one of the largest studies evaluating prognostic factors in relapsed HD. One-hundred and eighty-seven patients who relapsed after a first CR were included. At first relapse, treatment was conventional (CT and/or radiotherapy) in 44% and high-dose CT followed by autoSCT in 56%. Two prognostic factors were identified by multivariate analysis as correlating with both FF2F and OS. These factors were the initial duration of first remission (i.e. <12 months or >12 months; P <0.0001) and stage at relapse (I–II versus III–IV; P = 0.0013). FF2F was 62 and 32%, and OS was 44 and 87% according to the presence of no or two parameters, respectively. Laboratory data were not available in this retrospective analysis. The GHSG has recently performed a retrospective analysis including a much larger number of relapsed patients (n = 422) than previously reported. The analysis of prognostic factors suggests that the prognosis of a patient with relapsed HD can be estimated according to several factors. The most relevant factors were combined into a prognostic score. This score was calculated on the basis of duration of first remission, stage at relapse and anemia at relapse. Early recurrence within 3–12 months after the end of primary treatment, relapse stage
115 Table 3. Prognostic factors included in a prognostic score for relapsed HD (GHSG [27]) Factor
Groups with 4-year OS (%)
Duration of first remission Early relapse
47
Late relapse
73
Stage at relapse Stage III/IV
46
Stage I/II
77
Hemoglobin at relapse (g/dl) F <10.5; M <12
40
F ≥10.5; M ≥12
72
III or IV and hemoglobin at relapse (<10.5 g/dl female or <12 g/dl male) were counted in a score with possible values 0, 1, 2 and 3 in order of worsening prognosis (Table 3) [27]. This prognostic score allows one to distinguish between patients with different FF2F and OS. The actuarial 4-year FF2F and OS for patients relapsing after CT with three unfavorable factors were 17 and 27%, respectively. In contrast, patients with none of the unfavorable factors had FF2F and OS at 4-year of 48 and 83%, respectively. In addition, the prognostic score was also predictive for patients relapsing after radiotherapy, for patients relapsing after CT who were treated with conventional therapies or with high-dose CT followed by autoSCT, and for patients under 60 years and with a Karnofsky performance status ≥90% being the major candidate groups for dose intensification. Our prognostic factor score uses clinical characteristics which can be collected easily at the time of relapse. It separates groups of patients with substantially different outcomes. The prognostic factors identified may be useful to tailor the therapy for subgroups of patients, to define homogeneous cohorts for prospective randomized trials and to identify more precisely patients with high-risk relapse who should be treated with innovative approaches.
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 1992; 327: 1478–1483. 2. Canellos GP. Treatment of relapsed Hodgkin’s disease: strategies and prognostic factors. Ann Oncol 1998; 9 (Suppl 5): 91–98. 3. Josting A, Wolf J, Diehl V. Hodgkin’s disease. Prognostic factors and treatment startegies. Curr Opin Oncol 2000; 12: 403–411. 4. 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 1999; 10: 1485–1488.
5. Josting A, Rudolph D, Mapara M et al. Cologne high-dose sequential in patients with relapsed and refractory Hodgkin’s disease. Blood 2000; 96: 3428. 6. 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 1998; 16: 2817–2824. 7. Horwich A, Specht L, Ashley S. Survival analysis of patients with clinical stages I or II Hodgkin’s disease who have relapsed after initial treatment with radiotherapy alone. Eur J Cancer 1997; 33: 848–853. 8. Brierley JD, Rathmell AJ, Gospodarowicz MK et al. Late relapse after treatment for clinical stage I and II Hodgkin’s disease. Cancer 1997; 79: 1422–1427. 9. Bodis S, Henry-Amar M, Bosq J et al. Late relapse in early-stage Hodgkin’s disease patients enrolled on European Organization for Research and Treatment of Cancer protocols. J Clin Oncol 1993; 11: 225–232. 10. 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 1990; 8: 623–629. 11. Healey EA, Tarbell NJ, Kalish LA et al. Prognostic factors for patients with Hodgkin disease in first relapse. Cancer 1993; 71: 2613–2620. 12. Canellos GP, Young RC, DeVita VT. Combination chemotherapy for advanced Hodgkin’s disease in relapse following extensive radiotherapy. Clin Pharmacol Ther 1972; 13: 750–754. 13. 