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Previous Volume 329:1770-1776 December 9, 1993 Number 24 Next

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ABSTRACT

Background and Methods In 1981 the Clinical Trials Group of the National Cancer Institute of Canada completed a pilot study in patients with advanced-stage non-Hodgkin's lymphoma with aggressive tumor histology. That study demonstrated the potential efficacy of escalating the dose of doxorubicin used in a regimen of bleomycin, doxorubicin, cyclophosphamide, vincristine, and prednisone (BACOP). In the present study, we compared standard BACOP (s-BACOP) with BACOP that included escalated doses of doxorubicin (esc-BACOP) in 238 patients 16 to 70 years old with previously untreated, advanced-stage intermediate- or high-grade non-Hodgkin's lymphoma. During the first 28-day cycle all patients received doxorubicin in a dose of 25 mg per square meter of body-surface area on days 1 and 8. Patients randomly assigned to receive s-BACOP subsequently received five identical cycles, whereas those assigned to receive esc-BACOP received 40 mg of doxorubicin per square meter on days 1 and 8 of five subsequent cycles if granulocytopenia (<1000 cells per cubic millimeter) had not developed during the first cycle.

Results The 119 patients assigned to the esc-BACOP regimen received doxorubicin at a significantly higher mean weekly dose intensity (13.5 vs. 10.4 mg per square meter per week, P<0.001) and mean total dose (296 vs. 231 mg per square meter, P<0.001). Because of granulocytopenia during the first cycle of therapy, only 56 of these patients (47 percent) received the escalated doses of doxorubicin. During a median follow-up of 65 months, there were no differences between the s-BACOP and esc-BACOP groups in response rate, overall survival, or survival without disease progression. When the patients who actually received the escalated doses of doxorubicin were compared with the patients in the s-BACOP group in whom neutropenia did not develop during the first treatment cycle, no difference between their outcomes was observed. Toxicity was greater in the esc-BACOP group.

Conclusions In patients with advanced-stage intermediate- or high-grade non-Hodgkin's lymphoma, escalating the dose of doxorubicin in the BACOP regimen increases toxicity but does not improve the rate of response or survival.

Most multidrug regimens used in treating non-Hodgkin's lymphoma with aggressive histologic features include an anthracycline drug, such as doxorubicin^3,4,5,6,7,8. The importance of including an anthracycline was demonstrated in a randomized trial comparing a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus bleomycin with a regimen of cyclophosphamide, vincristine, and prednisone plus bleomycin¹³. In two other randomized trials, regimens that included doxorubicin were superior to those that did not^14,15.

To test whether a dose-response relation for doxorubicin might exist, the Clinical Trials Group of the National Cancer Institute of Canada completed a pilot study in patients who had non-Hodgkin's lymphoma with aggressive histologic features and bone marrow involvement; this study tested the feasibility and the effect of escalating the dose of doxorubicin in a regimen of bleomycin, doxorubicin, cyclophosphamide, vincristine, and prednisone (the BACOP regimen)^4,16. Of 18 patients treated, 17 entered remission; 11 patients remained disease-free at the time of the initial report¹⁶. These results encouraged the Clinical Trials Group to conduct a randomized trial comparing the standard BACOP regimen (s-BACOP) with a BACOP regimen in which the dose of doxorubicin was escalated (esc-BACOP).

Methods

Eligibility and Evaluation of Patients

Between March 1982 and April 1989, we evaluated 298 patients 16 to 70 years old with previously untreated, biopsy-confirmed, advanced-stage intermediate- or high-grade non-Hodgkin's lymphoma. Their tumors were initially classified histologically according to the Rappaport system,¹⁷ and subsequently according to the International Working Formulation¹⁸; all tumors originally classified with the Rappaport system were reclassified. Patients were eligible for this study if they had lymphomas of the following subtypes: follicular large cell; diffuse small cleaved cell; diffuse mixed; diffuse large cell; immunoblastic; or diffuse small noncleaved non-Burkitt's. Patients with lymphoblastic lymphoma or Burkitt's lymphoma were not eligible. The histologic findings were confirmed by a review panel of the Canadian Reference Centre for Cancer Pathology. Tumor stage was determined with the Ann Arbor staging system¹⁹. An advanced stage was defined as any stage with B (systemic) symptoms, stage IIA or IIAE with bulky disease (indicated by a tumor mass 10 cm in diameter), and any stage III or IV disease. In December 1983 the protocol was amended to redefine bulky disease as any tumor mass at least 5 cm in diameter. Patients were excluded if lymphoma cells were evident on a routinely stained peripheral-blood smear, if the lymphoma involved the central nervous system, or if the serum bilirubin concentration was 2.9 mg per deciliter or more ( 50 µmol per liter).

