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Abramson Cancer Center
NCI CANCERLIT® Search: Therapy of Non-Hodgkin's Lymphoma - March 2002
National Cancer Institute®
Last Modified: March 1, 2002
Table of Contents
1
UI - 11843810
AU - Chau I; Webb A; Cunningham D; Hill M; Rao S; Ageli S; Norman A; Gill K;
TI -
Howard A; Catovsky D
An oxaliplatin-based chemotherapy in patients with relapsed or
refractory intermediate and high-grade non-Hodgkin's lymphoma.
SO - Br J Haematol 2001 Dec;115(4):786-92
AD - Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton,
Surrey SM2 5PT, UK.
This study was designed to assess the efficacy and safety of
substituting cisplatin with oxaliplatin in the DHAP (dexamethasone,
cytarabine and cisplatin) regimen for patients with relapsed or
refractory non-Hodgkin's lymphoma. Twenty-four evaluable patients with
intermediate or high-grade non-Hodgkin's lymphoma were treated at
3-weekly intervals with oxaliplatin (130 mg/m2, d 1), cytarabine (2 g/m2
for two doses, d 2) and dexamethasone (40 mg, d 1-4). The median age of
the patients was 58 (range 18-70). Histological subtypes were diffuse
large B cell, 20; mantle cell, two; anaplastic large cell, one; and
peripheral T cell, one. The overall objective response rate (RR) was 50%
[95% confidence interval (CI) = 29-71%] including four complete
responses and eight partial responses. RR for those patients treated at
first relapse was higher than those treated at second and subsequent
relapse (77% versus 29%). Grade 3 and 4 toxicity was mainly
haematological: anaemia 17%, neutropenia 75% and thrombocytopenia 75%.
No grade 4 non-haematological toxicity was reported. No significant
renal and neurotoxicity was demonstrated. Median survival was 10.6
months. Probabilities of 1-year progression-free survival and overall
survival were 47% (95% CI = 26-66%) and 50% (95% CI = 23-72%)
respectively. In conclusion, dexamethasone, cytarabine and oxaliplatin
(DHAX) is a novel combination in salvage therapy for relapsed or
refractory non-Hodgkin's lymphoma. It has clinically significant
activity with an acceptable toxicity profile. Lack of renal toxicity
makes DHAX an attractive cytoreductive regimen before high-dose
chemotherapy.
2
UI - 11806987
AU - Rambaldi A; Lazzari M; Manzoni C; Carlotti E; Arcaini L; Baccarani M;
TI -
Barbui T; Bernasconi C; Dastoli G; Fuga G; Gamba E; Gargantini L; Gattei
V; Lauria F; Lazzarino M; Mandelli F; Morra E; Pulsoni A; Ribersani M;
Rossi-Ferrini PL; Rupolo M; Tura S; Zagonel V; Zaja F; Zinzani P; Reato
G; Foa R
Monitoring of minimal residual disease after CHOP and rituximab in
previously untreated patients with follicular lymphoma.
SO - Blood 2002 Feb 1;99(3):856-62
AD - Divisione di Ematologia, Ospedali Riuniti Bergamo, Largo Barozzi 1,
24100 Bergamo, Italy. arambaldfi@ospedaliriuniti.bergamo.it
Minimal residual disease (MRD) following sequential administration of
CHOP and rituximab was studied in previously untreated patients with
follicular lymphoma. At diagnosis, the presence of Bcl-2/IgH-positive
cells in the peripheral blood (PB) and/or bone marrow (BM) was
demonstrated in all patients (n = 128) by polymerase chain reaction
(PCR) analysis. Patients who achieved a clinical response following CHOP
but remained PCR-positive were eligible for rituximab (375 mg/m(2)
intravenously, weekly for 4 weeks). After CHOP, 57% achieved a complete
response (CR), 37% a partial response (PR), and 6% were nonresponders
(NR). At this stage, patients proving PCR-negative (n = 41) or failing
to achieve a clinical response (n = 8) were excluded from rituximab
treatment. Seventy-seven patients received rituximab and entered a
scheduled MRD follow-up program. At the first molecular follow-up (+12
weeks), 59% had converted to PCR negativity in the BM and PB, with a
further increase documented at the second control (+28 weeks) with 74%
PCR negative. At the last molecular follow-up (+44 weeks), 63% of the
patients remained PCR negative. At 3 years, the estimated overall
survival of all patients is 95% (95% confidence interval [CI], 86-98).
For patients achieving PCR-negative status following CHOP and therefore
excluded from rituximab treatment, freedom from recurrence (FFR) was 52%
(95% CI, 28-71). For patients treated with rituximab, a durable
PCR-negative status was associated with a better clinical outcome since
FFR was 57% (95% CI, 23-81) compared with 20% (95% CI, 4-46) in patients
who never achieved or lost the molecular negativity (P <.001).
3
UI - 11830549
AU - Vrana JA; Bieszczad CK; Cleaveland ES; Ma Y; Park JP; Mohandas TK; Craig
TI -
RW
An MCL1-overexpressing Burkitt lymphoma subline exhibits enhanced
survival on exposure to serum deprivation, topoisomerase inhibitors, or
staurosporine but remains sensitive to
1-beta-D-arabinofuranosylcytosine.
SO - Cancer Res 2002 Feb 1;62(3):892-900
AD - Department of Pharmacology, Dartmouth Medical School, Hanover, New
Hampshire 03755-3835, USA.