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 1988; 62: 233–239. 14. Timothy AR, Sutcliffe SB, Wrigley PF, Jones AE. Hodgkin’s disease: combination chemotherapy for relapse following radical radiotherapy. Int J Radiat Oncol Biol Phys 1979; 5: 165–169. 15. Canellos GP, Arseneau JC, DeVita VT et al. Second malignancies complicating Hodgkin’s disease in remission. Lancet 1975; 1: 947– 949. 16. Santoro A, Viviani S, Villarreal CJ et al. Salvage chemotherapy in Hodgkin’s disease irradiation failures: superiority of doxorubicincontaining regimens over MOPP. Cancer Treat Rep 1986; 70: 343– 348. 17. Fisher R, De VV, Hubbard S et al. Prolonged disease-free survival in Hodgkin’s disease with MOPP reinduction after first relapse. Ann Intern Med 1979; 90: 761–765. 18. Longo D, Duffey P, Young R et al. Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin’s disease after combination chemotherapy: the low probability for cure. J Clin Oncol 1992; 10: 210–218. 19. Bonfante V, Santoro A, Viviani S et al. Outcome of patients with Hodgkin’s disease failing after primary MOPP/ABVD. J Clin Oncol 1997; 15: 528–534. 20. Josting A, Rueffer U, Franklin J et al. Procnostic factors and treatment outcome in primary progressive Hodgkin’s lymphoma—a report from the German Hodgkin’s Lymphoma Study Group (GHSG). Blood 2000; 96: 1280–1286. 21. Linch D, Winfield D, Goldstone A et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomised trial. Lancet 1993; 341: 1051–1054. 22. Schmitz N, Sextro M, Pfistner B et al. High-dose therapy (HDT) followed by hematopoietic stem cell transplantation (HSCT) for
116 relapsed chemosensitive Hodgkin’s disease (HD): final results of a randomized GHSG and EBMT trial (HD-R1). Proc Am Soc Clin Oncol 1999; 18 : 18a (Abstr 5). 23. Lohri A, Barnett M, Fairey RN et al. Outcome of treatment of first relapse of Hodgkin’s disease after primary chemotherapy: identification of risk factors from the British Columbia experience 1970 to 1988. Blood 1991; 77: 2292–2298. 24. Fermé C, Bastion Y, Lepage E et al. The MINE regimen as intensive salvage chemotherapy for relapsed and refractory Hodgkin’s disease. Ann Oncol 1995; 6: 543–549. 25. Reece D, Barnett M, Shepherd J et al. High-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16–213) with or without
cisplatin (CBV +/– P) and autologous transplantation for patients with Hodgkin’s disease who fail to enter a complete remission after combination chemotherapy. Blood 1995; 86: 451–458. 26. Brice P, Bastion Y, Divine M et al. Analysis of prognostic factors after the first relapse of Hodgkin’s disease in 187 patients. Cancer 1996; 78: 1293–1299. 27. 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 2002; 20: 221–230.
Symposium article
Prognostic factors and treatment outcome in patients with primary progressive and relapsed Hodgkin’s disease A. Josting1*, A. Engert1, V. Diehl1 & G. P. Canellos2 1
Department of Internal Medicine I, University Hospital Cologne, Germany, and the German Hodgkin Lymphoma Study Group (GHSG); Department of Adult Oncology, Dana Faber Cancer Institute, Boston, MA, USA
2
Introduction Depending on stage and risk factor profile, up to 95% of patients with Hodgkin’s disease (HD) at first presentation reach complete remission (CR; disappearance of all detectable clinical and radiographic evidence of disease) after standard treatment [1]. Depending on their initial treatment, those patients relapsing have different treatment options, including radiotherapy for localized disease in previously non-irradiated areas, conventional salvage chemotherapy, or high-dose chemotherapy (CT) followed by autologous stem cell transplantation (autoSCT) [2, 3]. Conventional CT is the treatment of choice for patients relapsing after initial radiotherapy for early stage HD. The survival of these patients is at least equal compared with advanced-stage patients initially treated with CT [4]. In contrast, patients with relapsed HD after primary CT generally have a poorer prognosis. The therapeutic options include salvage radiotherapy, salvage CT, and high-dose CT with autoSCT. More recently, new approaches such as sequential highdose CT, tandem high-dose CT, allogeneic (allo) SCT, or nonmyeloablative conditioning with allogeneic blood progenitor cell transplantation (‘mini-transplants’) have been investigated in relapsed HD [4–6]. Since more aggressive approaches are associated with increased toxicity, an accurate pretreatment prognostic assessment of patients is required to help selection of the most appropriate therapeutic regimen.
