Chemotherapy Alone Compared with Chemotherapy plus Radiotherapy for Localized Intermediate- and High-Grade Non-Hodgkin's Lymphoma
Thomas P. Miller, M.D., Steve Dahlberg, M.S., J. Robert Cassady, M.D., David J. Adelstein, M.D., Catherine M. Spier, M.D., Thomas M. Grogan, M.D., Michael LeBlanc, Ph.D., Susan Carlin, B.A., Ellen Chase, B.S., and Richard I. Fisher, M.D.
Background Patients with clinically localized, intermediate-or high-grade non-Hodgkin's lymphoma usually receive initialtreatment with a doxorubicin-containing regimen such as cyclophosphamide,doxorubicin, vincristine, and prednisone (CHOP). Pilot studiessuggest that eight cycles of CHOP alone or three cycles of CHOPfollowed by involved-field radiotherapy are effective in suchpatients.
Methods We compared these two approaches in a prospective, randomized,multi-institutional study. The end points were progression-freesurvival, overall survival, and life-threatening or fatal toxiceffects. Two hundred eligible patients were randomly assignedto receive CHOP plus radiotherapy, and 201 received CHOP alone.
Results Patients treated with three cycles of CHOP plus radiotherapyhad significantly better progression-free survival (P=0.03)and overall survival (P=0.02) than patients treated with CHOPalone. The five-year estimates of progression-free survivalfor patients receiving CHOP plus radiotherapy and for patientsreceiving CHOP alone were 77 percent and 64 percent, respectively.The five-year estimates of overall survival for patients receivingCHOP plus radiotherapy and for patients receiving CHOP alonewere 82 percent and 72 percent, respectively. The adverse effectsincluded one death in each treatment group. Life-threateningtoxic effects of any type were seen in 61 of 200 patients treatedwith CHOP plus radiotherapy and in 80 of 201 patients treatedwith CHOP alone (P=0.06). The left ventricular function wasdecreased in seven patients who received CHOP alone, whereasno cardiac events were recorded in the group receiving CHOPplus radiotherapy (P=0.02).
Conclusions Three cycles of CHOP followed by involved-fieldradiotherapy are superior to eight cycles of CHOP alone forthe treatment of localized intermediate- and high-grade non-Hodgkin'slymphoma.
Patients with intermediate- or high-grade non-Hodgkin's lymphomacan be cured with doxorubicin-containing combination chemotherapy.1The cure rate varies according to several pretreatment prognosticvariables, including the stage of disease.2 Chemotherapy curesmost patients with localized disease (stage I or II), but onlyabout 30 to 40 percent of patients with advanced disease (stageIII or IV).1,3
Two strategies for treating localized intermediate- and high-gradehistologic subtypes of lymphoma have emerged in the past 15years: chemotherapy alone with a doxorubicin-containing combinationregimen such as cyclophosphamide, doxorubicin, vincristine,and prednisone (CHOP), administered for six to eight cycles,or a short course of chemotherapy (usually three cycles of CHOP)followed by involved-field radiotherapy.4 The presumed advantagesof chemotherapy alone are the avoidance of long-term complicationsof radiotherapy and the higher total doses of systemic therapy,which increase the potential for eliminating microscopic sitesof disease. The possible benefits of a short course of chemotherapyfollowed by radiotherapy are the reduction in the risk of cardiactoxicity due to the lower total dose of doxorubicin administered,the use of two mainly non–cross-resistant treatments,and the administration of radiotherapy directly to sites ofdetectable disease. There is no convincing evidence in favorof either strategy.3 Consequently, in 1988 the Southwest OncologyGroup began a prospective, randomized trial to compare thesetwo widely used treatments.
