1 Radiation Oncology, Brigham and Womens 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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The aim of this study was to determine salvage outcome in patients with Hodgkins 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 Hodgkins disease (97 with stage III 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 Hodgkins disease at an older age.
Key words: chemotherapy, Hodgkins disease, radiation therapy, relapse, salvage therapy
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 Hodgkins disease [9, 10]. However, limited information is available on how the two regimens compare as salvage treatment for patients with relapsed Hodgkins disease after radiation therapy alone.
We have previously published results from our institution on the salvage outcome of 127 patients with Hodgkins 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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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.
|
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 KaplanMeier 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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Predictive factors for salvage outcome in the post-1980 cohort
The median follow-up time after first relapse was 17.3 years (range 722) for the 41 patients who received MOPP for salvage, and 8.3 years (range 118) 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.
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In a previously published study from our institution, 110 patients with relapsed Hodgkins 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 Hodgkins Disease showed 10-year cause-specific and overall survival rates of 70% and 58%, respectively, for clinical stage III patients who relapsed after radiation therapy, and corresponding rates of 63% and 50%, respectively, for pathological stage III 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 IIII Hodgkins 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 Hodgkins 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 Hodgkins 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 |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Roach M 3rd, Brophy N, Cox R et al. Prognostic factors for patients relapsing after radiotherapy for early-stage Hodgkins disease. J Clin Oncol 1990; 8: 623629.[Abstract]
3. Hoppe RT. The management of Hodgkins disease in relapse after primary radiation therapy. Eur J Cancer 1992; 28A: 19201922.[ISI][Medline]
4. Healey EA, Tarbell NJ, Kalish LA et al. Prognostic factors for patients with Hodgkin disease in first relapse. Cancer 1993; 71: 26132620.[ISI][Medline]
5. Specht L, Horwich A, Ashley S. Salvage of relapse of patients with Hodgkins disease in clinical stages I or II who were staged with laparotomy and initially treated with radiotherapy alone. A report from the international database on Hodgkins disease. Int J Radiat Oncol Biol Phys 1994; 30: 805811.[ISI][Medline]
6. Horwich A, Specht L, Ashley S. Survival analysis of patients with clinical stages I or II Hodgkins disease who have relapsed after initial treatment with radiotherapy alone. Eur J Cancer 1997; 33: 848853.[CrossRef][Medline]
7. Santoro A, Bonfante V, Bonadonna G. Salvage chemotherapy with ABVD in MOPP-resistant Hodgkins disease. Ann Intern Med 1982; 96: 139143.[ISI][Medline]
8. Piga A, Ambrosetti A, Todeschini G et al. Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) salvage of mechlorethamine, vincristine, prednisone, and procarbazine (MOPP)-resistant advanced Hodgkins disease. Cancer Treat Rep 1984; 68: 947951.[ISI][Medline]
9. Canellos GP, Anderson JR, Propert KJ et al. Chemotherapy of advanced Hodgkins disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992; 327: 14781484.[Abstract]
10. Carde P, Hagenbeek A, Hayat M et al. Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage Hodgkins disease: the H6 twin randomized trials from the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 1993; 11: 22582272.[Abstract]
11. Mauch P, Goodman R, Hellman S. The significance of mediastinal involvement in early stage Hodgkins disease. Cancer 1978; 42: 10391045.[ISI][Medline]
12. Prosnitz LR, Curtis AM, Knowlton AH et al. Supradiaphragmatic Hodgkins disease: significance of large mediastinal masses. Int J Radiat Oncol Biol Phys 1980; 6: 809813.[ISI][Medline]
13. Lee CK, Bloomfield CD, Goldman AI et al. Prognostic significance of mediastinal involvement in Hodgkins disease treated with curative radiotherapy. Cancer 1980; 46: 24032409.[ISI][Medline]
14. Bosi A, Ponticelli P, Casini C et al. Clinical data and therapeutic approach in elderly patients with Hodgkins disease. Haematologica 1989; 74: 463473.[ISI]
15. Diaz-Pavon JR, Cabanillas F, Majlis A et al. Outcome of Hodgkins disease in elderly patients. Hematol Oncol 1995; 13: 1927.[ISI][Medline]
16. Weekes CD, Vose JM, Lynch JC et al. Hodgkins disease in the elderly: improved treatment outcome with a doxorubicin-containing regimen. J Clin Oncol 2002; 20: 10871093.
