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Blood, Vol. 95 No. 10 (May 15), 2000:
pp. 3052-3056
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Rituximab monoclonal antibody as initial systemic therapy for
patients with low-grade non-Hodgkin lymphoma
John D. Hainsworth,
Howard A. Burris III,
Lisa H. Morrissey,
Sharlene Litchy,
Daniel C. Scullin Jr,
James D. Bearden III,
Paul Richards, and
F. Anthony Greco
From the Sarah Cannon Cancer Center, Centennial Medical Center,
Nashville, TN; Tennessee Oncology PLLC, Nashville, TN; Consultants in
Blood Disorders and Cancer, Louisville, KY; Upstate Carolina, CCOP,
Spartanburg, SC; Oncology and Hematology Associates of Southwest
Virginia, Inc, Roanoke, VA.
 |
Abstract |
Rituximab, a chimeric antibody that targets CD20+ B
cells, produces a 48% response rate in patients with refractory
low-grade non-Hodgkin lymphoma. In this phase II trial, patients with
low-grade non-Hodgkin lymphoma who had previously received no systemic
therapy were treated with rituximab, 375 mg/m2,
administered by IV infusion for 4 consecutive weeks. Patients with
objective response or stable disease received repeat 4-week courses of
rituximab at 6-month intervals. At the time of initial reevaluation at
6 weeks, 21 of 39 patients (54%) had objective response to treatment,
and an additional 14 patients (36%) had stable disease or minor
response. Response rates were similar in patients with follicular and
small lymphocytic (CLL-type) lymphoma (52% versus 57%, respectively).
At present, follow-up is short and only 13 patients have undergone a
second course of rituximab treatment. However, 4 additional responses
were documented either prior to the second course of rituximab (2 patients) or following the second course (2 patients) and 4 patients
improved from partial to complete response. The current response rate
is 64%, with 6 complete responses (15%). Treatment with rituximab was
well tolerated, with only 1 patient experiencing grade 3/4
infusion-related toxicity. Rituximab is well tolerated and highly
active in patients with low-grade non-Hodgkin lymphoma previously
untreated with systemic therapy. Although further follow-up is
required, the demonstration of minimal toxicity and considerable
activity of this new biologic agent represents an important beginning
of more specific, less toxic treatment for this important group of
cancer patients.
(Blood. 2000;95:3052-3056)
© 2000 by The American Society of Hematology.
| |
Introduction |
The treatment of low-grade non-Hodgkin lymphoma has
changed very little during the last 20 years. Although these tumors are responsive to a number of standard chemotherapeutic agents, the large
majority of patients remain incurable. Patients with low-grade non-Hodgkin lymphoma usually receive a series of treatments, beginning with low-dose, relatively well-tolerated oral agents. However, remissions become shorter with each subsequent treatment, and treatments often become increasingly toxic. Treatment with intensive, combination chemotherapy results in a higher complete response rate;
however, any impact of this intensive approach on long-term survival
has been difficult to demonstrate.1,2
In 1982, Miller et al reported the first successful treatment of a
nodular B-cell lymphoma with a monoclonal antibody raised against the
unique surface immunoglobulin produced by this clonal B-cell
proliferation.3 This "anti-idiotype" antibody
produced a long-term remission in a patient refractory to chemotherapy and demonstrated the promise of tumor-specific therapy. Lymphomas have
provided the largest number of potential targets for monoclonal antibody therapy; in addition to the unique idiotype of each B-cell lymphoma clone, a number of surface protein-specific various lymphocyte subpopulations have been recognized. However, in the 17 years since the
first demonstration of activity, a variety of problems have prevented
targeted therapy from becoming a reality. These have included
difficulties in identifying a target antigen with ubiquitous expression
on tumor cells, problems with delivery of the monoclonal antibody to
the target and subsequent tumor cell destruction, and toxicity from the
monoclonal antibody itself.
Rituximab is a chimeric monoclonal antibody directed against the CD20
antigen, expressed on the surface of most B-cell lymphomas. Although
this antigen is also expressed by normal B cells, it is not found on
other normal cell types; therefore, the rituximab monoclonal antibody
provides targeted treatment but is not entirely tumor specific. After
attaching to the cell surface, the antibody activates the cell-mediated
and complement-mediated cytotoxicity mechanisms, resulting in cell death.