Methods
Patient Selection
This study (Southwest Oncology Group Study 8736) enrolled patientswith biopsy-proved intermediate- or high-grade non-Hodgkin'slymphoma (working-formulation groups D through J), excludingpatients with lymphoblastic lymphoma.5 Histologic specimenswere evaluated by independent expert reviewers. All patientshad stage I, stage IE (including bulky disease), nonbulky stageII, or nonbulky stage IIE disease. Bulky disease was definedas a mediastinal mass with a maximal diameter exceeding onethird the maximal chest diameter or any other mass 10 cm ormore in maximal diameter. For staging of their disease, allpatients underwent a physical examination, chest radiography,computed tomography of the abdomen and pelvis, and bone marrowbiopsy; measurement of serum aspartate aminotransferase, totalbilirubin, alkaline phosphatase, and lactate dehydrogenase;and peripheral-blood counts. Assignment of the Ann Arbor stagewas based on clinical findings and tumor measurements obtainedbefore excisional biopsy.6
All the patients were ambulatory, and no patient had a historyof congestive heart disease or another cancer, symptoms or findingscompatible with central nervous system involvement with lymphoma,or any prior treatment for lymphoma. At the time of randomization,patients were stratified according to age (65 years vs. <65years), stage (I vs. II), and histologic subtypes (diffuse large-cell[working-formulation groups G and H] vs. all other eligiblehistologic subtypes, including follicular large-cell, diffusesmall-cleaved-cell, diffuse mixed small- and large-cell, anddiffuse small-noncleaved-cell [working-formulation groups D,E, F, and J, respectively]), site of disease involvement (gastrointestinaltract vs. all other sites), and whether all visible and measurabletumors were resected. All patients gave written informed consentaccording to institutional guidelines.
Treatment
Patients were randomly assigned to receive eight cycles of CHOPalone or three cycles of CHOP followed by radiotherapy. TheCHOP regimen was the standard regimen, consisting of cyclophosphamide(750 mg per square meter of body-surface area, given as a 15-minuteintravenous infusion on day 1), doxorubicin (50 mg per squaremeter, given intravenously in a bolus over a period of 1 to2 minutes on day 1), vincristine (1.4 mg per square meter [maximaldose, 2.0 mg], given intravenously in a bolus over a periodof 1 to 2 minutes on day 1), and prednisone (100 mg daily, givenorally on days 1 to 5).1 The CHOP cycles were repeated at 21-dayintervals. Involved-field radiotherapy began three weeks afterthe third cycle of CHOP for the patients assigned to receivethree cycles of CHOP plus radiotherapy. The radiotherapy dosesranged from 4000 to 5500 cGy. The total dose was determinedby the treating radiotherapist; patients receiving higher dosesgenerally had clinical evidence of residual disease after havingreceived 4000 cGy (the majority of patients received 4500 to5000 cGy). The daily dose varied from 180 to 200 cGy. The radiotherapyports included all visible sites of disease determined beforebiopsy and treatment with CHOP. The treatment plans were reviewedby an independent radiotherapist before treatment was initiated.
Statistical Analysis
All eligible patients were included in comparisons of treatment.Life-table estimates of outcome used the Kaplan–Meiermethod.7 Progression-free survival was measured from the timeof randomization until progression of disease, relapse, or deathfrom any cause. Overall survival was measured from the timeof randomization until death from any cause. Comparisons wereadjusted for stratification factors by Cox regression, and alltests were two-sided.8,9 The hazard ratios for progression-freesurvival and overall survival were estimated by Cox regression.9Patient characteristics and toxic effects were compared betweengroups by the chi-square test. Toxic effects and responses totherapy were coded according to standard Southwest OncologyGroup guidelines.
Results
Patient Characteristics
Between March 1988 and June 1995, 442 patients were registeredfor the study. Of these, 41 were not eligible, mainly becausetheir biopsies showed low-grade histologic features (24 patients).All 401 patients who were eligible for the study were includedin all analyses; 201 patients were assigned to receive eightcycles of CHOP alone, and 200 patients were assigned to receivethree cycles of CHOP plus radiotherapy. The clinical characteristicsof the patients are summarized in Table 1. These characteristicscorrespond to those of the international prognostic index, exceptthat patients with stage I disease and those with stage II diseasewere classified separately.2 There were no patients with morethan one extranodal site of disease, a variable used in theinternational prognostic index, because patients were selectedfor stage I or II disease. The modified international prognosticindex used in this study tabulated the total number of high-riskfeatures applicable to each patient, including age greater than60 years, stage II disease, increased serum lactate dehydrogenaseconcentration, and decreased performance status. Risk was assignedaccording to the number of adverse prognostic features. Table 1also shows patients categorized according to risk group withthe international prognostic index modified for stage.
