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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 4 (February 15), 1998:
pp. 1178-1184
Risk Factors, Treatment, and Outcome of Central Nervous System
Recurrence in Adults With Intermediate-Grade and Immunoblastic
Lymphoma
By
Koen van Besien,
Chul S. Ha,
Sandy Murphy,
Peter McLaughlin,
Alma Rodriguez,
Kamal Amin,
Arthur Forman,
Jorge Romaguera,
Fredrick Hagemeister,
Anas Younes,
Carlos Bachier,
Andreas Sarris,
Kathleen
S. Sobocinski,
James D. Cox, and
Fernando Cabanillas
From The Division of Medicine, Department of Hematology and
Neuro-oncology, and the Division of Radiation Oncology, MD Anderson
Cancer Center, Houston, TX; and The Statistical Center, International
Bone Marrow Transplant Registry, Medical College of Wisconsin,
Milwaukee, WI.
 |
ABSTRACT |
To evaluate the incidence, risk factors, and outcome of central
nervous system (CNS) recurrence in adult patients with non-Hodgkin's lymphoma, we evaluated 605 newly diagnosed patients with large-cell and
immunoblastic lymphoma who participated in prospective chemotherapy studies. The Kaplan-Meier estimate of probability of CNS recurrence at
1 year after diagnosis was 4.5% (95% confidence interval [CI], 4.4 to 4.6). Twenty-four patients developed CNS recurrence after a median
of 6 months from diagnosis (range, 0 to 44 months). In univariate
analysis, an increased risk for CNS recurrence was associated with an
advanced disease stage (P = .0014), an increased LDH
(P = .0000), the presence of B-symptoms (P = .0037), involvement of more than one extranodal site (P = .0000), poor performance status (P = .0005), and B-cell
phenotype (P = .008). Bone marrow involvement (P = .005), involvement of parenchymal organs (P = .03), and
involvement of skin, subcutaneous tissue, and muscle (P = .002) were also associated with an increased risk for CNS disease.
Multivariate logistic regression analysis identified only involvement
of more than one extranodal site (P = .0005) and an increased
LDH (P = .0008) as independent predictors of CNS recurrence.
Established CNS recurrence had a poor prognosis. Only 1 of 24 patients
remains alive and the Kaplan-Meier estimate of probability of survival
at 1 year after the diagnosis of CNS recurrence is only 25.3% (95%
CI, 6.9 to 43.7). Intrathecal treatment provided symptomatic benefit in
only 1 of 6 patients. Radiation treatment provided symptomatic
improvement in 6 of 9 patients treated. However, remissions were short
and followed by systemic or CNS recurrence. Serum LDH and involvement
of more than one extranodal site are independent risk factors for CNS
recurrence in patients with large-cell lymphoma. The presence of both
risk factors identifies a patient group at high risk for CNS
recurrence. Established CNS recurrence can be rapidly fatal. Transient
responses occur after radiation treatment.
| |
INTRODUCTION |
CENTRAL NERVOUS SYSTEM (CNS) recurrence
is a devastating and almost uniformly fatal complication of
intermediate-grade or immunoblastic lymphoma (non-Hodgkin's lymphoma
[NHL]).1-10 Its incidence is not
sufficiently high to warrant the use of CNS prophylaxis in all
patients. The identification of patient subgroups for whom CNS
prophylaxis may be of benefit is therefore important.
An increased risk for CNS recurrence in NHL has been associated
with features of advanced disease and involvement of extramedullary sites such as blood,8 bone marrow,2-4,7,9
testicular,8,11 gastro-intestinal,12 or sinus
or orbital13 involvement; with serum lactate dehydrogenase
(LDH)10; or with specific histologic subtypes
of disease.13 However, the relative importance of any of
these risk factors has not been well defined, and data specific for
intermediate-grade lymphoma are scarce. Indeed, in the one study that
focuses on patients with intermediate-grade lymphoma, no predictive
value was assigned to involvement of any specific disease site except
for epidural disease.5
We attempted to develop a risk model that would be both sensitive and
specific for an increased risk of CNS recurrence in patients with
intermediate-grade NHL treated with modern combination chemotherapy.