The protocol was approved by the institutional review board of each treatment center, and written informed consent was given by each patient.

Pretherapy evaluation included a history and physical examination; complete blood and differential leukocyte counts, including a search for abnormal lymphoid cells; renal- and liver-function tests; measurement of serum lactate dehydrogenase, calcium, and uric acid and fasting blood glucose; urinalysis; chest radiography; and lymphangiography or abdominal computed tomography. Bilateral bone marrow aspirates and biopsy specimens from the iliac crest were required. Cerebrospinal fluid was obtained for analysis if clinically indicated or if the bone marrow contained lymphoma cells.

Of the 298 patients evaluated, 60 (20 percent) were subsequently considered ineligible for the following reasons: incorrect histologic subtype as determined by central review, 37 patients; incorrect stage, 2 patients; presence of lymphoid blast cells on a peripheral-blood smear, 3 patients; cerebrospinal fluid positive for lymphoma on cytologic examination, 2 patients; previous treatment, 2 patients; and failure to evaluate the cerebrospinal fluid in the presence of positive bone marrow, 14 patients. The clinical features of the 238 patients enrolled in the two treatment groups were similar (Table 1). A majority of patients in each group belonged to the two highest risk groups determined with use of the index of the International Non-Hodgkin's Lymphoma Prognostic Factor Project (the INHLPF index)²⁰.

View this table: [in this window] [in a new window]   Table 1. Pretherapy Characteristics of Patients with Non-Hodgkin's Lymphoma Treated with the Standard BACOP Regimen (s-BACOP) or the BACOP Regimen with Escalated Doses of Doxorubicin (esc-BACOP).

 
Treatment Protocol

Before receiving any therapy, the patients were stratified according to sex, age ( 55 vs. >55 years), and tumor stage (<IV vs. IV) and then randomly assigned to receive either s-BACOP or esc-BACOP. During the first cycle of treatment all patients received s-BACOP as shown in Table 2. The patients assigned to the s-BACOP group subsequently underwent identical cycles every 28 days. The patients assigned to the esc-BACOP group received doxorubicin in a dose of 40 mg per square meter of body-surface area on days 1 and 8 of all subsequent cycles, provided that their total granulocyte count was at least 1000 per cubic millimeter throughout the first cycle; if the granulocyte count fell below this level during that cycle, the dose of doxorubicin was kept at 25 mg per square meter.

View this table: [in this window] [in a new window]   Table 2. Treatment Schedule of the s-BACOP Regimen.

 
The doses of bleomycin, cyclophosphamide, vincristine, and prednisone were the same in the two regimens. Prophylactic central nervous system therapy was not given. During therapy, the doses of the various drugs were reduced when neutropenia and thrombocytopenia occurred, according to prearranged schedules of dose attenuation. The attenuation schedules of the two treatment groups differed; the doses given the s-BACOP group were reduced for lesser degrees of neutropenia than were the doses given the esc-BACOP group.^* If symptomatic mucositis developed in a patient receiving esc-BACOP, as determined by the treating physician, the dose of doxorubicin was reduced by 5 mg per square meter. All patients were to receive either a minimum of six treatment cycles or two additional cycles after they entered a complete remission. Response was assessed after the second, fourth, and sixth cycles of therapy. Patients who did not have a complete response after six cycles of therapy and who also did not have a continued response between the fourth and sixth cycles, as well as patients with evidence of disease progression during therapy, were withdrawn from therapy as defined by the protocol and were treated at the discretion of the attending physician.