Table 1. Clinical Characteristics of 401 Patients Treated with Eight Cycles of CHOP or Three Cycles of CHOP plus Radiotherapy.
The two treatment groups did not differ in clinical characteristicsor risk categories. For all 401 patients, the median age was59 years, and diffuse large-cell lymphoma (working-formulationgroups G and H) was the most common histologic subtype (75 percentof all patients). Other subtypes included follicular large-cell,10 percent; diffuse small-cleaved-cell, 2 percent; diffuse mixedsmall- and large-cell, 6 percent; and diffuse small-noncleaved-cell,6 percent (working formulation groups D, E, F, and J, respectively).Extranodal sites of disease were found in 150 of the 401 patients(37 percent).
Response to Treatment
All visible tumors were resected as a consequence of the diagnosticbiopsy before the start of treatment in 116 patients (58 patientsin each treatment group). There was a complete response (resolutionof all visible tumors) in 210 of 285 patients with residualdisease after the biopsy (74 percent). There were 104 completeresponses in 143 patients treated with CHOP alone (73 percent)and 106 complete responses in 142 patients treated with CHOPplus radiotherapy (75 percent).
Survival
Patients treated with three cycles of CHOP plus radiotherapyhad significantly better progression-free survival than patientstreated with eight cycles of CHOP alone (P=0.03) (Figure 1).The estimated hazard ratio for the CHOP-alone group as comparedwith the CHOP-plus-radiotherapy group was 1.5 (95 percent confidenceinterval, 1.0 to 2.2). The five-year estimates of progression-freesurvival for patients treated with CHOP plus radiotherapy andCHOP alone were 77 percent and 64 percent, respectively. Similarly,overall survival was better for patients treated with CHOP plusradiotherapy than for those treated with CHOP alone (P=0.02)(Figure 2). The estimated hazard ratio for the CHOP-alone groupas compared with the CHOP-plus-radiotherapy group was 1.7 (95percent confidence interval, 1.1 to 2.7). The five-year survivalestimates for patients treated with CHOP plus radiotherapy andCHOP alone were 82 percent and 72 percent, respectively. Themedian follow-up for patients still alive was 4.4 years forthese analyses.
Figure 1. Progression-free Survival of 201 Patients Receiving Eight Cycles of CHOP Alone and 200 Patients Receiving Three Cycles of CHOP plus Radiotherapy.
Sixty-five patients in the CHOP-alone group died or had progression of their disease, as compared with 45 patients in the CHOP-plus-radiotherapy group. The estimated rates of progression-free survival at five years were 64 percent and 77 percent, respectively.
Figure 2. Overall Survival of 201 Patients Receiving Eight Cycles of CHOP and 200 Patients Receiving Three Cycles of CHOP plus Radiotherapy.
There were 51 deaths in the CHOP-alone group, and 32 in the CHOP-plus-radiotherapy group. The estimated rates of survival at five years were 72 percent and 82 percent, respectively.
Progression-free survival and overall survival also varied accordingto the risk groups established according to the stage-modifiedinternational prognostic index, when all patients were consideredregardless of treatment (P=0.02 and P=0.01, respectively) (Figure 3and Figure 4). The five-year estimates of progression-freesurvival were 77 percent (95 percent confidence interval, 72to 83) for patients with zero or one risk factor, 60 percent(95 percent confidence interval, 48 to 72) for patients withtwo risk factors, and 34 percent (95 percent confidence interval,13 to 55) for patients with three risk factors. Only two patientshad four risk factors, and both died of recurrent lymphoma.The five-year estimates of overall survival according to thenumber of risk factors were 82 percent (95 percent confidenceinterval, 77 to 87) for patients with zero or one risk factor,71 percent (95 percent confidence interval, 60 to 83) for patientswith two risk factors, and 48 percent (95 percent confidenceinterval, 27 to 69) for patients with three risk factors.