Because the CD20 antigen is expressed by a variety of B-cell
non-Hodgkin lymphomas, rituximab has a number of potential therapeutic applications. Initial trials focused on previously treated patients with low-grade non-Hodgkin lymphoma. In a group of patients who had
previously received one or more chemotherapy regimens, treatment with 4 doses of this antibody, administered weekly, produced a response rate
of 45% to 50% and a median response duration of 12 months.4,5 Treatment-related toxicity was mild and limited primarily to infusion-related events. Although data are limited, responding patients can be retreated with rituximab at relapse and have
a second response rate of 40% without increased toxicity.6
The favorable toxicity profile, short treatment duration, and high
response rate in refractory patients suggest that first-line treatment
with rituximab may provide an excellent treatment option in patients
with low-grade non-Hodgkin lymphoma. Periodic retreatment, or
"maintenance" therapy at scheduled intervals may be effective in
prolonging remissions and avoiding the necessity for treatment with
cytotoxic agents. In this phase II trial, we report the preliminary results of treatment with rituximab in a group of patients with low-grade non-Hodgkin lymphoma previously untreated with chemotherapy. As part of this ongoing trial, we are also evaluating the duration of
remission with maintenance courses of rituximab administered every 6 months for a total of 2 years. In this preliminary report, we detail
the initial response rate and toxicity of rituximab treatment in
previously untreated patients with low-grade non-Hodgkin lymphoma.
Because follow-up and maintenance therapy are continuing in most
patients, the final assessment of the efficacy of this treatment
approach awaits further follow-up.
| |
Patients and methods |
Accrual to this phase II trial was initiated in March 1998 by
participating sites in the Minnie Pearl Cancer Research Network (see
Acknowledgments). All patients were required to have biopsy-proven low-grade B-cell non-Hodgkin lymphoma. The following histologic subtypes, as defined by the Revised European-American Lymphoma classification, were eligible: follicular small-cleaved cell; follicular mixed small-cleaved and large cell; plasmacytoid; and small
lymphocytic (chronic lymphocytic leukemia [CLL] type). Patients with
stages II, III, or IV disease at diagnosis were eligible, as were
patients with early stage disease (stage I, II) who had relapsed after
previous radiation therapy. No previous chemotherapy or monoclonal
antibody therapy was permitted. Additional eligibility criteria
included measurable or evaluable disease; ECOG performance status 0, 1, or 2; age over 18 years; white blood cell (WBC) count 3000/µL or
higher and platelets 100 000/µL or more; and adequate liver and
kidney function. Patients who had severe lymphoma-related symptoms
requiring a rapid response to therapy (eg, bowel obstruction, chylous
ascites, respiratory compromise due to large effusions or airway
obstruction) were not eligible; standard chemotherapeutic approaches
were recommended for this patient subset. Patients with central nervous
system involvement (brain or meningeal) were ineligible. All patients
were required to provide written informed consent before entering the
study. This study was approved by the Institutional Review Board at
Centennial Medical Center and by the review boards at participating sites.
Before beginning therapy, all patients underwent staging procedures
including history, physical examination, complete blood counts,
chemistry profile, computerized tomography of the chest and abdomen,
and bone marrow aspiration/biopsy. All patients were treated with
weekly doses of rituximab, 375 mg/m2, administered IV for 4 consecutive weeks. Rituximab was mixed with normal saline at a final
concentration of no more than 1 to 4 mg/mL. The first dose of rituximab
was infused at an initial rate of 50 mg/h. If no hypersensitivity or
infusion-related events occurred, the infusion rate was increased by
50-mg/h increments every 30 minutes, to a maximum of 400 mg/h.
Subsequent rituximab infusions were administered at an initial rate of
100 mg/h and escalated by 100-mg/h increments at 30-minute intervals to
a maximum of 400 mg/h. Thirty minutes before each dose of rituximab,
patients received premedication with oral acetaminophen 650 mg and
diphenhydramine 50 mg. Patients who experienced any treatment-related
nausea or vomiting with the first treatment received subsequent
premedication with a serotonin receptor antagonist. Administration of
dexamethasone was avoided. Serum levels of rituximab were not measured
as part of this study.