For this purpose, we analyzed the outcome of 605 patients who
participated in chemotherapy studies at MD Anderson Cancer Center. We
analyzed the incidence, risk factors, treatment, and outcome of
patients with CNS recurrence in this large prospectively collected
patient cohort. Our results indicate that the use of simple staging
parameters such as serum LDH and number of sites of extranodal
involvement allows the identification of a subgroup of patients at high
risk for CNS recurrence.
In addition, we evaluated the outcome of patients with established CNS
recurrence and confirmed their extremely poor outcome. These patients
do not appear to benefit from intrathecal treatment and derive only
symptomatic benefit from radiation treatment.
| |
PATIENTS AND METHODS |
Patient selection and work-up.
The outcome of 605 patients with newly diagnosed intermediate-grade or
immunoblastic lymphoma who participated in four consecutive studies of
newly diagnosed NHL was analyzed for this study. No prophylactic
intrathecal treatment was administered in any of these study protocols.
Protocols DM88-087 and DM90-093 accrued patients with favorable
prognostic features. In protocol DM88-087, this was defined as stage A
by the MD Anderson staging system,14 and in protocol DM93-003 this was defined as a tumor score of less than
3.15 Patients with disease involving 1 single nodal or
extranodal site or 1 single chain of lymph nodes less than 5 cm
received 3 cycles of CHOP-Bleo16 (750 mg/m2
cyclophosphamide intravenously [IV] on day 1, 50 mg/m2
doxorubicin IV on day 1, 2 mg vincristine IV on day 1, 100 mg prednisone orally [PO] on days 1 through 5, and 15 U bleomycin IV on
day 1) followed by involved field radiation. All other patients on
these protocols received 3 courses of CHOP-Bleo alternating with 3 courses of OPEN (2 mg vincristine IV on day 1, 100 mg prednisone PO on
days 1 through 5, 100 mg/m2 etoposide IV on days 1 through
3, and 10 mg/m2 mitoxantrone IV on day 1), followed by
involved field radiation to nodal disease that was  5 cm in diameter
at presentation. Protocols DM88-089 and DM92-054 were designed to treat
patients with poor prognostic features. Patients with MD Anderson
stages B, C, and D were eligible for protocol DM88-089.14
Treatment consisted of alternating triple therapy in which ASHAP,
M-BACOS, and MINE were alternated for a total of nine treatment cycles.
Details of this treatment have been reported.17,18 In
short, ASHAP consists of 50 mg/m2 doxorubicin administered
by continuous infusion over 96 hours, 500 mg methylprednisolone IV
daily for 5 days, 1.5 gr/m2 cytarabine IV over 2 hours on
day 5, and 100 mg/m2 cisplatinum administered by continuous
infusion over 96 hours. M-BACOS consists of 10 mg/m2
bleomycin IV on day 1, 50 mg/m2 doxorubicin IV administered
by continuous infusion over 72 hours on days 1 through 3, 750 mg/m2 cyclophosphamide IV on day 1, 1.4 mg/m2
vincristine IV on day 1, 500 mg methylprednisolone IV on days 1 through
3, and 1 g/m2 methotrexate IV on day 10. Methotrexate was
followed by leucovorin rescue. MINE consists of 1.5 g/m2
ifosfamide IV on days 1 through 3, 10 mg/m2 mitoxantrone IV
on day 1, and 80 mg/m2 etoposide IV on days 1 through 3. Patients with a single area of extensive involvement or with a single
residual tumor mass less than 5 cm at the end of chemotherapy were
referred for involved field radiotherapy.