Figure 3. Progression-free Survival of 201 Patients Receiving Eight Cycles of CHOP Alone and 200 Patients Receiving Three Cycles of CHOP plus Radiotherapy, According to the Number of Risk Factors.
Sixty-two of 289 patients with zero or one risk factor, 28 of 82 patients with two risk factors, and 18 of 28 patients with three risk factors died or had progression of their disease. The estimated rates of progression-free survival at five years were 77 percent, 60 percent, and 34 percent, respectively.
Figure 4. Overall Survival of 201 Patients Receiving Eight Cycles of CHOP Alone and 200 Patients Receiving Three Cycles of CHOP plus Radiotherapy, According to the Number of Risk Factors.
There were 47 deaths among the 289 patients with zero or one risk factor, 20 among the 82 patients with two risk factors, and 14 among the 28 patients with three risk factors. The estimated rates of survival at five years were 82 percent, 71 percent, and 48 percent, respectively.
Toxicity
Table 2 summarizes the toxicity of the two treatments. Two patientsdied as a result of treatment. One patient treated with CHOPalone died of sepsis associated with neutropenia, and one patienttreated with three cycles of CHOP plus radiotherapy died ofliver failure consistent with radiation-induced hepatitis. Theincidence of life-threatening toxic effects was higher in thegroup treated with eight cycles of CHOP alone. Life-threateningtoxic effects of any type occurred in 80 of 201 patients treatedwith CHOP alone (40 percent) and in 61 of 200 patients treatedwith CHOP plus radiotherapy (30 percent) (P=0.06).
Table 2. Number of Patients with Life-Threatening or Fatal Toxic Reactions to Eight Cycles of CHOP or Three Cycles of CHOP plus Radiotherapy.
The most common cause of life-threatening toxic effects wasmyelosuppression from chemotherapy, which caused grade 4 neutropenia(absolute neutrophil count, <500 per cubic millimeter) in71 patients treated with CHOP alone (35 percent) and 54 patientstreated with CHOP plus radiotherapy (27 percent) (P=0.09). Symptomsor signs of congestive heart failure or more than a 20 percentdecrease from base line in the left ventricular ejection fractionoccurred in seven patients during treatment with CHOP alonebut in no patients during treatment with CHOP plus radiotherapy(P=0.02).
Thirty-one patients did not complete the assigned regimen; 28of these patients were assigned to CHOP alone and 3 to CHOPplus radiotherapy (P<0.01). These patients were removed fromthe protocol at the discretion of the treating physician (20patients) or at their own request (11 patients). For 29 of these31 patients, the initiating event was a toxic reaction. Themost common and serious toxic effects were sepsis (nine patients)and decreased left ventricular function (seven patients). The28 patients assigned to CHOP alone received from one to sevencycles of chemotherapy (median, four), and nine received subsequentradiotherapy.
Discussion
Our results indicate that three cycles of CHOP followed by involved-fieldradiotherapy are superior to eight cycles of CHOP alone as treatmentfor localized stages of intermediate- and high-grade non-Hodgkin'slymphoma. The design of the study derives from a long historyof exploratory trials. Before 1980, patients with clinicallylocalized non-Hodgkin's lymphoma were treated with radiotherapy;the five-year survival rates were 56 to 100 percent for patientswith stage I disease and 0 to 55 percent for patients with stageII disease.10,11,12,13,14,15 The wide ranges are probably dueto the selection of patients, with higher five-year survivalrates in series that used aggressive staging techniques, includingsurgery.12,13
Since 1980, localized non-Hodgkin's lymphoma has usually beentreated initially with doxorubicin-containing chemotherapy,because Miller and Jones16 found that CHOP not only was effectivebut also obviated the need for surgical staging. Subsequentsingle-institution and cooperative-group series, in which chemotherapywas used for localized disease, with or without consolidationradiotherapy, reported five-year rates of relapse-free survivalof 94 to 100 percent for stage I disease17,18,19,20 and 72 to78 percent for stage II disease.17,18,20 Current practice isto treat patients with localized intermediate- and high-gradenon-Hodgkin's lymphomas initially with doxorubicin-containingchemotherapy, but the role of consolidation radiotherapy isunknown.21
Radiotherapy is effective for disease confined to treatmentfields and can cure some patients. Connors et al.18 have arguedthat radiotherapy is an effective consolidation treatment andpermits a reduction in the total dose of chemotherapy required,a potential advantage for elderly patients with reduced myocardialreserve. Our study shows that radiotherapy is valuable not onlyin reducing the number of courses of chemotherapy, but alsoin producing superior overall survival and progression-freesurvival. These results, combined with the preliminary reportby Glick et al.22 (who studied a group that included patientswith bulky stage II disease), suggest that radiotherapy is animportant component of treatment for clinically localized lymphomas.
