|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3307-3314
A Phase II Trial of 200% ProMACE-CytaBOM in Patients With Previously
Untreated Aggressive Lymphomas: Analysis of Response, Toxicity, and
Dose Intensity
By
Leo I. Gordon,
Mary Young,
Edie Weller,
Thomas M. Habermann,
Jane
N. Winter,
John Glick,
Chirantan Ghosh,
Patrick Flynn, and
Peter A. Cassileth
From Northwestern University Medical School, Chicago, IL; Dana Farber
Cancer Institute, Boston, MA; Mayo Clinic, Rochester, MN; University of
Pennsylvania Cancer Center, Philadelphia, PA; Cedar Rapids Oncology
Project, Cedar Rapids, IA; Metro-Minnesota CCOP, St Louis Park, MN; and
University of Miami, Sylvester Cancer Center, Miami, FL.
 |
ABSTRACT |
We showed in a phase I trial that the maximum tolerated dose of the
ProMACE-CytaBOM regimen in patients with aggressive lymphoma was 200%
(Gordon et al, J Clin Oncol 14:1275, 1996). Based on these
observations, we initiated a phase II trial designed to determine
response, toxicity, and dose intensity using this regimen. We analyzed
74 patients with advanced-stage (III or IV) or bulky stage II
aggressive lymphoma. The overall complete response rate was 69% (72%
in evaluable patients). With a median follow-up of 4.5 years, the
median survival has not yet been reached. The 4-year survival rate is
73% (95% confidence interval [CI] 62, 83%) and no difference was
observed among International Prognostic Index (IPI) groups. The 4-year
disease-free survival was 71% (95% CI 58, 84%) with no statistical
difference between patients with IPI 0 to 1 versus 2 to 4. The toxicity
was acceptable, though the grade 4 hematologic toxicity rate for this
regimen was 100%. Grade 4 nonhematologic toxicity was 36%. Three
cases of either myelodysplastic syndrome or acute leukemia occurred at
7 months, 3.4 years, and 4.2 years after registration. Cytogenic
analysis was available in two cases, showing inv(16) without French
American British classification (FAB) M4 EO histology in
one patient and a 5q-syndrome in the other. These data suggest that
200% ProMACE-CytaBOM with either granulocyte-macrophage
colony-stimulating factor (GM-CSF) or G-CSF results in a high complete
remission rate and a disease-free survival comparable to any prior
risk-based analysis in aggressive lymphoma. Before using this regimen
in general practice, phase III clinical trials should be conducted.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
INTENSIVE COMBINATION chemotherapy for
patients with aggressive non-Hodgkin's lymphoma results in complete
response rates of between 60% to 80% with long-term disease-free
survival in 30% to 40%.1 It has become clear that
inherent prognostic features are better predictors of outcome than the
choice of chemotherapy regimen.2-16 Because there are data
to support the concept that dose intensity may be important in the
treatment of cancer in general and in malignant lymphoma in
particular,17-22 we intensified the dose of the
ProMACE-CytaBOM regimen in a phase I dose-finding study,23
and found that patients could tolerate up to 200% dose of the
myelosuppressive agents with growth factor support without the need for
stem cell infusion. We now report mature phase II response, toxicity,
and survival data in a cohort of patients with aggressive lymphoma
treated with 200% ProMACE-CytaBOM.
| |
MATERIALS AND METHODS |
Patient characteristics.
A total of 77 patients (70 in the phase II and 7 from the phase I trial
treated at 200% ) were entered. There were 2 pathology exclusions and
1 patient was canceled and never received treatment, leaving 74 patients, 67 treated in the phase II portion of the study and 7 treated
in the phase I portion (Table 1). Included in this group
were 3 patients who were declared ineligible because they were not
registered to an ancillary laboratory study. They were nevertheless
treated according to protocol and were considered evaluable for
analysis of toxicity, response, and survival.
Eligibility.
Patients were eligible if they had a tissue diagnosis of non-Hodgkin's
lymphoma of intermediate or high-grade histology other than Burkitts,
non-Burkitts undifferentiated, or lymphoblastic lymphoma (Working
Formulation categories D to H), had at least bulky stage II
(mediastinal mass greater than 33% of chest diameter on chest
radiograph or any mass greater than 10 cm), stage III or IV disease by
Ann Arbor criteria, and at least one objective measurable parameter,
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, and age less than 65. Patients could not have other malignancies,
central nervous system lymphoma or human immunodeficiency virus
(HIV)-related lymphoma, or significant organ compromise. Approval was
obtained from the Institutional Review Board for these studies.
