Cancer Therapy Vol 1, 215-221 2003.
Phase II intergroup trial of
sequential chemotherapy and radiotherapy for AIDS-related primary central
nervous system lymphoma
Research
Article
RF
Ambinder1, S. Lee2, WJ Curran3, JA Sparano4*,
RL Krigel5, J McArthur1,
C Schultz6, CE Freter7, L
Kaplan8, JH VonRoenn9.
1Johns
Hopkins School of Medicine, Baltimore, MD, ambinri@jhmi.edu,
jm@jhmi.edu; 2Dana-Farber
Cancer Institute, Boston, MA, sjlee@jimmy.harvard.edu;
3Thomas Jefferson University Hospital, Philadelphia, PA, walter.curran@mail.tju.edu;
4Montefiore Medical Center, Bronx, NY, jsparano@montefiore.org; 5Lankenau
Hospital, Wynnewood PA; 6Medical College of Wisconsin, Milwaukee,
WI, cschultz@mcw.edu; 7Georgetown
University Medical Center, Washington, D.C., carl.freter@yvmh.org; 8Northwestern
University Medical Center, Chicago, IL, j-vonroenn@northwestern.edu
*Correspondence: Joseph A. Sparano, M.D.,
Montefiore Medical Center-Weiler Division, Department of Oncology, 2South, Room
47-48, 1825 Eastchester Road, Bronx, New York 10461; Phone 718-904-2555/Fax
718-904-2892; Email: jsparano@montefiore.org
Key Words: HIV, cyclophosphamide,
EBV, doxorubicin, vincristine, dexamethasone, radiation therapy, antiretroviral
therapy, cerebrospinal fluid
Abbreviations: primary central nervous
system lymphoma (PCNSL), Epstein-Barr virus (EBV), cerebrospinal fluid (CSF),
computerized tomography (CT), human immunodeficiency virus (HIV),
antiretroviral therapy (HAART), CHOD (cyclophosphamide, doxorubicin,
vincristine, and dexamethasone)
Received: 29
August 2003; Accepted: 15 September 2003; electronically published: September
2003
Summary
The purpose of this study is to determine the value
of a systemic evaluation in patients with primary central nervous system
lymphoma (PCNSL) associated with human immunodeficiency virus (HIV) infection,
to investigate the diagnostic utility of detection of Epstein-Barr virus (EBV)
DNA in cerebrospinal fluid (CSF), and to determine the overall survival in
patients treated with one cycle of chemotherapy followed by radiation therapy.
Patients underwent computerized tomography (CT) and bilateral bone marrow
biopsy. CSF was analyzed for EBV DNA. A single cycle of an anthracycline
containing combination chemotherapy regimen was followed by radiation therapy.
Thirty-five patients were enrolled. Bone marrow biopsy did not reveal lymphoma
in any case. Chest X ray identified one patient with a coexistent thoracic
lymphoma. EBV DNA was detected in CSF in 8 of 10
patients. The median survival was 2.4 months (C.I. 1.1 to 3.2 months).
Four patients survived more than a year. CONCLUSIONS: In HIV-infected patients
with intracranial mass lesions, systemic evaluation with CT scan and bone
marrow biopsy has a low yield. EBV DNA is usually detected in CSF. A single
cycle of an anthracycline-containing regimen followed by radiation was
associated with a poor survival.
I. Introduction
The incidence of
primary central nervous system lymphoma (PCNSL) in individuals infected with
the human immunodeficiency virus (HIV) was 3,600-fold greater than in the
general population in the era before highly active antiretroviral therapy (Cote et al, 1996). Since
the introduction of highly active antiretroviral therapy (HAART), there has
been a decline in the incidence of HIV-associated PCNSL (Sparano et al, 1999; Besson et
al, 2001; Kirk et al, 2001; Hoffmann et al, 2003). The diagnostic yield
of a systemic work up, including computerized tomography (CT) of the body and
bilateral bone marrow biopsy has not been previously evaluated. In addition, at
the time that this study was performed, brain biopsy was considered necessary
for establishing a definitive diagnosis, but was known to be associated with
considerable morbidity and occasional mortality (Corn et al, 1995; Skolasky et al, 1999).