We selected patients for treatment using criteria previouslythought to assure a homogeneous population. Of our 401 patients,350 (87 percent) were considered at low risk according to thecriteria of the international prognostic index.2 Furthermore,395 of the 401 eligible patients (99 percent) were in the twolowest risk groups of the international prognostic index. However,we found considerable heterogeneity in outcome among prognosticgroups when patients were separated into those with stage Iand those with stage II disease. This modification of the internationalprognostic index results in five-year estimates of progression-freesurvival of 77 percent for patients with zero or one risk factorand only 34 percent for patients with three risk factors (Figure 3).It is apparent that outcome analyses of patients with "localized"lymphoma who are lumped without regard to important prognosticfeatures are inadequate, and that future studies will have toaccount for extreme heterogeneity among patients with localizedlymphoma by using a stage-modified international prognosticindex.
The patients in this trial had more frequent and more severetoxic reactions than the patients in phase 2 trials of the sameregimens.17,18,20 Although only two patients died while receivingtreatment (one in each treatment group), life-threatening toxiceffects were common, occurring in 40 percent of the patientstreated with eight cycles of CHOP and in 30 percent of the patientstreated with three cycles of CHOP plus radiotherapy. The mostfrequent toxic effect, neutropenia, followed treatment withCHOP in both treatment groups.
Our study was conducted during the years when granulocyte growthfactors came into clinical use, and the complications of neutropeniamay be mitigated in future trials with the use of these factors.Even so, there remains the disconcerting finding of myocardialtoxicity associated with eight cycles of CHOP chemotherapy.Left ventricular function, usually associated with clinicalsymptoms of congestive heart failure, decreased substantiallyin seven patients who received eight cycles of CHOP chemotherapy.The finding is underscored by the fact that seven patients treatedwith eight cycles of CHOP but only two treated with three cyclesof CHOP plus radiotherapy subsequently died of apparent heartdisease. The apparent excess mortality from heart disease amongpatients receiving eight cycles of CHOP may be due to the olderage of the patients we treated and the relatively high survivalrate, which allows time for cardiac complications to becomemanifest. Longer follow-up may also reveal serious, and frequentlyfatal, complications of radiotherapy.23,24,25
Supported in part by cooperative-agreement grants from the NationalInstitutes of Health (CA387926, CA32102, CA13612, CA46282, CA04919,CA22433, CA20319, CA12644, CA04920, CA46441, CA27057, CA42777,CA46113, CA35281, CA42028, CA28862, CA35261, CA58861, CA45377,CA37981, CA58686, CA35431, CA45807, CA58416, CA35090, CA45807,CA32734, CA46136, CA35128, CA35119, CA35176, CA52772, CA58348,CA12213, CA45560, CA45466, CA58882, CA45450, CA35178, CA16385,CA52654, CA58415, CA35192, CA46368, CA35262, CA58723, CA52771,CA63850, and CA52654).
Source Information
From the Arizona Cancer Center, University of Arizona, Tucson (T.P.M., J.R.C., C.M.S., T.M.G., E.C.); the Southwest Oncology Group Statistical Center, Seattle (S.D., M.L., S.C.); the Cleveland Clinic Foundation, Cleveland (D.J.A.); and the Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, Ill. (R.I.F.).
Address reprint requests to Dr. Miller at the Southwest Oncology Group, Operations Office, 14980 Omicron Dr., San Antonio, TX 78245-3217.
