Autografting

Front-line high-dose therapy with autologous stem cell transplantation for high risk Hodgkin's disease: comparison with combined-modality therapy

Abstract

This retrospective study compares high-dose therapy (HDT) with autologous stem cell transplantation and combined-modality treatment (CT) as a first-line therapy for Hodgkin's disease (HD) for patients with both a clinical stage (CS) IV and/or a mediastinal mass 0.45 of the thoracic diameter (MM 0.45) at diagnosis, and an incomplete response after the first-line chemotherapy. Data on 42 grafted patients (GP) in Nantes Hospital, France and on 108 combined-modality treated patients (CTP) from two protocols of the GOELAMS group, France (POF 81 and H90) was analyzed. Both groups were comparable except for pulmonary disease in excess in the grafted group (P = 0.01). Among GP, 95% were in complete response at the end of first-line treatment and 77% among CTP. Median follow-up was 53 months (range, 7 to 128 months) for GP and 88 months (range, 25 to 181 months) for CTP. The 5-year freedom from progression (FFP) and event-free survival (EFS) rates were better for GP (87% vs 55% for FFP: P = 0.0004 and 81% vs 51% for EFS: P = 0.0004) whereas the overall survival (OS) rates did not differ significantly (85% for GP vs 71% for CTP: P = 0.06). Similar results were obtained for the groups with a response 50% after initial chemotherapy: 91% vs 65% for FFP, P = 0.01; 87% vs 61% for EFS, P = 0.02; and 92% vs 77% for OS, P = 0.2; and for the groups with a response <50%: 80% vs 22% for FFP, P = 0.0003; 72% vs 13% for EFS, P = 0.0001; and 76% vs 46% for OS, P = 0.04. This study shows a better control of the disease with HDT.

Main

There has been a dramatic improvement in the management of Hodgkin's disease during the last 40 years. Between 1960 and 1990 mortality due to this disease in the United States1 fell from 1.8 per 105 to 0.47 per 105 and the most recent 5-year survival rate is about 80%.2 However, for relapsed patients, conventional-dose salvage combination chemotherapy is not satisfactory as long-term survival is only about 20%.3 Such patient survival has been improved with the use of high-dose therapy and autologous stem cell transplantation (ASCT) that currently gives a 5-year survival of about 50%.4,5,6,7 However, these results also mean that at least half of the relapsed patients are not cured with ASCT. For this reason, ASCT has been proposed as the treatment of choice in first incomplete response (IR)8 or even in first complete response9 in a subset of patients at a high risk of relapse, the risk being defined mainly by the clinical stage (CS) and the tumor burden. Nevertheless, no study has compared ASCT with combined-modality treatment (chemotherapy + radiotherapy) in first IR. This retrospective study was undertaken to compare the outcome of a group of patients defined at diagnosis by a CS IV and/or mediastinal mass 0.45 of thoracic diameter, and autografted in first IR after 3 cycles of combination chemotherapy, with an historical group of patients with the same characteristics at diagnosis but treated without graft in first IR after three or four cycles of combination chemotherapy.

Patients and methods

Autografts

All patients autografted for Hodgkin's disease in Nantes Hospital, France between 1984 and 1999 were reviewed and all patients at diagnosis with CS IV and/or a very large mediastinal mass, ie a maximum width equal to or greater than 0.45 of the internal transverse diameter of the thorax at the level of T5–T6 (MM 0.45), and in IR after three cycles of combination chemotherapy were selected for the study. Forty-two patients who were treated between 1988 and 1998 fullfilled these criteria. All of them received three cycles of ABVD at diagnosis before assessing the response. Twenty-seven had a response 50%, 15 sustained a response <50%. All went on to receive ASCT. Some characteristics of these patients are listed in Table 1. Twenty-four patients, for whom the conditioning regimens were BEAM (16 patients) or CBV (eight patients), were irradiated (40 Gy) at sites of residual disease post transplant, mainly mediastinal. Seventeen of these 24 patients (71%) had a bulky mediastinal disease (BMD) with a MM 0.45, and 22 of them (92%) had a BMD with a MM 0.33.