Results of standard therapy with radiation were poor engendering therapeutic
nihilism (Baumgartner et
al, 1990). Finally, the relationship between PCNSL and systemic
lymphoma, particularly in the setting of acquired immunodeficiency syndrome
(AIDS) was not clear. Extranodal-presentations of systemic AIDS-related
lymphoma are common. The central nervous system is one of the most frequent
extranodal sites, raising the concern that central nervous system involvement
at presentation may be a manifestation of systemic disease. We sought to determine
whether a systemic work up (particularly bone marrow biopsy) was necessary to
exclude occult systemic disease. We also sought to determine whether in light
of the nearly uniform EBV-PCNSL association (MacMahon et al, 1991) a likely diagnosis
could be established without brain biopsy by sampling the cerebrospinal fluid
for EBV DNA by polymerase chain reaction (PCR) (Arribas et al, 1995; Antinori et al, 1997, 1999;
Cinque et al, 1993). Finally, we sought to determine whether
chemotherapy administered before radiation might improve the outcome (DeAngelis et al, 1992; Forsyth
et al, 1994).
In 1995, the Eastern Cooperative Oncology Group
(ECOG) initiated a multi-institutional study to address each of these issues.
Other participating groups included the Radiation Therapy Oncology Group
(RTOG), the Cancer and Acute Leukemia Group B (CALGB), and the AIDS Clinical
Trials Group (ACTG). This study forms the basis for this report.
II.
Patients and methods
A. Methods
This study plan included a diagnostic step (step 1),
a treatment step (step 2), and a correlative laboratory component. To be
eligible for step 1, patients were required to be HIV seropositive and to have
biopsy proven PCNSL of intermediate or high-grade histology involving the
parenchyma of the brain with an intracranial space-occupying lesion documented
on an imaging study. Other requirements included no prior chemotherapy (unless
given for KaposiÕs sarcoma), no prior cranial irradiation, to be within 3 weeks
of diagnostic brain biopsy, age 16 or older, no prior history of lymphoma or
clinical evidence of systemic lymphoma, no prior or concomitant malignancy
other than KaposiÕs sarcoma or curatively treated carcinoma of the cervix, or
squamous cell or basal carcinoma of the skin. To be eligible for step 2,
patients were required to have no evidence of systemic disease as documented by
computerized tomography (CT) of the chest, abdomen, and pelvis, and bilateral bone marrow biopsies. Other requirements
included an ECOG performance status of 0-3, adequate hematologic function
(absolute neutrophil count of ³ 1,000/mm3
and platelets ³ 50,000/mm3)
and adequate renal and hepatic function (serum creatinine £ 3.0 mg/dl and bilirurbin <
3 x the upper limit of normal), and no active acute infection. Lumbar puncture
was required for the evaluation of cerebrospinal fluid (CSF) for malignant
cells and EBV DNA unless clinically contraindicated. Patients were excluded if
they were receiving concurrent treatment with investigational agents other than
investigational antiretroviral agents, if they had an active duodenal ulcer,
uncontrolled diabetes mellitus, active heart disease, or were pregnant or
lactating. Patients were required to provide written informed consent. The
protocol was approved by the institutional review board at each participating
institution.
B.
Chemotherapy
Patients without systemic lymphoma
were registered on step 2 and received intravenous cyclophosphamide 750 mg/m2,
doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 (2 mg
maximum) and dexamethasone 16 mg/m2, followed by the same
dexamethasone dose orally or intravenously on a daily basis; daily
dexamethasone treatment was permitted to maintain the patient's best neurologic
function. Patients with positive CSF
cytology were treated with intrathecal cytarabine, 50 mg twice weekly
until cytology was negative, then once weekly for six weeks, and once monthly
for ten months.
C.
Radiotherapy
Patients started radiotherapy
7-10 days after chemotherapy. Daily treatments of 2.5 Gy were given 5 days per
week for 12 days to the entire cranial contents using opposed shaped lateral whole brain treatment portals. Four daily
2.5 Gy fractions where then delivered via shaped
reduced fields to the identifiable lesion(s) with a margin. The total tumor
dose was 40.0 Gy in 16 fractions given in less than 4 weeks. Treatment plans,
diagnostic imaging, and field localization were reviewed on all treated
patients by the radiation.
D. Supportive
care
Granulocyte
colony stimulating factor (G-CSF) was given at 5 ug/kg subcutaneously beginning
on day 2 for a minimum of 10 days until granulocyte counts exceeded 5000/ul for
two days. Prophylaxis for pneumocystis carinii (trimethoprim /sulfamethoxazole, dapsone or
aerosolized pentamidine) and fungal infection (fluconazole, ketoconazole, or
clotrimazole oral troches) were standard. As this trial was initiated before
the availability of highly active antiretroviral therapy, antiretroviral
therapy consisted of standard doses of didanosine, zidovudine,
or zalcitabine unless contraindicated.