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Treatment of Intermediate-Grade and High-Grade Non-Hodgkin's Lymphoma
Wirth A., Prince H. M., Wolf M., Machida U., Kami M., Hirai H., Mounier N., Gisselbrecht C., Lepage E., Kosmas C., Malamos N. A., Antonopoulos M. J., Decaudin D., Miller T. P., LeBlanc M., Fisher R. I., The Southwest Oncology Group
Extract |
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N Engl J Med 1998;
339:1475-1477, Nov 12, 1998.
Correspondence
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Miller, T. P., Unger, J. M., Spier, C., Stea, B., Cantu, E., LeBlanc, M., Fisher, R. I.
(2004). Effect of Adding Rituximab to Three Cycles of CHOP Plus Invoved-Field Radiotherapy for Limited-Stage Aggressive Diffuse B-Cell Lymphoma (SWOG-0014).. ASH ANNUAL MEETING ABSTRACTS
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Spier, C. M., LeBlanc, M., Chase, E. M., Fisher, R. I., Miller, T. P.
(2004). Histologic Subtypes Do Not Confer Unique Outcomes in Early-Stage Lymphoma: Long-Term Follow-Up of SWOG 8736.. ASH ANNUAL MEETING ABSTRACTS
104: 3263-3263
[Abstract]
Miller, T. P.
(2004). The Limits of Limited Stage Lymphoma. JCO
22: 2982-2984
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Horning, S. J., Weller, E., Kim, K., Earle, J. D., O'Connell, M. J., Habermann, T. M., Glick, J. H.
(2004). Chemotherapy With or Without Radiotherapy in Limited-Stage Diffuse Aggressive Non-Hodgkin's Lymphoma: Eastern Cooperative Oncology Group Study 1484. JCO
22: 3032-3038
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Pfreundschuh, M., Trumper, L., Kloess, M., Schmits, R., Feller, A. C., Rudolph, C., Reiser, M., Hossfeld, D. K., Metzner, B., Hasenclever, D., Schmitz, N., Glass, B., Rube, C., Loeffler, M., the German High-Grade Non-Hodgkin's Lymphoma Study,
(2004). Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood
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Aguiar Bujanda, D., Bohn Sarmiento, U., Aguiar Morales, J., Bolanos-Meade, J., Herishanu, Y., Zomas, A., Skandalis, A., Milpied, N.
(2004). Intensive Therapy for Aggressive Lymphoma. NEJM
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Bendandi, M., Pileri, S. A., Zinzani, P. L.
(2004). Challenging paradigms in lymphoma treatment. Ann Oncol
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Niitsu, N., Nakamine, H., Okamoto, M., Akamatsu, H., Higashihara, M., Honma, Y., Okabe-Kado, J., Hirano, M.
(2004). Clinical Significance of Intracytoplasmic nm23-H1 Expression in Diffuse Large B-Cell Lymphoma. Clin. Cancer Res.
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Reni, M., Ferreri, A. J.M.
(2004). Is Withdrawal of Consolidation Radiotherapy an Evidence-Based Strategy in Primary Central Nervous System Lymphomas?. JCO
22: 1165-1167
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Pless, M., Belhadj, K., Menssen, H. D., Kern, W., Coiffier, B., Wolf, J., Herrmann, R., Thiel, E., Bootle, D., Sklenar, I., Muller, C., Choi, L., Porter, C., Capdeville, R.
(2004). Clinical Efficacy, Tolerability, and Safety of SAM486A, a Novel Polyamine Biosynthesis Inhibitor, in Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma: Results from a Phase II Multicenter Study. Clin. Cancer Res.
10: 1299-1305
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Andre, M., Mounier, N., Leleu, X., Sonet, A., Brice, P., Henry-Amar, M., Tilly, H., Coiffier, B., Bosly, A., Morel, P., Haioun, C., Gaulard, P., Reyes, F., Gisselbrecht, C., the Groupe d'Etude des Lymphomes de l'Adulte,
(2004). Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients. Blood
103: 1222-1228
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Fisher, R. I., Miller, T. P., O'Connor, O. A.
