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Originally published as JCO Early Release 10.1200/JCO.2005.01.911 on April 18 2005 © 2005 American Society of Clinical Oncology.
Chemotherapy Alone for Early Hodgkin's Lymphoma: An Emerging OptionDana-Farber Cancer Institute, Boston, MA Early stage Hodgkin's lymphoma is a highly curable disease. Combined chemotherapy and radiation has resulted in high freedom-from-progression rates at 5 to 12 years in the range of 93% for stages I and II patients with asymptomatic presentations and approximately 85% for those with unfavorable disease characteristics.1-3 The revelation of serious cardiac and second malignancy issues in long-term survivors treated with radiotherapy has prompted a reconsideration of its role when used alone or combined with chemotherapy. Thus, there is a serious need to assess the benefits of chemotherapy alone in patients with early stage disease, especially in those without bulky presentations.
In this issue of the Journal of Clinical Oncology is the publication of a trial conducted by the National Cancer Institute of Canada (NCI-C) in collaboration with the Eastern Cooperative Oncology Group (ECOG) addressing the role of chemotherapy alone for early-stage Hodgkin's lymphoma.4 The trial was conceived in the early 1990s, when subtotal nodal radiation therapy with splenic irradiation was the standard treatment in Canada for clinically staged patients with early nonbulky stage I to IIA disease. The experimental arm was the chemotherapy regimen of doxorubicin, bleomycin, vincristine and dacarbazine (ABVD) alone for four cycles if a complete response (CR) was achieved after two cycles. Otherwise, patients received six cycles. The standard arm was radiation therapy alone, unless one of the following was present: erythocyte sedimentation rate (ESR) However, one conclusion that can be drawn from this trial is that chemotherapy alone with ABVD can be an option in the treatment of localized nonbulky disease. If the long-term toxic risks of radiation are to be avoided, then this approach should be the treatment of choice, especially for patients younger than 40 years. There have been a host of long-term follow-up studies that have clearly defined the carcinogenic and cardiotoxic risks of curative radiation therapy. The projected risk of one or both of these complications approaches 40% at 25 to 30 years, and is especially true for children and adolescents.6-11 The recent application of involved-field radiation at lower doses than in the past (in the 20- to 30-Gy range, rather than 30 to 45 Gy) is noteworthy, and less normal tissue would be at risk; however, there are no data on the long-term freedom from toxicity of even the lower doses. Patients with mediastinal tumors will still receive radiation to some cardiac and lung parenchymal tissue. If the risk of any radiation dose or field is unknown, does any risk need to be taken given the current information on ABVD alone? There are two other recent studies of ABVD alone, one from a Memorial Sloan-Kettering randomized trial with 152 patients, of whom 76 received ABVD alone, and 76, combined ABVD and irradiation.12 At 60 months, there were no differences in FFP or overall survival. The ABVD arm had a complete remission rate of 94%, CR duration of 87%, progression-free survival of 81% and an overall survival of 90%. A recent phase II Spanish series13 of ABVD alone for stage I to II A and B Hodgkin's lymphoma had a 94% CR rate with a median follow-up of 78 months; the progression-free survival of the 80 patients with nonbulky disease was 88%, exactly the same as the NCI-C trial, but with longer follow-up. The total reported number of patients with stage I to IIA nonbulky disease in the literature treated with ABVD alone over the last year is 252, with a progression-free survival of > 85% and no compromise of survival compared with radiation alone or combined-modality therapy. Further, as suggested in a recent editorial, 14 the more heavily radiated patients have a continuing risk of radiation-induced heart disease and cancer for years without, as yet, a plateau on the risk curve. Clearly, the opportunity for reducing the risk exists with administration of chemotherapy alone. The use of chemotherapy alone is not a new concept. In the late 1980s, a polemic in the literature existed between the use of MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone) alone and radiation alone for early Hodgkin's lymphoma. The National Cancer Institute (NCI; Bethesda, MD) series15 suggested that MOPP alone was at least as effective for early stage disease. Contrariwise, an Italian randomized trial16 of 89 patients purported to show a disproportionately low 56% survival at 8 years with MOPP, compared with 93% in the radiation arm. This observation was countered by a tabular analysis of 12 series of 420 patients (until 1992) treated with MOPP or MVPP (nitrogen mustard, vinblastine, procarbazine, and prednisone) with overall survivals of 75% to 96%, respectively, with up to 10 years of follow-up.17 The known bone marrow toxicity and infertility associated with MOPP or the MOPP-ABVD hybrid, however, limited the enthusiasm for chemotherapy alone for localized disease. In the last few years, the relative absence of permanent sterility and myelodysplasia with ABVD, plus the statistical revelations of radiation-induced toxicity in long-term survivors, has prompted a reconsideration of chemotherapy alone. The new challenges emerging from these efforts include the search for an even less toxic version of ABVD (perhaps with the elimination of bleomycin and the substitution of other active agents, such as gemcitabine) and the need to determine the minimum number of cycles, perhaps gauged by positron emission tomography (PET) scans after two cycles. Future clinical trials should consider withholding radiation from patients with bulky disease who achieve PET negativity in a prospective randomized trial comparing consolidation radiation to no further therapy. The only trial purporting a survival advantage for combined modality compared