Table 1 Characteristics of high-dose therapy group (ASCT, n = 42)

Combined-modality treatment

The comparison group consisted of a group of patients treated for Hodgkin's disease with combined-modality treatment (chemotherapy + radiotherapy) with curative intent. All patients from the two following protocols were reviewed: the POF (Paris-Ouest-France) 81 trial and the GOELAMS H90M multicentric randomized trial. Patients in the H81 trial were initially treated with three cycles of ABVD and then received a high-dose extended field irradiation.10,11 Patients in the H90 trial were initially treated with three or four cycles (according to a randomization) of a seven-drug combination chemotherapy and then received a high-dose extended field irradiation.12 Patients were identified through a search of the GOELAMS group's computerized Hodgkin's disease data base. We selected patients with CS IV and/or MM 0.45 at diagnosis, and in IR after initial combination chemotherapy. One hundred and eight patients fullfilled these criteria: 41 of them in the POF 81 (H81) trial who were treated between 1981 and 1988, and 67 in the GOELAMS H90M (H90) trial who were treated between 1990 and 1997. After initial chemotherapy, 85 patients had a response 50% (30 in the H81 trial, 55 in the H90 trial), and 23 had a response <50% (11 in the H81 trial, 12 in the H90 trial).

Response assessment

All patients in our study had the same assessment of response after the initial chemotherapy. This assessment included physical examination, hemogram and blood chemistry analysis, chest X-ray, thorax, abdomen and pelvis CT, bone marrow biopsy if positive at diagnosis, and technetium scintigraphy if positive at diagnosis. Neither group of patients had biopsies of residual masses or gallium scintigraphy performed after the first three or four cycles of chemotherapy. Most of the patients in our study had been treated before the gallium scintigraphy became widely accepted and validated. Incomplete responses included two groups: patients with at least a 50% decrease of all measurable lesions (response 50%) and patients with at least one measurable lesion which had decreased less than 50% (response <50%). Complete responses and progressing disease were excluded. A complete response (CR) was defined as the complete disappearance of clinical, radiological or other evidence of Hodgkin's disease, and patients with small residual radiographic abnormalities which did not progress for 6 months were also classified as CR.

High-dose therapy and chemotherapy

The three conditioning regimens were: BEAM (BCNU: 300 mg/m2 day 1; etoposide: 200 mg/m2 days 2–5; aracytine: 400 mg/m2 days 2–5 and melphalan: 140 mg/m2 day 6); CBV (cyclophosphamide: 1500 mg/m2 days 1–4; BCNU: 300 mg/m2 day 1; and etoposide: 200 mg/m2 days 2–4); and total body irradiation (TBI) of 12 G in six fractions over 3 days plus cyclophosphamide (60 mg/kg/day for 2 consecutive days).

The other main combination chemotherapies were: ABVD (doxorubicin: 25 mg/m2 day 1 and day 14; bleomycin: 10 mg/m2 day 1 and day 14; vinblastine: 6 mg/m2 day 1 and day 14; and dacarbazin: 375 mg/m2 day 1 and day 14); seven-drug combination chemotherapy that consisted of total doses of: cyclophosphamide: 4000 mg/m2; epirubicin: 240 mg/m2; vincristine: 4 mg/m2; vinblastine: 18 mg/m2; etoposide: 900 mg/m2; methotrexate: 180 mg/m2; bleomycin: 60 mg/m2; plus methylprednisolone: 500 mg/m2. This combination chemotherapy was administered for 12 weeks, in three or four cycles according to the H90 trial and all patients received the same doses.

Comparison between ABVD and seven-drug combination chemotherapy for CT patients

To assess if both treatments in the H81 and the H90 trials were comparable, we decided to compare responses after first-line treatment and FFP between both groups. After the first-line treatment, 73% of patients in the H81 trial and 79% in the H90 trial were in CR. Moreover, in the H81 trial, the 5-year FFP was 58% whereas it was 54% in the H90 trial (P = 0.9, data not shown). Taken together, these results indicate that the seven-drug combination chemotherapy was comparable to ABVD both for the response after first-line treatment and for the FFP. For this reason we considered that the whole group of CT patients was homogeneous enough to allow a comparison with the autografted patients.