(2004). Diffuse Aggressive Lymphoma. ASH Education Book
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Binn, M., Ruskone-Fourmestraux, A., Lepage, E., Haioun, C., Delmer, A., Aegerter, P., Lavergne, A., Guettier, C., Delchier, J.-C.
(2003). Surgical resection plus chemotherapy versus chemotherapy alone: comparison of two strategies to treat diffuse large B-cell gastric lymphoma. Ann Oncol
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Leitch, H. A., Gascoyne, R. D., Chhanabhai, M., Voss, N. J., Klasa, R., Connors, J. M.
(2003). Limited-stage mantle-cell lymphoma. Ann Oncol
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Seymour, J. F., Pro, B., Fuller, L. M., Manning, J. T., Hagemeister, F. B., Romaguera, J., Rodriguez, M. A., Ha, C. S., Smith, T. L., Ayala, A., Hess, M., Cox, J. D., Cabanillas, F., McLaughlin, P.
(2003). Long-Term Follow-Up of a Prospective Study of Combined Modality Therapy for Stage I-II Indolent Non-Hodgkin's Lymphoma. JCO
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Kattlove, H., Winn, R. J.
(2003). Ongoing Care of Patients After Primary Treatment for Their Cancer. CA Cancer J Clin
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Tuscano, J. M., O'Donnell, R. T., Miers, L. A., Kroger, L. A., Kukis, D. L., Lamborn, K. R., Tedder, T. F., DeNardo, G. L.
(2003). Anti-CD22 ligand-blocking antibody HB22.7 has independent lymphomacidal properties and augments the efficacy of 90Y-DOTA-peptide-Lym-1 in lymphoma xenografts. Blood
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Bessell, E. M., Burton, A., Haynes, A. P., Glaholm, J., Child, J. A., Cullen, M. H., Davies, J. M., Smith, G. M., Ellis, I. O., Jack, A., Jones, E. L.
(2003). A randomised multicentre trial of modified CHOP versus MCOP in patients aged 65 years and over with aggressive non-Hodgkin's lymphoma. Ann Oncol
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Zucca, E., Conconi, A., Mughal, T.I., Sarris, A.H., Seymour, J.F., Vitolo, U., Klasa, R., Ozsahin, M., Mead, G.M., Gianni, M.A., Cortelazzo, S., Ferreri, A.J.M., Ambrosetti, A., Martelli, M., Thieblemont, C., Moreno, H. G., Pinotti, G., Martinelli, G., Mozzana, R., Grisanti, S., Provencio, M., Balzarotti, M., Laveder, F., Oltean, G., Callea, V., Roy, P., Cavalli, F., Gospodarowicz, M.K.
(2003). Patterns of Outcome and Prognostic Factors in Primary Large-Cell Lymphoma of the Testis in a Survey by the International Extranodal Lymphoma Study Group. JCO
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Akhtar, S., Maghfoor, I., Coiffier, B., Gisselbrecht, C., Reyes, F.
(2002). Rituximab plus CHOP for Diffuse Large-B-Cell Lymphoma. NEJM
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Filipits, M., Jaeger, U., Pohl, G., Stranzl, T., Simonitsch, I., Kaider, A., Skrabs, C., Pirker, R.
(2002). Cyclin D3 Is a Predictive and Prognostic Factor in Diffuse Large B-cell Lymphoma. Clin. Cancer Res.
8: 729-733
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Shenkier, T. N., Voss, N., Fairey, R., Gascoyne, R. D., Hoskins, P., Klasa, R., Klimo, P., O'Reilly, S. E., Sutcliffe, S., Connors, J. M.
(2002). Brief Chemotherapy and Involved-Region Irradiation for Limited-Stage Diffuse Large-Cell Lymphoma: An 18-Year Experience From the British Columbia Cancer Agency. JCO
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Bessell, E. M., Lopez-Guillermo, A., Villa, S., Verger, E., Nomdedeu, B., Petit, J., Byrne, P., Montserrat, E., Graus, F.