Prognostic factors in patients relapsing after primary radiotherapy Primary radiotherapy is now used less often in the treatment of localized HD. It has been replaced by combined modality therapy, where various numbers of cycles of combined CT are given prior to lower dose radiotherapy, which is limited to the involved field rather than being extensive, as in the past. Combined modality therapy has reduced the relapse rate to <10%
*Correspondence to: Dr A. Josting, Department of Internal Medicine I, University Hospital Cologne, Joseph-Stelmann-Str. 9, D-50924 Cologne, Germany. Tel: +49-221-478-3745; Fax: +49-221-478-3577; E-mail: [email protected] © 2002 European Society for Medical Oncology
in patients presenting with clinical stage I/IIA. In the future, CT alone may replace combined modality treatment. Currently, this is the subject of a number of prospective controlled trials. The general relapse rate following primary radiotherapy averages between 30 and 35% [7–9]. With more intense staging procedures, including laparotomy and splenectomy, the proportion of those relapsing seems to be lower (20–25%) [10, 11]. The majority of relapses occur within 3 years of radiotherapy, although late relapse after 4 years or more have been noted to occur in the range of 5–7% [8, 9]. This small fraction of late recurrence is noteworthy, since this is generally a more favorable prognostic group when treated with systemic therapy. In fact, their overall survival (OS) is not different from those patients who never relapse [8, 9]. The majority of patients in relapse following radiotherapy are treated with systemic combination CT, often with the inclusion of involved-field radiotherapy if a nodal site was previously unirradiated. The general patterns of recurrence, especially after extensive radiation such as subtotal nodal irradiation, is more often in unirradiated visceral sites with 30–40% of relapses in stage III/IV [10, 11]. The long-term survival of patients ranges significantly according to the pattern of relapse. Three major prognostic factors for response to second-line therapy include age (>40 or 50 years), stage at relapse and the type of therapy used for the treatment of relapse, i.e. CT alone or CT and radiation (Table 1). In some serious mixed cellularity or lymphoid-depleted history were also negative prognostic factors. Second-line therapy for radiation relapse has been quite successful in most series with long-term follow-up, demonstrating a 10-year relapse-free survival of 60% (Table 1). The overall salvage of unirradiated nodal-only relapse is superior to symptomatic disseminated recurrence [7, 10]. Royal Marsden Hospital series indicated that age, histology and nodal versus extranodal relapse determined the sucess of second-line treatment. In that series, the relapse-free survival at 10 years was 63%; however, nodal recurrence had a 10-year survival rate of 74% compared with 51% for those with an extranodal relapse [7]. With relatively small numbers, the Stanford series suggested that combined modality therapy has a better 10-year progression-free rate than CT alone (62% versus 37%),
113 Table 1. Prognostic factors: salvage after relapse from radiotherapy (multivariate analysis) Series
Significant factors
10-year survival from relapse (%)
Royal Marsden (473 patients) [7]
Age (>40 years), unfavorable histology, extranodal relapse
63
Stanford (109 patients) [10]
Age (>50 years), stage II, IIIA/B or IV, treatment (CMT versus CT)
57
Harvard Joint Center (138 patients) [11]
Unfavorable histology
62
CMT, combined modality treatment; CT, chemotherapy.
especially in patients with more advanced stages at relapse (stages IIA–IV) [10]. Isolated stage IA relapse has a markedly high salvage rate (∼90%) as opposed to patients in stage IIIB and IV, where the long term salvage rate is ∼30%. Differences between types of salvage therapy—mainly CT alone versus combined modality—have not been corrected for the patterns of relapse. It is understandable that nodal relapses might be better treated with combined modality therapy as opposed to disseminated IIIB or IV recurrences, where the addition of radiotherapy might not be an advantage. Patients with a bulky mediastinal mass treated with radiation therapy alone have at least a 50% recurrence rate, compared with patients without mediastinal bulk, who have much more favorable freedom from progression. However, it is noteworthy that in most series the OS is similar, attesting to the potential value of systemic CT alone in the setting of relapse at this bulky site. The second-line combination CT used initially was the classical MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) or its variant MVPP (with vinblastine instead of vincristine) [12–14]. A high rate of CR was achieved in the range of 70–85%. There were, however, some secondary leukemias resulting from the alkylating agents contained in these regimens [14, 15]. The introduction of ABVD (doxurubicin, bleomycin, vinblastine, dacarbazine) as a primary systemic treatment for newly diagnosed advanced disease or disease in relapse from primary radiation demonstrated equivalence to MOPP. ABVD is associated with fewer secondary leukemias, resulting in its widespread use [1]. In the Milan series, a historical comparison of doxurubicin-containing regimens suggested that they were superior to MOPP in the setting of radiation relapse [16]. In most series, CT regimens have not been compared prospectively in the setting of relapse from primary radiation therapy. Although ABVD has generally replaced MOPP as the salvage CT of choice, some caution is indicated in patients with prior extensive thoracic irradiation requiring special attention to cardiac and pulmonary function. Patients who relapse from second-line therapy are often candidates for high-dose CT with stem-cell support. The salvage of relapsing patients is likely to get better than the 60% level with the potential for earlier diagnosis with
more sensitive diagnostic techniques such as PET scans. In addition, for those who fail conventional-dose salvage CT, high-dose therapy can still result in long-term disease-free survival in a further 30–50%.
