EXHIBIT 2010
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`EXHIBIT 2010EXHIBIT 2010
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`
`
`
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`

`
`1002 (cid:9)
`1002 (cid:9)
`1002
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`THE NEW ENGLAND JOURNAL OF MEDICINE (cid:9)
`THE NEW ENGLAND JOURNAL OF MEDICINE (cid:9)
`
`April 8, 1993
`April 8, 1993
`April 8, 1993
`
`
`COMPARISON OF A STANDARD REGIMEN (CHOP) WITH THREE INTENSIVE COMPARISON OF A STANDARD REGIMEN (CHOP) WITH THREE INTENSIVE
`COMPARISON OF A STANDARD REGIMEN (CHOP) WITH THREE INTENSIVE
`
`CHEMOTHERAPY REGIMENS FOR ADVANCED NON-HODGKIN'S LYMPHOMA CHEMOTHERAPY REGIMENS FOR ADVANCED NON-HODGKIN'S LYMPHOMA
`CHEMOTHERAPY REGIMENS FOR ADVANCED NON-HODGKIN'S LYMPHOMA
`
`RICHARD I. FISHER, M.D., ELLEN R. GAYNOR, M.D., STEVE DAHLBERG, M.S., MARTIN M. OKEN, M.D.,
`RICHARD I. FISHER, M.D., ELLEN R. GAYNOR, M.D., STEVE DAHLBERG, M.S., MARTIN M. 0KEN, M.D.,
`RICHARD I. FISHER, M.D., ELLEN R. GAYNOR, M.D., STEVE DAHLBERG, M.S., MARTIN M. OKEN, M.D.,
`THOMAS M. GROGAN, M.D., EVONNE M. MIZE, JOHN H. GLICK, M.D., CHARLES A. COLTMAN, JR., M.D.,
`THOMAS M. GROGAN, M.D., EVONNE M. MIZE, jOHN H. GLICK, M.D., CHARLES A. COLTMAN, JR., M.D.,
`THOMAS M. GROGAN, M.D., EVONNE M. MIZE, JOHN H. GLICK, M.D., CHARLES A. COLTMAN, JR., M.D.,
`AND THOMAS P. MILLER, M.D.
`AND THOMAS P. MILLER, M.D.
`AND THOMAS P. MILLER, M.D.
`
`Abstract Background. CHOP is a first-generation,
`Abstract Background. CHOP is a first-generation,
`Abstract Background. CHOP is a first-generation,
`
`combination-chemotherapy regimen consisting of cyclo-combination-chemotherapy regimen consisting of cyclo-
`combination-chemotherapy regimen consisting of cyclo(cid:173)
`phosphamide, doxorubicin, vincristine, and prednisone
`phosphamide, doxorubicin, vincristine, and prednisone
`phosphamide, doxorubicin, vincristine, and prednisone
`that has cured approximately 30 percent of patients
`that has cured approximately 30 percent of patients
`that has cured approximately 30 percent of patients
`with advanced stages of intermediate-grade or high-grade
`with advanced stages of intermediate-grade or high-grade
`with advanced stages of intermediate-grade or high-grade
`non-Hodgkin's lymphoma in national cooperative-group
`non-Hodgkin's lymphoma in national cooperative-group
`non-Hodgkin's lymphoma in national cooperative-group
`
`trials. However, studies at single institutions have sug-trials. However, studies at single institutions have sug-
`trials. However, studies at single institutions have sug(cid:173)
`gested that 55 to 65 percent of such patients might
`gested that 55 to 65 percent of such patients might
`gested that 55 to 65 percent of such patients might
`be cured by third-generation regimens such as ones
`be cured by third-generation regimens such as ones
`be cured by third-generation regimens such as ones
`consisting of low-dose methotrexate with leucovorin res-
`consisting of low-dose methotrexate with leucovorin res-
`consisting of low-dose methotrexate with leucovorin res(cid:173)
`cue, bleomycin, doxorubicin, cyclophosphamide, vincris-
`cue, bleomycin, doxorubicin, cyclophosphamide, vincris-
`cue, bleomycin, doxorubicin, cyclophosphamide, vincris(cid:173)
`
`tine, and dexamethasone (m-BACOD); prednisone, dox-tine, and dexamethasone (m-BACOD); prednisone, dox-
`tine, and dexamethasone (m-BACOD); prednisone, dox(cid:173)
`orubicin, cyclophosphamide, and etoposide, followed
`orubicin, cyclophosphamide, and etoposide, followed
`orubicin, cyclophosphamide, and etoposide, followed
`by cytarabine, bleomycin, vincristine, and methotrex-
`by cytarabine, bleomycin, vincristine, and methotrex-
`by cytarabine, bleomycin, vincristine, and methotrex(cid:173)
`ate with leucovorin rescue (ProMACE-CytaBOM); and
`ate with leucovorin rescue (ProMACE-CytaBOM); and
`ate with leucovorin rescue (ProMACE-CytaBOM); and
`methotrexate with leucovorin rescue, doxorubicin, cyclo(cid:173)
`
`methotrexate with leucovorin rescue, doxorubicin, cyclo-methotrexate with leucovorin rescue, doxorubicin, cyclo-
`phosphamide, vincristine, prednisone, and bleomycin
`
`phosphamide, vincristine, prednisone, and bleomycin phosphamide, vincristine, prednisone, and bleomycin
`(MACOP-B).