Informed consent was provided according to the Declaration of Helsinki.
Response criteria.
Complete response (CR) was defined as regression of all disease (by
physical examination and radiograph). Repeat bilateral bone marrow
examinations were required if the marrow was initially involved. A
partial response (PR) is defined as a 50% reduction in the sum of the
products of the dimensions of the measurable lesions, whereas stable
disease (SD) included patients who did not satisfy the requirements for
CR or PR. Progressive disease (PD) is an increase of 25% of the sum of
the products of the pretreatment lesions or the appearance of new
lesions. Relapse is defined as reappearance of any lymphoma in patients
who have had CR, and relapse for patients with PR is defined as
progression. Duration of response is measured from the documentation of
response to the time of relapse or progression.
Patients who had residual computed tomography (CT) scan abnormalities
were carefully evaluated. If the scans were stable and/or biopsies
negative, patients were judged to have a "clinical" CR (CCR).
Treatment regimen.
The regimen and dose adjustment guidelines are described in
Table 2. The growth factor used in the
phase I study was granulocyte-macrophage colony-stimulating factor
(GM-CSF; Schering-Plough, Nutley, NJ), an Esherichia coli-derived
nonglycosylated protein. In this trial, the GM-CSF was used in the 7 patients on the phase I portion treated at the maximum tolerated
disease (MTD) (200%) and the first 39 patients treated on the phase II
study (total, n = 46), whereas the remaining 28 patients received G-CSF
(Amgen, Thousand Oaks, CA) when it became clear that GM-CSF was
associated with more toxicity. No differences in myelotoxicity were
observed, however, after the change from GM-CSF to G-CSF. Intrathecal
chemotherapy was allowed but not required if the marrow was involved
with large cells or if there was testicular involvement; however, no
patient received intrathecal prophylaxis. Radiotherapy was not part of the protocol, but one patient had radiation to a bulky mediastinal mass.
Statistical methods.
Disease-free survival (DFS) was defined as the time from documentation
of a CR to the date of relapse or death from any cause. If a patient
did not relapse or die, DFS was censored at the last known date in
remission, or if unknown, the last survival date. Overall survival was
defined from the time of entry into the study to the date of death from
any cause. Time to treatment failure (TTF) was defined as the interval
from the date of entry on study to the date of relapse after a CR, the
date of progression from PR/SD, or the date of death from any cause
without documented relapse. Therefore, this analysis includes all
patients, not only those in CR. If a patient in CR did not relapse,
they were censored at the date last known in remission or the survival
date if the date last known in remission was missing. The survival
distribution for overall survival, TTF, and DFS was estimated by the
method of Kaplan and Meier.24 CR rates were compared by
patient characteristics using Fisher's Exact test.25
| |
RESULTS |
Patient characteristics.
Table 3 summarizes the distribution of
selected baseline patient characteristics at on-study for the 74 eligible patients. The median age was 43 years with a range of 19 to 65 years. There were 43 (58%) male patients and 67 (91%) of the patients
were white. Forty-five (61%) had a performance status (PS) of 0 and 29 (39%) had a PS of 1; 43 (58%) had no B symptoms. Sixty-one (82%) had
stage III/IV disease by Ann Arbor criteria.
The International Prognostic Index (IPI) defines five pretreatment
characteristics including age ( 60 v >60), Ann Arbor stage (I/II v III/IV), number of extranodal sites (0 to 1 v
>1), PS (0 to 1 v >2) and serum lactic dehydrogenase (LDH)
( normal vs > normal). The age-adjusted index defines three
pretreatment characteristics, excluding age and extranodal sites, so
that LDH, Ann Arbor stage, and performance status are the predictors of
outcome.26 Patients were analyzed both by index and by
age-adjusted index. Of the 68 eligible patients with data (6 were
missing LDH values), 29 (43%) had an IPI of 0 to 1, and 39 (57%) had
an IPI of 2 to 4, whereas 37 (54%) had an age-adjusted IPI of 0-1, and
31 (46%) had an age-adjusted IPI of 2 to 3. Only 1 patient had an IPI
score of 4 and no patients had an age-adjusted IPI score of 3. Median follow-up is 4.5 years.