Assessment of Response

Response to treatment was evaluated by reexamining all abnormal findings recorded at the pretherapy evaluation. Patients with no residual disease after the diagnostic surgical procedure were not evaluated for response, but were studied for survival without disease progression (progression-free survival) and overall survival. A complete response was defined as resolution of all features of disease for at least four weeks. Lymph nodes less than 1 cm in diameter were considered uninvolved; nodes of 1 cm or more were considered uninvolved if they were negative on subsequent biopsy. A partial response was defined as a reduction of at least 50 percent of the sum of the products of the largest tumor diameters recorded before treatment. Disease progression was defined as an increase of at least 25 percent of the sum of the products of the pretreatment tumor diameters or as the development of new abnormalities (e.g., pleural effusion) attributed to the lymphoma.

Statistical Analysis

            Outcome

All eligible patients were analyzed on an intention-to-treat basis. The chi-square test²¹ or Fisher's exact test²² was used to compare the two groups in terms of remission, disease progression, and death. Progression-free survival was defined as the time from randomization to the first evidence of disease progression; survival was defined as the time from randomization to death from any cause. Actuarial progression-free survival and overall survival were calculated with the life-table method of Kaplan and Meier²³ and compared by the log-rank test²⁴. Confidence intervals for five-year progression-free survival and overall survival were constructed with standard errors determined with Greenwood's formula²⁵. Toxic reactions were graded with the scale of the Eastern Cooperative Oncology Group²⁶. The treatment groups were compared by the chi-square test or Fisher's exact test in terms of each patient's worst toxic reaction in each category of toxicity.

Patients assigned to esc-BACOP who had neutropenia during the first treatment cycle did not subsequently receive escalated doses of doxorubicin. To assess the hypothesis about dose intensity further, a secondary efficacy analysis was performed in which the outcomes of the patients treated with esc-BACOP who were eligible to receive escalated doses of doxorubicin during the second treatment cycle and who did receive these doses were compared with the outcomes of the patients treated with s-BACOP who did not have neutropenia during the first treatment cycle (and who thus would have been eligible for dose escalation if they had been assigned to esc-BACOP).

            Prognostic Factors

Analyses of prognostic factors were performed that included the following variables: age ( 55 vs. >55 years), sex, Karnofsky performance status²⁷ (0 to 60 vs. 70 to 100), Ann Arbor tumor stage (<IV vs. IV), systemic (B) symptoms, bone marrow involvement, number of extranodal disease sites (treated as an ordinal variable), and treatment center. Interactions among treatment covariates were assessed by multivariate analyses²⁸. The INHLPF index²⁰ was used to classify patients into prognostic risk groups based on the number of the following adverse prognostic factors present: age above 60 years, Ann Arbor stage of III or IV, two or more extranodal disease sites, a performance status (Eastern Cooperative Oncology Group²⁶) of 2 or more, and an elevated serum lactate dehydrogenase concentration (i.e., a value above the upper normal limit at each participating institution). Four prognostic risk groups were formed: patients with zero or one adverse factor were considered at low risk, those with two factors were at low intermediate risk, those with three at high intermediate risk, and those with four or five factors at high risk. Two modifications were necessary for the application of this index: a Karnofsky performance status of 0 to 60 was considered to be an adverse prognostic factor; and because serum lactate dehydrogenase values recorded at pretherapy evaluation were available for only 178 patients, these values were assumed to be normal if unavailable. The s-BACOP and esc-BACOP groups were compared in terms of the number of patients in each of the risk groups, which were compared in terms of rates of complete response, progression-free survival, and overall survival.

            Dose Intensity

The dose intensity of each drug was expressed in milligrams of drug received per square meter per week during the first six treatment cycles, as described by Hryniuk¹. Patients who did not complete six cycles were evaluated according to the time they remained in the study. The received dose intensity of doxorubicin in each treatment group was compared with the projected dose intensity of this agent in the s-BACOP regimen. The received dose intensity of doxorubicin in the patients treated with esc-BACOP also was compared with the projected dose intensity in this group. The average relative received dose intensity was calculated by averaging the relative received dose intensity of each of the five drugs as compared with the projected dose intensity of each drug in the s-BACOP group. The mean received dose intensity of each drug and the mean average relative received dose intensity in each treatment group were compared by Student's t-test²⁹.