Members of the BCL2 gene family influence cell viability and can,
therefore, affect the susceptibility of cancer cells to multiple
chemotherapeutic agents. Thus, it is a challenge to devise approaches
for inducing the death of tumor cells in which the expression of
prosurvival family members is elevated or deregulated. BL41-3, a
spontaneously derived subline of BL41 Burkitt lymphoma cells, was found
to have amplified the prosurvival MCL1 gene (3-fold) and overexpressed
the MCL1 protein. The level of MCL1 protein was 5-fold elevated compared
with ML-1 cells expressing maximal MCL1 on exposure to
phorbol-12-myristate-13- acetate. To assess whether this increase in
MCL1 expression was associated with enhanced protection from cell death,
cells were exposed to conditions of growth factor deprivation or to
various cytotoxic agents. Whereas BL41-3 and BL41 cells exhibited
similar growth rates in logarithmic phase, BL41-3 cells remained largely
viable on reaching saturation phase in contrast to BL41 cells, which
began to die. Similarly, the BL41-3 subline remained viable for an
extended period under conditions of reduced serum. BL41-3 cells were
also more resistant to the apoptosis-inducing effects of etoposide,
camptothecin, and staurosporine (>3-fold more than BL41 cells).
Unexpectedly, these cells exhibited enhanced sensitivity to
1-beta-D-arabinofuranosylcytosine, but only on exposure for an extended
period (>10-fold more sensitive than BL41 cells with a 24-h but not a
6-h exposure). Thus, whereas cells expressing prosurvival BCL2 family
members are frequently resistant to a variety of chemotherapeutic
agents, the findings presented here, using a cell line exhibiting
amplification and overexpression of MCL1, indicate that such cells may
exhibit increased sensitivity to certain chemotherapeutic regimens.
4
UI - 11773279
AU - Esteller M; Gaidano G; Goodman SN; Zagonel V; Capello D; Botto B; Rossi
TI -
D; Gloghini A; Vitolo U; Carbone A; Baylin SB; Herman JG
Hypermethylation of the DNA repair gene O(6)-methylguanine DNA
methyltransferase and survival of patients with diffuse large B-cell
lymphoma.
SO - J Natl Cancer Inst 2002 Jan 2;94(1):26-32
AD - Division of Cancer Biology, The Johns Hopkins Oncology Center,
Baltimore, MD 21231, USA.
BACKGROUND: The gene encoding the DNA repair enzyme O(6)-methylguanine
DNA methyltransferase (MGMT) is transcriptionally silenced by promoter
hypermethylation in several human cancers, including diffuse large
B-cell lymphoma (B-DLCL). MGMT promoter hypermethylation is a favorable
prognostic marker in patients with brain tumors treated with alkylating
agents. METHODS: In a retrospective cohort study, we used
methylation-specific polymerase chain reaction to analyze the MGMT
promoter methylation status in tumor DNA of B-DLCL patients receiving
cyclophosphamide as part of multidrug regimens. Molecular data were
compared with patient response with the use of Student's t test.
Disease-free survival and overall survival were estimated by the
Kaplan-Meier method and compared with the use of the log-rank test.
Multivariable survival analyses were performed with the Cox proportional
hazards model. All statistical tests were two-sided. RESULTS: Thirty
(36%) of 84 B-DLCL patients showed MGMT promoter hypermethylation in
their lymphomas. The presence of MGMT methylation was associated with a
statistically significant increase in overall survival (hazard ratio for
time to death for nonmethylation versus methylation = 2.8; 95%
confidence interval (CI) = 1.2 to 7.5; P =.01) and progression-free
survival (hazard ratio for time to progression for nonmethylation versus
methylation = 2.6; 95% CI = 1.3 to 5.8; P =.02). MGMT promoter
hypermethylation was both independent of and stronger than established
prognostic factors, such as age, disease stage, serum lactic
dehydrogenase level, and performance status. CONCLUSION: MGMT promoter
hypermethylation appears to be a useful marker for predicting survival
in patients with B-DLCL treated with multidrug regimens including
cyclophosphamide.
5
UI - 11823692
AU - Briggs JH; Algan O; Miller TP; Oleson JR
TI -
External beam radiation therapy in the treatment of patients with
extranodal stage IA non-Hodgkin's lymphoma.
SO - Am J Clin Oncol 2002 Feb;25(1):34-7
AD - Department of Radiation Oncology, University of Arizona Cancer Center,
1501 North Campbell Avenue, Tucson, AZ 85724, U.S.A.
The purpose of this report was to study the results of external beam
radiotherapy for patients with extranodal stage IA non-Hodgkin's
lymphoma (NHL). A retrospective review was carried out on 27 patients
seen between 1984 and 1998 with stage IA NHL of extranodal sites, and
followed up for a minimum of 1 year. Sites involved included eye/orbit
(seven), parotid (five), breast (four), Waldeyer ring (four), thyroid
(three), other head and neck (two), stomach (one), and prostate (one).
All patients had biopsy-proven disease and underwent staging workup to
rule out other sites of disease. Histologic analysis revealed 16
patients with low-grade NHL, 9 with intermediate-grade, and 2 with
high-grade. Ten patients received chemotherapy before radiation therapy,
and eight of them had a complete response. The remaining 17 patients
were treated with external beam radiation therapy alone. Radiation was
directed to the involved field at 1.8 Gy to 2.0 Gy per fraction to a
median dose of 40 Gy (range: 20-50.4 Gy). The median patient age was 71
years (range: 39-85 years); 55% were female, and 45% were male. A
complete response was attained in all 27 patients after radiation
therapy. There were five failures (all in uninvolved distant sites), and
two deaths during the follow-up. Median disease free survival (DFS) and
overall survival (OS) have not been reached. The 5-year DFS and OS are
85% and 94%, respectively. Older age at presentation showed a trend
toward worse outcome (p = 0.07), but because of the relatively few
events, other factors (radiation dose, grade of disease, sex, or the use
of chemotherapy) showed no statistical differences among the patients.
External beam radiation therapy is a highly effective treatment for
stage IA NHL found in extranodal sites.
