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Originally published as JCO Early Release 10.1200/JCO.2004.05.926 on June 21 2004 © 2004 American Society of Clinical Oncology.
The Limits of Limited Stage LymphomaArizona Cancer Center, University of Arizona, Tucson, AZ In the wildly popular novel by Dan Brown, Angels and Demons, Robert Langdon, an academician from Harvard University, is inadvertently swept up in a plot to use antimatter to destroy civilization. Langdon sleuths unpublished manuscripts in the Vatican archives for clues to find the culprit and interrupt the sinister plot. In this issue of the Journal of Clinical Oncology, Horning et al1 dust off data from a 1984 Eastern Cooperative Oncology Group (ECOG) study in an attempt to find a lead to prevent death from lymphoma. The plan almost works. ECOG 1484 attempted to determine whether low-dose consolidative radiotherapy (RT) adds efficacy to systemic chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP]) in patients with limited-stage, aggressive-histology, non-Hodgkin's lymphoma (NHL). Of 399 patients registered, 352 (88%) were eligible and assessable and were randomly assigned to receive low-dose RT or observation alone after eight cycles of CHOP chemotherapy (CHOP[8]). However, only 282 patients (71% of initial registrations) were registered for the consolidation step, of which 243 (61%) were subsequently eligible and assessable. Among these 243 patients were 172 complete responders (or 43% of the initial patients registered) who then actually received RT (93 patients) or observation (79 patients). An intent-to-treat analysis was also performed to partially mitigate any potential bias. Efficacy was measured using a variety of end points, including disease-free survival; time to lymphoma progression, which censored the data for cause of death; failure-free survival, which included any cause of death; and overall survival. In this study, low-dose consolidative RT did not affect survival, whereas there was some marginal improvement in disease-free survival, time to lymphoma progression, and failure-free survival. From a patient's perspective, efficacy is measured by relief of symptoms or prolongation of survival. In ECOG study 1484, RT did neither, as all patients randomized had already achieved a complete remission (CR) (with any symptoms from lymphoma presumably relieved by the chemotherapy), and RT had no effect on survival. Importantly, the authors do not advocate combined treatment in patients who achieve CR with chemotherapy alone. This study is old—a fact that the authors note. But all published studies of limited-stage, aggressive histology NHL are relatively old. Having reported ECOG 1484, however, the authors raise an important and timely issue as investigators plan new studies of limited NHL. "Limited disease" must be more precisely defined. Limited disease and its pseudonyms, "early-stage disease," "low-stage disease," and "localized disease," have been used as definitions in every published study to date. It is, therefore, no wonder that Horning et al1 remark that, "Differences in outcomes of various studies are always challenging to explain." There is extreme heterogeneity within the group of patients described as having "limited-stage" lymphoma, and not only are comparisons across this heterogeneous population difficult, but treatments designed for one subgroup may not be appropriate for another subgroup. Major studies of limited disease, published or otherwise presented, have selected patients from the relatively broad stage I and stage II categories based on the Ann Arbor staging system. That staging system, designed primarily for use in Hodgkin's lymphoma, has prognostic value but lacks precision when applied to the spectrum of diseases comprising non-Hodgkin's lymphomas. Most of the differences in comparing the results among studies can be attributed to the imprecise nature and erratic application of this staging system. Stage I-II aggressive histology of NHL is too broad a category; thus, outcome varies considerably. However, both the current study and past reports of stage I-II disease are remarkably consistent when adjusted for stage. Consequently, consistent application of staging criteria in the future design of studies intended to define therapy for limited disease would likely improve comparability and allow cross-comparisons. Stage I-II aggressive histology of NHL can be easily divided into three subgroups using different average outcome, based on survival. Importantly, each of these three subgroups likely requires different therapeutic strategies to optimize outcome (Table 1). Patients in the first subgroup have very limited disease and a corresponding 5-year survival exceeding 90%.2–4 These patients are easily identified using a stage-modified version of the International Prognostic Index (IPI). In the stage-modified version of the IPI, risk factors are used exactly as initially described by Shipp et al,5 except that the adverse risk factor for limited stage is stage II or stage IIE disease (not stage III or IV). Using the stage-modified version of the IPI, these patients have no adverse risk factors. They have stage I or IE disease, are younger than 60 years, have a normal serum lactate dehydrogenase, and are fully ambulatory with a performance status of 0 or 1. They comprise approximately 30% of stage I-II aggressive NHL cases. These patients do well whether they are treated with brief chemotherapy followed by involved-field RT (CHOP[3] plus RT) or with chemotherapy alone.2–4 Because these patients do well, regardless of treatment, there are few statistical events, making trial designs difficult. By including these patients in future trials, statistical estimates of the numbers of patients required to test an expected difference in outcome would, therefore, be artifactually and unnecessarily increased. These patients were largely excluded from the ECOG trial, which, in retrospect, was an inspired decision.