Trial Monitoring

Patient accrual was ended in April 1989, when 298 patients had been recruited. The trial committee decided against continuing recruitment to make up for the exclusion of patients found to be ineligible after randomization. One interim analysis was performed to exclude large differences in outcome and ensure that the trial could ethically continue.

Results

Chemotherapy Received

One hundred eighty of the 238 patients studied (76 percent) completed at least six cycles of a doxorubicin-containing regimen; they included 95 patients (80 percent) treated with s-BACOP and 85 (71 percent) treated with esc-BACOP. Twenty-nine of the 119 patients (24 percent) treated with s-BACOP underwent more than 6 cycles of treatment (7 or 8 cycles in 21 patients, 9 or 10 cycles in 7, and 12 cycles in 1), as compared with 18 patients (15 percent) treated with esc-BACOP (7 or 8 cycles in 16 patients, and 9 or 10 cycles in 2). Fifty-eight patients (24 percent) did not complete the planned six cycles, including 24 (20 percent) in the s-BACOP group and 34 (29 percent) in the esc-BACOP group.

The s-BACOP regimen called for a projected total dose of doxorubicin of 300 mg per square meter to be administered over a period of 24 weeks (dose intensity, 12.5 mg per square meter per week), as compared with 450 mg per square meter (18.75 mg per square meter per week) with esc-BACOP. The mean received dose intensity of doxorubicin was 10.4 mg per square meter per week (95 percent confidence interval, 10.0 to 10.7) with s-BACOP and 13.5 mg per square meter per week (95 percent confidence interval, 12.9 to 14.1) with esc-BACOP (P<0.001). In relation to the projected dose intensity of 12.5 mg per square meter for s-BACOP, the received dose intensities were 80 percent for s-BACOP and 110 percent for esc-BACOP. The mean total dose of doxorubicin was greater in the patients treated with esc-BACOP (296 vs. 231 mg per square meter, P<0.001).

Despite this increase in the dose intensity of doxorubicin, the received dose intensity in the patients treated with esc-BACOP was only 70 percent of the projected dose intensity for that regimen, largely because patients in whom granulocytopenia developed during the first treatment cycle did not receive escalated doses during subsequent cycles. Because of this protocol specification, only 56 patients (47 percent) received escalated doses of doxorubicin starting with the second cycle of therapy. The received dose intensity of doxorubicin in these 56 patients was 15.8 mg per square meter per week (95 percent confidence interval, 15.1 to 16.5). In the comparable group of 53 patients in the s-BACOP group who did not have neutropenia during the first cycle, the dose intensity was significantly lower (11.0 mg per square meter per week; 95 percent confidence interval, 10.8 to 11.2; P<0.001). The mean total doses of doxorubicin in these two groups of patients were 362 and 258 mg per square meter, respectively (P<0.001).

Because of differences in schedules for dose attenuation, it was anticipated that the received dose intensities of the other drugs might also differ; this did not occur. The received dose intensity (relative to the projected intensity in the s-BACOP regimen) of bleomycin in the s-BACOP group and the esc-BACOP group was 80 percent and 80 percent, respectively; that of cyclophosphamide, 82 percent and 87 percent; that of vincristine, 65 percent and 66 percent; and that of prednisone, 98 percent and 100 percent. The average relative received dose intensity of all five drugs was 82 percent in the patients treated with s-BACOP and 88 percent in those treated with esc-BACOP (P<0.001). This difference was due to the greater dose intensity of doxorubicin in the patients receiving esc-BACOP.

Response to Treatment

            Initial Response

The responses of the two treatment groups to therapy did not differ significantly. The overall rate of response was 88 percent in the patients treated with esc-BACOP and 84 percent in those treated with s-BACOP (P = 0.44; 95 percent confidence interval for the difference, -5 to +13 percent). A complete response was achieved in 59 percent of the esc-BACOP group and 61 percent of the s-BACOP group (P = 0.78; 95 percent confidence interval for the difference, -15 to +11 percent). Multivariate analysis demonstrated that only the number of extranodal sites (P<0.001) was predictive of remission. Analysis according to the prognostic risk groups defined with the INHLPF index showed that 79 percent of the patients at low risk, 64 percent of those at low intermediate risk, 54 percent of those at high intermediate risk, and 54 percent of those at high risk had a complete response (P = 0.03).