6
UI - 11876162
AU - Anonymous
TI -
Current and ongoing clinical development of immunotherapy in B-cell
Hawaii, USA.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):1-112; quiz 113-21
7
UI - 11842397
AU - Grillo-Lopez AJ; Hedrick E; Rashford M; Benyunes M
TI -
Rituximab: ongoing and future clinical development.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):105-12
AD - Antonio J. Grillo-Lopez, Consultant Clinical Research and Regulatory
Strategy, Genentech, Inc, South San Francisco, CA 94080-4990, USA.
Monoclonal antibodies have been used as therapeutic agents for many
years. In 1997, rituximab (Rituxan; Genentech, Inc, South San Francisco,
CA, and IDEC Pharmaceuticals, San Diego, CA) became the first monoclonal
antibody to be approved by the US Food and Drug Administration for a
cancer indication. The use of rituximab in the treatment of low-grade or
follicular, relapsed, or refractory CD20-positive B-cell non-Hodgkin's
European Union countries under the trade name MabThera as therapy for
patients with stage III/IV, follicular, chemoresistant, or relapsed (>
or = 2 relapses) non-Hodgkin's lymphoma. To date, rituximab has been
approved in 56 countries. Over 125,000 patients have been treated with
this antibody in the United States alone. Rituximab served to heighten
interest in the therapeutic applications of monoclonal antibodies.
Literally dozens of antibodies are currently under investigation for a
variety of malignant and non-neoplastic indications. The US Food and
Drug Administration approved a new (revised) package insert in early
2001. These revisions have been communicated to physicians via a "Dear
Doctor Letter" and will appear in the 2002 edition of the Physicians'
Desk Reference. A significant amount of clinical research has been
performed over the past 9 years, which has served to further our
understanding of the potential clinical applications for this novel
therapeutic agent. Ongoing and future clinical trials are reviewed in
this article. However, much remains to be accomplished in key areas such
as combinations with chemotherapy, biologics (including other
antibodies), and radiotherapy/radioimmunotherapy; its role within
multimodality regimens; and other malignant (beyond low-grade
non-Hodgkin's lymphoma) and nonmalignant applications. Copyright 2002 by
W.B. Saunders Company.
8
UI - 11842385
AU - Hainsworth JD
TI -
Rituximab as first-line and maintenance therapy for patients with
indolent non-Hodgkin's lymphoma: interim follow-up of a multicenter
phase II trial.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):25-9
AD - Sarah Cannon Cancer Center, Centennial Medical Center, Nashville, TN.
The purpose of this study is to evaluate the activity of rituximab
(Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC
Pharmaceuticals, San Diego, CA) in the first-line treatment of patients
with indolent non-Hodgkin's lymphoma, and to evaluate the role of
scheduled maintenance courses of rituximab in prolonging duration of
remission. Sixty-two patients with stages II to IV indolent
non-Hodgkin's lymphoma (follicular or small lymphocytic) who had
received no previous systemic therapy entered this multicenter,
community-based trial. All patients received rituximab 375 mg/m(2)
weekly for 4 consecutive weeks, and were evaluated for response at week
6. Patients who had an objective response or stable disease continued
treatment every 6 months with repeat 4-week courses of rituximab for a
total of four treatment courses. Interim results of this ongoing trial
are available. When evaluated at week 6, 28 of 60 evaluable patients
(47%) had objective response and 27 patients (45%) had minor response or
stable disease. With further follow-up and repeat courses of rituximab,
the major response rate increased from 47% to 65% and the complete
response rate increased from 7% to 27%. Response rates were similar in
patients with follicular lymphoma and small lymphocytic lymphoma (63%
and 66%, respectively). Median progression-free survival has not been
reached, but will be greater than 24 months. There has been no
cumulative toxicity observed with repeat courses of rituximab. Rituximab
is highly effective as a first-line single agent for the treatment of
indolent non-Hodgkin's lymphoma. The initial response rate can be
improved by using scheduled maintenance courses of rituximab
administered every 6 months. Final information regarding duration of
response and time to progression awaits further follow-up. Copyright
2002 by W.B. Saunders Company.
9
UI - 11842386
AU - Coiffier B
TI -
Rituximab in the treatment of diffuse large B-cell lymphomas.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):30-5
AD - Hospices Civils de Lyon and Universite Claude Bernard, Lyon, France.
A review of the use of rituximab (Rituxan; Genentech, Inc, South San
Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) in diffuse large
B-cell lymphomas is presented, focusing on the recent presentation of
the combination of CHOP
(cyclophosphamide/doxorubicin/vincristine/prednisone) plus rituximab in
elderly patients. This combination increased the response rates,
event-free survival, and overall survival of patients older than 60
years in comparison with CHOP alone. The toxic events observed with the
combination were not more numerous or severe than those observed with
CHOP alone. Rituximab is a chimeric anti-CD20 antibody that increases
the treatment options in patients with B-cell lymphomas. Copyright 2002
by W.B. Saunders Company.
10
UI - 11842387
AU - Czuczman MS; Fallon A; Mohr A; Stewart C; Bernstein ZP; McCarthy P;
TI -
Skipper M; Brown K; Miller K; Wentling D; Klippenstein D; Loud P; Rock
MK; Benyunes M; Grillo-Lopez AJ; Bernstein SH
Rituximab in combination with CHOP or fludarabine in low-grade lymphoma.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):36-40
AD - Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Non-Hodgkin's lymphoma (NHL) is composed of a group of lymphoid
malignancies that has been increasing in incidence at an annual rate of
4% to 7% over the last 20 years in both the United States and Europe.