Number of cycles.
A total of 461 cycles of therapy were administered to 74 eligible
patients. The median number of cycles was 6 (range, 1 to 8 cycles).
Eleven patients (15%) received less than the protocol-specified minimum of 6 cycles: 1 patient received only 1 cycle, 2 received 3 cycles, 6 received 4 cycles, and 2 received 5 cycles. Reasons for early
treatment termination include excessive complications/toxicity (8 cases) and patient withdrawal/refusal (3 cases, all received 4 cycles).
Dose intensity.
Dose intensity was calculated as the dose received/m2 body
surface area (BSA) for each cycle. The normalized dose
intensity is defined as the actual dose/intended dose, and serves as a
measure of the ability to deliver the regimen as designed. These data are summarized in Table 4. For the most
part, the escalated doses of cyclophosphamide, etoposide, and
doxorubicin could be administered with minimal cycle delays and at
close to 95% normalized dose intensity for up to cycle 8. However, the
dose of the day-8 drug, cytosine arabinoside, could be maintained at
about 95% dose intensity for 6 cycles, but had to be reduced to 82%
by cycle 7 and 50% by cycle 8.
Toxicity.
Table 5 summarizes the acute toxicity
associated with the phase II portion of the study. Toxicity information
is available on 76 patients (including the 2 pathology exclusions).
Seventy-four (97%) of the patients had grade 4 leukopenia, 37 (49%)
experienced grade 4 thrombocytopenia, and 63 (83%) had grade 4 granulocytopenia. The nonhematologic grade 4 toxicity included 16 (21%) cases of anemia, 7 (9%) cases of infection, 3 (4%) cases of
liver toxicity, and 1 (1%) case each of pulmonary embolus, allergy,
and neuromotor toxicity. The grade 4 hematologic toxicity rate for the
ProMACE-CytaBOM regimen was 100%. The grade 4 nonhematologic toxicity
rate was 36% (27 of the 76 patients had at least 1 grade 4 nonhematologic toxicity) with an exact 95% confidence interval (CI) of
(25%, 47%). No toxic deaths occurred.
Late effects.
Three patients later developed myelodysplastic syndrome (MDS) or acute
leukemia at 7 months, 3.4 years, and 4.2 years after registration on
study. The patient who developed acute nonlymphocytic leukemia (ANLL)
at 7 months had achieved PR of lymphoma, and died of leukemia (no
cytogenetics were available). The other two cases were in CR and are
still alive. The patient who developed ANLL at 3.4 years had inv(16)
without FAB M4 EO histology and the patient with MDS at 4.2 years had
the 5q- abnormality. The incidence of either MDS or acute leukemia is
therefore 4.1 %, with 90% CI (1.1, 10.2). Three cases (incidence of
4.1%, 90% CI 1.1, 10.2) of aseptic necrosis of the femoral head also occurred.
Response.
The objective response is summarized in
Table 6. There were 51 CR/CCR (69%), 17 PR
(23%), 2 SD (3%), 1 PD (1%), and 3 (4%) with missing or unevaluable
response. The CR/CCR rate among evaluable cases was therefore 72% with
a 95% CI (60, 82%).
Table 7 summarizes the CR rate by selected
baseline patient characteristics. There were slightly higher CR rates
observed for patients who were younger, had lower anatomic stage and
lower IPI scores, but none of these differences were statistically
significant.
Survival.
With a median follow-up of 4.5 years, 22 of 74 eligible patients have
died (30%). The median survival has not yet been reached (range, 0.6 to 6.5 + years). The 4-year survival rate is 73% with a 95% CI (62, 83%). Figure 1A gives the Kaplan-Meier
estimate of the survival distribution for the overall group. Figure 1B depicts the overall survival by IPI groupings. There was no significant difference in survival among patients with an IPI of 0 to 1 versus 2 to
4 (only 1 patient had an IPI score of 4), though the sample size for
each group was small. Analysis of prognostic factors by the
age-adjusted IPI groups (0 to 1 v 2) also showed no differences in survival (data not shown).
View larger version (22K):
[in this window]
[in a new window]
| Fig 1.
(A) Kaplan Meier estimate of the overall survival for all
74 patients is shown here. (B) The same analysis depicting overall
survival by IPI groupings 0 to 1 and 2 to 4. IPI low (0 to 1), low
intermediate (2), high intermediate (3), and high (4). Only 1 patient
had an IPI score of 4.
|
|
TTF.