Study parameters

The following information was extracted from hospital records for the autografted patients and from a computerized Hodgkin's disease data base for the conventionally treated group: age and sex at diagnosis; histology; stage of disease at diagnosis; presence of B symptoms at diagnosis; hemogram and blood chemistry characteristics at diagnosis; size of mediastinal mass at diagnosis; number of involved nodes including the spleen and number of involved visceral areas at diagnosis; response to initial combination chemotherapy and to initial complete treatment; date of relapse; date and cause of death; and secondary toxicities. The following information was collected concerning patients in the autograft group: conditioning regimens; source of autologous stem cells; post-tranplantation irradiation; and use of growth factors.

Statistical analysis

Overall survival (OS) was calculated from the date of assessment (DA), immediately after the initial chemotherapy, to the date of death from any cause or last follow-up. Freedom from progression (FFP) was calculated from DA to the date of progression, relapse or last follow-up. Event-free survival (EFS) was calculated from DA to the date of death from any cause or progression, relapse or last follow-up. Survival analyses were performed using the Kaplan and Meier method. Differences between groups were identified by generalized log-rank analysis. The distribution of variables between both groups was calculated using the chi-square test. The software used was Statistica 6.0 (Statsoft).

Results

Initial characteristics of patients

The initial characteristics of patients are listed in Tables 2 and 3. Only the incidence of pulmonary involvment differed between both groups. Occurrence of pulmonary involvment was 43% and 22% in the ASCT group and CT group respectively (P = 0.01). In the ASCT group, the majority of patients had CS IV (69%), a MM 0.45 (55%), and B symptoms (76%). In the CT group, the majority had CS IV (63%), B symptoms (70%) and 46% had a MM 0.45. Autografted patients were diagnosed more recently than patients in the CT group (Table 4) with 79% diagnosed after 1990 compared with 61% in the CT group.

Table 2 Characteristics of high-dose therapy (ASCT, n = 42) and combined-modality therapy (CT, n = 108) groups
Table 3 Initial risk factors in high-dose therapy (ASCT) and combined-modality (CT) groups
Table 4 Years of diagnosis in high-dose therapy (ASCT) and combined-modality therapy (CT) groups

Response and survival

Among the grafted patients, survival did not differ according to conditioning regimen (BEAM: n = 21 or CBV: n = 9 or TBI+Cy: n = 12): P = 0.8 for the FFP, P = 0.6 for the EFS, and P = 0.8 for the OS (data not shown). After the first-line treatment, 95% of patients were in CR in the ASCT group, and 77% in the CT group. Figure 1 shows the FFP, EFS and OS for both groups. In the ASCT group, the median follow-up was 53 months (range, 7 to 128 months); in the CT group, it was 88 months (range, 25 to 181 months). The 5-year FFP was 87% in the ASCT group and 55% in the CT group (P = 0.0004). In the ASCT group, five patients progressed or relapsed: two patients did not achieve a CR after the first-line therapy, then quickly progressed and three patients relapsed from a CR at 9, 10 and 15 months. In the CT group, 48 patients progressed or relapsed: 25 patients did not achieve a CR after the first-line therapy then quickly progressed and 23 patients relapsed from a CR between 6 and 67 months (median time = 14 months). The 5-year EFS was 81% in the ASCT group and 51% in the CT group (P = 0.0004). The 5-year OS was 85% in the ASCT group and 71% in the CT group (P = 0.06). There were five deaths in the ASCT group of which three were from disease progression, one from myocardial infarction and one from acute pulmonary embolism. There were 36 deaths in the CT group of which 20 were from disease progression, seven from infectious causes, one from myocardial infarction, two from acute myeloid leukemia, one from acute lymphoid leukemia, one from drug toxicity, one from veno-occlusive disease, one committed suicide, and two from an unknown cause.