`(MACOP-B).
`(MACOP-B).
`Methods. To make a valid comparison of these reg-
`Methods. To make a valid comparison of these reg-Methods. To make a valid comparison of these reg(cid:173)
`
`imens, the Southwest Oncology Group and the East-
`imens, the Southwest Oncology Group and the East-
`imens, the Southwest Oncology Group and the East(cid:173)
`
`ern Cooperative Oncology Group initiated a prospec-ern Cooperative Oncology Group initiated a prospec-
`ern Cooperative Oncology Group initiated a prospec(cid:173)
`
`tive, randomized phase Ill trial. The study end points tive, randomized phase Ill trial. The study end points
`tive, randomized phase Ill trial. The study end points
`were the response rate, time to treatment failure, overall
`were the response rate, time to treatment failure, overall
`were the response rate, time to treatment failure, overall
`survival, and incidence of severe or life-threatening
`survival, and incidence of severe or life-threatening
`survival, and incidence of severe or life-threatening
`
`T HE development of curative combination chemo(cid:173)
`THE development of curative combination chemo-
`THE development of curative combination chemo-
`
`therapy for patients with advanced stages of ag(cid:173)
`therapy for patients with advanced stages of ag-
`therapy for patients with advanced stages of ag-
`gressive non-Hodgkin's lymphoma has been one of
`
`gressive non-Hodgkin's lymphoma has been one of gressive non-Hodgkin's lymphoma has been one of
`the major successes of cancer therapy during the past
`the major successes of cancer therapy during the past
`the major successes of cancer therapy during the past
`two decades. First-generation regimens, which gener(cid:173)
`two decades. First-generation regimens, which gener-
`two decades. First-generation regimens, which gener-
`ally included four chemotherapeutic agents, produced
`ally included four chemotherapeutic agents, produced
`ally included four chemotherapeutic agents, produced
`complete remission in 45 to 55 percent of patients and
`
`complete remission in 45 to 55 percent of patients and complete remission in 45 to 55 percent of patients and
`cure in approximately 30 to 35 percent.'-5 Among
`cure in approximately 30 to 35 percent. 1· 5 Among
`cure in approximately 30 to 35 percent.' 5 Among
`these first-generation regimens, CHOP ( cyclophos(cid:173)
`these first-generation regimens, CHOP (cyclophos-
`these first-generation regimens, CHOP (cyclophos-
`phamide, doxorubicin, vincristine, and prednisone)
`phamide, doxorubicin, vincristine, and prednisone)
`phamidc, doxorubicin, vincristine, and prednisone)
`was studied extensively in national cooperative-group
`
`was studied extensively in national cooperative-group was studied extensively in national cooperative-group
`trials and has been considered standard therapy.
`trials and has been considered standard therapy.
`trials and has been considered standard therapy.
`In the 1980s, several large lymphoma-referral cen(cid:173)
`
`In the 1980s, several large lymphoma-referral cen-In the 1980s, several large lymphoma-referral cen-
`ters conducted pilot trials of second-generation and
`ters conducted pilot trials of second-generation and
`ters conducted pilot trials of second-generation and
`third-generation treatment programs that used six to
`
`third-generation treatment programs that used six to third-generation treatment programs that used six to
`eight chemotherapeutic drugs. 6 These third-genera(cid:173)
`eight chemotherapeutic drugs.' These third-genera-
`eight chemotherapeutic drugs.' These third-genera-
`tion regimens included ones consisting of methotrex-
`tion regimens included ones consisting of methotrex-
`tion regimens included ones consisting of methotrex-
`
`From the Stritch School of Medicine, Loyola University, Maywood, Ill.