Median TTF for the 74 eligible patients has not yet been reached; 26 have died/relapsed/progressed (35%) at a median follow-up of 4.5 years. TTF ranges from 0.3+ to 6.5+ years.
Figure 2A gives the Kaplan-Meier estimate
of the survival distribution for TTF. The 4-year TTF is 58% with a
95% CI (47, 70%). Figure 2B shows similar data by IPI groupings,
showing no difference by IPI score. There is no statistical difference
between patients with age-adjusted IPI groups 0 to 1 versus 2 (data not
shown).
View larger version (25K):
[in this window]
[in a new window]
| Fig 2.
(A) Kaplan Meier estimate of the survival distribution
for TTF, showing a 4-year TTF of 58% with 95% confidence interval
(47, 70%). (B) The same analysis depicting TTF by IPI groupings 0 to 1 and 2 to 4. IPI low (0 to 1), low intermediate (2), high intermediate
(3), and high (4).
|
|
DFS.
Median DFS for the 51 patients who achieved CR has not yet been
reached. Of these 51 cases, 14 have died or relapsed (27%). The DFS
ranges from 0.3 to 6.1 + years. The 4-year DFS rate is 71% with 95%
CI (58, 84%). Figure 3A depicts the
Kaplan-Meier estimates of the survival distributions for DFS and Fig 3B
shows similar data by IPI score. There were no differences in DFS by IPI groups or age-adjusted IPI groups (data not shown).
View larger version (23K):
[in this window]
[in a new window]
| Fig 3.
(A) Kaplan Meier estimate of DFS for the 51 patients who
achieved CR showing a 4-year DFS of 71% with 95% CI (58, 84%). (B)
The same analysis depicting DFS by IPI groupings 0 to1 and 2 to 4. IPI
low (0 to1), low intermediate (2), high intermediate (3), and high
(4).
|
|
| |
DISCUSSION |
The treatment of aggressive lymphomas has not changed dramatically over
the past 20 years despite the use of aggressive combination chemotherapy, better support with antibiotics, and more precise staging. Although single institution studies have suggested improvement in CR rates and DFS, randomized trials balancing prognostic features have failed to validate these smaller trials of third generation chemotherapy regimens.6,10
Studies conducted by ECOG in conjunction with Cancer and Acute Leukemia
Group B (CALGB) showed that there were no significant differences in
response or survival when cyclophosphamide, doxorubicin, vincristine,
and prednisone (CHOP) was compared with methotrexate, bleomycin,
cyclophosphamide, doxorubicin, vincristine, and dexamethasone (m-BACOD), but there was more toxicity associated with the m-BACOD regimen.10 Further, it was found that doses of some active
drugs (cyclophosphamide and doxorubicin) had to be reduced to allow for
the addition of other drugs at midcycle, perhaps obscuring any
potential benefit that might have accrued from the newer regimen. Similarly, Fisher et al7 found that CHOP resulted in
equivalent response and survival when compared with three other
regimens in patients with aggressive lymphomas. Additional data show
there is no evidence that there is a "tail" in survival curves in
the more intensively treated groups, nor do patients who are
"sicker" benefit from more intensive therapy.6,27
In an attempt to improve response and disease-free survival, a series
of studies using non-cross-resistant drugs was
developed.28 One approach was to use non-cross-resistant
chemotherapy administered midcycle to prevent the emergence of drug
resistance. An alternate idea was to exploit the dose-response
relationship in malignant lymphoma. Some studies suggested improved
outcome with higher doses,17-20,29-32 but this impression
remains controversial.22,33-35
This trial was initiated for a high-risk group of patients for whom
standard CHOP therapy was thought to be inadequate. Thus, patients were
required to have advanced (Ann Arbor stage III or IV or bulky stage II)
disease. Indeed, 84% of patients had either stage III or IV disease.
Because of the concern about toxicity in the higher-dose regimen,
patients greater than 65 years or patients with poor performance status
were excluded. Thus, when we analyzed our data by the IPI criteria (not
available when this trial was designed), we found that 43% were in
index groups 0 to 1, and 57% were in the higher-risk groups 2 to 4. By
age-adjusted index, 54% were in groups 0 to 1, and 46% were in group
2. Only one patient had an IPI score of 4 and no patients had an
age-adjusted IPI score of 3. These data, then, do not apply to patients
with lymphoma in the highest risk groups by the IPI.