The reasons for this rise in incidence in NHL are not yet defined but
most likely involve environmental exposures. Low-grade and follicular
lymphomas account for approximately 40% of the incidences of NHL in the
United States. While patients with intermediate- and high-grade
lymphomas are potentially curable with combination chemotherapy,
low-grade and follicular lymphomas are still considered to be
essentially incurable with standard therapy. Although low-grade
lymphomas characteristically respond well to treatment with
chemotherapeutic agents, the disease typically follows a course of
recurrent relapse and progressively shorter remissions, and ultimately
death from lymphoma. Median survival for patients with low-grade
lymphoma is 6.2 years from diagnosis and just 5 years from time of first
relapse. Therefore, novel therapeutic strategies are urgently needed for
these patients. One approach to the development of innovative strategies
for treatment of NHL has been the generation of monoclonal antibodies to
specific B-cell antigens expressed on NHL cells. Copyright 2002 by W.B.
Saunders Company.
11
UI - 11842388
AU - Wilson WH; Gutierrez M; O'Connor P; Frankel S; Jaffe E; Chabner BA;
TI -
Grossbard ML
The role of rituximab and chemotherapy in aggressive B-cell lymphoma: a
preliminary report of dose-adjusted EPOCH-R.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):41-7
AD - Center for Cancer Research, National Cancer Institute, Bethesda, MD
20892, USA.
Accumulating evidence suggests that the ability to activate apoptotic
pathways may be an important determinant of chemotherapy sensitivity and
presents a potentially important new therapeutic strategy. Monoclonal
antibodies against the CD20 antigen directly induce apoptosis and may
serve to modulate the threshold for chemotherapy-induced apoptosis.
Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC
Pharmaceuticals, San Diego, CA), a monoclonal antibody against CD20, was
combined with dose-adjusted EPOCH (infusional
etoposide/vincristine/doxorubicin/bolus cyclophosphamide/prednisone)
chemotherapy and tested in 38 untreated or relapsed poor-prognosis
aggressive lymphomas. Twenty-three patients were untreated. Of these
patients, all had large B-cell histologies, a median age of 52 years,
Eastern Cooperative Oncology Group performance status > or = 2 in 30%,
and high-intermediate or high International Prognostic Index scores in
61%. Fifteen patients had relapsed or refractory lymphomas. These
patients had received a median of two (range, one to four) prior
regimens, 67% had aggressive histologies, and 60% had high-intermediate
or high International Prognostic Index scores. Complete remissions were
achieved in 85% and 64% of untreated and previously treated patients,
respectively; additionally 42% of patients with disease refractory
before therapy achieved complete remission. At a median follow-up of 12
months, progression-free and overall survival in the previously
untreated group was 85% and 79%, respectively, and no patient in
complete remission has relapsed. These results suggest that rituximab
may modulate the sensitivity of B-cell lymphomas to chemotherapy.
12
UI - 11842389
AU - Sarris AH; Jiang Y; Tsimberidou AM; Thomaides A; Rassidakis GZ; Ford RJ;
TI -
Medeiros LJ; Cabanillas F; McLaughlin P
Quantitative real-time polymerase chain reaction for monitoring minimal
residual disease in patients with advanced indolent lymphomas treated
with rituximab, fludarabine, mitoxantrone, and dexamethasone.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):48-55
AD - Department of Lymphoma and Myeloma, The University of Texas M. D.
Anderson Cancer Center, Houston, TX 77030, USA.
Fludarabine and rituximab (Rituxan; Genentech, Inc, South San Francisco,
CA, and IDEC Pharmaceuticals, San Diego, CA) are active against indolent
lymphomas. We have previously shown the safety and efficacy of the
combination of FND (fludarabine/mitoxantrone/dexamethasone) in relapsed
and subsequently untreated patients with stage IV indolent lymphomas.
Currently, we treat patients with stage IV indolent lymphomas who are
previously untreated, younger than 60 years, human immunodeficiency
virus-negative, and have adequate organ and marrow function with FND and
random assignment to concurrent or delayed administration of rituximab.
We have developed a quantitative real-time polymerase chain reaction
assay for t(14;18). With 1 microg of DNA, this assay detects 0.6 copies
in 55% of reactions, as expected for the Poisson distribution. When
1microg of DNA was analyzed in duplicate, cells with the t(14;18) were
detected in peripheral blood of 22% of 152 volunteer blood donors.
Quantitation showed that numbers of t(14;18) cells were higher than the
statistical upper normal limit (mean of all volunteer values plus
standard deviations) in 2% of volunteer blood donors. By contrast, 36%
of blood or marrow specimens from follicular lymphoma patients were
positive, and the number of cells with t(14;18) was higher than the
normal upper limit in 26%. The presence of cells with t(14;18) and their
numbers are prospectively quantitated in blood and marrow of patients
treated with FND plus rituximab to determine their clinical significance
both at presentation and during therapy. Copyright 2002 by W.B. Saunders
Company.
13
UI - 11842393
AU - Leonard JP; Link BK
TI -
Immunotherapy of non-Hodgkin's lymphoma with hLL2 (epratuzumab, an
anti-CD22 monoclonal antibody) and Hu1D10 (apolizumab).
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):81-6
AD - Center for Lymphoma and Myeloma and Division of Hematology/Oncology,
Weill Medical College of Cornell University and New York Presbyterian
Hospital, New York, NY 10021, USA.
Clinical activity of anti-CD20 monoclonal antibodies both in the
unlabeled (rituximab [Rituxan; Genentech, Inc, South San Francisco, CA,
and IDEC Pharmaceuticals, San Diego, CA]) and radiolabeled forms, as
well as radioimmunoconjugates targeting other antigens, has resulted in
the exploration of alternative targets for immunotherapeutic strategies
in lymphoma. We report on the rationale for and initial efforts in the
development of two unlabeled, humanized monoclonal antibodies directed
against molecules commonly expressed in B-cell malignancies. hLL2
(epratuzumab; Immunomedics, Inc, Morris Plains, NJ) binds to the CD22
antigen, while Hu1D10 (apolizumab; Protein Design Labs, Inc, Fremont,
CA) reacts with a polymorphism on the HLA-DR beta chain. Preclinical
studies and early clinical evaluations suggest that these agents have a
potential role as novel therapeutic targets for lymphoma with acceptable
toxicity profiles. Further efforts will explore optimal clinical
settings for their use, as well as define treatment regimens either as
single agents or in combination with chemotherapy or other biologics.