to ABVD alone was a trial from India18 comprising a variety of stages, including approximately 45% stages III to IV. Half of the patients were younger than 15 years, 70% had mixed-cellularity histology, and the majority did not have mediastinal disease. These clinical features are considerably different from those in adult trials in North America and Western Europe. These discrepancies were well documented in the article's accompanying editorial.19 Clearly a new option for the treatment of early stage asymptomatic nonbulky Hodgkin's lymphoma is needed. Given the excellent results of the NCI-C, Memorial Sloan-Kettering and the Spanish phase II results with ABVD alone, it behooves the clinician seeing a young patient with early nonbulky disease to strongly consider the chemotherapy-only option. More clinical research could improve the toxicity profile and therapeutic results of chemotherapy. Cancer and Leukemia Group B (CALGB) has initiated a phase II trial in stage I to IIA patients without bulky disease exploring a new regimen of doxorubicin, vinblastine, and gemcitabine with monitoring by PET scans. Longer follow-up of the involved-field treated patients is also needed, to document that the potential for lower doses of radiation to vital organs will reduce late toxicity, which is only an assumption at present. Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: George P. Canellos, Bristol-Myers Squibb. Honoraria: George P. Canellos, Bristol-Myers Squibb. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue. REFERENCES
1. Bonadonna G, Bonfante V, Viviani S, et al: ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin's disease: Long-term results. J Clin Oncol 22:2835-2841, 2004
2. Feugier P, Labouyrie E, Djeridane M, et al: Comparison of initial characteristics and long-term outcome of patients with lymphocyte-predominant Hodgkin lymphoma and classical Hodgkin lymphoma at clinical stages IA and IIA prospectively treated by brief anthracycline-based chemotherapies plus extended high-dose irradiation. Blood 104:2675-2681, 2004
3. 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 Hodgkin's disease. J Clin Oncol 19:4238-4244, 2001 4. Meyer RM, Gospodarowicz MK, Connors JM, et al: A randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma. J Clin Oncol 23:4634-4642, 2005
5. Engert A, Schiller P, Josting A, et al: Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: Results of the HD8 trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol 21:3601-3608, 2003
6. Adams MJ, Lipsitz SR, Colan SD, et al: Cardiovascular status in long-term survivors of Hodgkin's disease treated with chest radiotherapy. J Clin Oncol 22:3139-3148, 2004
7. Aleman BMP, van den Belt-Dusebout AW, Klokman WJ, et al: Long-term cause-specific mortality of patients treated for Hodgkin's disease. J Clin Oncol 21:3431-3439, 2003
8. Bhatia S, Yasui Y, Robison LL, et al: High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: Report from the Late Effects Study Group. J Clin Oncol 21:4386-4394, 2003
9. Dores GM, Metayer C, Curtis RE, et al: Second malignant neoplasms among long-term survivors of Hodgkin's disease: A population-based evaluation over 25 years. J Clin Oncol 20:3484-3494, 2002
10. Van Leeuwen FE, Klokman WJ, van't Veer MB, et al: Long-term risk of second malignancy in survivors of Hodgkin's disease treated during adolescence or young adulthood. J Clin Oncol 18:487-497, 2000
11. Ng AK, Bernardo MVP, Weller E, et al: Second malignancy after Hodgkin disease treated with radiation therapy with or without chemotherapy: Long-term risks and risk factors. Blood 100:1989-1996, 2002
12. Straus DJ, Portlock CS, Qin J, et al: Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood 104:3483-3489, 2004
13. Domínguez AR, Márquez A, Gumá J, et al: Treatment of stage I and II Hodgkin's lymphoma with ABVD chemotherapy: Results after 7 years of a prospective study. Ann Oncol 15:1798-1804, 2004
14. Longo DL: Hodgkin disease: The sword of Damocles resheathed. Blood 104:3418, 2004 15. Longo DL, Glatstein E, Duffey PL, et al: Radiation therapy versus combination chemotherapy in the treatment of early-stage Hodgkin's disease: Seven-year results of a prospective randomized trial. J Clin Oncol 9:906-917, 1991[Abstract]
16. Biti GP, Cimino G, Cortoni C, et al: Extended-field radiotherapy is superior to MOPP chemotherapy for the treatment of pathologic stage I-IIA Hodgkin's disease: Eight-year update of an Italian prospective randomized study. J Clin Oncol 10:378-382, 1992 17. Longo DL: Chemotherapy alone in the treatment of patients with early stage Hodgkin's disease. Ann Oncol 7:S85-S89, 1996 (suppl 4)
18. Laskar S, Gupta T, Vimal S, et al: Consolidation radiation after complete remission in Hodgkin's disease following six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy: Is there a need? J Clin Oncol 22:62-68, 2004
19. Diehl V: Chemotherapy or combined modality treatment: The optimal treatment for Hodgkin's disease. J Clin Oncol 22:15-18, 2004
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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50 mm/h, or four or more nodal sites, in which case patients received two cycles of ABVD before protocol irradiation. Approximately 70% of 399 total patients had one or two of these unfavorable features. Thus, for a considerable fraction of the patient population, the study was a comparison of combined-modality therapy with chemotherapy alone. At a median follow-up of 4.3 years, freedom from progression (FFP) was the only parameter that reached statistical significance, in which the standard arm had a FFP of 94% compared with 88% for chemotherapy alone (P = .04). This difference was confined to the unfavorable group. Further, there were no differences in the event-free and overall survivals. Although the standard arm of this trial is no longer used, subsequent trials have confirmed that combined-modality therapy is superior in FFP compared to radiation alone and that chemotherapy with involved-field radiation therapy is comparable in benefit to more extensive-field radiation plus the same chemotherapy.