Figure 1
figure1

Survivals in high-dose therapy (ASCT, n = 42) and combined-modality therapy (CT, n = 108) groups. Five-year FFP: 87% vs 55% (P = 0.0004); 5-year EFS: 81% vs 51% (P = 0.0004); 5-year OS: 85% vs 71% (P = 0.06).

A 50% or greater response after initial chemotherapy was sustained in 27 ASCT patients and 85 CT patients. Among all these patients we obtained comparable results with 91% vs 65% for FFP, P = 0.01; 87% vs 61% for EFS, P = 0.02; and 92% vs 77% for OS, P = 0.2 (Figure 2). The only significant difference at presentation was a higher incidence of pulmonary involvement in the ASCT group (56% vs 20%, P = 0.0004; data not shown).

Figure 2
figure2

Survivals in high-dose therapy (ACST, n = 27) and combined-modality therapy (CT, n = 85) groups, for patients with a response 50% after initial chemotherapy. Five-year FFP: 91% vs 65% (P = 0.01); 5-year EFS: 87% vs 61% (P = 0.02); 5-year OS: 92% vs 77% (P = 0.2).

Fifteen ASCT patients and 23 CT patients showed less than 50% response after initial chemotherapy. Among these patients we also observed an advantage for ASCT: 80% vs 22% for FFP, P = 0.0003; 72% vs 13% for EFS, P = 0.0001; and 76% vs 46% for OS, P = 0.04 (Figure 3). There were no significant differences among the initial characteristics between both groups.

Figure 3
figure3

Survivals in high-dose therapy (ACST, n = 15) and combined-modality therapy (CT, n = 23) groups, for patients with a response <50% after initial chemotherapy. Five-year FFP: 80% vs 22% (P = 0.0003); 5-year EFS: 72% vs 13% (P = 0.0001); 5-year OS: 76% vs 46% (P = 0.04).

Therapy after relapse or progression in the CT group

In the CT group, 48 patients relapsed (n = 23) or progressed (n = 25) after the first-line therapy. The salvage treatment is unknown for three of them. The subsequent treatment of 23 patients included high-dose therapy and ASCT; among them, we observed eight deaths (five from disease progression, two from infectious causes and one from an unknown cause) and 15 patients were still alive without relapse at the last follow-up. Among the 23 patients, 18 were treated after 1990 (in the H90 trial). The remaining 22 patients were subsequently treated with variable combinations of chemotherapy: eight received the VABEM regimen13 (vindesine, adriamycin, BCNU, etoposide, methylprednisolone) and 14 received other regimens, but all without ASCT; among them, we observed 20 deaths (11 from disease progression, five from infectious causes, two from acute myeloid leukemia, one from veno-occlusive disease and one from drug toxicity) and two patients were still alive without relapse at the last follow-up.

Non-relapse mortality

Table 5 outlines the causes of mortality in both groups. In the ASCT group, two patients (4.8%) died of non-relapse causes. One patient died at 56 months from a myocardial infarction. The conditioning regimen was TBI (12 Gy) plus cyclophosphamide and this patient did not receive any irradiation after the ASCT. The other patient died from an acute pulmonary embolism at 20 months. This followed a splenectomy performed to treat refractory autoimmune hemolytic anaemia diagnosed 14 months after ASCT.

Table 5 Mortality in high-dose therapy (ASCT) and combined-modality therapy (CT) groups

In the CT group, 14 patients (13%) died of non-relapse causes and two of unknown causes. Seven patients died from infectious causes at 4, 8, 18, 19, 19, 58 and 80 months (the last five deaths occurred after multiples courses of chemotherapy). One died from myocardial infarction at 43 months, one from drug toxicity at 10 months, two from acute myeloid leukemia (AML) at 41 and 45 months, one from acute lymphoid leukemia (ALL) at 15 months, one from veno-occlusive disease at 15 months and one committed suicide at 118 months.