Although myelosuppression was not an expected treatment-related
toxicity, parameters for dose modification were established as follows:
WBC 2000/µL or more and platelets 75 000/µL or higher, full dose
administered; WBC less than 2000/µL or platelets 75 000/µL, dose
withheld, blood counts repeated after 1 week, and full dose resumed if
WBC was 2000/µL or higher and platelets 75 000/µL or higher.
Infusion-related events were expected to be the most common toxicity in
this trial. If serious events occurred (ie, hypotension, angioedema,
bronchospasm), infusion of rituximab was stopped, and then restarted at
very low rates. The rate of infusion was subsequently escalated as
previously described, until a maximum tolerated infusion rate was
reached. Treatment of infusion-related symptoms was at the discretion
of the treating physician, but could include additional
diphenhydramine, 25 to 50 mg IV, bronchodilators, or IV normal saline.
Meperidine, 25 to 50 mg IV, was given for moderate to severe chills or
rigors. If severe hypersensitivity occurred even after maximum
premedication and slowing of the infusion rate, rituximab infusion was
terminated and the patient was removed from study.
If any other grade 3 or 4 nonhematologic toxicity
occurred, rituximab was held for 1 week or until the toxicity had
decreased to grade 2 or less. Rituximab was then reinstituted at full
dose. If nonhematologic toxicity had not resolved after 2 weeks,
therapy was discontinued and the patient removed from study. All
courses of rituximab consisted of 4 doses, whether or not any treatment delays were necessary.
Patients were evaluated for response to treatment 2 weeks after
completing the 4-week course of rituximab. Restaging included a repeat
of all previously abnormal staging tests. Patients with progressive
disease were removed from the study and considered treatment failures.
Patients with objective response or stable disease remained in the
study. Courses of rituximab were repeated in these patients at 6-month
intervals for a maximum of 4 courses (2 years of therapy), as long as
disease progression did not occur. Prior to each maintenance course of
rituximab, restaging was performed to document that remission was
continuing. The dose and schedule of rituximab used in the maintenance
courses were identical to the initial course.
Patients who had an initial objective response to rituximab but showed
evidence of progressive disease prior to the 6-month interval were
eligible to receive the next course of rituximab prior to the scheduled
6-month interval. This decision was made by the treating physician,
based on the patient's initial response and symptomatic benefit from
treatment. The intervals between courses of rituximab could never be
less than 4 months; all patients progressing earlier than 4 months were
removed from trial.
Following completion of the initial course of rituximab, all patients
were assigned a response category using standard definitions of
response. Complete response required the total disappearance of
clinically and radiologically detectable disease for at least 4 weeks.
Partial response required at least 50% reduction of all measurable
lesions, as measured by the product of the perpendicular diameters of
the greatest dimensions of tumor size, with no new lesions appearing.
For patients with evaluable disease, partial response required
objective improvement in evaluable lesions, with accompanying
symptomatic improvement. Patients had stable disease if tumor size
reduced by less than 50% or increased by less than 25%, with no new
lesions appearing. For patients with evaluable disease, stable disease
required no change in the evaluable lesions, with no new lesions
appearing, and no worsening of objective symptoms. Progressive disease
was defined as an increase of more than 25% in any measurable or
evaluable lesion or the appearance of any new lesion.
All patients who completed 4 weeks of therapy were considered evaluable
for response. Patients who received at least 1 dose of rituximab were
included in the analysis of toxicity. Time to progression was
calculated from the first day of treatment until the time progressive
disease was documented.
Between March 1998 and February 1999, 41 patients entered this trial
and are evaluable for response to initial treatment. Patient
characteristics are summarized in Table 1.
The median age of the patients was 65 years, typical of the population
of patients with low-grade non-Hodgkin lymphoma. Most patients (71%) had stage III or IV disease, and 11 patients (27%) had systemic symptoms. Distribution of the various low-grade histologic subtypes was
also typical of the population of low-grade lymphoma patients; 26 patients (64%) had follicular lymphoma. Four patients (2 with stage I
and 2 with stage II lymphoma at diagnosis) had relapsed after previous
radiation therapy. Thirty-seven patients (90%) had received no
previous treatment. Eighteen patients (44%) received treatment at the
Sarah Cannon Cancer Center, and the remaining 56% were treated at
other sites in the Minnie Pearl Cancer Research Network.
| |
Results |
Thirty-nine of 41 patients (95%) completed the first 4-week course
of rituximab and were evaluable for response. One patient developed
flushing, dyspnea, and chest pain radiating to the jaw shortly after
the first dose of rituximab was initiated. An electrocardiogram (ECG)
revealed ischemic changes; the patient was admitted to the hospital for
observation, and all symptoms resolved completely. This patient was
removed from study and not rechallenged with rituximab. A second
patient, an 89-year-old man, was put in a nursing home by his family
after completing the first course (4 weeks) of rituximab and could not
continue follow-up.
