Comparison of MOPP versus ABVD as salvage therapy in patients who relapse after radiation therapy alone for Hodgkin’s disease

A. K. Ng1,*, S. Li2, D. Neuberg2, B. Silver1, M. A. Stevenson3, D. C. Fisher4 and P. M. Mauch1

1 Radiation Oncology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA; 2 Biostatistical Sciences and 4 Adult Oncology, Dana-Farber Cancer Institute, Boston, MA; 3 Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA

Received 17 September 2003; accepted 28 October 2003


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

The aim of this study was to determine salvage outcome in patients with Hodgkin’s disease who relapse after radiation therapy, and to compare the efficacy of mechlorethamine, Oncovin, procarbazine and prednisone (MOPP) versus Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) as salvage treatment.

Patients and methods:

One hundred patients with Hodgkin’s disease (97 with stage I–II disease at presentation) who relapsed after radiation therapy alone were salvaged with either MOPP or ABVD. Freedom from second relapse (FFSR) and overall survival (OS) were determined, and prognostic factors for salvage outcome were evaluated.

Results:

The median follow-up time since salvage therapy was 12 years. The 10-year FFSR and OS rates were 70% and 89%, respectively. Forty-one patients were salvaged with MOPP and 59 received ABVD. The type of salvage chemotherapy did not significantly influence FFSR or OS. Age >50 years at initial diagnosis was the only significant predictor for an inferior FFSR and OS on both univariate and multivariate analyses.

Conclusions:

The two salvage regimens of MOPP and ABVD had similar efficacy in this group of patients with predominantly early-stage disease at initial radiation therapy. The inferior salvage outcome in patients aged >50 years is a contributing factor to the overall poor prognosis of patients presenting with Hodgkin’s disease at an older age.

Key words: chemotherapy, Hodgkin’s disease, radiation therapy, relapse, salvage therapy


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Hodgkin’s disease is one of the few cancers in which relapsed disease is associated with a reasonably good prognosis. This is especially true in patients who were initially treated with radiation therapy alone, without exposure to chemotherapy. The chance of successful salvage without having to resort to high-dose therapy with stem-cell rescue is excellent in these patients. A number of studies have reviewed the outcome of conventional-dose salvage therapy in patients with relapsed Hodgkin’s disease after radiation therapy alone [16]. These studies have examined potential prognostic factors, including initial disease characteristics, time to relapse and characteristics of relapsed disease. However, less information is available on the influence of the type of salvage chemotherapy regimen on the long-term treatment outcome.

The Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) regimen was initially introduced as a form of second-line therapy for patients who had a poor response to, or relapsed after, mechlorethamine, Oncovin, procarbazine and prednisone (MOPP) chemotherapy [7, 8]. Randomized studies subsequently showed that ABVD-containing regimens were superior to MOPP as first-line treatment for both advanced- and early-stage Hodgkin’s disease [9, 10]. However, limited information is available on how the two regimens compare as salvage treatment for patients with relapsed Hodgkin’s disease after radiation therapy alone.

We have previously published results from our institution on the salvage outcome of 127 patients with Hodgkin’s disease in first relapse after initial radiation therapy alone or combined modality therapy [4]. In this current update, we limited the study population to patients who relapsed after initial radiation therapy alone and received either MOPP or ABVD-based chemotherapy with or without radiation therapy as salvage. In addition to evaluating disease characteristics in predicting long-term outcome, we also compared the efficacy of the two chemotherapy salvage regimens.


    Patients and methods
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Between 1969 and 1997, 157 patients with Hodgkin’s disease who subsequently experienced a relapse were initially treated with radiation therapy alone at the Brigham and Women’s Hospital, Dana-Farber Cancer Institute or Beth Israel Deaconess Medical Center. All patients were salvaged with either MOPP or an ABVD-based chemotherapy, with or without radiation therapy. A total of 52 patients had limited relapses (excluding relapses in the lungs, liver, bone or bone marrow) outside of the initial radiation field, and would therefore have been eligible for further radiation therapy at the time of relapse. Nineteen of these patients did receive combined chemotherapy and radiation therapy as salvage, and the remaining 33 patients were treated with chemotherapy alone.