Non-fatal toxicity

Table 6 shows the causes of non-fatal toxicity in both groups. In the ASCT group we observed one coronaropathy, eight VZV (varicella zoster virus) infections, two hypothyroidisms, two cases of pericarditis and two of tuberculosis. Gonadal function was not routinely evaluated, but we observed three pregnancies at 33, 50 and 80 months, among the 15 grafted females.

Table 6 Non-fatal toxicity in high-dose therapy (ASCT) and combined-modality therapy (CT) groups

In the CT group, we observed five cancers (one urethral cancer at 44 months, at the age of 24; one melanoma at 55 months, at the age of 20; two breast cancers at 73 and 79 months, at the ages of 38 and 41; and one oropharyngeal carcinoma at 116 months, at the age of 51), two coronaropathies, five cases of pulmonary fibrosis, three of mediastinal fibrosis, eight VZV infections, four cases of hypothyroidism, two of hyperthyroidisms, two cases of pericarditis and one of tuberculosis.

Second cancers

In the CT group, where the median follow-up was 88 months, the incidence of second cancers (including leukemias and solid tumors) was 19% with eight second cancers occurring at 14, 39, 41, 44, 55, 73, 79 and 116 months. With a median follow-up of 53 months, there were no second cancers in the ASCT group (P = 0.1).

Discussion

At present, the exact place (if any) of high-dose therapy with ASCT as a first-line therapy for Hodgkin's disease remains to be defined. Some teams suggested high-dose therapy immediately after initial chemotherapy in responding patients with a high risk of relapse. Carella et al9 reported such ASCT in complete remission and an overall survival of 80% with a median follow-up of 86 months. Two other reports have described ASCT in first complete response or partial response according to the Cotswold meeting.14 The first report by Fleury et al15 showed a 5-year overall survival of 92%, and the second one by Nademanee et al16 showed that all patients remained alive and in complete remission with a median follow-up of 43 months. Similar results were found by Moreau et al8 for patients in incomplete response (30 patients had a response 50% after initial chemotherapy and five patients had one <50%); indeed, they reported an 8-year overall survival of 76% with a median follow-up of 51 months. These results were encouraging but were achieved in a very selected population that makes comparison with other therapies difficult. Our study was undertaken in this setting. To our knowledge, it is the first to compare ASCT to combined-modality treatment for patients defined by CS IV and/or MM 0.45 at diagnosis and in IR after three cycles of combination chemotherapy. Our survival results indicate that ASCT is better than combined-modality treatment to control the disease (FFP: 87% vs 55%, P = 0.0004; EFS: 81% vs 51%, P = 0.0004). However, the overall survival is not significantly different (ASCT: 85% vs CT: 71%, P = 0.06). In the subset of patients with a response of 50% after initial chemotherapy, we found a similar advantage for ASCT for controlling the disease: 91% vs 65% for FFP, P = 0.01; 87% vs 61% for EFS, P = 0.02; but not for improving significantly the survival: 92% vs 77% for OS, P = 0.2. It is interesting to note that, even in responding patients (50%), the risk of progression or relapse was higher after the conventional treatment. For patients with a response <50%, ASCT allows a better control of the disease: 80% vs 22% for FFP, P = 0.0003; 72% vs 13% for EFS, P = 0.0001; and also a better survival: 76% vs 46% (P = 0.04); but the number of patients (15 vs 23) and the statistical differences are too small to draw conclusions about survival. However, the very poor results of conventional treatment for refractory diseases reported indicate that early ASCT is probably the most useful in this subset of patients.

One explanation for similar survivals in both groups, when taking into account all the patients, could be the type of salvage therapy used. Indeed, among patients who relapsed or progressed in the whole CT group (n = 48), 23 of them underwent a salvage therapy including an ASCT, resulting in the survival (without relapse) of 15 patients at the last follow-up. On the other hand, of 22 patients who received a conventional salvage therapy, only two patients were alive at the last follow-up.