Thirty-nine patients were evaluated for response 2 weeks after
completing the first course of rituximab. Twenty-one of 39 patients
(54%) had objective responses with 2 complete responses (5%) and 19 partial responses (49%). Fourteen additional patients (36%) had minor
response or stable disease and continued treatment with rituximab per
protocol. Only 4 patients (10%) had progression during the first
course of treatment; these patients were removed from study and
received treatment with standard chemotherapy. Initial response rates
were similar in the various histologic subtypes; 13 of 25 patients
(52%) with follicular lymphoma responded, and 8 of 14 patients (57%)
with a small lymphocytic (CLL type) lymphoma responded.
Because some delayed responses were expected to occur after the first
reevaluation at 6 weeks, all patients with initial objective response
or stable disease were reevaluated at 6 months, prior to the second
scheduled course of rituximab. Of the 35 patients who remained in the
study after the first reevaluation, 2 patients (1 stable, 1 partial
responder) progressed during the first 6 months and were removed from
study. An additional patient, who had stable disease as best response,
progressed after the second course of rituximab. Restaging at 6 months
(prior to the second scheduled course of rituximab) resulted in
reclassification of response category in 5 patients; 2 additional
patients achieved partial remission, and 3 patients converted from
partial to complete response. Three patients had further decrease in
tumor size during this interval, but remained in partial response.
Thirteen patients have completed a second 4-week course of rituximab.
Following the second rituximab course, 3 patients had improvement in
their response category (stable to partial response, 2 patients;
partial to complete response, 1 patient).
When the additional responses after initial (6-week) reevaluation are
included, 25 of 39 patients (64%) achieved a response, with 6 complete
responses (15%). After a median follow-up of 8 months, 32 of 39 patients are free of disease progression; actuarial 1-year
progression-free survival is 77% (Figure
1).
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| Fig 1.
Progression-free survival for 39 evaluable patients.
The actuarial 12-month progression-free survival is 77%.
|
|
Toxicity encountered during the first course of rituximab therapy is
summarized in Table 2. Most of the toxicity
related to rituximab was infusion-related and of brief duration. One
67-year-old woman with follicullar small cleaved-cell lymphoma
developed severe flushing, dyspnea, chest pain, and ischemic ECG
changes during the first infusion, and was removed from study. This
patient had stage IV lymphoma with bone marrow involvement, but had a
normal leukocyte count and no bulky lymph nodes. No other grade 3 or 4 toxicity was observed, and all other patients completed the first
treatment course without dose delays or reductions. Grade 1 and 2 infusion-related toxicities were the only common side effects: fever (22%), chills/rigors (29%), flushing (10%), and nausea/vomiting (12%). The incidence of grade 1 and 2 infusion-related toxicities was highest with the first infusion of rituximab: week 1, 37%; week 2, 2%; week 3, 0%; week 4, 0%. Three of 12 patients over
70 years of age (25%) had grade 1/2 infusion-related toxicity, versus
14 of 29 patients (48%) who were less than 70 years old. Mild fatigue
was reported by 11 patients (27%). There have been no hospitalizations
for treatment of infections, no recognized opportunistic infections,
and no fevers of undetermined etiology. Four patients had circulating
malignant lymphocyte counts of more than 50 000/µL, and 4 patients
had counts of 10 000 to 50 000/µL when they began treatment. None
of these patients had grade 3 infusion-related toxicity, and 4 of 8 (50%) had grade 1/2 toxicity.