            Progression-free Survival

Progression-free survival is shown in Figure 1; there was no significant difference between the treatment groups (P = 0.97). With a median follow-up of 65 months, 5-year progression-free survival was 51 percent in the esc-BACOP group and 53 percent in the s-BACOP group (95 percent confidence interval for the difference, -16 to +12 percent). Multivariate analysis showed that poor Karnofsky performance status (P<0.001), bone marrow involvement (P = 0.002), and male sex (P = 0.02) were predictive of disease progression. Progression-free survival at five years was 70 percent in the low-risk group, 54 percent in the group at low intermediate risk, 50 percent in the group at high intermediate risk, and 45 percent in the high-risk group (P = 0.21).

View larger version (40K): [in this window] [in a new window]   Figure 1. Kaplan-Meier Estimates of Progression-free and Overall Survival among 238 Patients with Non-Hodgkin's Lymphoma Treated with s-BACOP or esc-BACOP. There were no significant differences between the treatment groups in progression-free survival (P = 0.97) or overall survival (P = 0.17).

 
            Overall Survival

There was no difference in overall survival between the two treatment groups (P = 0.17) (Figure 1). The five-year survival was 48 percent in the esc-BACOP group and 60 percent in the s-BACOP group (95 percent confidence interval for the difference, -27 to +3 percent). Multivariate analysis demonstrated that the variables of poor Karnofsky performance status (P<0.001), immunoblastic tumor (P = 0.008), and bone marrow involvement (P = 0.02) were associated with shortened survival. Survival at five years was 71 percent in the low-risk group, 56 percent in the group at low intermediate risk, 51 percent in the group at high intermediate risk, and 47 percent in the high-risk group (P = 0.57).

Efficacy Analysis

There were no differences in outcomes between the 56 patients in the esc-BACOP group who actually received escalated doses of doxorubicin and the 53 patients in the s-BACOP group who did not have neutropenia during the first treatment cycle. Sixty-five percent of the patients in both groups had a complete response. The five-year progression-free survival was 57 percent in the esc-BACOP group and 54 percent in s-BACOP group (P = 0.66), and overall survival at five years was 60 percent in the esc-BACOP group and 59 percent in the s-BACOP group (P = 0.88) (Figure 2).

View larger version (38K): [in this window] [in a new window]   Figure 2. Kaplan-Meier Estimates of Progression-free and Overall Survival among 109 Patients with Non-Hodgkin's Lymphoma in Whom Granulocytopenia Did Not Develop during the First Cycle of Chemotherapy. Fifty-six patients in the esc-BACOP group did not have granulocytopenia during the first cycle and therefore received escalated doses of doxorubicin (40 mg per square meter) during subsequent cycles. Their outcomes were compared with those of the 53 patients in the s-BACOP group who were without granulocytopenia during the first cycle. There were no significant differences between the groups in progression-free survival (P = 0.66) or overall survival (P = 0.88).

 
Causes of Death and Toxicity

The causes of death are listed in Table 3. To be attributed to a complication of treatment, a death had to be due to a well-recognized toxic reaction developing during therapy. Therefore, the number of deaths due to treatment-related toxic reactions may be underestimated. Virtually all other causes of death could be related to the lymphoma or to the results of lymphoma and therapy combined. When the one patient whose cause of death was unknown was excluded, more patients in the esc-BACOP group were found to have died for reasons that included a complication of treatment or some other cause than in the s-BACOP group (16 vs. 6, P = 0.03). Drug toxicity was more severe in the esc-BACOP group; more patients had grade 3 or 4 leukopenia or grade 3 mucositis. There were no differences between the two treatment groups in the incidence of other toxic reactions (Table 4).

View this table: [in this window] [in a new window]   Table 3. Causes of Death, According to Treatment Group.

 

View this table: [in this window] [in a new window]   Table 4. Worst Toxic Reaction, According to Treatment Group.