At 4 years, the overall survival was 73% and TTF was 58%, with no
differences between the index groups. Importantly, the overall 4-year
DFS rate was 71% and was greater than 60% for the index groups 2 to
4, with no significant differences between the lower- and the
higher-risk groups. These data compare favorably to any prior
risk-based analysis in aggressive lymphoma.13,26,31,36 The
5-year relapse-free survival for index group 2 to 4 in a large retrospective analysis reported by Shipp26 was 40% to
50%, and 5-year survival was between 26% to 51%. The 5-year
disease-free survival for age-adjusted index group 1 was 66% and for
group 2 was 53%, and 5-year survival was 69% and 46%
respectively.26 These data cannot be compared with those
reported in the current study nor across any study, but such
comparisons provide a framework to help determine which randomized
phase III trials need to be pursued.
The toxicity of this regimen was acceptable. We found that the day-1
drugs were administered at nearly 100% dose intensity, whereas the
day-8 drug cytosine arabinoside had to be modified according to the
dose-adjustment criteria specified in the protocol. Nevertheless, there
were no grade 5 (fatal) toxicities in any of the patients treated both
in the phase I and the phase II protocols.
There was 1 case of myelodysplastic syndrome and there were 2 cases of
acute leukemia in the 74 patients available for analysis, with an
incidence of 4.1% for the 74 patients. One of the cases of leukemia
occurred as early as 7 months after the treatment for lymphoma, and
although no cytogenetics were done, this clinical syndrome is
consistent with treatment-related leukemia with 11q23 rearrangement.37 The recent demonstration of secondary
leukemias arising either after alkylating agent exposure38
or developing with specific cytogenetic abnormalities shortly after
exposure to topoisomerase inhibitors and growth factors37
raises concerns about the routine use of high-dose therapy and growth
factors. If the incidence of secondary leukemias proves to be high,
then clearly any superiority in CR rates and DFS rates in this and in
any other dose-intense regimen, including stem-cell
transplantation,39 would have to balance morbidity and
mortality that might increase with these important late effects.
These data suggest that this regimen of 200% ProMACE-CytaBOM with
growth factor is tolerated without grade 5 toxicity, and that the
results of the phase II study compare favorably with other phase II
trials in aggressive lymphomas. We found that even in the index risk
groups 2 to 4, the survival and disease-free survival compare favorably
to other regimens. Phase III randomized trials are needed to determine
whether this approach to the treatment of aggressive lymphomas will
prove superior to CHOP.
| |
FOOTNOTES |
Submitted March 26, 1999; accepted July 7, 1999.
This study was conducted by the Eastern Cooperative Oncology Group
(Robert L. Comis, MD, Chair) and supported in part by Public Health
Service grants CA 17145, CA 23318, CA 13650, CA 15488, and CA 21115 from the National Cancer Institute, National Institutes of Health, and
the Department of Health and Human Services.
The contents are solely the responsibility of the authors and do not
necessarily represent the official views of the National Cancer Institute.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Leo I. Gordon, MD, Northwestern University
Medical School, Department of Medicine, Chief, Division of
Hematology/Oncology and Associate Director for Clinical Sciences,
Robert H. Lurie Comprehensive Cancer Center, 303 E. Chicago Ave,
Chicago, IL 60611-3008.
| |
REFERENCES |
1.
Armitage J:
Drug therapy: Treatment of non-Hodgkin's lymphoma.
N Engl J Med
328:1023, 1993[Free Full Text]
2.
Anderson JR, Vose JM, Bierman PJ, Weisenberger DD, Sanger WG, Pierson J, Bart M, Armitage JO:
Clinical features and prognosis of follicular large-cell lymphoma: A report from the Nebraska Lymphoma Study Group.
J Clin Oncol
11:218, 1993[Abstract/Free Full Text]
3.
Aviles A, Yanez J, Lopez T, Garcia EL, Guzman R, Diaz-Maqueo JL:
Malnutrition as an adverse prognostic factor in patients with diffuse large cell lymphoma.
Arch Med Res
26:31, 1995[Medline]
[Order article via Infotrieve]
4.
Aviles A, Zepeda G, Diaz-Maqueo JC, Rodriguez L, Guzman R, Garcia EL, Tulavera A:
Beta 2 microglobulin level as an indicator of prognosis in diffuse large cell lymphoma.