E.
Cerebrospinal fluid polymerase chain reaction to detect EBV DNA
CSF
samples from patients enrolled in this study and specimens that had been
archived in the Johns Hopkins AIDS Neurological Tissue Bank were studied for
EBV DNA by polymerase chain reaction (PCR). CSF from study participants was
shipped overnight on dry ice and stored at Ð70oC until analysis. CSF
archived in the AIDS Neurological Tissue Bank were collected from patients
treated at Johns Hopkins with HIV infection who had neurological signs or
symptoms or who were asymptomatic. These samples were amplified with PCR primers to
two regions of the genome in two separate assays as described (Ambinder et al, 1990;
Arribas et al, 1995). For
these assays, a 20mL aliquot of CSF was heated at 95oC
for 10 minutes. PCR products were analyzed by agarose gel electrophoresis with
Southern blot transfer and hybridization with 32P-labeled
oligonucleotide probes. Autoradiography was carried out overnight with Kodak
X-Omat film. To prevent contamination PCR set up and amplification were
performed in separate rooms.
F. Statistical
considerations
The
primary objectives of the trial were descriptive. The methods of Kaplan and
Meier were used to estimate survival curves. With the intent of estimating
one-year survival with a maximum 90% confidence interval width of +/- 16%, the
goal was to enroll at least 30 patients. The sensitivity, specificity, positive
predictive value, negative predictive value, and accuracy of CSF EBV DNA in
patients not yet treated for PCNSL were calculated using standard definitions (Dunn, 1995).
III. Results
A. Patient Characteristics
This
study accrued 35 patients between April 1994 and April 1997 to step 1,
including patients accrued from ECOG (N=24), CALGB (N=6), RTOG (N=3), and ACTG
(N=2). The characteristics of the study population are summarized in Table 1. The median age was 36 years and 33 (94%)
were male. The median CD4 count was 10.5/mL (range 1-91/mL). The ECOG performance status was 0 or 1
in 11 (34%), 2 in 10 (31%) and 3 in 10 (31%). Prior opportunistic infection
included pneumocystis carinii in 10 (33%), cytomegalovirus infection in 9 (30%), candida esophagitis
in 7 (24%), mycobacterium avium intracellulare in 6 (19%), and other infections in 11 (42%). CSF
cytology was performed in 16 patients, of whom three were positive for
malignant cells consistent with meningeal lymphoma. In many instances lumbar
puncture was felt to be contraindicated and CSF cytology not available.
B.
Systemic diagnostic workup
Bone marrow biopsy revealed no evidence of lymphoma in
any patient. In one patient the CXR revealed coexistant lymphoma in the lung,
which was confirmed on computerized tomography (CT) of the chest.
C. Clinical and
radiographic presentation of CNS disease
Clinical and radiographic features are shown in Table
2. All patients had neurologic symptoms at
diagnosis. The most common presenting signs and/or symptoms included motor
deficits in 13 (37%), altered mental status in 11 (31%), headache in 10 (29%),
visual disturbance in 9 (26%), cranial nerve deficits in 8 (23%), speech
impairment in 8 (23%), cerebellar deficits in 7 (20%), sensory deficits in 6
(17%), and papilledema in 1 (4%). Imaging studies of the brain revealed the
tumors to be unilateral in 23 patients (66%), and the median tumor size was 5.2
cm2 (1.5-27.5). Supratentorial structures were involved in 20
patients (57%) and infratentorial structures were involved in 4 patients (11%).
D. Response and
survival
Thirty-four patients proceeded to step 2 and
received protocol treatment. Complete response occurred in 3 patients (9%), and
partial response in 1 patient (3%).
Fifteen patients (43%) did not complete radiation
therapy, including seven patients who died before completion, five patients who
declined to complete therapy, and three patients who had showed tumor
progression during radiation therapy. The
median survival was 2.4 months (95% confidence intervals 1.1, 3.2 months) (Figure
1). Four patients survived at least one
year. The characteristics of the responders and/or long-term survivors are
summarized in Table 3.