Copyright 2002 by W.B. Saunders Company.
14
UI - 11842394
AU - Gordon LI; Witzig TE; Wiseman GA; Flinn IW; Spies SS; Silverman DH;
TI -
Emmanuolides C; Cripe L; Saleh M; Czuczman MS; Olejnik T; White CA;
Grillo-Lopez AJ
Yttrium 90 ibritumomab tiuxetan radioimmunotherapy for relapsed or
refractory low-grade non-Hodgkin's lymphoma.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):87-92
AD - Division of Hematology/Oncology, Department of Medicine, Northwestern
University Medical School and the Robert H. Lurie Comprehensive Cancer
Center of Northwestern University, Chicago, IL 60611-2927, USA.
The treatment of malignant lymphoma has improved over the past 20 years,
but the majority of patients are not cured. New modalities using
targeted therapy based on new information in molecular biology and
immunology hold promise for better outcomes with less toxicity. We
review data on the use of radiolabeled monoclonal antibodies directed
against the CD20 antigen on malignant B cells. We discuss the major
radionuclides available, iodine 131 ((131)I), tositumomab, and yttrium
90 ((90)Y) ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals, San
Diego, CA) and present data on new approaches in labeling antibodies
that have facilitated their use. Clinical trial data with the
yttrium-labeled antibodies are discussed. The use of dosimetry as a
means for predicting toxicity is discussed, and the questions of
long-term toxicity (late effects) are addressed. These targeted
approaches to the treatment of malignancy, and lymphoma in particular,
hold great promise. Copyright 2002 by W.B. Saunders Company.
15
UI - 11842396
AU - Kipps TJ
TI -
Advances in classification and therapy of indolent B-cell malignancies.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):98-104
AD - Department of Medicine, University of California, San Diego School of
Medicine, La Jolla, CA 92093, USA.
Advances in our understanding of normal B-cell differentiation have
allowed for improved classification and therapy of B-cell malignancies.
B-cell neoplastic diseases may be classified more accurately according
to the differentiation stages of presumed normal B-cell counterparts.
These advances have challenged the notion that chronic lymphocytic
leukemia represents a malignancy of naive CD5 B cells. Analyses of
immunoglobulin genes and gene expression patterns through microarray
have defined at least two types of chronic lymphocytic leukemia that
differ in their tendency toward disease progression. Nevertheless, these
types still share more in common than they do with other lymphoid
malignancies, and both may be derived from memory-type B cells. Advances
in immune therapy are revolutionizing the approach to therapy. B-cell
surface differentiation antigens constitute tissue-specific targets for
passive immune therapy. Since the US Food and Drug Administration
approval of rituximab (Rituxan; Genentech, Inc, South San Francisco, CA,
and IDEC Pharmaceuticals, San Diego, CA) for use in the treatment of
follicular lymphoma, monoclonal antibody therapy is being considered for
all types of B-cell malignancies. The ability to transform leukemia and
lymphoma B cells into effective antigen-presenting cells through CD40
ligation allows for autologous immune recognition of neoplastic cells.
Together, active and passive immune approaches have potential for
effective treatment of patients with these diseases. Copyright 2002 by
W.B. Saunders Company.
16
UI - 11857288
AU - Seymour JF; Grigg AP; Szer J; Fox RM
TI -
Cisplatin, fludarabine, and cytarabine: a novel, pharmacologically
designed salvage therapy for patients with refractory, histologically
aggressive or mantle cell non-Hodgkin's lymphoma.
SO - Cancer 2002 Feb 1;94(3):585-93
AD - Department of Hematology, The Peter MacCallum Cancer Institute, East
Melbourne, Victoria, Australia. jseymour@petermac.unimelb.edu.au
BACKGROUND: Based on in vitro synergism, the combination of cytarabine
(ara-C) and cisplatin is the basis of many salvage regimens for patients
with aggressive non-Hodgkin lymphoma (NHL). However, patients with
previously refractory disease are significantly less likely to respond,
stimulating the search for novel salvage regimens. In vitro, fludarabine
enhances the cytotoxicity of both ara-C and cisplatin, increasing ara-C
incorporation into DNA and inhibiting repair of platinum/DNA adducts,
suggesting that the combination of cisplatin, fludarabine, and ara-C
(PFA) may have clinical utility. METHODS: A Phase-II study of a 96 hour
continuous infusion of cisplatin with two timed-sequential couplets of
fludarabine and ara-C together with granulocyte colony stimulating
factor was performed in 45 patients with previously refractory,
histologically aggressive or mantle cell NHL. RESULTS: Patients had
predominantly diffuse large cell and/or immunoblastic NHL or its
variants (80%), or they had mantle cell lymphoma (18%). Overall, 93% of
patients had previously refractory disease, with a median International
Prognostic Index score of 3. A median of 2 cycles per patient were
delivered (range, 1-4 cycles) with significant myelosuppression; there
were medians of 2 days of neutropenia < 0.5 x 10(9)/L (range, 0-12 days)
and 3 days of thrombocytopenia < 20 x 10(9)/L (range, 0-24 days). This
was more severe in older patients and was cumulative with successive
cycles. Thirty-five percent of cycles were complicated by infections,
nausea and emesis were prominent, but other nonhematologic toxicity was
mild. Peripheral blood progenitor cells were mobilized adequately after
the first cycle, but collections were impaired after more prolonged
therapy. The overall response rate was 48% (7% of patients had complete
responses, and 41% of patients had partial responses), with one toxic
death due to tumor-lysis syndrome. Patients with mantle cell lymphoma
were more likely to respond than patients with other histologies (88%
vs. 39%, respectively; P = 0.019), although three of eight patients had
relapsed rather than refractory disease. The median remission duration
was 4 months, with 28% of potentially eligible patients able to proceed
to subsequent high dose therapy. The actuarial 2 year survival rates
were 20% +/- 6% overall and 50 +/- 18% for patients with mantle cell
lymphoma. CONCLUSIONS: Given the adverse outlook for these patients, the
results are promising, particularly for patients with mantle cell
lymphoma, and suggest that the addition of fludarabine as a potential
biochemical modulator may enhance the activity of cisplatin and ara-C.