The second course of rituximab therapy was tolerated well in all 13 patients, with no new or unusual toxicities recognized. Grade 1 and 2 infusion-related events during the first rituximab dose of the second
course occurred in 3 of 13 patients (23%). At the time the second
rituximab course was initiated, only 1 of 13 patients had an elevated
circulating lymphocyte count (13 500/µL). There were no grade 3/4
toxicities during the second treatment course.
| |
Discussion |
The recent introduction of rituximab into clinical practice was
based on its demonstrated efficacy in the treatment of refractory low-grade non-Hodgkin lymphoma. In this role, rituximab has provided an
additional treatment option, producing a response rate of 48% in
patients previously treated with standard chemotherapy.5 However, the optimal role of rituximab in the treatment of non-Hodgkin lymphoma remains undefined. In the initial trials, the dose and schedule of rituximab administration were chosen empirically, and very
little information with alternate doses or different schedules of
administration exists. The efficacy of rituximab in the initial
treatment of low-grade non-Hodgkin lymphoma has not been defined.
Additionally, the relative activity in various low-grade lymphoma
subtypes was not well defined, although, the small lymphocytic (CLL)
subtype responded less well in the refractory disease
trials.5 The use of rituximab in other types of
CD20-expressing lymphomas (eg, large-cell lymphoma) is also
incompletely defined, although responses have been observed in
refractory patients.7
The trial reported here was designed to address several of the
unresolved issues regarding the use of rituximab in low-grade non-Hodgkin lymphoma. Initial treatment with rituximab, rather than
chemotherapy, has not been previously investigated. However, the use of
a highly effective, short duration treatment with low toxicity would
certainly be attractive to patients, when compared to a 4- to 6-month
course of induction chemotherapy. The possibility of a higher response
rate in previously untreated patients is suggested by subset analysis
of previous trials with rituximab in previously treated patients.
Patients who had received only 1 previous chemotherapy regimen had a
response rate of 57%, versus a response rate of 38% in patients who
had received 3 previous treatment regimens.5 In addition to
assessing response rates in previously untreated patients, this trial
evaluates the feasibility of administering periodic maintenance courses
of rituximab to prolong remission duration. Maintenance therapy has not
been previously investigated, although retreatment at the time of
progression in refractory patients previously responding to rituximab
produced a second remission rate of 40%.6 We selected a
6-month interval for the time between maintenance courses of rituximab,
based on the continued detection of antibody for up to 6 months
following a 4-week initial treatment, as well as the median response
duration of 12 months observed in previously treated patients.
The preliminary results of this trial document a high response rate to
a 4-week course of rituximab in patients previously untreated for
low-grade non-Hodgkin lymphoma. When assessed at 6 weeks, the overall
objective response rate was 54%, with an additional 36% of patients
having stable disease or minor response, and only 10% experiencing
disease progression. Continued shrinkage of measurable lymphoma
occurred in several patients between the first reevaluation at 6 weeks
and the reevaluation at 6 months, and improvement in response also
occurred following the second course of rituximab. When the additional
responses are included, overall response rate has already improved from
54% to 64%, and complete response rate has risen from 5% to 15%. As
additional patients are reevaluated, and receive maintenance courses of
rituximab, it seems likely that additional responses will be documented.
Preliminary results of a similar trial have recently been reported by
Solal-Celigny et al.8 Fifty patients with previously untreated low-grade follicular non-Hodgkin lymphoma received a standard
4-week course of rituximab. Patients were required to have low tumor
burden (no tumor mass > 7 cm, no B symptoms, no organ compression or
effusion, normal lactic dehydrogenase), and 92% had World Health
Organization performance status 0. Results of treatment were similar to
our results. Initial response rate (assessed at day 50) was 65%; with
additional follow-up, 3 patients with stable disease improved to
partial response, for a final response rate of 71%. Treatment was well
tolerated, with no grade 3 or 4 toxicity. Response duration is not yet available.
As anticipated, patients with objective response to the initial course
of rituximab rarely experienced disease progression prior to the
scheduled 6-month retreatment. Early progression occurred in only 1 partial responder, and in 2 of 14 patients with stable disease at first
reevaluation. The initial course of treatment was well tolerated; 40 of
41 patients received the entire scheduled treatment, with only 1 patient being withdrawn from treatment due to severe hypersensitivity symptoms.
In this trial, the initial response rates were similar in all subtypes
of low-grade non-Hodgkin lymphoma. The achievement of major responses
in 8 of 14 evaluable patients (57%) with small lymphocytic (CLL type)
lymphoma is of particular interest. In previously treated patients with
this histologic subtype, rituximab produced a response rate of only
13%.5 Low-density expression of surface CD20 antigen has
been postulated as the cause of lower response rates in these patients.