Leuk Lymphoma
7:135, 1992[Medline]
[Order article via Infotrieve]
5.
Coiffier B:
Prognostic factors in large-cell lymphomas.
Pathol Biol (Paris)
41:92, 1993[Medline]
[Order article via Infotrieve]
6.
Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP:
Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma.
N Engl J Med
328:1002, 1993[Abstract/Free Full Text]
7.
Gascoyne RD:
Pathologic prognostic factors in diffuse aggressive non-Hodgkin's lymphoma.
Hematol Oncol Clin North Am
11:847, 1997[Medline]
[Order article via Infotrieve]
8.
Gascoyne RD, Adomat SA, Krajewski S, Krajewska M, Horsman DE, Tolcher AW, O'Reilly SE, Hoskins P, Coldman AJ, Reed JC:
Prognostic significance of Bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin's lymphoma.
Blood
90:244, 1997[Abstract/Free Full Text]
9.
Gascoyne RD, Krajewska M, Krajewski S, Connors JM, Reed JC:
Prognostic significance of Bax protein expression in diffuse aggressive non-Hodgkin's lymphoma.
Blood
90:3173, 1997[Abstract/Free Full Text]
10.
Gordon LI, Harrington D, Andersen J, Colgan J, Glick J, Neiman R, Mann R, Resnick GD, Barcos M, Gottlieb A:
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
327:1342, 1992[Abstract]
11.
Kovner F, Merimsky O, Inbar M, Soyfer V, Cahan Y, Rachmani R, Chaitchik S:
Prognostic importance of advanced age in aggressive non-Hodgkin's malignant lymphoma.
Oncology
53:435, 1996[Medline]
[Order article via Infotrieve]
12.
Hill ME, Maclennan KA, Cunningham DC, Vaughan Hudson B, Burke M, Clarke P, Di Stefano F, Anderson L, Vaughan Hudson G, Mason D, Selby P, Linch DC:
Prognostic significance of bcl-2 expression and bcl-2 major breakpoint region rearrangement in diffuse large cell non-Hodgkin's lymphoma: A British National Lymphoma Investigation study.
Blood
88:1046, 1996[Abstract/Free Full Text]
13.
Shipp M, Harris N, Mauch P:
The Non-Hodgkin's Lymphomas. Philadelphia, PA, Lippincott, 1997
14.
Nicolaides C, Fountzilas G, Zoumbos N, Skarlos D, Kosmidis P, Pectasides D, Karabelis A, Giannakakis T, Symeonidis A, Papadopoulos A, Antoniou F, Pavidis N:
Diffuse large cell lymphomas: Identification of prognostic factors and validation of the International Non-Hodgkin's Lymphoma Prognostic Index. A Hellenic Cooperative Oncology Group Study.
Oncology
55:405, 1998[Medline]
[Order article via Infotrieve]
15.
Winter J, Andersen J, Variakojis D, Gordon LI, Fisher RI, Oken MM, Neiman RS, Jiang S, Bauer KD:
Prognostic implications of ploidy and proliferative activity in the diffuse, aggressive non-Hodgkin's lymphomas.
Blood
88:3919, 1996[Abstract/Free Full Text]
16.
Winter J, Andersen J, Reed J, Krajewski S, Variakojis D, Bauer KD, Fisher RI, Gordon LI, Oken MM, Jiang S, Jeffries D, Domer P:
BCL-2 expression correlates with lower proliferative activity in the intermediate and high-grade non-Hodgkin's lymphomas: An Eastern Cooperative Oncology Group and Southwest Oncology Group Cooperative Laboratory Study.
Blood
91:1391, 1998[Abstract/Free Full Text]
17.
Anderson JR, Santarelli MT, Peterson B:
Dose intensity in the treatment of diffuse large-cell lymphoma.
J Clin Oncol
8:1927, 1990[Medline]
[Order article via Infotrieve] (letter; comment)
18.
Epelbaum R, Faraggi D, Ben-Arie Y, Ben-Shahar M, Haim N, Ron Y, Robinson E, Cohen Y:
Survival of diffuse large cell lymphoma. A multivariate analysis including dose intensity variables.
Cancer
66:1124, 1990[Medline]
[Order article via Infotrieve]
19.
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
24:533, 1988[Medline]
[Order article via Infotrieve]
20.