The characteristics of the 57 patients who relapsed prior to 1980 and the 100 patients who relapsed after 1980 are summarized in Table 1. Patients who relapsed before 1980 were significantly more likely to have had advanced-stage disease at initial diagnosis, mixed cellularity/lymphocyte-depleted histology, four or more sites of disease, large mediastinal adenopathy (defined as the width of the mediastinal mass greater than one-third of the maximum thoracic diameter) and extranodal disease. The differences in baseline characteristics between the two groups of patients are likely a reflection of the changes in initial treatment recommendations over time to include chemotherapy in more patients with intermediate-prognosis disease. Patients from the earlier time period were more likely to be offered radiation therapy alone, despite the presence of unfavorable features, such as advanced stage or bulky disease.


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Table 1. Characteristics of pre- and post-1980 patients according to salvage regimen
 
For salvage therapy, patients who relapsed prior to 1980 received predominantly MOPP at the time of relapse (92%). After 1980, ABVD became a more widely used salvage regimen, with 59% of patients receiving ABVD at the time of relapse. Because of the differences in initial presentation, as well as distribution of type of salvage therapy between patients from the two time periods, their treatment outcomes were analyzed separately.

Freedom from second relapse (FFSR), defined as time from the end of salvage treatment to second relapse, and overall survival (OS), defined as time from the end of initial treatment to death or end of follow-up, were estimated using the Kaplan–Meier technique. In identifying prognostic factors for treatment outcome, including comparing the efficacy of the two chemotherapy salvage regimens, only the 100 patients from the later time period were included in the analysis to ensure more uniform baseline characteristics and a comparable length of follow-up time between the two salvage groups. Survival curves were compared using log rank tests. Cox proportional regression models were used to evaluate potential predictive factors. Variables analyzed were: age at diagnosis, histology, number of initial sites, time to first relapse, relapse stage, extranodal disease at time of relapse and salvage chemotherapy regimen. P-values ≤0.05 were considered statistically significant. All the tests were two-sided.


    Results
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Treatment outcome in the pre-1980 cohort
For the 57 patients who had a relapse prior to 1980, the median follow-up time since the end of initial radiation therapy was 27 years (range 16–30). The median time to first relapse after radiation therapy was 2.4 years (range 0.4–9), and the median follow-up time since salvage therapy was 26 years (range 12–28). Fifty-two of the 57 patients received MOPP for salvage and five received ABVD. The 10-year FFSR rate was 58%. The 10- and 15-year OS rates were 46% and 40%, respectively (Figure 1A and B). Among 43 patients who initially presented with clinical stage I–II disease and subsequently relapsed, the 10-year FFSR and OS rates were 58% and 47%, respectively. For the 14 patients who had clinical stage III–IV disease at initial presentation, the 10-year FFSR and OS rates were 56% and 43%, respectively (P = 0.85 for FFSR; P = 0.35 for OS). Forty of the 57 patients were deceased at the time of last follow-up, 27 from Hodgkin’s disease, five from second malignancies, six from cardiac causes and two from other causes.



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Figure 1. (A) Freedom from second relapse in the pre-1980 cohort and post-1980 cohort. (B) Overall survival in the pre-1980 cohort and post-1980 cohort.

 
Treatment outcome in the post-1980 cohort
One hundred patients with Hodgkin’s disease initially treated with radiation therapy alone subsequently experienced a relapse between 1980 and 1997. Forty-one patients were salvaged with MOPP and 59 received an ABVD-containing regimen. The median follow-up time since the end of radiation therapy was 16 years (range 2–31), the median time to first relapse after initial radiation therapy was 2.8 years (range 0–25) and the median follow-up time since salvage therapy was 12 years (range 1–22) for all patients. Forty-one of the 100 patients received MOPP for salvage, and 59 received ABVD. The 10-year FFSR rate was 70%. The 10- and 15-year OS rates were 89% and 78%, respectively (Figure 1A and B). There was a total of 24 deaths. Causes of death were Hodgkin’s disease in nine patients, second malignancy in 10, cardiopulmonary disease in three and other in two.

