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Originally published as JCO Early Release 10.1200/JCO.2006.09.5562 on January 16 2007 © 2007 American Society of Clinical Oncology.
Role of Radiation Therapy in Localized Aggressive Lymphoma
Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA To date, there have been four randomized trials, including the Groupe d'Etudes des Lymphomes de l'Adulte (GELA) LNH 93-4 trial reported by Bonnet et al1 in this issue of the Journal of Clinical Oncology, that compare chemotherapy alone to chemotherapy followed by radiation for patients with stage I-II aggressive lymphoma. Although these four trials appeared to address a similar question in a group of patients with localized disease, each of these trials differed in patient characteristics, study design, and number of cycles or type of chemotherapy administered to the treatment arms. These factors, along with the strengths and caveats of each individual trial, need to be taken into consideration in the interpretation of the trials' results. One trial, the Southwest Oncology Group (SWOG) 8736 trial, was designed to address the question of whether the addition of involved-field radiation therapy allows the use of less chemotherapy.2 At its initial publication, the answer appeared to be affirmative, in that not only did the addition of radiation therapy allow the use of three cycles instead of eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), but there was also a significant 5-year progression-free and overall survival benefit with combined-modality therapy using abbreviated chemotherapy compared with a prolonged course of chemotherapy alone. In addition, there were more life-threatening events, including left ventricular dysfunction and cardiac deaths, in patients who received eight cycles of chemotherapy compared with patients who received three cycles of chemotherapy followed by radiation therapy. However, updated results of this trial,3 reported in abstract form, show that there were no longer differences in failure-free survival and overall survival between the two treatment arms. This was largely due to late relapses and lymphoma deaths after 5 years in patients who received abbreviated chemotherapy followed by radiation therapy. These findings suggest that three cycles of CHOP is inadequate systemic therapy, despite the fact that this trial included a relatively favorable group of patients. In this trial, half of the patients were younger than 60 years, two thirds of the patients had stage I disease, and patients with bulky stage II disease were excluded. A second such trial, GELA LNH 93-1, which was conducted in patients with stage I-II mostly low-risk aggressive lymphoma,4 had a similar design comparing aggressive chemotherapy alone with abbreviated chemotherapy followed by radiation therapy. Patients in this trial were all age 60 years or younger, with normal lactate dehydrogenase (LDH) levels and performance status, and two thirds of the patients had stage I disease. The comparison arms were dose-intensified doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) plus sequential consolidation (a regimen originally developed for patients with poor-risk disease, which had been shown to be superior to eight cycles of CHOP),5 compared with three cycles of CHOP plus involved-field radiation therapy. Not surprisingly, patients randomly assigned to receive ACVBP, which has a theoretical dose-intensity of at least 150% of that delivered by three cycles of CHOP, had significantly higher 5-year event-free and overall survival rates. Although the addition of radiation therapy after three cycles of CHOP reduced relapses at initial sites of disease, it was not enough to overcome the excessive distant relapses after the abbreviated therapy. Although the SWOG 8736 and GELA LNH 93-1 trials have often been quoted to refute the role of radiation therapy in patients with localized aggressive lymphoma, the results of these trials essentially showed that radiation therapy cannot be used to replace inferior and inadequate chemotherapy. There is, however, a subgroup of patients for whom three cycles of chemotherapy followed by radiation therapy may be adequate, namely, patients with a stage-adjusted international prognostic index (IPI) of 0 (patient characteristics: age < 60, normal LDH, performance status of 0-1, and stage I disease). In a subsequent analysis of the SWOG 8736 trial, patients without any stage-adjusted IPI risk factors had a 5-year overall survival rate of 94% after three cycles of CHOP and radiation therapy.6 However, in those patients with one or more risk factors, the 5-year overall survival was only 70% after the same treatment. These findings are consistent with the long-term results of the British Columbia group reported by Shenkier et al.7 In that study, patients with localized aggressive lymphoma received three cycles of CHOP-like chemotherapy followed by radiation therapy. Among those patients with a stage-adjusted IPI of 0, the 5- and 10-year disease-specific survival rates were 98% and 95%, respectively, and the 5- and 