E. Toxicity
There were 8 patients (23%) who died within 30 days
of initiating treatment, including four patients who died of infectious
complications, two patients who had pulmonary failure, one patient who had a brain
herniation, and one patient who died during a grandmal seizure. Grade 4
toxicity included leukopenia in 63%, thrombocytopenia in 20%, and liver,
pulmonary, neurosensory, neuromotor, and metabolic toxicities one patient each
(3%).
Table
1. Patient Characteristics
Age
Median 36
years
Range 22
- 54 years
ECOG Performance Status (N=32)
0,
1 11
(34.4%)
2 10
(31.3%)
3 10
(31.3%)
4 1
(3.1%)
CD 4 Count (N=26)
Median 10.5/uL
Range 1-91/uL
Neutrophil Count (N=31)
Median 2800/ul
Range 1000-15,100/ul
Hemoglobin (N=31)
Median 12.0
g/dl
Range 9.2-15.7
Platelet Count (N=31)
Median 210,000/ul
Range 64,000-452,000
Table
2. Clinical and Radiographic Findings
|
Clinical
Findings
Motor deficits
Altered mental status
Headache
Visual disturbance
Cranial nerve deficits
Speech impairment
Cerebellar deficits
Sensory deficits
Papilledema
|
Number
13
11
10
9
8
8
7
6
1
|
Percent
37%
31%
29%
26%
23%
23%
20%
17%
4%
|
|
Radiographic
Findings
Unilateral lesions
Supratentorial lesions
Infratentorial lesions
|
23
20
4
|
66%
57%
11%
|
Figure.1. Overall survival
of treated patients (N=-34).
In addition, the same group reported that EBV DNA in the CSF usually disappears with treatment
of the lymphoma (Antinori
et al, 1999). Our findings are consistent with these previous reports.
In combination with imaging techniques, a positive EBV PCR result may obviate
the need for brain biopsy in some patients with intracranial mass lesions and
HIV infection. The identification of EBV in the CSF of some patients with HIV
is consistent with the occasional identification of EBV in patients with
infectious mononucleosis and associated neurological symptoms. It is curious
that in this series (Table 4), EBV
in the CSF in patients without lymphoma was most commonly found in HIV patients
with cytomegalovirus encephalitis. Whether the detection of EBV in this setting
points to some specific interaction between the two viruses or simply reflects
profound cellular immunodeficiency is not clear. Future studies using
quantitative methods for EBV load in CSF may facilitate differentiation between
benign and malignant central nervous system disease.
Chemotherapy
used alone or in combination with brain irradiation has been used for the
treatment of non-HIV-associated PCNSL (Dahlborg et al, 1996; Freilich et al, 1996; Mead et al, 2000).
The Radiation Therapy Oncology Group (RTOG) reported that CHOD
(cyclophosphamide, doxorubicin, vincristine, and dexamethasone) chemotherapy
preceding brain irradiation was not associated with improved survival when
compared with historical data employing radiation alone in
non-immunocompromised patients (Schultz et al, 1996). A study from the United Kingdom also showed
no advatage to CHOP (cyclophosphamide, doxorubicin, vincristine, and
prednisone) chemotherapy following radiation therapy (Mead et al, 2000). Recent evidence suggests
that high-dose methotrexate based regimens may be effective for immunocompetent
patients with PCNSL. (DeAngelis
et al, 1992; Glass et al, 1994; Guha-Thakurta et al, 1999; O'Brien et al, 2000;
Batchelor et al, 2003). For example, DeAngelis and colleagues (1992) reported a five-year survival
of 22% for patients treated with methotrexate, high dose cytarabine, and
irradiation, compared with 4% for historical controls treated with radiation
alone. A subsequent
multicenter study confirmed improved survival compared with historical data
using irradiation alone, although delayed neurotoxicity was a major
complication of therapy, especially in patients older than 60 years of age
(DeAngelis et al, 2002). Likewise, Sandor and
colleagues (1998) treated 14 patients with PCNSL or intraocular
lymphoma with high dose methotrexate with leucovorin rescue, thiotepa,
vincristine, and dexamethasone. The complete response rate was 79%, and 69% of
the patients survived nearly five years, of whom about one-half were
progression-free. Others have also evaluated high-dose methotrexate
alone, with deferral of irradiation until relapse or progression, with
encouraging results (Batchelor et al, 2003). An expert panel has
recommended high-dose methotrexate-based regimen with deferred irradiation for
older (more than 60 years) in order to reduce the risk of delayed neurotoxicity
in this group, and high-dose methotrexate and cytarabine based-combinations in
conjunction with irradiation in younger patients; the panel did not address
treatment of primary CNS lymphoma in patients with HIV infection (Ferreri et al, 2003).