 
Discussion

In this study we assessed whether a multidrug regimen that included increased doses of doxorubicin improved the outcome of patients with advanced-stage non-Hodgkin's lymphoma found to be aggressive on histologic examination. Two groups balanced with respect to prognostic factors present before therapy received therapy that differed only in the dose of doxorubicin. Higher doses of doxorubicin did not improve outcome but did result in greater toxicity. Therefore, we conclude that escalating the dose of doxorubicin used in the BACOP regimen is not indicated.

In assessing this test of the dose-intensity hypothesis, one needs to consider whether the dose intensities of doxorubicin in the two groups were sufficiently different to allow a dose-response relation to be detected. The projected dose intensity of this drug in the esc-BACOP group was 50 percent greater than that in the s-BACOP group. The mean received dose intensity in the esc-BACOP group was only 30 percent greater than that in the s-BACOP group. This difference between the projected and the received dose intensity was due in large part to the stipulation that patients in the esc-BACOP group be given standard rather than escalated doses of doxorubicin if they had neutropenia during the first treatment cycle; consequently, only 47 percent of the group received escalated doses. Since the received dose intensity of doxorubicin in the esc-BACOP group was only 73 percent of that planned, it remains possible that the hypothesis was insufficiently addressed.

However, we believe that our results demonstrate that BACOP therapy is unlikely to be improved by increasing the dose intensity of doxorubicin. No improvement was evident in progression-free or overall survival. In fact, since more patients in the esc-BACOP group died of treatment-related toxic reactions or other causes, survival may be superior with s-BACOP treatment; the 95 percent confidence interval for the difference in five-year survival showed that s-BACOP could be superior by 27 percent or inferior by 3 percent. Furthermore, there was no increase in efficacy among the patients who actually received escalated doses of doxorubicin as compared with a matched group of patients treated with the s-BACOP regimen (i.e., those without neutropenia during the first treatment cycle). Mucositis and leukopenia were more severe in the esc-BACOP group, a finding consistent with the effect of an increased dose intensity.

At least with respect to doxorubicin, therefore, we could not confirm the hypothesis that dose intensity influences outcome in patients with aggressive non-Hodgkin's lymphoma. This trial -- testing dose intensity directly -- provides a higher level of evidence³⁰ than previous analyses that have used calculated measures of dose intensity to compare outcomes in case series or comparative trials that were not initially designed to assess dose intensity, or that retrospectively assessed the prognostic importance of received dose intensity. Our results are also consistent with the results of other randomized trials of lymphoma therapy. Despite promising results in preliminary testing, second- and third-generation regimens have not proved superior to first-generation regimens when compared in randomized trials. A comparison of the CHOP regimen with a regimen of methotrexate with leucovorin, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) revealed no differences in outcome, but more severe toxic reactions occurred among patients treated with the m-BACOD regimen³¹. The results were similar in a trial comparing CHOP with a regimen of methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B)³². A trial comparing CHOP, m-BACOD, MACOP-B, and a regimen of prednisone, methotrexate with leucovorin, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, and vincristine (ProMACE-CytaBOM) also showed no differences in the rates of remission or disease-free or overall survival³³; toxicity was lower among the patients treated with CHOP. Therefore, a first-generation regimen, such as CHOP, should continue to be the standard against which new therapies are measured³⁴. We have no reason to believe that the outcome of patients treated with BACOP differs from that of patients treated with CHOP. Our results reinforce the need to evaluate new therapeutic strategies in randomized trials. Such evaluation will be important in assessing recently described treatments in which markedly increased drug doses are used in conjunction with hematopoietic growth factor, autologous bone marrow, or peripheral-blood stem-cell support.

^* See NAPS document no. 05071 for two pages of supplementary material. To order, contact NAPS c/o Microfiche Publications, 248 Hempstead Tpk., West Hempstead, NY 11552.