`From the Stritch School of Medicine, Loyola University, Maywood, Ill.
`From the Stritch School of Medicine, Loyola University, Maywood, lll.
`(R.I.F., E.R.G.); Southwest Oncology Group Statistical Center, Seattle (S.D.,
`(R.I.F., E.R.G.); Southwest Oncology Group Statistical Center, Seattle (S.D.,
`(R.l.F., E.R.G.); Southwest Oncology Group Statistical Center, Seattle (S.D.,
`E.M.M.); Virginia Piper Cancer Institute, Abbott Northwestern Hospital, Minne-
`E.M.M.); Virginia Piper Cancer Institute, Abbott Northwestern Hospital, Minne-
`E.M.M.); Virginia Piper Cancer Institute, Abbott Northwestern Hospital, Minne(cid:173)
`
`apolis (M.M.O.); the University of Arizona, Tucson (T.M.G., T.P.M.); the apolis (M.M.O.); the University of Arizona, Tucson (T.M.G., T.P.M.); the
`apolis (M.M.O.); the University of Arizona, Tucson (T.M.G., T.P.M.); the
`University of Pennsylvania, Philadelphia (.1.H.G.); and the University of Texas
`University of Pennsylvania, Philadelphia (I.H.G.); and the University of Texas
`University of Pennsylvania, Philadelphia (J.H.G.); and the University of Texas
`Health Science Center, San Antonio (C.A.C.). Address reprint requests to the
`Health Science Center, San Antonio (C.A.C.). Address reprint requests to the
`Health Science Center, San Antonio (C.A.C.). Address reprint requests to the
`
`Southwest Oncology Group (SWOG-8516), Operations Office, 5430 Fredericks-Southwest Oncology Group (SWOG-8516), Operations Office, 5430 Fredericks-
`Southwest Oncology Group (SWOG-8516), Operations Office, 5430 Fredericks(cid:173)
`burg Rd., Suite No. 618, San Antonio, TX 78229-6197.
`burg Rd., Suite No. 618, San Antonio, TX 78229-6197.
`burg Rd., Suite No. 618, San Antonio, TX 78229-6197.
`Supported in part by grants (CA-46282, CA-37429, CA-13612, CA-22433,
`Supported in part by grants (CA-46282, CA-37429, CA-13612, CA-22433,
`Supported in part by grants (CA-46282, CA-37429, CA-13612, CA-22433,
`CA-04919, CA-04920, CA-46136, CA-35995, CA-35117, CA-46441, CA-
`CA-04919, CA-04920, CA-46136, CA-35995, CA-35117, CA-46441, CA-
`CA-04919, CA-04920, CA-46136, CA-35995, CA-35117, CA-46441. CA-
`
`04915, CA-35128, CA-13238, CA-16385, CA-37981, CA-35281, CA-35090, 04915, CA-35128, CA-13238, CA-16385, CA-37981, CA-35281, CA-35090,
`04915, CA-35128, CA-13238, CA-16385, CA-37981, CA-35281, CA-35090,
`
`CA-12213, CA-36020, CA-35261, CA-12644, CA-27057, CA-46113, CA-CA-12213, CA-36020, CA-35261, CA-12644, CA-27057, CA-46113, CA-
`CA-12213, CA-36020, CA-35261, CA-12644, CA-27057, CA-46113, CA-
`35119, CA-03096, CA-203I9, CA-14028, CA-35431, CA-42777, CA-35176,
`35119, CA-03096, CA-20319, CA-14028, CA-35431, CA-42777, CA-35176,
`35119, CA-03096, CA-20319, CA-14028, CA-35431, CA-42777, CA-35176,
`
`CA-35283, CA-22411, CA-32734, CA-45466, CA-52386, CA-45807, CA-CA-35283, CA-22411, CA-32734, CA-45466, CA-52386, CA-45807, CA-
`CA-35283, CA-22411, CA-32734, CA-45466, CA-52386, CA-45807, CA-
`
`35200, CA-28862, CA-45560, CA-35262, CA-37445, CA-35596, CA-35192, 35200, CA-28862, CA-45560, CA-35262, CA-37445, CA-35596, CA-35192,
`35200, CA-28862, CA-45560, CA-35262, CA-37445, CA-35596, CA-35192,
`
`CA-45450, CA-35084, CA-52420, CA-45377, CA-35438, CA-52757, CA-CA-45450, CA-35084, CA-52420, CA-45377, CA-35438, CA-52757, CA-
`CA-45450, CA-35084, CA-52420, CA-45377, CA-35438, CA-52757, CA-
`35178, CA-52772, and CA-32102) from the National Cancer Institute under a
`35178, CA-52772, and CA-32102) from the National Cancer Institute under a
`35178, CA-52772, and CA-32102) from the National Cancer Institute under a
`
`cooperative agreement with the Public Health Service. cooperative agreement with the Public Health Service.