One important issue when proposing high-dose therapy with ASCT as a first-line therapy is the selection of the patients. Our goal with this study was to assess the benefit, if any, of front-line intensive therapy with autologous stem cell transplantation as compared with standard treatment in comparable selected patients with Hodgkin's disease, not necessarily those with the worst prognosis. When this strategy was planned in Nantes in the 1980s, three risk factors were selected, based on available studies: CS IV at diagnosis, MM 0.45 at diagnosis, and incomplete response to the first-line chemotherapy. CS IV is a well-known unfavorable factor that was identified more particularly in four studies reporting on prognostic scores, which included a large number of patients (Hasenclever and Diehl,17 Wagstaff et al,18 Proctor et al,19 and Gobbi et al20). The second poor prognostic factor is MM 0.45 at diagnosis, that we chose as an indicator of tumor burden. Desablens et al21 and Straus et al,22 by studying prognostic factors among adults with newly diagnosed Hodgkin's disease treated with conventional chemotherapy, found MM 0.45 as being an independent unfavorable factor, and Colonna et al10 also demonstrated its independent impact on prognosis. This factor was not identified by Hasenclever and Diehl in the prognostic score for advanced Hodgkin's disease. This may be due, as stated by the authors, to the lack of precise information on that item for many patients. However the results of the univariate analysis show a rate of FFP and OS for the 176 patients with ‘a very large’ mediastinal mass of 56% ± 4 and 68% ± 4, respectively, and these results are at most comparable to those observed in patients with the worst values of the factors incorporated in the final model. The third unfavorable factor considered in our study is an incomplete response after the first-line chemotherapy. Three studies published in 198323 and 198724,25 showed that the response to initial chemotherapy could provide a prognostic factor that might serve to delineate a high risk group of patients. More recently, Levis et al26 showed that the early response to chemotherapy evaluated after three cycles might be useful for identifying a high risk group of patients that can benefit from ASCT as the first-line therapy. In our study, none of the patients had a gallium scan or a PET scan as part of restaging after the initial courses of chemotherapy. It is thus possible that some of these patients with partial response by CT scan criteria might already have achieved remission. However, this applies equally to both groups of CT and ASCT patients and there is little chance that the proportion of remission in partial reponder patients is different between the two group of patients. Nevertheless, it is obvious that these modern tools are useful to select patients who may most benefit from ASCT.27

The benefit of ASCT cannot be explained by an unusually poor outcome in our CT group. Indeed, Canellos et al28 reported for advanced Hodgkin's disease patients a CR rate of 77% after the first-line treatment, a 5-year EFS of 60%, and a 5-year OS of 73%. Moreover, also for patients treated without graft, Hasenclever and Diehl17 reported 5-year FFP, OS of 60%, 73% for CS IV patients, and 56%, 68% for patients with an IMT 0.45. Our CT patients obtained very similar results: CR = 77%, 5-year FFP, EFS and OS of 55%, 51% and 73%.

More recent chemotherapies can now be proposed in advanced-stage Hodgkin's disease: BEACOPP, Stanford V regimen, MOPP/ABV, whose results seem particularly good. In an interim report, Diehl et al29 reported a 2-year FFTP (freedom from second treatment failure) of 84% with a median follow-up of 23 months using BEACOPP in advanced-stage Hodgkin's disease. Concerning the Stanford V regimen for patients with an MM 0.3 or stage III, IV, Horning et al30 reported a 5-year FFP and OS of 85% and 96%, respectively, with a median follow-up of 4.8 years. Moreover, an EORTC/GPMC trial published by Raemaekers et al31 showed for stage III or IV patients in PR after 6 MOPP/ABV, a 5-year FFP and OS of 75% and 87%, respectively, with a median follow-up of 43 months. Should these excellent results be confirmed with longer follow-up it will be unnecessary to discuss ASCT as part of first-line therapy.