Patients with a tumor score 3 were eligible for protocol
DM92-054.15 On this protocol, patients were randomized
between idarubicin- and adriamycin-containing regimens. Treatment
consisted of 2 cycles of ASHAP (or IDSHAP) alternating with 2 cycles of MBACOS (or MBIDCOS), followed by three cycles of MINE chemotherapy. IDSHAP and MBIDCOS are identical to ASHAP and MBACOS, except that doxorubicin was replaced by 10 mg/m2 idarubicin. Patients
with a partial remission after three cycles of chemotherapy were
referred for intensification with high-dose thiotepa, busulfan, and
cyclophosphamide and autologous stem cell rescue.19
Staging procedures included physical exam; computed tomographic
(CT) scan of chest, abdomen, and pelvis; gallium scan;
bilateral bone marrow biopsy; and aspirate and lymphangiogram when
indicated. A lumbar puncture was not performed unless CNS involvement
was suspected. Patients who were seropositive for human
immunodeficiency virus or hepatitis B were excluded. Patients with
active CNS disease at presentation were eligible for these studies, but
are not included in the analysis. At the time of analysis, the median
follow-up for patients enrolled on these protocols was 4 years (range,
1 to 8 years).
Diagnosis of CNS disease.
For this analysis, only patients whose initial site of recurrence
included symptomatic CNS disease were included. The diagnosis of CNS
disease was based on the presence of malignant cells on cytocentrifuge
preparations of spinal fluid in 19 cases and on brain biopsy in 2 cases. In 3 cases of parenchymal brain involvement, the diagnosis of
CNS disease was based on symptoms and radiologic findings.
Statistical methods.
Probability of CNS recurrence and of survival after CNS recurrence was
estimated using Kaplan-Meier plots.20 Exact methods of
analysis were applied for further analysis of the data because of the
low incidence of CNS recurrence.21 Because CNS recurrence is most likely to occur within the first year after diagnosis, the
outcome of interest for the multivariate analysis was CNS recurrence at
1 year. Patients who died without CNS recurrence within 1 year from
diagnosis were excluded from the analysis. The Fisher-Freeman-Halton
exact test was used to assess the ability of covariates to predict CNS
recurrence.22 Those covariates with a P value less
than .10 were included in the multivariate analysis. An exact logistic
model was built using forward selection.21 Covariates were
added as long as the P value of a factor adjusted for all other
factors already in the model was less than .05.
| |
RESULTS |
Patient characteristics and prognostic factors for CNS recurrence.
Patient-, disease-, and treatment-related characteristics of the 605 patients are listed in Table 1. The median
age was 54 years (range, 16 to 84 years). As expected, more than half
of the patients were men, half had an elevated LDH, and one third had
B-symptoms. Most (88.7%) were classified as having diffuse large-cell
lymphoma, 9.5% as follicular large-cell lymphoma and 1% as diffuse
mixed-cell lymphoma. Thirty six percent of the patients had stage IV
disease, 14% had stage III disease, and 48% had stage I or II
disease. Approximately one fifth of the patients had more than one site
of extranodal involvement. Involvement of the sinuses and testicular
involvement occurred in only 9 patients (1.5%) and 5 patients (1%),
respectively. The international index could be calculated for 564 patients. Ten percent had high-risk disease, 20% had high-intermediate
risk disease, 22.5% had low-intermediate risk disease and 42.5% had
low-risk disease.
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Table 1.
Initial Features of 605 Patients With NHL and Kaplan
Meier Estimate of Probability of CNS Recurrence at 1 Year After
Diagnosis
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Incidence of CNS recurrence and risk factors.
The Kaplan Meier estimate of probability of CNS recurrence at 1 year
after diagnosis is 4.5% (95% confidence interval [CI], 4.4 to 4.6).
Twenty-four patients developed CNS recurrence a median of 6 months
after diagnosis (range, 0 to 44 months). Only 1 CNS recurrence occurred
more than 13 months after initial diagnosis, ie, in a patient with a
testicular lymphoma who developed a brain lesion 44 months after
diagnosis.
A variety of symptoms led to the diagnosis of CNS recurrence
(Table 2). The most common findings were
mental status changes, headaches, and cranial nerve palsies. Seizures
occurred in only 1 patient. In 18 of 22 cases, lymphoma cells were
detected in the spinal fluid. Leptomeningeal disease was documented
radiographically in 7 patients and intraparenchymal disease in 8 of 21 patients.