`cooperative agreement with the Public Health Service.
`
`toxicity. Dose intensity was calculated and analyzed.
`toxicity. Dose intensity was calculated and analyzed.
`toxicity. Dose intensity was calculated and analyzed.
`Results. Of the 1138 patients registered for the trial,
`Results. Of the 1138 patients registered for the trial,
`Results. Of the 1138 patients registered for the trial,
`899 were eligible. Each treatment group contained at least
`899 were eligible. Each treatment group contained at least
`899 were eligible. Each treatment group contained at least
`218 patients. Known prognostic factors were equally dis-
`218 patients. Known prognostic factors were equally dis-
`218 patients. Known prognostic factors were equally dis(cid:173)
`tributed among the groups. There were no significant dif-
`tributed among the groups. There were no significant dif-
`tributed among the groups. There were no significant dif(cid:173)
`ferences among the groups in the rates of partial and com-
`ferences among the groups in the rates of partial and com-
`ferences among the groups in the rates of partial and com(cid:173)
`
`plete response. At three years, 44 percent of all patients plete response. At three years, 44 percent of all patients
`plete response. At three years, 44 percent of all patients
`were alive without disease; there were no significant dif-
`were alive without disease; there were no significant dif-
`were alive without disease; there were no significant dif(cid:173)
`ferences between the groups (41 percent in the CHOP
`ferences between the groups (41 percent in the CHOP
`ferences between the groups (41 percent in the CHOP
`and MACOP-B groups and 46 percent in the m-BACOD
`and MACOP-B groups and 46 percent in the m-BACOD
`and MACOP-B groups and 46 percent in the m-BACOD
`and ProMACE-CytaBOM groups; P = 0.35). Overall sur-
`and ProMACE-CytaBOM groups; P = 0.35). Overall sur-
`and ProMACE-CytaBOM groups; P = 0.35). Overall sur(cid:173)
`
`vival at three years was 52 percent (50 percent in the vival at three years was 52 percent (50 percent in the
`vival at three years was 52 percent (50 percent in the
`ProMACE-CytaBOM and MACOP-B groups, 52 percent
`ProMACE-CytaBOM and MACOP-B groups, 52 percent
`ProMACE-CytaBOM and MACOP-B groups, 52 percent
`in the m-BACOD group, and 54 percent in the CHOP
`in the m-BACOD group, and 54 percent in the CHOP
`in the m-BACOD group, and 54 percent in the CHOP
`group; P = 0.90). There was no subgroup of patients in
`group; P = 0.90). There was no subgroup of patients in
`group; P = 0.90). There was no subgroup of patients in
`which survival was improved by a third-generation regi(cid:173)
`
`which survival was improved by a third-generation regi-which survival was improved by a third-generation regi-
`
`men. Fatal toxic reactions occurred in 1 percent of the men. Fatal toxic reactions occurred in 1 percent of the
`men. Fatal toxic reactions occurred in 1 percent of the
`CHOP group, 3 percent of the ProMACE-CytaBOM group,
`CHOP group, 3 percent of the ProMACE-CytaBOM group,
`CHOP group, 3 percent of the ProMACE-CytaBOM group,
`5 percent of the m-BACOD group, and 6 percent of the
`5 percent of the m-BACOD group, and 6 percent of the
`5 percent of the m-BACOD group, and 6 percent of the
`MACOP-B group (P = 0.09).
`MACOP-B group (P = 0.09).
`MACOP-B group (P = 0.09).