(2002). Importance of Radiotherapy in the Outcome of Patients With Primary CNS Lymphoma: An Analysis of the CHOD/BVAM Regimen Followed by Two Different Radiotherapy Treatments. JCO
20: 231-236
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Thieblemont, C., Mayer, A., Dumontet, C., Barbier, Y., Callet-Bauchu, E., Felman, P., Berger, F., Ducottet, X., Martin, C., Salles, G., Orgiazzi, J., Coiffier, B.
(2002). Primary Thyroid Lymphoma Is a Heterogeneous Disease. J. Clin. Endocrinol. Metab.
87: 105-111
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van Besien, K., Kelta, M., Bahaguna, P.
(2001). Primary Mediastinal B-Cell Lymphoma: A Review of Pathology and Management. JCO
19: 1855-1864
[Abstract][Full Text]
Sarris, A. H., Braunschweig, I., Medeiros, L. J., Duvic, M., Ha, C. S., Rodriguez, M. A., Hagemeister, F. B., McLaughlin, P., Romaguera, J., Cox, J., Cabanillas, F.
(2001). Primary Cutaneous Non-Hodgkin's Lymphoma of Ann Arbor Stage I: Preferential Cutaneous Relapses but High Cure Rate With Doxorubicin-Based Therapy. JCO
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Filipits, M., Jaeger, U., Simonitsch, I., Chizzali-Bonfadin, C., Heinzl, H., Pirker, R.
(2000). Clinical Relevance of the Lung Resistance Protein in Diffuse Large B-Cell Lymphomas. Clin. Cancer Res.
6: 3417-3423
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Moreno, A., Colon-Otero, G., Solberg, L. A. Jr.
(2000). The Prednisone Dosage in the CHOP Chemotherapy Regimen for Non-Hodgkin's Lymphomas (NHL): Is There a Standard?. The Oncologist
5: 238-249
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Tilly, H., Mounier, N., Lederlin, P., Briere, J., Dupriez, B., Sebban, C., Bosly, A., Biron, P., Nouvel, C., Herbrecht, R., Bordessoule, D., Coiffier, B.
(2000). Randomized Comparison of ACVBP and m-BACOD in the Treatment of Patients With Low-Risk Aggressive Lymphoma: The LNH87-1 Study. JCO
18: 1309-1315
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O’Brien, P., Roos, D., Pratt, G., Liew, K., Barton, M., Poulsen, M., Olver, I., Trotter, G.
(2000). Phase II Multicenter Study of Brief Single-Agent Methotrexate Followed by Irradiation in Primary CNS Lymphoma. JCO
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Cabanillas, F., Horning, S., Kaminski, M., Champlin, R.
(2000). Managing Indolent Lymphomas in Relapse: Working Our Way Through a Plethora of Options. ASH Education Book
2000: 166-179
[Abstract][Full Text]
Levinson, W., Gorawara-Bhat, R., Dueck, R., Egener, B., Kao, A., Kerr, C., Lo, B., Perry, D., Pollitz, K., Reifsteck, S., Stein, T., Santa, J., Kemp-White, M.
(1999). Resolving Disagreements in the Patient-Physician Relationship: Tools for Improving Communication in Managed Care. JAMA
282: 1477-1483
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Wirth, A., Prince, H. M., Wolf, M., Machida, U., Kami, M., Hirai, H., Mounier, N., Gisselbrecht, C., Lepage, E., Kosmas, C., Malamos, N. A., Antonopoulos, M. J., Decaudin, D., Miller, T. P., LeBlanc, M., Fisher, R. I., The Southwest Oncology Group,
(1998). Treatment of Intermediate-Grade and High-Grade Non-Hodgkin's Lymphoma. NEJM
339: 1475-1477
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65 years vs. <65 years), stage (I vs. II), and histologic subtypes (diffuse large-cell [working-formulation groups G and H] vs. all other eligible histologic subtypes, including follicular large-cell, diffuse small-cleaved-cell, diffuse mixed small- and large-cell, and diffuse small-noncleaved-cell [working-formulation groups D, E, F, and J, respectively]), site of disease involvement (gastrointestinal tract vs. all other sites), and whether all visible and measurable tumors were resected. All patients gave written informed consent according to institutional guidelines. 
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