Further evaluation of rituximab in previously untreated patients with
small lymphocytic lymphoma, and with classic CLL, is indicated to
confirm these preliminary observations.
Although the high initial response rate in previously untreated
patients is noteworthy, several important questions regarding this
treatment approach remain unanswered by these preliminary data. Due to
the short follow-up, the current report allows only a preliminary
assessment of the efficacy of maintenance therapy. Already, the
improved response to therapy in some patients has been noted, but the
frequency of such additional response remains undetermined. Most
importantly, the median duration of response remains unknown, and in
large part will determine the desirability of this new treatment
approach. The efficacy of subsequent chemotherapy in patients
progressing after initial rituximab is also unknown. Although there is
no strong rationale to suspect decreased efficacy, further experience
is necessary to definitively address this question.
The high initial response rate to rituximab suggests a number of new
possibilities for the treatment of low-grade non-Hodgkin lymphoma. In
addition to providing an excellent treatment option for patients who
may have difficulty tolerating chemotherapy, the high single-agent
response rate suggests that addition of rituximab to standard
chemotherapy may be effective in prolonging remission duration or
survival in these patients. Although limited data exist, the concurrent
administration of CHOP chemotherapy and rituximab has been proved
feasible and highly active in previously untreated patients with
low-grade non-Hodgkin lymphoma. In a phase II study recently reported
by Czuczman et al, 38 of 40 patients (95%) obtained objective response
after combination therapy, and 55% of patients had complete
response.9 In this trial, cytogenetics were assessed in a
small cohort of patients. Seven patients with clinical complete
response also had clearance of bc1-2 translocations detected by
polymerase chain reaction examination of the bone marrow. Although no
definitive conclusions can be made from these small numbers of
patients, further evaluation of concurrent chemotherapy and rituximab,
with particular attention to cytogenetics, is of great importance.
The optimal role of rituximab in the treatment of low-grade non-Hodgkin
lymphoma continues to be defined. In addition to treatment of
refractory disease, rituximab produces a high response rate with
minimal toxicity in patients previously untreated with systemic therapy. In some patients who are elderly or who have poor performance status, initial treatment with rituximab may provide an attractive treatment option. The efficacy of initial treatment with rituximab as
compared to standard chemotherapy, as well as the value of maintenance
courses of rituximab, await clarification by further clinical trials,
as well as additional follow-up of patients in this trial. However,
additional indications for the use of rituximab are likely to be
defined in the near future.
The use of a relatively specific target-directed biologic therapy
represents an important beginning for mechanistic-based therapy for
patients with neoplasms. The demonstration of substantial antitumor
effects with minimal toxicity in previously untreated patients
represents an exciting clinical success derived from a rational
target-based approach. These preliminary results provide encouragement
for further development of targeted biologic agents for patients with
various advanced cancers.
| |
Acknowledgments |
Minnie Pearl Cancer Research Network Participating Sites include:
Tennessee Oncology, PLLC, Nashville, TN; Consultants in Blood Disorders
and Cancer, Louisville, KY; Graves-Gilbert Clinic, Bowling Green, KY;
Florida Oncology Associates, Orange Park, FL; Louisiana Oncology
Associates, Lafayette, LA; The Medical Oncology Group, Gulfport, MS;
Upstate Carolina CCOP, Spartanburg, SC; King's Daughters' Medical
Center, Ashland, KY; Greenview Hospital, Bowling Green, KY; McLeod
Cancer and Blood Center, Johnson City, TN; University Oncology
Associates, Chattanooga, TN; The Hematology and Oncology Clinic,
Hattiesburg, MS; Northeast Alabama Regional Medical Center, Anniston,
AL; Atlanta Cancer Care, Atlanta, GA; Oncology and Hematology of
Southwest Virginia, Roanoke, VA; Oncology Hematology of South Florida,
Miami, FL; Winter Park Memorial Hospital, Winter Park, FL; Hematology
Oncology Services, New Orleans, LA; and Medical Oncology, LLC Baton
Rouge, LA.
| |
Footnotes |
Submitted September 22, 1999; accepted January 10, 2000.
Supported in part by grants from Genentech Inc and the Minnie Pearl Foundation.
Reprints: John D. Hainsworth, Sarah Cannon Cancer Center,
250 25th Avenue, North, Suite 412, Nashville, TN 37203.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Top
Abstract
Introduction