`
`Conclusions. CHOP remains the best available treat-Conclusions. CHOP remains the best available treat-
`Conclusions. CHOP remains the best available treat(cid:173)
`
`ment for patients with advanced-stage intermediate-grade ment for patients with advanced-stage intermediate-grade
`ment for patients with advanced-stage intermediate-grade
`or high-grade non-Hodgkin's lymphoma. (N Engl J Med
`or high-grade non-Hodgkin's lymphoma. (N Engl J Med
`or high-grade non-Hodgkin's lymphoma. (N Engl J Med
`1993;328:1002-6.)
`1993;328:1002-6.)
`1993;328:1 002-6.)
`
`ate in a low dose with leucovorin rescue, bleomycin,
`
`ate in a low dose with leucovorin rescue, bleomycin, ate in a low dose with leucovorin rescue, bleomycin,
`doxorubicin, cyclophosphamide, vincristine, and dex(cid:173)
`doxorubicin, cyclophosphamide, vincristine, and dex-
`doxorubicin, cyclophosphamide, vincristine, and dex-
`amethasone (m-BACOD) 7; prednisone, doxorubicin,
`
`amethasone (m-BACOD)'; prednisone, doxorubicin, amethasone (m-BACOD)'; prednisone, doxorubicin,
`cyclophosphamide, and etoposide, followed by cy(cid:173)
`cyclophosphamide, and etoposide, followed by cy-
`cyclophosphamide, and etoposide, followed by cy-
`tarabine, bleomycin, vincristine, and methotrexate.
`tarabine, bleomycin, vincristine, and methotrexate
`tarabine, bleomycin, vincristine, and methotrexate
`with leucovorin rescue (ProMACE-CytaBOM) 8 ; and
`
`with leucovorin rescue (ProMACE-CytaBOM)8; and with leucovorin rescue (ProMACE-CytaBOM)8; and
`methotrexate with leucovorin rescue, doxorubicin, cy(cid:173)
`
`methotrexate with leucovorin rescue, doxorubicin, cy-methotrexate with leucovorin rescue, doxorubicin, cy-
`clophosphamide, vincristine, prednisone, and bleomy(cid:173)
`clophosphamide, vincristine, prednisone, and bleomy-
`clophosphamide, vincristine, prednisone, and bleomy-
`cin (MACOP-B).9 Initially increased rates of com(cid:173)
`cin (MACOP-B).6 Initially increased rates of com-
`cin (MACOP-B).9 Initially increased rates of com-
`plete remission and survival rates of 55 to 65 percent
`plete remission and survival rates of 55 to 65 percent
`plete remission and survival rates of 55 to 65 percent
`were reported, but follow-up was limited and these
`
`were reported, but follow-up was limited and these were reported, but follow-up was limited and these
`new treatment programs were more difficult to admin(cid:173)
`new treatment programs were more difficult to admin-
`new treatment programs were more difficult to admin-
`ister, more toxic, and more costly.
`
`ister, more toxic, and more costly. ister, more toxic, and more costly.
`Therefore, in April 1986 the Southwest Oncology
`Therefore, in April 1986 the Southwest Oncology
`Therefore, in April 1986 the Southwest Oncology
`Group initiated a phase III comparison of CHOP,
`
`Group initiated a phase III comparison of CHOP, Group initiated a phase III comparison of CHOP,
`m-BACOD, ProMACE-CytaBOM, and MACOP-B
`m-BACOD, ProMACE-CytaBOM, and MACOP-B
`m-BACOD, ProMACE-CytaBOM, and MACOP-B
`for the treatment of patients with intermediate-grade
`for the treatment of patients with intermediate-grade
`for the treatment of patients with intermediate-grade
`or high-grade non-Hodgkin's lymphoma, in order to
`or high-grade non-Hodgkin's lymphoma, in order to
`or high-grade non-Hodgkin's lymphoma, in order to
`evaluate in a randomized setting the response rate,
`
`evaluate in a randomized setting the response rate, evaluate in a randomized setting the response rate,
`time to treatment failure, survival, and toxicity of
`time to treatment failure, survival, and toxicity of
`time to treatment failure, survival, and toxicity of
`standard chemotherapy -
`i.e., to compare CHOP
`standard chemotherapy - i.e., to compare CHOP
`standard chemotherapy - i.e., to compare CHOP
`with the third-generation regimens. The Eastern Co(cid:173)
`with the third-generation regimens. The Eastern Co-
`with the third-generation regimens. The Eastern Co-
`operative Oncology Group joined the study on Janu(cid:173)
`
`operative Oncology Group joined the study on Janu-operative Oncology Group joined the study on Janu-
`ary IS, 1988, and the trial was designated the National
`ary 15, 1988, and the trial was designated the National