Kwak LW, Halpern J, Olshen RA, Horning SJ:
Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: Results of a tree-structured survival analysis.
J Clin Oncol
8:963, 1990[Abstract]
21.
Meyer RM, Hryniuk WM, Goodyear MD:
The role of dose intensity in determining outcome in intermediate-grade non-Hodgkin's lymphoma.
J Clin Oncol
9:339, 1991[Abstract]
22.
Meyer RM, Quirt IC, Skillings JR, Cripps MC, Bramwell VH, Weineman BH, Gospodarowicz MK, Burns BF, Sargeant AM, Shepherd LE:
Escalated as compared with standard doses of doxorubicin in BACOP therapy for patients with non-Hodgkin's lymphoma.
N Engl J Med
329:1770, 1993[Abstract/Free Full Text]
23.
Gordon L, Andersen J, Habermann T, Winter JN, Glick J, Schilder RJ, Cassileth P:
Phase I trial of dose escalation with growth factor support in patients with previously untreated diffuse aggressive lymphomas: Determination of the maximum tolerated dose of ProMACE-CytaBOM.
J Clin Oncol
14:1275, 1996[Abstract/Free Full Text]
24.
Kaplan E, Meier P:
Nonparametric estimation from incomplete observations.
J Am Stat Assoc
53:457, 1958
25.
Cox D:
Analysis of Binary Data. London, UK, Methuen, 1970
26.
Shipp MR:
The international non-Hodgkin's lymphoma prognostic factors project: A predictive model for aggressive non-Hodgkin's lymphoma.
N Eng J Med
329:987, 1993[Abstract/Free Full Text]
27.
Gordon L, Andersen J, Colgan J, Glick J, Resnick GD, O'Connell M, Cassileth PA:
Advanced diffuse non-Hodgkin's lymphoma. Analysis of prognostic factors by the international index and by lactic dehydrogenase in an intergroup study.
Cancer
75:865, 1995[Medline]
[Order article via Infotrieve]
28.
Yuen AR, Sikic BI:
Multidrug resistance in lymphomas.
J Clin Oncol
12:2453, 1994[Abstract/Free Full Text]
29.
Aviles A, Calva A, Diaz-Maqueo JC, Talavera A, Huestra-Guzman J, Vasquez E:
Dose escalation of epirubicin in the CEOP-BLEO regimen: A controlled clinical trial comparing standard doses for the treatment of diffuse large cell lymphoma.
Leuk Lymphoma
25:319, 1997[Medline]
[Order article via Infotrieve]
30.
Cortelazzo S, Rossi A, Viero P, Bellavita P, Marchiolli R, Marfisi RM, Rambaldi A, Barbui T:
BEAM chemotherapy and autologous haemopoietic progenitor cell transplantation as front-line therapy for high-risk patients with diffuse large cell lymphoma.
Br J Haematol
99:379, 1997[Medline]
[Order article via Infotrieve]
31.
Gianni A, Bregni M, Siena S, Brambilla C, Di Nicola M, Lombardi F, Gandola L, Tarella C, Pileri A, Ravagnani F, Valagussa P, Bonadonna G:
High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-b in aggressive B-cell lymphoma.
N Engl J Med
336:1290, 1997[Abstract/Free Full Text]
32.
Gisselbrecht C, Bosly A, Lepage E, Reyes F, Philip T, Haioun C, Tilly H, Coiffier B:
Autologous hematopoietic stem cell transplantation in intermediate and high grade non-Hodgkin's lymphoma: A review.
Ann Oncol
4:7, 1993[Free Full Text]
33.
Longo DL:
Chemotherapy for advanced aggressive lymphoma: More is better, isn't it?
J Clin Oncol
8:952, 1990[Medline]
[Order article via Infotrieve]
34.
Pettengell R, Crowther D:
Haemopoietic growth factor and dose intensity in high-grade and intermediate-grade lymphoma.
Ann Oncol
5:133, 1994[Abstract/Free Full Text]
35.
Verdonck L, Von Putten WV, Hagenbeek A, Schouten HC, Sonneveld P, van Imhoff GW, Kluin-Nelemans HC, Raemaekers JM, van Oers RH, Haak HL:
Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin's lymphoma.
N Engl J Med
332:1045, 1995[Abstract/Free Full Text]
36.