Five patients had systemic disease documented at the time of recurrence
or within 40 days thereafter. Seven other patients developed systemic
relapse between 40 days and 6 months after recurrence of CNS disease.
In 5 patients who survived from 40 days to 3 years after diagnosis of
CNS recurrence, no systemic disease recurrence was ever documented.
By univariate analysis an increased risk for CNS recurrence was
associated with more advanced stage (P = .0014), an increased LDH (P = .00008), the presence of B-symptoms (P = .005), and involvement of more than one extranodal site
(P = .00009) (Table 2). There was also an increased risk for
CNS recurrence associated with the use of the alternating
triple-therapy regimen. However, this association is explained by the
fact that this regimen was used exclusively for patients with advanced
disease stages. Complete information on disease sites was available for
369 patients. Bone marrow involvement (P = .005), involvement
of parenchymal organs (P = .01), and involvement of skin,
subcutaneous tissue, and muscle (P = .002) were associated with
an increased risk for CNS disease in these patients
(Table 3). However, multivariate logistic
regression analysis only identified involvement of more than one
extranodal site (P = .0005) and an increased LDH (P = .0008) as independent predictors of CNS recurrence
(Table 4). The risk of CNS recurrence associated with these covariates is illustrated in
Fig 1. Ninety-three patients (15.4%) had
both an increased LDH and involvement of more than one extranodal site.
For these patients, the Kaplan-Meier estimate of probability of CNS
recurrence at 1 year after diagnosis was 17.4% (95% CI, 7.0 to 27.8).
For the remaining 512 patients (84.6%), the Kaplan-Meier estimate of
probability of CNS recurrence at 1 year after diagnosis was 2.8% (95%
CI, 2.7 to 2.9).
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Table 3.
Sites of Extranodal Involvement (369 Patients) and
Kaplan Meier Estimate of Probability of CNS Recurrence at 1 Year
After Diagnosis
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| Fig 1.
Incidence of CNS recurrence in patients with increased
LDH and involvement of more than one extranodal site (n = 93;
···) versus all other patients (n = 512;  ).
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Treatment of CNS recurrence and outcome.
Patients with leptomeningeal involvement without focal neurologic
deficits received intrathecal cytarabine, methotrexate, and
hydrocortisone twice a week. An Ommaya reservoir was usually placed.
Although intrathecal treatment invariably resulted in a decrease in the
percentage of blasts in the spinal fluid, symptomatic improvement
occurred in only 1 of 6 patients.
Patients with focal neurologic deficits or intraparenchymal lesions in
the brain or spinal cord were offered radiation treatment. This
consisted of whole brain radiation for those with brain lesions or
cranial nerve palsies and of spinal irradiation or irradiation to
segments of the spinal cord for those with lesions of the spinal cord.
Radiation treatment resulted in symptomatic neurologic improvement in 6 of 9 patients. However, the responses were transient. The principal
cause of treatment failure was progression of CNS disease in 5 patients
and systemic recurrence in 4.
Five patients received systemic chemotherapy, combined in 2 cases with
intrathecal treatment. The chemotherapy was platinum-based in 4 patients and consisted of MINE in the fifth patient. Responses of the
CNS disease were observed in 3 patients and 1 patient has obtained a
durable remission.
Of the 24 patients, only 1 is currently alive and in remission at 1,150 days after diagnosis of CNS recurrence. Kaplan-Meier estimate of
probability of survival at 1 year after diagnosis of CNS recurrence is
25.3% (95% CI, 6.9% to 43.7%).