The treatment of PCNSL in AIDS patients presents two obstacles:
the blood brain barrier and the patients profound immunocompromised status.
With regard to the blood brain barrier, imaging studies make clear that the
integrity of this barrier evolves with therapy. Contrast enhancement of tumors
prior to treatment suggests that the tumor itself leads to profound disruption
of the barrier. As treatment proceeds, the barrier is often reestablished. Poor
tolerance of chemotherapy in AIDS patients has established a role for
reduced-dose or reduced-length treatment in some settings (Kaplan et al, 1997). Thus for our
study we reasoned that a single cycle of chemotherapy administered prior to the
initiation of radiation therapy might increase tumor kill with only minimal
increase in toxicity. We gave one cycle of CHOD chemotherapy followed by
irradiation in a manner similar to that employed by the RTOG for PCNSL in
immunocompetent patients. Our
results are similar to other reports that included radiation therapy alone (Donahue et al, 1995; Bower et
al, 1999). Although those who survived more than 1 year had CD4 counts
that exceeded the median in every case in which they were available, and the
patient with the highest CD4 count was among the longer survivors. CD4 count
was not a very good prognosticator. Thus, the longest survivor (37.9 months)
had a CD4 count of only 11Ñbarely above the median. Our findings suggest that
administration of a single cycle of an anthracycline containing combination
chemotherapy regimen before radiation in patients with PCNSL and HIV infection
fails to improve patient outcome.
Our study was conducted prior to the use of HAART
in clinical practice. Several reports have indicated that patients with
HIV-associated PCNSL treated in the post- HAART era had a much improved
prognosis, especially those who had a substantial reduction in viral load due
to HAART therapy (Skiest
and Crosby, 2003). This finding parallels improvements in survival also
noted for patients with systemic HIV-associated lymphoma treated with standard
cytotoxic therapy (Vaccher
et al, 2001). Spontaneous remission of PCSNL has been
reported in immunocompetent patients after treatment with dexamethasone (Al-Yamany et al, 1999),
and in patients with HIV infection after treatment with HAART and
corticosteroids (Terriff
et al, 1992; McGowan and Shah, 1998). In addition, Raez reported the use
of parenteral zidovudine (1.6 g twice daily), gancyclovir (5 mg/kg twice
daily), and interleukin-2 (2 million units twice daily) in five patients with
HIV-associated PCNSL, some of whom had progressive disease after prior brain
irradiation (Raez et al,
1999). The treatment regimen was based upon the premise that the
treatment was effective against Epstein-Barr virus-positive B-cell lymphoma
cell lines in vitro. Four of five had an objective response, of whom two were
alive and disease-free at 22 and 13 months. These findings suggest that the prognosis
may be improved for patients with PCNSL diagnosed in the post-HAART era,
Treatment with high-dose methotrexate-based regimens plus optimization of HAART
therapy may therefore represent a prudent strategy for patients with
HIV-associated PCNSL that merits evaluation in clinical trials.
Acknowledgements
This study was
conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, MD,
Chair) and was open in the Radiation Therapy Oncology Group, The Southwest
Oncology Group, the Cancer and Leukemia Group B, and the AIDS Clinical Trials
Group. It was supported in part by Public Health Service grants CA14958,
CA23318, CA13650, CA 16116, CA15488, CA17145, CA66636, CA21115 from the
National Cancer Institute, National Institutes of Health and the Department of
Health and Human Services. Its contents are solely the responsibility of the
authors and do not necessarily represent the official views of the National
Cancer Institute. It is with great sadness and gratitude that the authors acknowledge
Dr. Robert L. Krigel, who conceived of and designed this study, but who passed
away before it could be completed.