`ary 15, 1988, and the trial was designated the National
`High Priority Lymphoma Study by the National Can(cid:173)
`High Priority Lymphoma Study by the National Can-
`High Priority Lymphoma Study by the National Can-
`cer Institute on November 14, 1988,
`cer Institute on November 14, 1988:
`cer Institute on November 14, 1988:
`
`Treatment Protocol
`Treatment Protocol
`Treatment Protocol
`
`
`METHODS METHODS
`METHODS
`
`
`Patients were eligible if they had measurable, biopsy-confirmed Patients were eligible if they had measurable, biopsy-confirmed
`Patients were eligible if they had measurable, biopsy-confirmed
`non-Hodgkin's lymphoma; bulky stage II, stage III, or stage IV
`non-Hodgkin's lymphoma; bulky stage II, stage III, or stage IV
`non-Hodgkin's lymphoma; bulky stage II, stage III, or stage IV
`
`disease; and histologic features representing any intermediate-grade disease; and histologic features representing any intermediate-grade
`disease; and histologic features representing any intermediate-grade
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 27, 2015. For personal use only. No other uses without permission.
`
` Copyright © 1993 Massachusetts Medical Society. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2010
`
`

`
`Vol. 328 No. J4.
`Vol. 328 No. 14
`Vol. 328 No. 14
`
`CHOP VS. INTENSIVE REGIMENS IN NON-HODGKIN'S LYMPHOMA- FISHER ET AL.
`CHOP VS. INTENSIVE REGIMENS IN NON-HODGKIN'S LYMPHOMA — FISHER ET AL. (cid:9)
`CHOP VS. INTENSIVE REGIMENS IN NON-HODGKIN'S LYMPHOMA — FISHER ET AL. (cid:9)
`
`1003
`1003
`1003
`
`or high-grade disorder other than lymphoblastic lymphoma (i.e.,
`or high-grade disorder other than lymphoblastic lymphoma (i.e.,
`or high-grade disorder other than lymphoblastic lymphoma (i.e.,
`patients in working formulation groups D through H and group
`patients in working formulation groups D through H and group
`patients in working formulation groups D through H and group
`J) .10 There were no age restrictions. Patients were excluded if they
`J)." There were no age restrictions. Patients were excluded if they
`J). lo There were no age restrictions. Patients were excluded if they
`had any of the following: previous treatment with chemotherapy or
`had any of the following: previous treatment with chemotherapy or
`had any of the following: previous treatment with chemotherapy or
`radiotherapy; lymphoma associated with the acquired immunodefi(cid:173)
`radiotherapy; lymphoma associated with the acquired immunodefi-
`radiotherapy; lymphoma associated with the acquired immunodefi-
`ciency syndrome; a history of low-grade lymphoma; a history of
`
`ciency syndrome; a history of low-grade lymphoma; a history of ciency syndrome; a history of low-grade lymphoma; a history of
`neoplasm; overt central nervous system disease; marked impair(cid:173)
`neoplasm; overt central nervous system disease; marked impair-
`neoplasm; overt central nervous system disease; marked impair-
`ment of cardiac function, indicated by an abnormal result on multi(cid:173)
`ment of cardiac function, indicated by an abnormal result on multi-
`ment of cardiac function, indicated by an abnormal result on multi-
`ple-gated acquisition scanning in patients with a history of such im(cid:173)
`ple-gated acquisition scanning in patients with a history of such im-
`ple-gated acquisition scanning in patients with a history of such im-
`pairment; a carbon monoxide-diffusing capacity below 50 percent;
`pairment; a carbon monoxide-diffusing capacity below 50 percent;
`pairment; a carbon monoxide-diffusing capacity below 50 percent;
`or a serum creatinine concentration of I. 7 mg per deciliter ( 150
`or a serum creatinine concentration of 1.7 mg per deciliter (150
`or a serum creatinine concentration of 1.7 mg per deciliter (150
`p.mol per liter) or more and a calculated serum creatinine clearance
`pmol per liter) or more and a calculated serum creatinine clearance
`.cmol per liter) or more and a calculated serum creatinine clearance
`of 60 ml per minute or less. All patients gave written informed
`
`of 60 ml per minute or less. All patients gave written informed of 60 ml per minute or less. All patients gave written informed
`consent.