| |
DISCUSSION |
The identification of risk factors for CNS recurrence in
intermediate-grade NHL has been attempted previously. Several large studies containing analysis of potential risk factors are summarized in
Table 5. Whereas these and similar studies
contributed in important ways to the identification of risk factors for
CNS disease, all of them have a number of problems that makes their
interpretation difficult. Most studies are based on retrospective
analysis of heterogeneously treated patients. In addition, the majority
of studies concern patients treated in the 1970s before the widespread use of modern chemotherapeutic regimens and at a time when important entities such as lymphoblastic lymphoma were not reliably recognized. The assessment of risk factors for intermediate-grade NHL is therefore obscured by the inclusion of patients with other histologies. We are
aware of only one study that specifically addresses the issue of CNS
recurrence in intermediate-grade lymphoma in patients treated with
modern chemotherapy.5 This report, like many others, does
not differentiate between patients with CNS involvement at presentation, those in which CNS involvement occurs at the time of
initial recurrence, and those in which CNS involvement is an expression
of terminal disease. In this study, only the presence of epidural
disease (P < .001) and age younger than 60 years (P = .046) were found to be significant risk factor for CNS recurrence. Other risk factors, including gender, response to treatment, stage of
disease (P = .083 stage I-II v stage III-IV),
involvement of more than one extranodal site (P = .077), and
involvement of specific disease sites were not found to be
significantly correlated with the risk of CNS recurrence. Hence,
considerable controversy remains regarding the impact of patient and
disease characteristics on the incidence of CNS disease in
intermediate-grade lymphoma, preventing a rational approach to
preventive strategies.
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Table 5.
Incidence of and Risk Factors for CNS Recurrence:
Selected Studies With Univariate Analyses of Risk Factors
|
|
The current study documents the incidence of CNS recurrence in a cohort
of 605 patients with intermediate-grade lymphoma who received their
initial treatment at a single institution and who participated in four
prospective studies of modern combination chemotherapy. Therefore, the
patients received uniform and consistent treatment throughout the
course of the study. Our regimen for patients with unfavorable
characteristics includes three doses of high-dose cytarabine and three
doses of intermediate-dose methotrexate. These drugs penetrate into the
CNS and are thought to be useful in the treatment and prophylaxis of
CNS leukemia.23 The incidence of CNS recurrence in this
patient cohort may therefore be slightly lower than would be
anticipated if all patients were treated with CHOP-like regimens.
Nevertheless, the cumulative incidence of CNS recurrence of 5.1% (95%
CI, 4.9% to 5.3%) is consistent with the incidence reported in one
other recent study.5 Almost all the risk occurred in the
first year after diagnosis.
It is important to distinguish between patients whose CNS disease is
the initial site of recurrence from those where CNS disease occurs long
after systemic recurrence. In the former group, CNS recurrence may be
potentially treatable. In the latter, CNS recurrence is an expression
of end-stage disease, not necessarily predicted by the same risk
factors and unlikely to be amenable to therapeutic strategies with
curative intent. Our study excluded from analysis the latter patients.
Thus defined, the risk for CNS recurrence was associated with
indicators of advanced disease such as serum LDH and stage of disease,
bone marrow involvement, and skin and parenchymal involvement. For
reasons that are unclear to us, B-cell phenotype was also associated
with a significantly increased risk of CNS recurrence. The importance
of other risk factors, such as sinus involvement, testicular
involvement, pulmonary involvement, and gastro-intestinal involvement,
could not be confirmed. In cases of testicular and sinus involvement,
this may be due to the very low accrual of cases with this particular
site of involvement.
A multivariate logistic regression identified only the presence of more
than one site of extranodal involvement and an increased LDH as
independent risk factors for CNS recurrence. This suggest that, in the
majority of cases, the risk for CNS recurrence is determined by disease
extent and proliferation rather than by any particular disease
localization. The use of these two factors allowed us to identify a
group of patients for whom the cumulative risk for CNS recurrence is
almost 20%. Serum LDH and involvement of more than one extranodal site
are also associated with increased overall risk for treatment failure
in patients receiving conventional chemotherapy regimens.24
Radically new treatment approaches are needed for such patients, taking
into account their risk for CNS recurrence. The initial staging work-up
for such patients should include a lumbar puncture. Their treatment
should contain CNS prophylaxis similar to what is recommended for
patients with acute lymphoblastic leukemia (ALL) or
high-grade lymphoma.23,25,26 This should include the use of
systemic drugs with activity across the blood-brain barrier as well as
frequent intrathecal injections. A similar approach may be necessary
for the relatively uncommon patients who present with primary
testicular or sinus lymphoma. On the other hand, for the large majority
of patients, the risk for CNS recurrence is very low with currently
used chemotherapy, and no specific CNS prophylaxis or work-up appears
to be necessary.