References
Al-Yamany M,
Lozano A, Nag S, Laperriere N, Bernstein M (1999) Spontaneous
remission of primary central nervous system lymphoma: report of 3 cases and
discussion of pathophysiology. J Neurooncol 42, 151-159
Ambinder RF, Lambe BC, Mann RB, et al (1990)
Oligonucleotides for polymerase chain reaction amplification and hybridization
detection of Epstein-Barr virus DNA in clinical specimens. Mol Cell Probes 4,
397-407
Antinori A,
Ammassari A, De Luca A, et al (1997) Diagnosis of AIDS-related focal brain
lesions: a decision-making analysis based on clinical and neuroradiologic
characteristics combined with polymerase chain reaction assays in CSF. Neurology 48, 687-94
Antinori A,
Cingolani A, De Luca A, et al (1999) Epstein-Barr virus in monitoring the
response to therapy of acquired immunodeficiency syndrome-related primary
central nervous system lymphoma. Ann Neurol 45, 259-61
Arribas JR,
Clifford DB, Fichtenbaum CJ, et al (1995) Detection of Epstein-Barr virus
DNA in cerebrospinal fluid for diagnosis of AIDS-related central nervous system
lymphoma. J Clin Microbiol 33, 1580-3
Batchelor T,
Carson K, O'Neill A, et al (2003) Treatment of primary CNS lymphoma
with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin
Oncol 21. 1044-1049
Baumgartner JE,
Rachlin JR, Beckstead JH, et al (1990) Primary central nervous system
lymphomas: natural history and response to radiation therapy in 55 patients
with acquired immunodeficiency syndrome. J Neurosurg 73:206-11
Besson C, Goubar
A, Gabarre J, et al (2001) Changes in AIDS-related lymphoma since the era of
highly active antiretroviral therapy. Blood 98, 2339-44
Bower M, Fife K,
Sullivan A, et al (1999) Treatment outcome in presumed and confirmed
AIDS-related primary cerebral lymphoma. Eur J Cancer 35, 601-4
Carraway H,
Ambinder RF (2002) Plasma cell dyscrasia, Hodgkin lymphoma, HIV, and
Kaposi sarcoma-associated herpesvirus. Curr Opin Oncol 14, 543-5
Cingolani A, De
Luca A, Larocca LM, et al (1998) Minimally invasive diagnosis of
acquired immunodeficiency syndrome-related primary central nervous system
lymphoma. J Natl Cancer Inst 90, 364-9
Cinque P,
Brytting M, Vago L, et al (1993) Epstein-Barr virus DNA in
cerebrospinal fluid from patients with AIDS-related primary lymphoma of the
central nervous system. Lancet 342, 398-401
Corn BW, Trock
BJ, Curran WJ, Jr (1995) Management of primary central nervous system
lymphoma for the patient with acquired immunodeficiency syndrome. Confronting a
clinical catch-22. Cancer 76, 163-6
Cote TR, Manns
A, Hardy CR, et al (1996) Epidemiology of brain lymphoma among people with
or without acquired immunodeficiency syndrome. AIDS/Cancer Study Group. J
Natl Cancer Inst 88, 675-9
Dahlborg SA,
Henner WD, Crossen JR, et al (1996) Non-AIDS Primary CNS Lymphoma: First
Example of a Durable Response in a Primary Brain Tumor using Enhanced
Chemotherapy Delivery without Cognitive Loss and without Radiotherapy. Cancer
J Sci Am 2, 166, 1996
DeAngelis LM,
Seiferheld W, Schold SC, Fisher B, Schultz CJ (2002) Combination
chemotherapy and radiotherapy for primary central nervous system lymphoma:
Radiation Therapy Oncology Group Study 93-10. J Clin Oncol 20, 4643-4648
DeAngelis LM,
Yahalom J, Thaler HT, et al (1992) Combined modality therapy for primary
CNS lymphoma. J Clin Oncol 10, 635-43
Donahue BR,
Sullivan JW, Cooper JS (1995) Additional experience with empiric
radiotherapy for presumed human immunodeficiency virus-associated primary
central nervous system lymphoma. Cancer 76, 328-32
Dunn GE (1995) Clinical biostatistics:
an introduction to evidence-based medicine. London, E Arnold
Ferreri AJ,
Abrey LE, Blay JY, et al (2003) Summary statement on primary central
nervous system lymphomas from the Eighth International Conference on Malignant
Lymphoma, Lugano, Switzerland, June 12 to 15, 2002. J Clin Oncol 21, 2407-2414
Forsyth PA,
Yahalom J, DeAngelis LM (1994) Combined-modality therapy in the
treatment of primary central nervous system lymphoma in AIDS. Neurology 44, 1473-9
Freilich RJ,