This is associated with significant cumulative (but manageable)
myelosuppression. This paradigm, in which a nucleoside analogue is used
to inhibit the repair of platinum/DNA adducts, also may be applicable
for the treatment of patients with other types of platinum-sensitive
tumors. Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10240
17
UI - 11857289
AU - Sugiyama K; Omachi K; Fujiwara K; Saotome T; Mizunuma N; Takahashi S;
TI -
Ito Y; Aiba K; Horikoshi N
Irinotecan hydrochloride for the treatment of recurrent and refractory
non-Hodgkin lymphoma: a single institution experience.
SO - Cancer 2002 Feb 1;94(3):594-600
AD - Department of Medical Oncology, Cancer Institute Hospital, Japanese
Foundation for Cancer Research, Tokyo, Japan.
BACKGROUND: Irinotecan hydrochloride (CPT-11) has a broad range of
antitumor activity and has demonstrated little cross-resistance with
doxorubicin or vincristine. In the current study, the authors
investigated the efficacy and adverse effects of irinotecan in the
treatment of recurrent and refractory non-Hodgkin lymphoma, for which
current therapies appear to be unsatisfactory. METHODS: Irinotecan was
administered by intravenous infusion at a dose of 40 mg/m(2)/day for 3
days, and this regimen was repeated 2-3 times at weekly intervals,
followed by 2 weeks off therapy. The subjects were 48 patients with
recurrent or refractory non-Hodgkin lymphoma. The histologic
classification (Working Formulation) was low grade in 8 patients,
intermediate grade in 36 patients, high grade in 1 patient, and other
(angiocentric lymphoma, Ki-1 lymphoma, and unidentified) in 3 patients.
RESULTS: Forty-five patients were determined to be evaluable. Therapy
resulted in a complete disease remission in 2 patients and a partial
remission in 15 patients. The response rate was 37.8%. The median
duration of response was 64 days and the median time to disease
progression was 77 days. The median survival time was 422 days. Major
adverse reactions included myelosuppression and gastrointestinal
toxicity. Leukopenia, anemia, and thrombocytopenia of Grade 3 or 4
(according to the National Cancer Institute Common Toxicity Criteria)
was observed in 63.0%, 30.4%, and 6.5% of the patients, respectively,
and Grade 3 or 4 diarrhea occurred in 30.4% of patients. Treatment was
withdrawn because of diarrhea in three patients. Because of
myelosuppression and diarrhea, approximately 67% of the patients
required changes to the regimen, including dose reduction, prolongation
of the interval between treatments, and reducing the number of days of
consecutive treatment. CONCLUSIONS: The results of the current study
suggest the activity of irinotecan as salvage therapy for patients with
recurrent and refractory non-Hodgkin lymphoma. However, the optimum
dosing schedule remains to be determined. Copyright 2002 American Cancer
Society. DOI 10.1002/cncr.10266
18
UI - 11857290
AU - Wilder RB; Romaguera JE; Tucker SL; Ha CS; Hess MA; Cabanillas F; Cox JD
TI -
Results with chemotherapy comprised of cyclophosphamide, doxorubicin,
vincristine, and prednisone followed by radiotherapy with or without
prechemotherapy surgical debulking for patients with bulky, aggressive
lymphoma.
SO - Cancer 2002 Feb 1;94(3):601-5
AD - Department of Radiation Oncology, The University of Texas M. D. Anderson
Cancer Center, Houston, Texas 77030-4009, USA. rwilder@mdanderson.org
BACKGROUND: The authors performed a case-control analysis of local
control, progression free survival, and overall survival in patients
with Stage I-II aggressive lymphomas measuring > or = 7 cm in greatest
dimension who were treated initially with or without surgical debulking:
All patients then received cyclophosphamide, doxorubicin, vincristine,
and prednisone (CHOP) based chemotherapy followed by involved field
treated with (n = 25 patients) or without (n = 25 patients) resection of
> 80% of their bulky lymphomas. Chemotherapy consisted of 3-12 cycles of
CHOP. In general, patients who underwent debulking received three cycles
of chemotherapy, whereas patients who did not undergo debulking received
at least six cycles of chemotherapy. The total radiotherapy dose was
40.8 grays (Gy) +/- 4.2 Gy (mean +/- standard deviation). RESULTS: The
median follow-up was 62 months. Patients who underwent debulking were
similar prognostically to patients who did not. There was a trend toward
improved local control (5 year rates: 96% vs. 80%; P = 0.10) and overall
survival (5 year rates: 83% vs. 71%; P = 0.18) in patients who underwent
debulking compared with patients who did not, respectively. Progression
free survival was significantly better for patients who underwent
debulking compared with patients who did not (5 year rates: 88% vs. 62%,
respectively; P = 0.04). CONCLUSIONS: Because this study was
retrospective, selection bias may account for the observed difference in
progression free survival. Because it is unlikely that a trial
randomizing patients with bulky, aggressive lymphoma to surgery will be
conducted, the authors' current efforts are focused on escalation of the
total radiotherapy dose as a possibly less costly and less morbid
approach toward improving progression free survival for these patients.
Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10260
19
UI - 11877754
AU - Koral KF; Francis IR; Kroll S; Zasadny KR; Kaminski MS; Wahl RL
TI -
Volume reduction versus radiation dose for tumors in previously
untreated lymphoma patients who received iodine-131 tositumomab therapy.