An ideal risk model would allow identification of all patients at risk
for a particular event. The discomfort and side-effects of preventive
therapy would be avoided for those not at risk. Because of the low
incidence of CNS disease in this patient population, our model is less
than optimal. Its use would have resulted in specific CNS-directed
treatment for 15% of all patients with intermediate-grade NHL accrued
to this study. However, only 11 of the 24 patients destined to develop
CNS recurrence would have been identified. Therefore, the sensitivity
of our model in predicting CNS recurrence is slightly less than 50%,
only marginally better than could be achieved if patients had been
selected on the basis of bone marrow, testicular, and sinus
involvement. On the other hand, an increased serum LDH correctly
identified 21 of the 24 patients destined to develop CNS prophylaxis,
but more than 50% of the patients in this study had an elevated LDH.
The median survival after CNS recurrence was only 88 days, consistent
with the known poor prognosis of CNS recurrence.27 Prior
studies of end-stage lymphoma have emphasized the fact that most
patients die from systemic disease rather than from CNS complications. Our study included a more selected patient group; the patients had
received adequate systemic treatment and had CNS involvement as their
initial site of recurrence. CNS complications were the main cause of
death in these patients.
Intrathecal treatment did not result in meaningful responses. Radiation
therapy resulted in rapid but transient symptomatic relief in most
cases. Five of 9 patients developed recurrences in the CNS. The fact
that most patients had lymphoma cells in the spinal fluid is consistent
with findings from previous reports1,3,4,6,28 and indicates
that CNS involvement is a complication that affects the entire
neuraxis. Effective long-term treatment at the time of CNS relapse
should be aimed at sites of systemic disease and at the craniospinal
axis. Chemotherapy, using agents that are effective across the
blood-brain barrier, is theoretically appealing. However, in our
series, it was rarely possible to devise such regimens, because most
patients had relapse during or shortly after completing programs
incorporating most known active agents. Because allogeneic or
autologous transplantation can overcome chemotherapy resistance, this
approach may prove beneficial for selected patients.29,30
In conclusion, the risk of CNS recurrence in intermediate-grade
lymphoma treated with modern chemotherapy regimens is approximately 5%. Our analysis confirms the importance of previously identified risk
factors, but in addition establishes the predictive value of increased
serum LDH and the involvement of multiple extranodal sites as risk
factors for CNS recurrence. In univariate analysis, these two features
are stronger predictors than any of the commonly used risk factors. In
multivariate analysis, they emerge as the only significant ones. The
identification of additional independent risk factors in future studies
may allow a more accurate identification of those at risk for CNS
recurrence.
Established CNS recurrence is usually rapidly fatal. Intrathecal
chemotherapy alone is not effective palliation for intermediate-grade lymphomas, and radiation treatment results in rapid symptomatic improvement but is usually followed by systemic or CNS recurrence. New
treatment strategies should be developed for patients at high risk for
CNS recurrence and explored in a prospective fashion.
| |
FOOTNOTES |
Submitted June 17, 1997;
accepted October 10, 1997.
Address reprint requests to Koen van Besien, MD, Hematology/Oncology
Section, University of Illinois at Chicago, 840 S Wood St (MC 787),
Chicago, IL 60612.
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.
| |
REFERENCES |
1.
Recht L,
Straus DJ,
Cirrincione C,
Thaler HT,
Posner JB:
Central nervous system metastases from non-Hodgkin's lymphoma: Treatment and prophylaxis.
Am J Med
84:425,
1988[Medline]
[Order article via Infotrieve]
2.