Delattre JY, Monjour A, et al (1996) Chemotherapy without radiation
therapy as initial treatment for primary CNS lymphoma in older patients. Neurology 46, 435-9
Glass J, Gruber
ML, Cher L, et al (1994) Preirradiation methotrexate chemotherapy of
primary central nervous system lymphoma: long-term outcome. J Neurosurg 81, 188-95
Guha-Thakurta N,
Damek D, Pollack C, et al (1999) Intravenous methotrexate as initial
treatment for primary central nervous system lymphoma: response to therapy and
quality of life of patients. J Neurooncol 43, 259-68
Hoffmann C, Wolf
E, Fatkenheuer G, et al (2003) Response to highly active
antiretroviral therapy strongly predicts outcome in patients with AIDS-related
lymphoma. Aids 17, 1521-1529
Kaplan LD,
Straus DJ, Testa MA, et al (1997) Low-dose compared with standard-dose
m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with human
immunodeficiency virus infection. National Institute of Allergy and Infectious
Diseases AIDS Clinical Trials Group. N Engl J Med 336, 1641-8
Kirk O, Pedersen
C, Cozzi-Lepri A, et al (2001) Non-Hodgkin lymphoma in HIV-infected
patients in the era of highly active antiretroviral therapy. Blood 98, 3406-12
Levine AM (1998)
Hodgkin's disease in the setting of human immunodeficiency virus infection. J
Natl Cancer Inst Monogr 37-42
Levine AM,
Scadden DT, Zaia JA, et al (2001) Hematologic Aspects of HIV/AIDS. Hematology
(Am Soc Hematol Educ Program) 463-78
MacMahon EG,
Hayward SD, Mann RB, Becker PS, Charache P, McArthur J, Ambinder, RF (1991) Epstein-Barr
virus (EBV): A tumor marker for primary central nervous system lymphoma (PCNSL)
in AIDS? Blood 78S, 399a
MacMahon EM,
Glass JD, Hayward SD, et al (1991) Epstein-Barr virus in AIDS-related
primary central nervous system lymphoma. Lancet 338, 969-73
McGowan JP, Shah
S (1998) Long term remission of AIDS-related primary CNS lymphoma associated
with highly active antiretroviral therapy. AIDS 12, 952-958
Mead GM, Bleehen
NM, Gregor A, et al (2000) A medical research council randomized trial in
patients with primary cerebral non-Hodgkin lymphoma: cerebral radiotherapy with
and without cyclophosphamide, doxorubicin, vincristine, and prednisone
chemotherapy. Cancer 89, 1359-70
O'Brien P, Roos
D, Pratt G, et al (2000) Phase II multicenter study of brief single-agent
methotrexate followed by irradiation in primary CNS lymphoma. J Clin Oncol 18, 519-26
Raez L, Cabral
L, Cai JP, et al (1999)Treatment of AIDS-related primary central nervous
system lymphoma with zidovudine, ganciclovir, and interleukin 2. AIDS Res
Hum Retroviruses 15, 713-719.
Sandor V,
Stark-Vancs V, Pearson D, et al (1998) Phase II trial of chemotherapy alone
for primary CNS and intraocular lymphoma. J Clin Oncol 16, 3000-6
Schultz C, Scott
C, Sherman W, et al (1996) Preirradiation chemotherapy with
cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS
lymphomas: initial report of radiation therapy oncology group protocol 88-06. J
Clin Oncol 14, 556-64
Skiest DJ,
Crosby C (2003) Survival is prolonged by highly active
antiretroviral therapy in AIDS patients with primary central nervous system
lymphoma. Aids. 17, 1787-1793
Skolasky RL, Dal
Pan GJ, Olivi A, et al (1999) HIV-associated primary CNS
lymorbidity and utility of brain biopsy. J Neurol Sci 163, 32-8
Sparano JA (2001) Clinical
aspects and management of AIDS-related lymphoma. Eur J Cancer 37, 1296-305
Sparano JA,
Anand K, Desai J, et al (1999) Effect of highly active
antiretroviral therapy on the incidence of HIV-associated malignancies at an
urban medical center. J AIDS 21 Suppl 1, S18-22
Terriff BA, Harrison
P, Holden JK (1992) Apparent spontaneous regression of primary CNS
lymphoma mimicking resolving toxoplasmosis. J AIDS 5, 953-954
Vaccher E, Spina
M, di Gennaro G, Talamini R, Nasti G, Schioppa O, Vultaggio G, Tirelli U (2001) Concomitant
cyclophosphamide, doxorubicin and prednisone chemotherapy plus highly active
antiretroviral therapy in patients with human immunodeficiency virus-related
non-Hodgkin lymphoma. Cancer 91, 155-163