Conjugate views compared with a hybrid method.
SO - Cancer 2002 Feb 15;94(4 Suppl):1258-63
AD - University of Michigan Medical Center, Ann Arbor, Michigan 48109-0552,
USA. kenkoral@umich.edu
BACKGROUND: A Phase II study of previously untreated patients with
malignant low grade follicular lymphoma given a combination of unlabeled
tositumomab and tositumomab labeled with iodine-131 has recently been
completed. The responses of these patients have been characterized, and
for some of them tumor dosimetry during therapy has been estimated not
only by pretherapy tracer conjugate views but also by a hybrid method.
METHODS: Available patients were studied if they had had a pelvic or
abdominal tumor evaluation by single photon emission computed tomography
(SPECT) and achieved a partial response. A tumor outlined on the
iodine-131 conjugate-view images was called a composite tumor. Its
volume estimate came from multiple, not necessarily contiguous, regions
of interest (ROI) on the pretherapy computed tomography (CT) scan. Its
radiation dose was estimated from the weeklong series of pretherapy
images and standard Medical Internal Radiation Dose methods. Computed
tomography ROI were also grouped into smaller, contiguous volumes that
defined individual tumors. Their radiation doses were estimated by the
hybrid method. This method employed the activity measured for each
individual tumor by a single intratherapy SPECT scan, as well as the
tumor's volume, to individually normalize the composite time-activity
curve as appropriate. The individual normalization factors then
converted the composite radiation dose to radiation doses for individual
tumors. Reduction in tumor volume was calculated for both composite and
individual tumors at 12 weeks posttherapy. RESULTS: For 14 composite
tumors in 10 patients, the median pretherapy volume was 170 cm(3).
Application of a sigmoidal curve function to the plot of volume
reduction versus radiation absorbed dose resulted in degeneration of the
curve into a straight line with a negative slope. There was no
statistical significance in the relationship (P = 0.73). For 43
individual tumors, the median pretherapy tumor volume was 26 cm(3). The
plot of volume reduction versus dose was fairly well fit by a sigmoidal
curve, and the relationship approached statistical significance (P =
0.06). The representation assigned 56% of the shrinkage to the effects
of unlabeled tositumomab. For the subset of individual tumors with a
pretherapy volume less than 10 cm(3) from 6 patients (n = 15), the
relationship was significant (P = 0.03). The sigmoidal representation
assigned only 12% of the shrinkage to unlabeled tositumomab, as
contrasted with 72% for tumors with pretherapy volume greater than 10
cm(3). CONCLUSIONS: For patients who attained a partial response,
analysis of individual tumors by a hybrid dosimetric method led to a
dependence between volume reduction at 12 weeks and radiation dose that
tended to be significant. The same was not true with dosimetry of
composite tumors based on pretherapy conjugate views alone. It appeared
that volume reductions from both unlabeled antibody and radiation dose
were important in tositumomab therapy of lymphoma patients, with
unlabeled antibody relatively more important for larger tumors.
Copyright 2002 American Cancer Society.
20
UI - 11877765
AU - Wiseman GA; Leigh B; Erwin WD; Lamonica D; Kornmehl E; Spies SM;
TI -
Silverman DH; Witzig TE; Sparks RB; White CA
Radiation dosimetry results for Zevalin radioimmunotherapy of
rituximab-refractory non-Hodgkin lymphoma.
SO - Cancer 2002 Feb 15;94(4 Suppl):1349-57
AD - Division of Nuclear Medicine, Mayo Clinic and Mayo Foundation,
Rochester, Minnesota 55905, USA. gwiseman@mayo.edu
BACKGROUND: Zevalin consists of a murine anti-CD20 monoclonal antibody
(ibritumomab) conjugated to the linker-chelator tiuxetan, which securely
chelates indium-111 ((111)In) for imaging and dosimetry and yttrium-90
((90)Y) for radioimmunotherapy (RIT). Previous trials involving
rituximab-naive patients have demonstrated excellent targeting of
Zevalin to CD20+ B-cell non-Hodgkin lymphoma with minimal uptake in
normal organs. The purpose of this trial was to perform (111)In-Zevalin
imaging in patients with rituximab-refractory tumors to determine normal
organ dosimetry. METHODS: Twenty-seven patients were given an imaging
dose of 5 mCi (185 MBq) (111)In-Zevalin on Day 0, evaluated with
dosimetry, and then given a therapeutic dose of 0.4 mCi/kg (15 MBq/kg)
(90)Y-Zevalin on Day 7. Both Zevalin doses were preceded by an infusion
of 250 mg/m(2) rituximab to clear peripheral B cells and improve Zevalin
biodistribution. Residence times for (90)Y in blood and major organs
were estimated from (111)In biodistribution, and the MIRDOSE3 computer
software program was used to calculate absorbed radiation doses to
organs and red marrow. RESULTS: Median estimated absorbed radiation
doses from (90)Y-Zevalin were 8.1 Gray (Gy) (range, 4.2-23.0 Gy) to the
spleen, 5.1 Gy (range, 2.6-12.0 Gy) to the liver, 2.0 Gy (range, 1.4-5.3
Gy) to the lungs, 0.22 Gy (range, < 0.01-0.66 Gy) to the kidneys, and
0.74 Gy (range, 0.29-1.2 Gy) to the red marrow. These results are
consistent with those from earlier Zevalin trials in rituximab-naive
patients. Hematologic toxicity was manageable and did not correlate with
estimates of red marrow or total-body absorbed radiation dose.
CONCLUSIONS: Zevalin treatment of rituximab-refractory follicular NHL
patients at 0.4 mCi/kg resulted in acceptable estimates of absorbed
radiation dose to organs, similar to those observed in other
Zevalin-treated populations. Copyright 2002 American Cancer Society.