Predictive factors for salvage outcome in the post-1980 cohort
The median follow-up time after first relapse was 17.3 years (range 7–22) for the 41 patients who received MOPP for salvage, and 8.3 years (range 1–18) for the 59 patients who received ABVD. On univariate analysis, the treatment outcome was not significantly influenced by the type of salvage chemotherapy regimen. The 10-year FFSR rates for patients who received MOPP at the time of relapse and those who were salvaged with ABVD were 72% and 68%, respectively (P = 0.62, log rank test) (Figure 2). The 10-year OS rates for the two salvage groups were 85% and 92%, respectively (P = 0.64, log rank test) (Figure 3). We also compared the treatment results of the 19 patients who received combined modality therapy as salvage with the 33 patients who would have been candidates for further radiation therapy but received chemotherapy only. There were no significant differences between these two groups with regard to both FFSR (P = 0.74) and OS (P = 0.94). The only factor that significantly predicted for salvage outcome on univariate analysis was the age at initial diagnosis. Patients who were >50 years old at presentation had a significantly lower FFSR (5-year FFSR rates 55%, compared with 83% for younger patients; P = 0.001, log rank test) and OS (10-year OS rates 71%, compared with 91%; P = 0.001, log rank test). On multivariate analysis, age >50 years significantly predicted for inferior FFSR [hazard ratio (HR) 9.1; P = 0.0001] and OS (HR 8.5; P = 0.001). None of the remaining factors, including histology, number of initial sites, time to first relapse, relapse stage, extranodal disease at relapse and type of salvage regimen, were significant.



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Figure 2. Freedom from second relapse in patients who received MOPP versus ABVD as salvage therapy (P = 0.62).

 


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Figure 3. Overall survival in patients who received MOPP versus ABVD as salvage therapy (P = 0.64).

 
Second malignancy in the post-1980 cohort
A total of 23 second malignancies were observed, of which 22 occurred after relapse and salvage therapy (one skin cancer occurred prior to relapse). Of the 41 patients who received MOPP as salvage treatment, 12 (29.3%) developed a second malignancy: two cases of leukemia, one non-Hodgkin’s lymphoma and nine solid tumors. Of the 59 patients salvaged with ABVD, 11 (18.6%) developed a second malignancy: one case of leukemia, two non-Hodgkin’s lymphomas and eight solid tumors. The cumulative risks of developing a second malignancy in the two salvage groups are displayed in Figure 4; the differences were not significant (P = 0.65). Details of the types of second malignancies by salvage treatment are displayed in Table 2.



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Figure 4. Cumulative incidence of second malignancy in patients who received MOPP versus ABVD as salvage therapy (P = 0.65).

 

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Table 2. Types of second malignancy by salvage therapy in the post-1980 cohort
 

    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patients with relapsed Hodgkin’s disease after initial radiation therapy alone have an excellent prognosis with salvage treatment consisting of conventional-dose combination chemotherapy. The results were especially favorable among patients from the more recent cohort. For the 100 patients who relapsed between 1980 and 1997, the 10-year FFSR and OS rates were 70% and 89%, respectively. Patients salvaged with MOPP and those who received ABVD at the time of relapse had similar outcomes.

In a previously published study from our institution, 110 patients with relapsed Hodgkin’s disease initially treated with radiation therapy alone were found to have 10-year FFSR and OS rates of 58% and 62%, respectively [4]. At Stanford University, the 10-year FFSR and OS rates were both 57% in patients who relapsed after radiation therapy alone [2]. The International Database on Hodgkin’s Disease showed 10-year cause-specific and overall survival rates of 70% and 58%, respectively, for clinical stage I–II patients who relapsed after radiation therapy, and corresponding rates of 63% and 50%, respectively, for pathological stage I–II patients. In the current study, the salvage outcome of the more recent cohort of patients is notably better than that of the earlier patients, and the results are also superior to those of the other series. This may be because patients in our study who were treated in the earlier era were more likely to have presented with advanced-stage disease and/or large mediastinal adenopathy, characteristics that would preclude the use of radiation therapy alone by current standards [1113]. The findings suggest that patients with unfavorable features treated with radiation therapy alone are not only at a higher risk of relapse, but the chance of successful salvage after relapse is also diminished.