Source Information

From the Hamilton Civic Hospitals and McMaster University, Hamilton, Ont. (R.M.M.); Princess Margaret Hospital and University of Toronto, Toronto (I.C.Q., M.K.G.); Nova Scotia Cancer Treatment and Research Foundation and Dalhousie University, Halifax, N.S. (J.R.S.); Ottawa Regional Cancer Centre (M.C.C.) and Ottawa Civic Hospital (B.F.B.), University of Ottawa, Ottawa, Ont.; London Regional Cancer Centre and University of Western Ontario, London, Ont. (V.H.C.B.); University of Manitoba and Manitoba Cancer Treatment and Research Foundation, Winnipeg, Man. (B.H.W.); National Cancer Institute of Canada Clinical Trials Group (A.M.S.) and Queen's University (L.E.S., B.Z.), Kingston, Ont.; and the Gildred Cancer Center-University of California, San Diego (W.M.H.). Conducted by the Clinical Trials Group (Joseph L. Pater, M.D., chairman) of the National Cancer Institute of Canada; participating investigators are listed in the Appendix.

Address reprint requests to Dr. Meyer at the McMaster Medical Unit, Henderson General Hospital, 711 Concession St., Hamilton, ON L8V 1C3, Canada.

References

1. Hryniuk WM. The importance of dose intensity in the outcome of chemotherapy. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Important advances in oncology 1988. Philadelphia: J.B. Lippincott, 1988:121-41. 
2. DeVita VT Jr, Canellos GP, Chabner B, Schein P, Hubbard SP, Young RC. Advanced diffuse histiocytic lymphoma, a potentially curable disease. Lancet 1975;1:248-250. [CrossRef][Medline]
3. McKelvey EM, Gottlieb JA, Wilson HE, et al. Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer 1976;38:1484-1493. [CrossRef][Medline]
4. Schein PS, DeVita VT Jr, Hubbard S, et al. Bleomycin, adriamycin, cyclophosphamide, vincristine, and prednisone (BACOP) combination chemotherapy in the treatment of advanced diffuse histiocytic lymphoma. Ann Intern Med 1976;85:417-422.
5. Fisher RI, DeVita VT Jr, Hubbard SM, et al. Diffuse aggressive lymphomas: increased survival after alternating flexible sequences of proMACE and MOPP chemotherapy. Ann Intern Med 1983;98:304-309.
6. Skarin AT, Canellos GP, Rosenthal DS, et al. Improved prognosis of diffuse histiocytic and undifferentiated lymphoma by use of high dose methotrexate alternating with standard agents (M-BACOD). J Clin Oncol 1983;1:91-98. [Abstract]
7. Klimo P, Connors JM. MACOP-B chemotherapy for the treatment of diffuse large-cell lymphoma. Ann Intern Med 1985;102:596-602.
8. Longo DL, DeVita VT Jr, Duffey PL, et al. Superiority of ProMACE-CytaBOM over ProMACE-MOPP in the treatment of advanced diffuse aggressive lymphoma: results of a prospective randomized trial. J Clin Oncol 1991;9:25-38. [Erratum, J Clin Oncol 1991;9:710.] [Free Full Text]
9. DeVita VT Jr, Hubbard SM, Longo DL. The chemotherapy of lymphomas: looking back, moving forward. Cancer Res 1987;47:5810-5824. [Free Full Text]
10. Meyer RM, Hryniuk WM, Goodyear MDE. The role of dose intensity in determining outcome in intermediate-grade non-Hodgkin's lymphoma. J Clin Oncol 1991;9:339-347. [Abstract]
11. Kwak LW, Halpern J, Olshen RA, Horning SJ. Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured analysis. J Clin Oncol 1990;8:963-977. [Abstract]
12. Epelbaum R, Haim N, Ben-Shahar M, Ron Y, Cohen Y. Dose-intensity analysis for CHOP chemotherapy in diffuse aggressive large cell lymphoma. Isr J Med Sci 1988;24:533-538. [Medline]
13. Jones SE, Grozea PN, Metz EN, et al. Improved complete remission rates and survival for patients with large cell lymphoma treated with chemoimmunotherapy: a Southwest Oncology Group Study. Cancer 1983;51:1083-1090. [CrossRef][Medline]
14. Hagberg H, Bjorkholm M, Glimelius B, Lindemalm C, Mellstedt H, Killander A. CHOP vs MEV for the treatment of non-Hodgkin's lymphoma of unfavourable histopathology: a randomized clinical trial. Eur J Cancer Clin Oncol 1985;21:175-179. [CrossRef][Medline]
15. Gams RA, Rainey M, Dandy M, Bartolucci AA, Silberman H, Omura G. Phase III study of BCOP v CHOP in unfavourable categories of malignant lymphoma: a Southeastern Cancer Study Group trial. J Clin Oncol 1985;3:1188-1195. [Free Full Text]
16. Hryniuk WM. Escalated bleomycin, adriamycin, cyclophosphamide, oncovin, prednisone, septra for poor prognosis lymphomas with bone marrow involvement. Proc Am Soc Clin Oncol 1982;1:156. abstract.
17. Rappaport H. Tumors of the hematopoietic system. Atlas of tumour pathology. Section 3. Fascicle 8. Washington, D.C.: Armed Forces Institute of Pathology, 1966.
18. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage: the Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer 1982;49:2112-2135. [CrossRef][Medline]
19. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res 1971;31:1860-1861. [Free Full Text]
20. International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 1993;329:987-994. [Free Full Text]
21. Fleiss JL. Statistical methods for rates and proportions. New York: John Wiley, 1973.
22. Fisher RA. Statistical methods for research workers. 14th ed. New York: Hafner Press, 1970:76-96.
23. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81.
24. Peto R, Peto J. Asymptomatically efficient rank invariant test procedures. J R Stat Soc [A] 1972;135:185-206.
25. Friedman LM, Furberg CD, DeMets DL. Fundamentals of clinical trials. 2nd ed. Littleton, Mass.: PSG Publishing, 1985:196-201.
26. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. [Medline]
27. Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH. The use of nitrogen mustards in the palliative treatment of carcinoma: with particular reference to bronchogenic carcinoma. Cancer 1948;1:634-656. [CrossRef]
28. Cox DR. Regression models and life-tables. J R Stat Soc [B] 1972;34:187-220.
29. Mood AM, Graybill FA, Boes DC. Introduction to the theory of statistics. 3rd ed. New York: McGraw-Hill, 1973.
30. Sackett DL. Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest 1989;95:Suppl:2S-4S. [Free Full Text]
31. Gordon LI, Harrington D, Andersen J, et al. Comparison of a second-generation combination chemotherapeutic regimen (m-BACOD) with a standard regimen (CHOP) for advanced diffuse non-Hodgkin's lymphoma. N Engl J Med 1992;327:1342-1349. [Abstract]
32. Cooper IA, Ding JC, Matthews JP, et al. A randomized comparison of MACOP-B and CHOP in intermediate grade non-Hodgkin's lymphoma. Proc Am Soc Clin Oncol 1991;10:271. abstract.
33. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 1993;328:1002-1006. [Free Full Text]
34. Fisher RI. CHOP chemotherapy as standard therapy for treatment of patients with diffuse histiocytic lymphoma. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Important advances in oncology 1990. Philadelphia: J.B. Lippincott, 1990:217-25.