Law IP,
Dick FR,
Blom J,
Bergevin PR:
Involvement of the central nervous system in non-Hodgkin's lymphoma.
Cancer
36:225,
1975[Medline]
[Order article via Infotrieve]
3.
Young RC,
Howser DM,
Anderson T,
Fisher RI,
Jaffe E,
DeVita VT Jr:
Central nervous system complications of non-Hodgkin's lymphoma. The potential role of prophylactic therapy.
Am J Med
66:435,
1979[Medline]
[Order article via Infotrieve]
4.
Bunn PA,
Schein PS,
Banks PM,
DeVita VT Jr:
Central nervous system complications in patients with diffuse histiocytic and undifferentiated lymphoma/leukemia revisited.
Blood
47:3,
1976[Abstract/Free Full Text]
5.
Bashir RM,
Bierman PJ,
Vose JM,
Weisenburger DD,
Armitage JO:
Central nervous system involvement in patients with diffuse aggressive non-Hodgkin's lymphoma.
Am J Clin Oncol
14:478,
1991[Medline]
[Order article via Infotrieve]
6.
Herman TS,
Hammond N,
Jones SE,
Butler JJ,
Byrne GE,
McKelvey EM:
Involvement of the central nervous system by non-Hodgkin's lymphoma. The Southwest Oncology Group Experience.
Cancer
43:390,
1979[Medline]
[Order article via Infotrieve]
7.
Levitt LJ,
Dawson DM,
Rosenthal DS,
Moloney WC:
CNS involvement in the non-Hodgkin's lymphomas.
Cancer
45:545,
1980[Medline]
[Order article via Infotrieve]
8.
MacKintosh FR,
Colby TV,
Podolsky WJ,
Burke JS,
Hoppe RT,
Rosenfelt FP,
Rosenberg SA,
Kaplan HS:
Central nervous system involvement in non-Hodgkin's lymphoma: An analysis of 105 cases.
Cancer
49:586,
1982[Medline]
[Order article via Infotrieve]
9.
Litam JP,
Cabanillas F,
Smith TL,
Bodey GP,
Freireich EJ:
Central nervous system relapse in malignant lymphomas: Risk factors and implications for prophylaxis.
Blood
54:1249,
1979[Abstract/Free Full Text]
10.
Perez-Soler R,
Smith TL,
Cabanillas F:
Central nervous system prophylaxis with combined intravenous and intrathecal methotrexate in diffuse lymphoma of aggressive histologic type.
Cancer
57:971,
1986[Medline]
[Order article via Infotrieve]
11.
Touroutouglou N,
Dimopoulos MA,
Younes A,
Hess M,
Pugh W,
Cox J,
Cabanillas F,
Sarris AH:
Testicular lymphoma: Late relapses and poor outcome despite doxorubicin-based therapy.
J Clin Oncol
13:1361,
1995[Abstract]
12.
Liang R,
Chiu E,
Loke SL:
Secondary central nervous system involvement by non-Hodgkin's lymphoma: The risk factors.
Hematol Oncol
8:141,
1990[Medline]
[Order article via Infotrieve]
13.
Montserrat E,
Bosch F,
Lopez-Guillermo A,
Graus F,
Terol MJ,
Campo E,
Rozman C:
CNS involvement in mantle-cell lymphoma.
J Clin Oncol
14:941,
1996[Abstract/Free Full Text]
14.
Jagannath S,
Velasquez WS,
Tucker SI,
McLaughlin PW,
Manning JJ,
North LB,
Cabanillas FC:
Tumor burden assessment and its implication for a prognostic model in advanced diffuse large-cell lymphoma.
J Clin Oncol
4:859,
1986[Abstract/Free Full Text]
15.
Rodriguez J,
Cabanillas F,
McLaughlin P,
Swan F,
Rodriguez MA,
Hagemeister F,
Romaguera J:
A proposal for a simple staging system for intermediate grade lymphoma and immunoblastic lymphoma based on the `tumor score'.
Ann Oncol
3:711,
1992[Abstract/Free Full Text]
16.