Prognostic factors in patients relapsing after primary CT It was first noted in 1979 that the length of remission after first-line CT had a marked effect on the ability of patients to respond to subsequent salvage treatment [17]. In 1992 the National Cancer Institute (NCI) updated their experience with the long-term follow-up of patients who relapsed after polychemotherapy [18]. Derived primarily from investigations involving failures after MOPP and MOPP variants, the conclusions are relevant to other CT programs. On this basis, CT failures can be divided into three subgroups: • Primary progressive HD (∼10% of all cases), i.e. patients who never achieved a CR • Early relapses within 12 months of CR (∼15% of all cases) • Late relapses after CR lasting >12 months (∼15% of all cases) Using conventional CT for patients with primary progressive disease, virtually no patient survives >8 years. In contrast, the projected 20-year survival for patients with early relapse or late relapse was 11 and 22%, respectively [18].
Primary progressive HD Patients with primary progressive HD, defined as progression during induction treatment or within 90 days after the end of treatment, have a particularly poor prognosis. Treatment of patients with primary progressive HD has consisted of salvage CT, radiotherapy, and high-dose CT with autoSCT. Conventional salvage regimens have given disappointing results in the vast majority of patients: response to salvage treatment is low and the duration of response is often short. The 8-year OS ranges between 0 and 8%. Freedom from treatment failure (FFTF) in second remission is 0% at 4–8 years in small series reported [18, 19]. Extensive disease often limits the use of radiotherapy. The German Hodgkin’s Lymphoma Study Group (GHSG) retrospectively analyzed 206 patients with progressive disease to determine outcome after salvage therapy and identify prognostic factors [20]. The 5-year freedom from second failure (FF2F) and OS for all patients was 17 and 26%, respectively. As reported from transplant centers, the 5-year FF2F and OS for patients treated with high-dose CT was 42 and 48%, respectively, but only 33% of all patients received high-dose CT. A high proportion of those patients will rapidly succumb to progressive disease. Life-threatening severe toxicity upon salvage treatment occurred in 11% of patients. Insufficient stem-cell harvest, poor performance status and older age also contributed to ineligibility for high-dose CT. In a multivariate
114 analysis, Karnofsky performance score at progress (P <0.0001), age (Cox regression P = 0.019) and attainment of a temporary remission to first-line CT (P = 0.0003) were significant prognostic factors for survival. Patients with none of these risk factors had a 5-year OS of 55%, compared with 0% for patients with all three of these unfavorable prognostic factors (Table 2). In conclusion, high-dose CT is an effective treatment for a proportion of patients with primary progressive HD. Owing to the poor outcome of HD patients with progressive disease, future trials must aim to identify patients at very high risk for induction failure and to modify at primary treatment in this group to avoid progressive disease.