`consent.
`consent.
`Randomization was stratified according to five factors: bone mar(cid:173)
`
`Randomization was stratified according to five factors: bone mar-Randomization was stratified according to five factors: bone mar-
`row infiltration (present vs. absent); bulky disease (present vs. ab(cid:173)
`row infiltration (present vs. absent); bulky disease (present vs. ab-
`row infiltration (present vs. absent); bulky disease (present vs. ab-
`sent), indicated by a mediastinal mass that was greater than one
`sent), indicated by a mediastinal mass that was greater than one
`sent), indicated by a mediastinal mass that was greater than one
`third of the maximal diameter of the chest or any mass more than
`third of the maximal diameter of the chest or any mass more than
`third of the maximal diameter of the chest or any mass more than
`10 em in diameter; age ( <65 vs. ;;;.65 years); lactate dehydrogenase
`10 cm in diameter; age (<65 vs. ..?--65 years); lactate dehydrogenase
`years); lactate dehydrogenase
`10 cm in diameter; age (<65 vs. (cid:9)
`concentration (.;;250 vs. >250 U per liter); and working formula(cid:173)
`concentration (250 vs. >250 U per liter); and working formula-
`concentration (250 vs. >250 U per liter); and working formula-
`tion group (group D or E vs. group F, G, or H vs. group J). 10
`tion group (group D or E vs. group F, G, or H vs. group J).'°
`tion group (group D or E vs. group F, G, or H vs. group J).10
`All chemotherapy was administered exactly as described in the
`
`All chemotherapy was administered exactly as described in the All chemotherapy was administered exactly as described in the
`original reports of the regimens. 5•7•9 •11 CHOP was given in eight
`original reports of the regimens.5'''9." CHOP was given in eight
`original reports of the regimens.5,7," CHOP was given in eight
`consecutive 21-day courses unless progressive disease developed.
`consecutive 21-day courses unless progressive disease developed.
`consecutive 21-day courses unless progressive disease developed.
`Central nervous system prophylaxis was carried out in the Pro(cid:173)
`Central nervous system prophylaxis was carried out in the Pro-
`Central nervous system prophylaxis was carried out in the Pro-
`MACE-CytaBOM and MACOP-B groups, as was initially recom(cid:173)
`MACE-CytaBOM and MACOP-B groups, as was initially recom-
`MACE-CytaBOM and MACOP-B groups, as was initially recom-
`mended, but not in the CHOP and m-BACOD groups. Vincristine
`mended, but not in the CHOP and m-BACOD groups. Vincristine
`mended, but not in the CHOP and m-BACOD groups. Vincristine
`doses did not exceed 2.0 mg in the m-BACOD group. Modification
`doses did not exceed 2.0 mg in the m-BACOD group. Modification
`doses did not exceed 2.0 mg in the m-BACOD group. Modification
`of dosages because of hematologic or other toxicity was based on
`
`of dosages because of hematologic or other toxicity was based on of dosages because of hematologic or other toxicity was based on
`precise guidelines in the initial reports. 7•9• 11
`
`precise guidelines in the initial reports.'•9° 11 precise guidelines in the initial reports.7'9.11
`All patients underwent repeat staging after therapy ended. Com(cid:173)
`
`All patients underwent repeat staging after therapy ended. Com-All patients underwent repeat staging after therapy ended. Com-
`plete remission has traditionally been defined as the disappear(cid:173)
`
`plete remission has traditionally been defined as the disappear-plete remission has traditionally been defined as the disappear-
`ance of all clinical evidence of active tumor for a minimum of
`ance of all clinical evidence of active tumor for a minimum of
`ance of all clinical evidence of active tumor for a minimum of
`four weeks; remission is verified by repeating all radiographic tests
`four weeks; remission is verified by repeating all radiographic tests
`four weeks; remission is verified by repeating all radiographic tests
`previously yielding positive findings. With the advent of modern
`previously yielding positive findings. With the advent of modern
`previously yielding positive findings. With the advent of modern
`radiographic techniques such as computed tomography and mag(cid:173)
`radiographic techniques such as computed tomography and mag-
`radiographic techniques such as computed tomography and mag-
`netic resonance imaging, residual abnormalities of various sizes
`netic resonance imaging, residual abnormalities of various sizes
`netic resonance imaging, residual abnormalities of various sizes
`have frequently been detectable after treatment, making an accu(cid:173)
`
`have frequently been detectable after treatment, making an accu-have frequently been detectable after treatment, making an accu-