Rodriguez V,
Cabanillas F,
Burgess M,
McKelvey EM,
Valdivieso M,
Bodey GP,
Freireich EJ:
Combination chemotherapy (CHOP-Bleo) in advanced (non-Hodgkin's) malignant lymphoma.
Blood
49:325,
1977[Abstract/Free Full Text]
17.
Cabanillas F,
Rodriguez M,
Swan F:
Recent trends in the management of lymphomas at MD Anderson Cancer Center.
Semin Oncol
17:28,
1990[Medline]
[Order article via Infotrieve]
18. (abstr)
Cabanillas F,
McLaughlin P,
Hagemeister F,
Swan F,
Rodriguez MA,
Romaguera J,
Majlis A,
Jendiroba D,
Rodriguez J:
Improvement in survival and disease free survival of intermediate grade and immunoblastic lymphomas treated with the novel ATT regimen.
Proc Am Soc Clin Oncol
13:388,
1994
19.
Przepiorka D,
Nath R,
Ippoliti C,
Mehra R,
Hagemeister F,
Diener K,
Dimopoulos M,
Giralt S,
Khouri I,
Samuels B,
van Besien K,
Andersson B,
Deisseroth AB,
Luna M,
Cabanillas F,
Champlin R:
A phase I-II study of high-dose thiotepa, busulfan and cyclophosphamide as a preparative regimen for autologous transplantation for malignant lymphoma.
Leuk Lymphoma
17:427,
1995[Medline]
[Order article via Infotrieve]
20.
Kaplan EL,
Meier P:
Nonparametric estimation from incomplete observations.
J Am Stat Assoc
53:457,
1958
21.
Mehta R,
Patel NR:
Exact logistic regression, theory and examples.
Stat Med
14:2143,
1995[Medline]
[Order article via Infotrieve]
22.
Mehta R,
Patel NR:
A hybrid algorithm for Fisher's exact test on unordered r × c contingency tables.
Comm Stat
15:387,
1986
23.
Pinkel D,
Woo S:
Prevention and treatment of meningeal leukemia in children.
Blood
84:355,
1994[Abstract/Free Full Text]
24.
The International Non-Hodgkin's Lymphoma Prognostic Factors Project:
A predictive model for aggressive non-Hodgkin's lymphoma.
N Engl J Med
329:987,
1993[Abstract/Free Full Text]
25.
Cortes J,
O'Brien SM,
Pierce S,
Keating MJ,
Freireich EJ,
Kantarjian HM:
The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia.
Blood
86:2091,
1995[Abstract/Free Full Text]
26.
Coleman CN,
Picozzi VJ,
Cox RS,
McWirter K,
Weiss LM,
Cohen JR,
Yu KP,
Rosenberg SA:
Treatment of lymphoblastic lymphoma in adults.
J Clin Oncol
4:1628,
1986[Abstract/Free Full Text]
27.
van Besien K,
Forman A,
Champlin RE:
CNS relapse of lymphoid malignancies in adults: The role of high-dose chemotherpay.
Ann Oncol
8:515,
1997[Abstract/Free Full Text]
28.
Monfardini S,
Ficarra G,
Giardini R,
Santoro A:
Central nervous system involvement in non-Hodgkin's lymphomas: Value of lumbar puncture as initial staging procedure.
Tumori
67:197,
1980
29.
Williams CD,
Pearce R,
Taghipour G,
Green ES,
Philip T,
Goldstone AH:
Autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma and CNS involvement: Those transplanted with active CNS disease have a poor outcomeA report by the European Bone Marrow Transplant Lymphoma Registry.
J Clin Oncol
12:2415,
1994[Abstract/Free Full Text]
30.
van Besien K,
Przepiorka D,
Mehra R,
Giralt S,
Khouri I,
Gajewski J,
Andersson B,
Champlin RE:
High-dose thiotepa, busulfan and cyclophosphamide for patients with hematologic malignancies and CNS involvement.
J Clin Oncol
14:3036,
1996[Abstract]
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Abstract
Introduction
Abstract