Shpilberg O, Shiff J, Chetrit A, Ramot B, Ben-Bassat I:
The cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin, and procarbazine (COPBLAM-I) regimen for intermediate-grade non- Hodgkin's lymphoma. Long term follow-up in 51 patients.
Cancer
74:3029, 1994[Medline]
[Order article via Infotrieve]
37.
Thirman M, Gill H, Burnett R, Mbangkollo D, McCabe NR, Kobayashi H, Ziemin-vander Poel S, Kaneko Y, Morgan R, Sandberg AA:
Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations.
N Engl J Med
329:909, 1993[Abstract/Free Full Text]
38.
Travis L, Curtis R, Stovall M, Holowaty EJ, Van Leeuwen FE, Glimelius B, Lynch CF, Haganbeek A, Li CY, Banks PM:
Risk of leukemia following treatment for non-Hodgkin's lymphoma.
J Natl Cancer Inst
86:1450, 1994[Abstract/Free Full Text]
39.
Deeg HJ, Socié G:
Malignancies after hematopoietic stem cell transplantation: Many questions, some answers.
Blood
91:1833, 1998[Free Full Text]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
L. F. Verdonck, A. Notenboom, D. D. de Jong, M. A. MacKenzie, G. E. G. Verhoef, M. H. H. Kramer, G. J. Ossenkoppele, J. K. Doorduijn, P. Sonneveld, and G. W. van Imhoff
Intensified 12-week CHOP (I-CHOP) plus G-CSF compared with standard 24-week CHOP (CHOP-21) for patients with intermediate-risk aggressive non-Hodgkin lymphoma: a phase 3 trial of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON)
Blood,
April 1, 2007;
109(7):
2759 - 2766.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Papaldo, M. Lopez, P. Marolla, E. Cortesi, M. Antimi, E. Terzoli, P. Vici, C. Barone, G. Ferretti, S. Di Cosimo, et al.
Impact of Five Prophylactic Filgrastim Schedules on Hematologic Toxicity in Early Breast Cancer Patients Treated With Epirubicin and Cyclophosphamide
J. Clin. Oncol.,
October 1, 2005;
23(28):
6908 - 6918.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Gregory and L. Trumper
Chemotherapy dose intensity in non-Hodgkin's lymphoma: is dose intensity an emerging paradigm for better outcomes?
Ann. Onc.,
September 1, 2005;
16(9):
1413 - 1424.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Adachi, M. Suzuki, T. Sugimoto, K. Yorozu, H. Takai, K. Uetsuka, H. Nakayama, and K. Doi
Effects of Granulocyte Colony-Stimulating Factor (G-CSF) on Bleomycin-Induced Lung Injury of Varying Severity
Toxicol Pathol,
October 1, 2003;
31(6):
665 - 673.
[Abstract]
[PDF]
|
|
|
|
|
|
|
J. A. Sparano, E. Weller, T. Nazeer, T. Habermann, A. E. Traynor, J. Manalo, and P. Cassileth
Phase 2 trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with poor-prognosis, intermediate-grade non-Hodgkin lymphoma: an Eastern Cooperative Oncology Group trial (E3493)
Blood,
August 13, 2002;
100(5):
1634 - 1640.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. H. Wilson, M. L. Grossbard, S. Pittaluga, D. Cole, D. Pearson, N. Drbohlav, S. M. Steinberg, R. F. Little, J. Janik, M. Gutierrez, et al.
Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy
Blood,
April 15, 2002;
99(8):
2685 - 2693.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Azoulay, H. Attalah, A. Harf, B. Schlemmer, and C. Delclaux
Granulocyte Colony-Stimulating Factor or Neutrophil-Induced Pulmonary Toxicity: Myth or Reality? : Systematic Review of Clinical Case Reports and Experimental Data
Chest,
November 1, 2001;
120(5):
1695 - 1701.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Ozer, J. O. Armitage, C. L. Bennett, J. Crawford, G. D. Demetri, P. A. Pizzo, C. A. Schiffer, T. J. Smith, G. Somlo, J. C. Wade, et al.
2000 Update of Recommendations for the Use of Hematopoietic Colony-Stimulating Factors: Evidence-Based, Clinical Practice Guidelines
J. Clin. Oncol.,
October 20, 2000;
18(20):
3558 - 3585.
[Full Text]
[PDF]
|
|
|
|
|
TOP
ABSTRACT
INTRODUCTION