`rate assessment of complete responses very difficult. Therefore, in
`
`rate assessment of complete responses very difficult. Therefore, in rate assessment of complete responses very difficult. Therefore, in
`this study the rate of complete response was estimated conservative(cid:173)
`this study the rate of complete response was estimated conservative-
`this study the rate of complete response was estimated conservative-
`ly: no peripheral disease could be present, and any abnormalities
`ly: no peripheral disease could be present, and any abnormalities
`ly: no peripheral disease could be present, and any abnormalities
`detected on abdominal or chest radiography had to be less than 2.5
`detected on abdominal or chest radiography had to be less than 2.5
`detected on abdominal or chest radiography had to be less than 2.5
`em in diameter. A partial remission was indicated by a decrease of
`cm in diameter. A partial remission was indicated by a decrease of
`cm in diameter. A partial remission was indicated by a decrease of
`more than 50 percent in the sum of the products of the maximal
`more than 50 percent in the sum of the products of the maximal
`more than 50 percent in the sum of the products of the maximal
`perpendicular diameters of the measured lesions, lasting at least
`
`perpendicular diameters of the measured lesions, lasting at least perpendicular diameters of the measured lesions, lasting at least
`four weeks. Disease progression was indicated by the appearance of
`
`four weeks. Disease progression was indicated by the appearance of four weeks. Disease progression was indicated by the appearance of
`new lesions or by a 25 percent increase in the size of preexisting
`
`new lesions or by a 25 percent increase in the size of preexisting new lesions or by a 25 percent increase in the size of preexisting
`lesions.
`
`lesions. lesions.
`
`Statistical Analysis
`Statistical Analysis
`Statistical Analysis
`
`All eligible patients were included in the comparisons of the treat(cid:173)
`All eligible patients were included in the comparisons of the treat-
`All eligible patients were included in the comparisons of the treat-
`ment groups. The patients' characteristics, responses, and toxic re(cid:173)
`
`ment groups. The patients' characteristics, responses, and toxic re-ment groups. The patients' characteristics, responses, and toxic re-
`actions were compared by chi-square tests. The time to treatment
`actions were compared by chi-square tests. The time to treatment
`actions were compared by chi-square tests. The time to treatment
`failure was measured from the date of randomization to disease
`
`failure was measured from the date of randomization to disease failure was measured from the date of randomization to disease
`progression, relapse, or death. Only the data on patients alive with(cid:173)
`progression, relapse, or death. Only the data on patients alive with-
`progression, relapse, or death. Only the data on patients alive with-
`out disease were censored at the time of the last contact. Survival
`
`out disease were censored at the time of the last contact. Survival out disease were censored at the time of the last contact. Survival
`was measured from the date of randomization to death (from any
`was measured from the date of randomization to death (from any
`was measured from the date of randomization to death (from any
`cause) or the date of the last contact. Only the data on patients
`
`cause) or the date of the last contact. Only the data on patients cause) or the date of the last contact. Only the data on patients
`known to be alive at the most recent follow-up visit were censored in
`known to be alive at the most recent follow-up visit were censored in
`known to be alive at the most recent follow-up visit were censored in
`the survival analysis. The rates of treatment failure and survival
`the survival analysis. The rates of treatment failure and survival
`the survival analysis. The rates of treatment failure and survival
`were estimated according to the method of Kaplan and Meier. 12
`
`were estimated according to the method of Kaplan and Meier." were estimated according to the method of Kaplan and Meier."
`The treatment groups were compared by log-rank tests 13 and Cox
`The treatment groups were compared by log-rank tests' and Cox
`The treatment groups were compared by log-rank tests' and Cox
`partial-likelihood-score tests. 14 Relative risks were estimated with
`
`partial-likelihood-score tests.' Relative risks were estimated with partial-likelihood-score tests.' Relative risks were estimated with
`the Cox regression model. 15 All tests for significance were two-sided
`the Cox regression model." All tests for significance were two-sided
`the Cox regression model.' All tests