Drs. Yuen and Horning provide an excellent, detailed review of the current status of salvage therapy for patients who have relapsed after initial treatment for Hodgkin's disease. The authors cover the various scenarios that confront the oncologist who manages patients with this illness. Most patients who present with early-stage Hodgkin's disease (stage IA and IIA) are still treated with primary radiation therapy, although there is an increasing trend toward combined-modality therapy in early-stage disease. As is mentioned in the article, despite excellent complete response rates with current treatment, there is still a substantial rate of relapse, which can be as high as 25%.\n\nMost patients treated with primary radiation therapy can be salvaged with standard chemotherapy regimens for Hodgkin's disease, with excellent overall response rates. In this population, remission rates seem to be no different from those seen in patients who receive up-front treatment with combination chemotherapy.\n\nStandard-Dose Salvage Chemotherapy Options\n\nThe vast majority of patients with relapsed Hodgkin's disease have already been treated with chemotherapy. In the United States, most of these patients have been treated initially with one of three standard chemotherapy regimens: MOPP (mechlorethamine, Oncovin, procarbazine, and prednisone), ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine), or the hybrid MOPP/ABVD or alternating MOPP/ABVD regimens. The prognosis of these patients depends on a number of factors, including the tumor bulk at relapse, presence of B symptoms, and duration of complete remission, as well as other factors, such as an elevated serum lactic dehydrogenase (LDH) level, the presence of anemia, and an elevated erythrocyte sedimentation rate (ESR) [1,2]. Patients who have none of these poor prognostic factors and who have had a prolonged disease-free survival may do well with standard-dose salvage chemotherapy.\n\nMany salvage chemotherapy options are available and are listed in the article by Drs. Yuen and Horning. These include retreatment with MOPP in patients who have had a prolonged disease-free survival after initial MOPP chemotherapy . There is an increased risk of secondary leukemia in patients who have received intensive treatment with mechlorethamine and procarbazine, however. ABVD is a popular choice for salvage therapy in patients who have failed initial MOPP chemotherapy [4-7].\n\nInvestigators at the National Cancer Institute have developed the EPOCH regimen, which consists of infusional etoposide, Adriamycin, and Oncovin, along with bolus cyclophosphamide, plus prednisone. Rates of response to this regimen have ranged from 70% to 75%.\n\nInvestigators at the Dana-Farber Cancer Institute in Boston have used the combination of etoposide (300 mg/m²), vinblastine (6 mg/m²), and doxorubicin (50 mg/m²). The overall response rate was 73% in 45 eligible patients treated. The median time to treatment failure was 10 months [8,9].\n\nHigh-Dose Chemotherapy With Autologous Marrow Support\n\nHigh-dose chemotherapy followed by autologous bone marrow transplantation is now being offered to most patients with relapsed Hodgkin's disease. Phase II studies using high-dose chemotherapy with bone marrow transplantation in these patients have been very encouraging, with overall survival rates as high as 60% to 65% [9,10-12]. A randomized trial performed by the British National Lymphoma Investigation also appears to suggest a benefit of high-dose BEAM (BCNU, etoposide, ara-C, and melphalan) chemotherapy, as compared to conventional-dose BEAM, in patients with Hodgkin's lymphoma . The choice of induction chemotherapy prior to bone marrow transplantation is not yet defined.\n\nApproaches for Poor-Risk Patients With Relapsed Disease\n\nIt is known that only about half of patients with recurrent Hodgkin's disease will achieve durable disease-free survival even with a bone marrow transplant. Patients who present with poor prognostic factors, including an elevated LDH, B symptoms, or a short duration of remission, may have a salvage rate of less than 30% with bone marrow transplantation. Therefore, improvements need to be made in both pretransplant and post-transplant treatments to improve these response rates.\n\nOne approach is to use more intensive induction chemotherapy. Investigators at the Milan Cancer Institute are trying a combination of a high dose (12 g/m²) of ifosfamide (Ifex) with vinorelbine (Navelbine) at a dose of 50 mg/m² in patients with poor-risk relapsed Hodgkin's lymphoma. The early results are quite promising (Valeria Bonafante, MD, personal communication, February, 1994).\n\nA sequential high-dose chemotherapy approach similar to that used in patients with poor-risk non-Hodgkin's lymphoma can also potentially be used in Hodgkin's disease. Such an approach is being tried by Dr. Bonnadonna for initial treatment of high-risk Hodgkin's disease at the Milan Cancer Institute. As described by Dr. Bonnadonna at the Third International Symposium on Hodgkin's Lymphoma in Cologne in 1995, this approach consists of high-dose cyclophosphamide followed by high-dose etoposide and doxorubicin in a sequential fashion in patients with Hodgkin's disease A similar approach, in conjunction with bone marrow transplantation, may provide higher salvage rates in patients with poor-risk relapsed Hodgkin's disease.\n\nPost-transplant treatment may also be important in increasing salvage rates in these patients. This would include radiation therapy to sites of bulky disease. There is also some suggestion that interferon-alfa may be of some benefit in patients with Hodgkin's lymphoma (Dr. Fernando Cabanillas, MD, personal communication, August, 1994). Hence, it may be useful to conduct trials evaluating the efficacy of interferon-alfa after transplantation in Hodgkin's lymphoma [14,15].