Early and late relapsed HD The overall prognosis is worse for patients relapsing after first-line CT when treated with conventional CT. At present, high-dose CT followed by autoSCT is the treatment of choice for patients with relapsed HD after first-line polychemotherapy. Two randomized studies performed by the British National Lymphoma Investigation (BNLI) and the GHSG/European Bone-Marrow Transplant Registry (EBMT) (HDR-1) have shown improved outcome in patients with relapsed HD treated with high-dose CT [21, 22]. Although the results reported with high-dose CT in patients with late relapse have been superior to those reported in most series of conventional CT, the use of high-dose CT in late relapses had been an area of controversy. Patients with late relapse have satisfactory second CR rates when treated with conventional CT, with OS ranging from 40 to 55%. However, the HDR-1 trial of the GHSG showed improved FFTF after high-dose CT compared with conventional CT in patients with late relapse. Therefore, high-dose CT should be considered as standard treatment for all patients with previous CT, including those with late relapse. Although these results indicate the superiority of high-dose CT compared with conventional CT in patients with relapsed HD, a proportion of patients with early relapse will develop recurTable 2. Predicted OS by prognostic factor distribution in patients with primary progressive HD Age (years)
Temporary remission
Karnofsky performance score
Percentage of patients
Predicted OS at 36 months
≤50
Yes
≥90
49
55
<90
15
23
≤50
No
≥90
16
25
<90
6
3
>50
Yes
≥90
5
34
<90
4
7
>50
No
≥90
3
8
<90
2
0
rent disease after high-dose CT. On the other hand, a considerable number of low risk patients might be overtreated with high-dose CT. Thus, an effective assessment of prognostic factors, evaluable at the time of relapse, is required to guide the physician in selecting the most appropriate therapeutic regimen and to evaluate new experimental approaches in very high-risk relapses. Many prognostic factors have been described for patients relapsing after first-line CT. These include age, sex, histology, relapse sites, stage at relapse, B symptoms, performance status and extranodal relapse. The impact of these factors is difficult to assess because of confounding factors such as small number of patients and inclusion of primary progressive HD. In addition, multivariate analyses were not performed systematically. Lohri et al. [23] observed a favorable outcome for patients with favorable risk factors such as no stage IV at diagnosis, absence of B symptoms at relapse and initial remission duration of >12 months. The 5-year failure-free survival was 82% for those lacking all three (n = 22) and 17% for those in whom one or more risk factor was present (n = 49). Fermé et al. [24] analyzed 100 patients with relapsed or refractory HD who were treated with salvage therapy prior to high-dose therapy. By univariate analysis, patients with a long initial remission (<12 months), untreated relapse and good performance status showed improved OS. Reece et al. [25] reported an analysis on 58 patients treated with high-dose CT and autoSCT at the same institution. Four prognostic subgroups were identified according to the presence of the following parameters at relapse: B symtoms, extranodal disease and initial remission duration of <12 months. Patients with no risk factor had a 3-year progression-free survival of 100%, compared with 81% in patients with one factor, 40% in those with two factors and 0% in patients with all three factors. Brice et al. [26] performed one of the largest studies evaluating prognostic factors in relapsed HD. One-hundred and eighty-seven patients who relapsed after a first CR were included. At first relapse, treatment was conventional (CT and/or radiotherapy) in 44% and high-dose CT followed by autoSCT in 56%. Two prognostic factors were identified by multivariate analysis as correlating with both FF2F and OS. These factors were the initial duration of first remission (i.e. <12 months or >12 months; P <0.0001) and stage at relapse (I–II versus III–IV; P = 0.0013). FF2F was 62 and 32%, and OS was 44 and 87% according to the presence of no or two parameters, respectively. Laboratory data were not available in this retrospective analysis. The GHSG has recently performed a retrospective analysis including a much larger number of relapsed patients (n = 422) than previously reported. The analysis of prognostic factors suggests that the prognosis of a patient with relapsed HD can be estimated according to several factors. The most relevant factors were combined into a prognostic score. This score was calculated on the basis of duration of first remission, stage at relapse and anemia at relapse. Early recurrence within 3–12 months after the end of primary treatment, relapse stage
115 Table 3. Prognostic factors included in a prognostic score for relapsed HD (GHSG [27]) Factor
Groups with 4-year OS (%)
Duration of first remission Early relapse
47
Late relapse
73
Stage at relapse Stage III/IV
46
Stage I/II
77
Hemoglobin at relapse (g/dl) F <10.5; M <12
40
F ≥10.5; M ≥12
72
III or IV and hemoglobin at relapse (<10.5 g/dl female or <12 g/dl male) were counted in a score with possible values 0, 1, 2 and 3 in order of worsening prognosis (Table 3) [27]. This prognostic score allows one to distinguish between patients with different FF2F and OS. The actuarial 4-year FF2F and OS for patients relapsing after CT with three unfavorable factors were 17 and 27%, respectively. In contrast, patients with none of the unfavorable factors had FF2F and OS at 4-year of 48 and 83%, respectively. In addition, the prognostic score was also predictive for patients relapsing after radiotherapy, for patients relapsing after CT who were treated with conventional therapies or with high-dose CT followed by autoSCT, and for patients under 60 years and with a Karnofsky performance status ≥90% being the major candidate groups for dose intensification. Our prognostic factor score uses clinical characteristics which can be collected easily at the time of relapse. It separates groups of patients with substantially different outcomes. The prognostic factors identified may be useful to tailor the therapy for subgroups of patients, to define homogeneous cohorts for prospective randomized trials and to identify more precisely patients with high-risk relapse who should be treated with innovative approaches.
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