The following investigators of the Clinical Trials Group participated in this study: Toronto: D. Bergsagel, S. Sutcliffe, R.E. Alison, J. Sturgeon, J. Meharchand, R. Hasselback, J.J. Wilson, A. Seidenfeld, L. Rudinskas, M. Baker, F. Shepherd, W. Evans, D. Sutton, D. Cowan, J. Rusthoven, J. Senn, W. Chow, R. Buckman, and D. Osoba; Manitoba: E. Bow, H. Schipper, J. Johnston, T. Shore, B. Schacter, M. Levitt, H. Rayner, and P. Harris; Hamilton: A. Benger, M. Levine, G. Browman, A. Figueredo, A. Neville, W.E.C. Wilson, I. Walker, M. Brain, and J.D. Gowing; St. Catharine's: B. Findlay and M. Samosh; London: A. Smith, R. Lohmann, H. Bush, B. Dingle, and T. Vandenberg; Thunder Bay: M. Goodyear, S.D. Zaentz, and J. Kotalik; Kingston: J. Pater, P. Galbraith, P. Hughes, D. Ginsburg, B. Campling, and W. Lofters; Ottawa: D. Perrault, S. Verma, J. Maroun, S.J. Markman, L. Huebsch, J. Bormanis, V. Young, and H. Hirte; Windsor: H. Abu-Zahra.

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