\n\nConfirm Hodgkin's Disease Diagnosis Before Beginning Salvage Chemotherapy\n\nFinally, I believe that it is important to confirm the diagnosis of Hodgkin's disease before initiating any sort of salvage chemotherapy. It is not uncommon to confuse, on a morphologic basis, Hodgkin's lymphoma with other non-Hodgkin's lymphomas, including anaplastic large-cell lymphomas and peripheral T-cell lymphomas [16-21]. Hodgkin's disease presenting as a mediastinal mass can sometimes be confused with mediastinal B-cell lymphoma with sclerosis [22,23]. Therefore, it is important to obtain immunophenotypic data to confirm the morphologic diagnosis of Hodgkin's disease. This should include CD15, CD30, CD45, and B- and T-cell markers. The distinction between Hodgkin's disease and these non-Hodgkin's lymphomas may be important in choosing appropriate induction salvage regimens.\n\nFurthermore, it is not uncommon to find patients with Hodgkin's lymphoma who relapse with a non-Hodgkin's lymphoma. This entity of so-called composite lymphoma appears to have elements of both Hodgkin's and non-Hodgkin's lymphomas.\n\nThe Biology of Hodgkin's\n\nIn addition, our understanding of the biology of Hodgkin's lymphoma is improving. Patients with lymphocyte-predominant Hodgkin's disease may have a clinical course similar to that of low-grade B-cell lymphomas. (They tend to have a pattern of multiple relapses with prolonged survival similar to patients with follicular lymphomas). In this setting, it may be reasonable not to offer bone marrow transplantation at the time of first relapse but rather, to use salvage chemotherapy similar to that used in low-grade lymphomas. Patients with lymphocyte-predominant Hodgkin's disease may be candidated for interferon-alfa and other approaches that are often used in patients with low-grade lymphomas.\n\nSignificant improvements have been made in the management of patients with relapsed Hodgkin's disease. Almost half of these patients now achieve a durable complete remission with various treatment modalities, including high-dose chemotherapy and bone marrow transplantation. It is important to confirm the diagnosis of Hodgkin's lymphoma by immunophenotyping before determining the appropriate salvage chemotherapy for an individual patient. The intensity of induction chemotherapy and consolidation should be tailored to the presence of poor prognostic factors in each patient. Other treatment modalities, such as radiation therapy and, possibly, interferon-alfa, should also be considered in an attempt to maximize the chance of disease-free survival.\n\nReferences:\n\n1. 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Papa G, Mandelli F, Anselmo AP, et al: Treatment of MOPP-resistant Hodgkin's disease with Adriamycin, bleomycin, vincristine and dacarbazine (ABVD). Eur J Cancer 18:803-806, 1982.\n\n7. Piga A, Ambrosetti A, Todeschini G, et al: Doxorubicin, bleomycin, vincristine and dacarbazine (ABVD) salvage of mechlorethamine, vincristine, prednisone and procarbazine (MOPP)-resistant advanced Hodgkin's disease. Cancer Treat Rep 68:947-951, 1984.\n\n8. Richards MA, Waxman JH, Man T, et al: EVA treatment for recurrent or unresponsive Hodgkin's disease. Cancer Chemother Pharmacol 18:51-53, 1986.\n\n9. Canellos GP, Petroni GR, Barcos M, et al: Etoposide, vinblastine, and doxorubicin: An active regimen for the treatment of Hodgkin's disease in relapse following MOPP. J Clin Oncol 13:2005-2011, 1995.\n\n10. Gribben JG, Linch DC, Singer CR, et al: Successful treatment of refractory Hodgkin's disease by high-dose combination chemotherapy and autologous bone marrow transplantation. Blood 73:340-344.\n\n11. Armitage JO, Bierman PJ, Vose JM, et al: Autologous bone marrow transplantation for patients with relapsed Hodgkin's disease. Am J Med 91:605-611, 1991.\n\n12. Reece DE, Barnett MJ, Sheperd JD, et al: High-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP-16-213) 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 86:451-456, 1995.\n\n13. Linch DC, Winfield D, Goldstone AH, et al: Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: Results of a BNLI randomized trial. Lancet 341:1051-1054, 1993.\n\n14. Ascensao JL, Miller KB, Bergstrom SB, et al: Immunotherapy following autologous marrow transplantation for relapsed lymphomas: The role of interferon alpha-2B (IF) (abstract). Exp Hematol 19:545, 1991.\n\n15. Slavin S, Or R, Klapelushnik Y, et al: Immunotherapy of minimal residual disease in conjunction with autologous and allogeneic bone marrow transplant (BMT). Leukemia 6:164, 1992.\n\n16. Stein H, Mason D, Gerdes J, et al: The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: Evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood 66:848, 1985.\n\n17. Delso G, Al Saati T, Gatter K, et al: Coexpression of epithelial membrane antigen (EMA), Ki-1, and interleukin-2 receptor by anaplastic large cell lymphomas: Diagnostic value in so-called malignant histiocytosis. Am J Pathol 130:59, 1988.\n\n18. Pileri S, Falini B, Delso G, et al: Lymphohistiocytic T-cell lymphoma (anaplastic large cell lymphoma CD30+/Ki1+) with a high content of reactive histiocytes. Histopathology 16:383, 1990.\n\n19. Pileri S, Mazza P, Zinzani P, et al: Ki-1 lymphoma and Hodgkin's disease (letter). Haematologica (Pavia) 74:333, 1989.\n\n20. Stein H, Herbst H, Anagnostopoulos I, et al: The nature of Hodgkin and Reed-Sternberg cells, their association with EBV, and their relationship to anaplastic large-cell lymphoma. Ann Oncol 2(suppl 2):33, 1991.\n\n21. Pileri S, Bocchia M, Baroni C, et al: Anaplastic large cell lymphoma (CD30+/Ki-1+): Results of a prospective clinicopathologic study of 69 cases. Br J Haematol 86:513, 1994.\n\n22. Addis B, Isaacson P: Large cell lymphoma of the mediastinum: A B-cell tumor of probable thymic origin. Histopathology 10:379, 1986.\n\n23. Lamarre L, Jacobson J, Aisenberg A, et al: Primary large cell lymphoma of the mediastinum. Am J Surg Pathol 13:730, 1989.