10-year overall survival rates were 97% and 90%, respectively. The third trial conducted by the Eastern Oncology Group (ECOG) used the same chemotherapy regimen in the two comparison arms,8 and is therefore positioned to directly address the role of radiation therapy. This study included less favorable patients, in that all stage I patients had bulky or extranodal disease and patients with bulky stage II disease were included in the study. Two thirds of the patients who participated in this trial had stage II disease and almost one third had bulky disease. Unlike the two trials described earlier, in the ECOG study, only patients with a complete response (defined as resolution of all palpable nodes and radiographic disease) after eight cycles of CHOP were randomly assigned to observation versus radiation therapy, whereas patients with a partial response all went on to receive radiation therapy. This trial also has the longest median follow-up (12 years). Despite a slight imbalance in patient characteristics between the two arms, with more patients with bulky disease in the combined-modality therapy arm and the somewhat suboptimal adherence to the assigned treatments, there was a significant disease-free survival benefit favoring the addition of radiation therapy. There was a 12% gain in overall survival at 6 years with radiation therapy, although this was not statistically significant. However, this trial was only powered to detect a 20% difference in disease-free survival. Notably, among patients with only a partial response to chemotherapy, half of whom had initial bulky disease and received involved-field radiation therapy, a 6-year failure free survival rate of 63% and overall survival of 69% were achieved. In this issue of the Journal of Clinical Oncology, Bonnet et al1 report results of the GELA LNH 93-4 trial on patients older than 60 years with localized aggressive lymphoma and normal LDH levels and performance status. Two thirds of the patients had stage I disease and 8% had bulky disease. Patients were randomly assigned at diagnosis to four cycles of CHOP alone or four cycles of CHOP followed by radiation therapy to 40 Gy. The investigators are to be applauded for conducting a trial that was appropriately designed to test the role of radiation therapy by using the same systemic therapy in both treatment arms. Although the final number of patients was slightly lower than the target accrual, the recruitment of 574 patients gave this trial an 85% power to detect a 10% event-free survival difference. Patient and disease characteristics were well-balanced in the two arms and a central review of the technical details of the radiation therapy was conducted. At a median follow-up of 7 years, there were no significant differences in 5-year event-free survival (61% v 64% for chemotherapy alone and combined-modality therapy, respectively) and overall survival (72% v 68%, respectively) between the two arms. An intriguing finding in this trial is that the chemotherapy-alone arm, which used only four cycles of CHOP, yielded very similar survival rates as those after eight cycles of CHOP in the SWOG 8736 study2; both of which had a 5-year overall survival rate of 72%. Twenty percent of the patients on the SWOG trial had abnormal LDH, whereas all patients had normal LDH on the GELA LNH 93-4 trial. However, the median age of patients on the SWOG trial was almost 10 years younger than patients on the GELA LHN 93-4 trial. This highlights the heterogeneity of this disease and the importance of careful patient selection for reduced treatment. The risk of second malignancy is often raised as a concern with the use of radiation therapy. Although this is true in Hodgkin's lymphoma, which affects a much younger group of patients, the data are less convincing for non-Hodgkin's lymphoma, for which the median age at presentation is 65 years. In the report by Shenkier et al,7 there was a higher than expected risk of developing another cancer after three cycles of a CHOP-like regimen and radiation therapy. However, only 14% of the second malignancies developed within the radiation field. More important, the authors found a similar significantly increased cancer risk before the diagnosis and treatment of the non-Hodgkin's lymphoma, suggesting that these cancers were related to underlying susceptibility rather than treatment. In the GELA LNH 93-4 trial, the incidence of second malignancy of the two arms was not available. Death from second malignancies was reported, and was similar to findings from the British Columbia group; only three of the 20 second malignancy deaths in the combined-modality therapy arm were from cancers arising in the radiation treatment field. The authors discussed the issue of quality-of-life impairment from the addition of radiation therapy, an important consideration—especially with respect to treatment to the head and neck area—as older patients often have more difficulty in regaining their salivary gland function after radiation therapy. It is worth pointing out, however, that in recent years intensity-modulated radiation