Another subset of patients sometimes included within limited-stage disease are patients with bulky stage II disease (commonly defined as having any tumor mass exceeding 10 cm or a mediastinal mass exceeding one-third of the maximum transthoracic diameter). These patients are known to have a prognosis similar to patients with advanced disease.6 Bulky stage II patients accrued to Southwest Oncology Group studies throughout the last 30 years have a 5-year survival of 49%. Patients with stage III or IV disease have a 5-year survival of 46%, and, therefore, patients with bulky stage II or any stage III or IV disease are considered to have advanced disease. Additional evidence that bulky stage II disease requires treatment designed for advanced disease has been presented by Reyes et al.3 In the study by the Groupe d'Etude des Lymphomes de l'Adulte (GELA), patients with bulky stage II disease were randomized to a short course of chemotherapy plus RT (CHOP[3] plus RT) designed to treat limited disease, or to an intensive chemotherapy regimen (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone [ACVBP]) originally designed for treating advanced disease. The 5-year estimates of survival were 50% and 82% for patients treated with CHOP(3) plus RT and ACVBP, respectively (P = .03). Bulky stage II patients were included in ECOG 1484, and these patients rightly received CHOP(8) chemotherapy. Bulky disease was one of two clinical features that were adversely associated with achieving a CR. Although the authors state that patients with bulky disease did not have an adverse outcome, that statement fails to account for the fact that less than half of the patients with bulky disease qualified to be randomized. A majority of these patients failed to obtain a CR, or perhaps even a partial remission, and are therefore not included in the analysis of low-dose RT versus observation. Patients with bulky stage II disease do not have limited disease and seem better served by receiving treatment designed for advanced disease.3 So, who are the patients with limited disease? As summarized in Table 1, patients with limited disease have stage I disease plus one or more adverse risk factors or nonbulky stage II disease. These patients have an intermediate survival of approximately 70% at 5 years.2,4 Optimal treatment has not been identified for this group, but the frequency of survival events allows for sound statistical design of future trials. These patients should be the focus of future trials of limited disease. Future trials of limited disease must include similarly staged patients to allow comparison with the current benchmark of efficacy and toxicity, CHOP(3) plus RT. CHOP(3) plus RT results in improved survival and lessened toxicity through 7 to 9 years of follow-up, compared with CHOP(8).2,7 Increasing treatment duration (CHOP[8] plus RT) as administered in the current study did not improve overall survival or decrease toxicity compared with CHOP(8); therefore, one can assume that CHOP(8) plus RT offers no advantage over CHOP(3) plus RT. Increasing the dose-intensity of the chemotherapy, as Reyes et al3 did by using the ACVBP regimen, did not improve overall survival, but did greatly increase toxicity in patients with limited disease after correcting for bulky stage II disease. Thus, novel approaches are needed. The obvious trials, based on the paradigm that what works in advanced disease will likely work in limited disease, will likely test the additive effect of adding monoclonal antibodies to CHOP(3) plus RT. Since rituximab added to CHOP has improved outcome in advanced disease, it seems reasonable, if not inspired, to test the combination of CHOP(3) plus RT plus rituximab in limited disease.8,9 In addition, the consistent observation that patients with limited disease rarely relapse within radiated areas (as demonstrated in the current study) suggests that radioimmunoconjugates may effectively eliminate microscopic disease that has persisted after treatment with initial chemotherapy. Pilot trials of CHOP(3), with or without involved-field RT, followed by radioimmunoconjugates, are currently underway. However, judging the results of these trials relative to a historical benchmark will require a consistent approach to defining limited disease. 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: Thomas P. Miller, IDEC. Honoraria: Thomas P. Miller, IDEC. Research Funding: Thomas P. Miller, IDEC. 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 form and the "Disclosures of Potential Conflicts of Interest" section of Information for Contributors, found in the front of every issue of the Journal.
REFERENCES
1. Horning SJ, Weller E, KyungMann 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
2. Miller TP, Dahlberg S, Cassady JR, et al: Chemotherapy alone compared to chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med 339:21–26, 1998 3. Reyes F, Lepage E, Munck JN, et al: Superiority of chemotherapy alone with the ACVBP regimen over treatment with three cycles of CHOP plus radiotherapy in low risk localized aggressive lymphoma: The LNH93-1 GELA study. Blood 100:93a, 2002 (abstr 343)
4. 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
5. A predictive model for aggressive non-Hodgkin's lymphoma: The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329:987–994, 1993 6. Fisher RI, DeVita VT, Johnson BL, et al: Prognostic factors for advanced diffuse histiocytic lymphoma following treatment with combination chemotherapy: Am J Med 63:177–182, 1977[CrossRef][Medline] 7. Miller TP, 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–725a, 2001 (abstr 3024)
8. 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 9. Sehn LH, Donaldson J, Chhanabhai M, et al: Introduction of combined CHOP-rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma (DLBC) in British Columbia (BC). Blood 102:29a, 2003 (abstr 3024)
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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