In evaluating prognostic factors for salvage outcome in our more recent patient cohort, the only significant predictor was age at diagnosis. None of the remaining factors evaluated, including initial histology, number of sites, time to relapse, relapse disease characteristics and type of salvage therapy, significantly predicted for treatment results. In the other series, which included patients from all time periods, several factors were identified that predicted salvage outcome in patients who relapsed after radiation therapy alone. These included age at diagnosis [2, 46], histology [4, 5], extranodal relapse [6], relapse stage [2] and the addition of radiation therapy to the salvage treatment [2]. However, age at diagnosis is the only factor that has consistently been shown to significantly influence salvage outcome in all studies. It has been well-documented in the literature that older age at diagnosis is associated with poor outcome in newly diagnosed patients [1417]. Our results indicate that one of the key contributing factors to the overall inferior prognosis in older patients is probably their lower probability of successful salvage after relapse.

In our study comparing MOPP and ABVD as salvage therapy in the post-1980 cohort, we attempted to minimize bias associated with longer follow-up time and poorer presenting features in the MOPP group by excluding the earlier patient cohort from the analysis. However, there was still some imbalance between the two salvage groups, biasing against patients who received MOPP. Despite this, MOPP and ABVD were still found to have similar efficacy as salvage treatments. Our findings are in contrast to those reported by Santoro et al. [18], who compared MOPP with doxorubicin-containing regimens in 122 consecutive patients with stage I–III Hodgkin’s disease who relapsed after definitive radiation therapy. In their study, the disease characteristics at initial presentation and at the time of relapse were comparable between the two salvage groups. The authors found a significantly lower freedom from disease progression (42% versus 73%), relapse-free survival (54% versus 81%) and OS (44% versus 80%) in patients who received MOPP after irradiation failure.

A potential explanation for the discrepancy between our findings and the results of the study by Santoro et al. [18] is differences in initial disease presentation. Patients in our post-1980 cohort mostly had early-stage, favorable-prognosis disease at initial diagnosis. In patients with newly diagnosed Hodgkin’s disease, the superiority of ABVD-based chemotherapy over MOPP had been demonstrated only in patients with advanced-stage disease and patients with early-stage, unfavorable-prognosis disease, but not in patients with early-stage, favorable-prognosis disease [9, 10]. In the European Organisation for Research and Treatment of Cancer H7 trial, the MOPP/ABV hybrid regimen was superior to the monthly (epirubicin, bleomycin, vinblastine and prednisone) EBVP II regimen among unfavorable-prognosis patients, while patients with favorable-prognosis disease had excellent treatment results with EBVP II and involved-field radiation therapy [19]. These findings suggest that for both newly diagnosed patients and for patients who relapse after initial radiation therapy, the type of chemotherapy regimen may significantly influence treatment results for patients with advanced-stage or unfavorable-prognosis disease. However, patients with favorable-prognosis, early-stage disease at presentation have such an excellent prognosis with combination chemotherapy, either as initial treatment or as salvage therapy, that the type of regimen has little impact on the overall outcome.

In the current treatment of early-stage Hodgkin’s disease, combined modality therapy has largely replaced radiation therapy alone, because it affords significantly higher relapse-free survival and the ability to use smaller radiation fields [2023]. However, in determining treatment approaches, consideration should also be given to salvage potential after a relapse. Even though radiation therapy alone is associated with a higher relapse risk, the chance of successful salvage with further conventional therapy is excellent. Although we were not able to detect a significant difference in salvage outcome between MOPP and ABVD after radiation therapy failure, ABVD should remain the salvage regimen of choice, given the known acute effects, including myelosuppression, leukemogenesis and sterility, associated with MOPP [2429].


    FOOTNOTES
 
* Correspondence to: Dr A. K. Ng, 75 Francis Street, ASB1-L2, Boston, MA 02115, USA. Tel: +1-617-732-6310; Fax: +1-617-732-7347; E-mail: ang{at}lroc.harvard.edu Back


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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
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