Overall, the toxicity of ASCT was low with only two therapy-related deaths (5%). We did not observe any secondary hematological malignancy (SHM) in the ASCT group. The leukemias related to alkylating agents characteristically occur 4 to 5 years after treatment.32 Although still short, the median follow-up of 53m for the ASCT patients can be regarded as long enough to expect a very low incidence (if any) of SHM in this cohort. There is currently a general agreement that the risk of SHM after ASCT is mostly the consequence of combination chemotherapy administered before ASCT rather than the ASCT procedure itself. Indeed, Pedersen-Bjergaard et al33 first showed in a study published in 1997 that therapy-related leukemia after BEAM chemotherapy and ASCT for patients with previous chemotherapy for Hodgkin's and non-Hodgkin's lymphoma, was mainly related to the number of combination chemotherapy MOPP and not to the transplantation procedure. Two recent studies described risk factors for the development of SHM after ASCT. Harrison et al34 in 1999 found three risk factors that were number of prior combination chemotherapies, prior exposure to MOPP, and prior exposure to lomustine chemotherapy. Additionally, Pedersen-Bjergaard et al32 in 2000, showed two main risk factors, namely prior chemotherapy with large cumulative doses of alkylating agents and an age at ASCT >35 or 40 years. Patients that relapse after conventional treatment are often exposed to alkylating agents in salvage regimens before ASCT, such as mechloretamin or ifosfamid. Thus, even if patients with Hodgkin's disease with a high risk of relapse can be efficiently treated at relapse with ASCT, all data available at present indicate that such patients could have a higher risk of SHM than if they had been grafted as part of a first-line therapy.

We observed three secondary leukemias in the CT group (two AML and one ALL). The two AMLs occurred in patients who received a second-line chemotherapy for relapse.

As SHM, secondary solid tumors (SST) are a major problem in the management of Hodgkin's disease. In our study, we observed five SST in the CT group (urethra = one, melanoma = one, breast = two, tongue = one) at a median time of 73 months and none in the ASCT group but with too small a median follow-up (53 months) to draw any conclusions about SST, which can occur more than 10 years after treatment.35,36 In 1998, André et al37 published a comparative study between autografted (n = 393) and ungrafted patients (n = 1179) for Hodgkin's disease. This study showed more SST in the grafted group (15 vs 8, P = 0.001). However, these results were obtained among grafted patients with progressing or relapsing disease and 42% of grafted patients had had an extended field irradiation that is a well-known risk factor for SST.38 More particularly, patients who received mantle irradiation have a high risk of developing breast or lung cancers many years after the treatment.38,39,40 With these data, it seems reasonable to think that, for patients considered at a high risk of relapse, an initial therapeutic strategy that avoids an extended field irradiation because of an early ASCT with secondary focal irradiation could protect patients from SST without altering the chances of cure. This hypothesis cannot be clearly verified by our study because grafted patients still have too short a median follow-up to completely reassure us about future risks of SST. Moreover, even if median ages are not significantly different between both groups, we cannot exclude that some SST be related to an higher median age in the CT group (33 vs 24).

Whether or not ASCT is superior to other forms of currently available treatments programs for newly defined high risk patients remains to be evaluated in prospective trials. One such study from the GOELAMS group13 is already under way and preliminary data show no difference between the chemotherapy and the ASCT arms after a median follow-up of 20 months. The final results of this study in terms of disease control, survival and secondary malignancies are still pending.

Concerning our study, taking into account all the inherent bias to such a retrospective analysis, our conclusion is that front-line high-dose therapy with stem cell transplant provides better disease control with minimal short-term toxicity for the patients that we selected. Moreover, it seems that for such young patients, ASCT as a first-line therapy could avoid some risks of secondary malignancies because of less exposure to alkylating agents and less extended field irradiation before ASCT.

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Acknowledgements

We are indebted to the GOELAMS group, France for facilitating our access to the necessary data, and we thank Brigitte Gueglio for her skillfull assistance and Martin Pule for reviewing the manuscript.

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Correspondence to N Milpied.

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Vigouroux, S., Milpied, N., Andrieu, J. et al. Front-line high-dose therapy with autologous stem cell transplantation for high risk Hodgkin's disease: comparison with combined-modality therapy. Bone Marrow Transplant 29, 833–842 (2002). https://doi.org/10.1038/sj.bmt.1703547

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Keywords

  • Hodgkin's disease
  • first-line treatment
  • autologous stem cell transplantation
  • combined modality treatment

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