17. Kim HK, Silver B, Li S et al. Hodgkins disease in elderly patients (> or =60): clinical outcome and treatment strategies. Int J Radiat Oncol Biol Phys 2003; 56: 556560.[ISI][Medline]
18. Santoro A, Viviani S, Villarreal CJ et al. Salvage chemotherapy in Hodgkins disease irradiation failures: superiority of doxorubicin-containing regimens over MOPP. Cancer Treat Rep 1986; 70: 343348.[ISI][Medline]
19. Noordijk E, Carde P, Hagenbeek A et al. Combination of radiotherapy and chemotherapy is advisable in all patients with clinical stage III Hodgkins disease. Six-year results of the EORTC-GPMC controlled clinical trials H7-VF, H7-F and H7-U. Proceedings of the Thirty-ninth Annual ASTRO Meeting, Orlando, FL 1997. 39 (suppl 2): 173.
20. Hoppe RT, Coleman CN, Cox RS et al. The management of stage III Hodgkins disease with irradiation alone or combined modality therapy: the Stanford experience. Blood 1982; 59: 455465.[Abstract]
21. Noordijk EM, Carde P, Mandard AM et al. Preliminary results of the EORTC-GPMC controlled clinical trial H7 in early-stage Hodgkins disease. EORTC Lymphoma Cooperative Group. Groupe Pierre-et-Marie-Curie. Ann Oncol 1994; 5: 107112.[Medline]
22. Specht L, Gray RG, Clarke MJ et al. Influence of more extensive radiotherapy and adjuvant chemotherapy on long-term outcome of early-stage Hodgkins disease: a meta-analysis of 23 randomized trials involving 3,888 patients. International Hodgkins Disease Collaborative Group. J Clin Oncol 1998; 16: 830843.[Abstract]
23. Press OW, LeBlanc M, Lichter AS et al. Phase III randomized intergroup trial of subtotal lymphoid irradiation versus doxorubicin, vinblastine, and subtotal lymphoid irradiation for stage IA to IIA Hodgkins disease. J Clin Oncol 2001; 19: 42384244.
24. Valagussa P, Santoro A, Fossati-Bellani F et al. Second acute leukemia and other malignancies following treatment for Hodgkins disease. J Clin Oncol 1986; 4: 830837.[Abstract]
25. Kaldor JM, Day NE, Clarke EA et al. Leukemia following Hodgkins disease. N Engl J Med 1990; 322: 713.[Abstract]
26. Andrieu J, Ifrah N, Payen C et al. Increased risk of secondary acute nonlymphocytic leukemia after extended-field radiation therapy combined with MOPP chemotherapy for Hodgkins disease. J Clin Oncol 1990; 8: 11481154.[Abstract]
27. van Leeuwen FE, Chorus AM, van den Belt-Dusebout AW et al. Leukemia risk following Hodgkins disease: relation to cumulative dose of alkylating agents, treatment with teniposide combinations, number of episodes of chemotherapy, and bone marrow damage. J Clin Oncol 1994; 12: 10631073.[Abstract]
28. Viviani S, Santoro A, Ragni G et al. Gonadal toxicity after combination chemotherapy for Hodgkins disease. Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol 1985; 21: 601605.[ISI][Medline]
29. Bokemeyer C, Schmoll HJ, van Rhee J et al. Long-term gonadal toxicity after therapy for Hodgkins and non-Hodgkins lymphoma. Ann Hematol 1994; 68: 105110.[ISI][Medline]