21
UI - 11877766
AU - Harwood SJ; Gibbons LK; Goldner PJ; Webster WB; Carroll RG
TI -
Outpatient radioimmunotherapy with Bexxar. Closed, clean air reservoir
minimizes personnel radiation exposure.
SO - Cancer 2002 Feb 15;94(4 Suppl):1358-62
AD - Department of Nuclear Medicine, Veterans Affairs Medical Center (VAMC)
Bay Pines, Bay Pines, Florida 33744, USA. Steven_J@Bay-Pines.va.gov
BACKGROUND: Radioimmunotherapy (RIT) with Bexxar (tositumomab and
iodine-131 tositumomab; Coulter Pharmaceutical, South San Francisco, CA)
has been shown to be effective in the treatment of low-grade and
transformed low-grade non-Hodgkin lymphoma (NHL). METHODS:
Patient-specific dosimetry with 5 mCi of iodine-131 tositumomab preceded
by 450 mg of tositumomab was utilized to calculate the radionuclide dose
needed to deliver 75 cGy whole-body radiation (65 cGy for platelet
counts of 100,000-149,000/mm(3)). To safely infuse the approximately 95
mCi (range, 52-211mCi) of iodine-131 needed for this treatment, a
shielded, closed system was developed to minimize radiation exposure for
personnel administering the treatment infusions and to eliminate
possible release of aerosolized iodine-131. RESULTS: Twenty-five
patients who could be evaluated were infused with a single course of
iodine-131 tositumomab therapy and achieved a 76% total response rate at
3 months (32% complete response [CR], 44% partial response [PR]); 59%
total response at 6 months (40% CR, 18% PR); and 38% total response at
12 months (31% CR, 6% PR). Administration of RIT using our unique,
totally closed system significantly reduced personnel exposure and
potential for radioactive spills. The sum of all individuals who
administered and monitored the infusions was < 120 mRem whole body
exposure over 22 months, well within the ALARA (as low as reasonably
achievable) Level I guideline limits. No radioiodide was detectable in
the thyroid of any staff member. CONCLUSIONS: In NHL patients who had
experienced failure with conventional therapy, RIT with iodine-131
tositumomab therapy was safe and effective. Response rates obtained were
equivalent to those obtained at the university medical centers where the
Phase I-III clinical trials were performed. Copyright 2002 American
Cancer Society.
22
UI - 11877767
AU - Behr TM; Griesinger F; Riggert J; Gratz S; Behe M; Kaufmann CC; Wormann
TI -
B; Brittinger G; Becker W
High-dose myeloablative radioimmunotherapy of mantle cell non-Hodgkin
lymphoma with the iodine-131-labeled chimeric anti-CD20 antibody C2B8
and autologous stem cell support. Results of a pilot study.
SO - Cancer 2002 Feb 15;94(4 Suppl):1363-72
AD - Department of Nuclear Medicine, Georg-August-University of Gottingen,
Gottingen, Germany. tmbehr@mailer.uni-marburg.de
BACKGROUND: CD20 has been used successfully as a target molecule for
conventional low-dose, as well as high-dose, myeloablative
radioimmunotherapy (RIT) of B-cell non-Hodgkin lymphoma (NHL). Mantle
cell lymphoma (MCL) is an especially aggressive, prognostically
unfavorable subtype of B-cell NHL, associated with an overall 5-year
survival rate of less than 20%. Recent evidence has failed to show
convincing therapeutic efficacy of conventional, nonmyeloablative RIT in
patients with MCL. The aim of this pilot study was to investigate
whether high-dose, myeloablative RIT with the iodine-131
((131)I)-labeled chimeric anti-CD20 antibody C2B8 (rituximab, obtained
as Mabthera from Roche Pharma, Reinach, Switzerland) is therapeutically
effective in MCL patients. METHODS: A total of seven patients with
chemorefractory or relapsed MCL were studied in this pilot trial. All
had relapsed after high-dose chemotherapy with autologous stem cell
transplantation (four of them combined with 12 grays (Gy) total-body
irradiation). A diagnostic-dosimetric study was performed with
approximately 10 mCi of (131)I-labeled C2B8 at a protein dose of 2.5 mg
per kg body weight, in order to assess its biodistribution and
dosimetry. If splenic pooling was observed, as is typically the case in
patients with splenomegaly, the protein dose was doubled in additional
studies until a "favorable" biodistribution was obtained. Therapy was
performed with myeloablative doses of 261-495 mCi of (131)I-labeled C2B8
at the previously optimized protein dose, aiming at lung doses
less-than-or-equal 27 Gy. Homologous stem cell support was provided.
Clinical follow-up was obtained at 3-month intervals for up to 38 months
(median observation time, 25 months). Overall, in six patients the 2.5
mg/kg protein dose was used, whereas in one patient with splenomegaly,
10 mg/kg was necessary to overcome the splenic antigenic sink. RESULTS:
Blood cell nadirs were reached at 2-3 weeks after therapy infusion, but
all patients reengrafted at 7-10 days after stem cell reinfusion.
Nonhematologic toxicity was restricted to mild-to-moderate nausea,
fever, transient bilirubin, or liver enzyme elevations. One patient with
preexisting alcoholic cirrhosis experienced a deterioration of liver
function. Despite thyroid blocking, 5 of 7 patients developed
hypothyroidism, requiring thyroxine substitution at 6-18 months after
RIT. Six patients experienced a complete and one a good partial
remission. Five patients were still in CR at the time this article was
written, and six are still alive for more than 3 years; one patient
relapsed locally at 3 months and one systemically at 26 months after
RIT. CONCLUSIONS: High-dose myeloablative radioimmunotherapy with
(131)I-labeled anti-CD20 antibodies seems to be associated with a high
response rate and moderate toxicity in patients with MCL. Further
follow-up to monitor the long-term outcome as well
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