therapy is increasingly used for head and neck irradiation.9 This technique of highly conformal therapy can substantially limit doses to the salivary glands and has been shown in a recent randomized trial to be associated with significantly reduced risk of xerostomia and improved quality of life when compared with 3-dimensional radiation treatment in head and neck cancer patients.10 Can we conclude from results of the GELA LNH 93-4 trial that four cycles of CHOP alone is adequate therapy in older patients with localized aggressive lymphoma? As we have learned from the SWOG 8736 trial, which showed continued late relapses after 5 years with the use of abbreviated chemotherapy, it will be important to obtain results beyond the 5 years of the GELA LNH 93-4 trial before definitive conclusions are reached. In contrast, the median age of patients in the GELA LNH 93-4 trial was 68 years. In a frail, elderly patient with limited life expectancy due to other comorbid illnesses, four cycles of CHOP (and rituximab) may be reasonable. This approach needs to be used with caution, however, in an otherwise healthy, older patient with a life expectancy of more than 5 years, in whom salvage options with high-dose therapy and stem-cell rescue may be limited at the time of relapse. The ECOG trial and the GELA LNH 93-4 trial, both of which used the same systemic therapy on both study arms, showed that the addition of radiation therapy reduced the percentage of isolated relapse at initial sites from 48% (15 of 31 relapses) to 17% (3 of 17 relapses), and from 47% (37 of 79 relapses) to 21% (14 of 66 relapses), respectively. It is becoming apparent that the benefit of improved local control with the addition of radiation therapy will only translate into a disease-free and overall survival improvement when it is combined with effective systemic therapy that allows for the eradication of occult distant disease. The principle of improved local control with radiation therapy leading to a disease-specific and overall survival benefit as more effective systemic therapy became available has been well-demonstrated in the treatment of breast cancer.11 Currently, the CHOP and rituximab regimen is considered the standard systemic therapy for diffuse large B-cell lymphoma,12-14 whereas all four of the trials used CHOP in the combined-modality therapy arm. To meaningfully clarify the role of radiation therapy in localized aggressive lymphoma, the most informative trial will be one that employs CHOP and rituximab, followed by either radiation therapy using modern technique or no additional therapy. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Manuscript writing: Andrea K. Ng, Peter M. Mauch Final approval of manuscript: Andrea K. Ng, Peter M. Mauch NOTES published online ahead of print at www.jco.org on January 16, 2007. REFERENCES
1. Bonnet C, Fillet G, Mounier N, et al: CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients. J Clin Oncol 25:787-792, 2007 2. Miller TP, Dahlberg S, Cassady JR, et al: Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med 339:21-26, 1998 3. Miller T, Leblanc M, Spier C, et al: CHOP alone compared to CHOP plus radiotherapy for early stage aggressive non-Hodgkin's lymphomas: Update of the Southwest Oncology Group (SWOG) randomized trial. Blood 98:724a, 2001 4. Reyes F, Lepage E, Ganem G, et al: ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 352:1197-1205, 2005 (abstr 3024) 5. Tilly H, Lepage E, Coiffier B, et al: Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood 102:4284-4289, 2003 6. Fisher RI, Miller TP, O'Connor OA: Diffuse aggressive lymphoma. Hematology Am Soc Hematol Educ Program 2004:221-236, 2004 7. Shenkier TN, Voss N, Fairey R, et al: Brief chemotherapy and involved-region irradiation for limited-stage diffuse large-cell lymphoma: An 18-year experience from the British Columbia Cancer Agency. J Clin Oncol 20:197-204, 2002 8. Horning SJ, Weller E, Kim K, et al: Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin's lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol 22:3032-3038, 2004 9. Chao KS, Majhail N, Huang CJ, et al: Intensity-modulated radiation therapy reduces late salivary toxicity without compromising tumor control in patients with oropharyngeal carcinoma: A comparison with conventional techniques. Radiother Oncol 61:275-280, 2001[CrossRef][Medline] 10. Pow EH, Kwong DL, McMillan AS, et al: Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: Initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys 66:981-991, 2006[CrossRef][Medline] 11. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005[Medline] 12. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002 13. Habermann TM, Weller EA, Morrison VA, et al: Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 24:3121-3127, 2006 14. Pfreundschuh M, Trumper L, Osterborg A, et al: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: A randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7:379-391, 2006[CrossRef][Medline] Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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