Journal of Clinical Oncology, Vol 20, Issue 20
(October), 2002: 4261-4267
© 2002 American Society for Clinical Oncology
Rituximab as First-Line and Maintenance Therapy for Patients With Indolent Non-Hodgkin’s Lymphoma
By John D. Hainsworth,
Sharlene Litchy,
Howard A. Burris, III,
Daniel C. Scullin, Jr,
Steven W. Corso,
Denise A. Yardley,
Lisa Morrissey,
F. Anthony Greco
From the Sarah Cannon Cancer Center and Tennessee Oncology, Professional Limited Liability Corporation, Nashville, TN; Consultants in Blood Disorders and Cancer, Louisville, KY; and Upstate Carolina Community Clinical Oncology Program, Spartanburg, SC.
Address reprint requests to John D. Hainsworth, MD, Sarah Cannon Cancer Center, 250 25th Ave N, Suite 412, Nashville, TN 37203; email: jhainsworth{at}tnonc.com
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ABSTRACT
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PURPOSE: To evaluate response to single-agent rituximab in patients with indolent non-Hodgkin’s lymphoma (NHL) and no previous systemic therapy, and the feasibility, toxicity, and efficacy of maintenance rituximab, administered at 6-month intervals, in patients with objective response or stable disease after first-line rituximab therapy.
PATIENTS AND METHODS: Patients with indolent NHL (follicular or small lymphocytic subtypes) previously untreated with systemic therapy received rituximab 375 mg/m2 intravenously weekly for 4 weeks. Patients were restaged at week 6 for response; those with objective response or stable disease received maintenance rituximab courses (identical dose and schedule) at 6-month intervals. Maintenance was continued for a maximum of four rituximab courses or until progression. Between March 1998 and May 1999, 62 patients were entered onto this trial; minimum follow-up was 24 months.
RESULTS: Sixty patients (97%) completed the first 4-week course of rituximab and were assessable for response. All have now completed rituximab therapy; 36 (58%) received four courses at 6-month intervals. The objective response rate at 6 weeks was 47%; 45% of patients had stable disease. With continued maintenance, final response rate increased to 73%, with 37% complete responses. Response was similar in patients with follicular versus small lymphocytic subtypes (76% v 70%, respectively). Median actuarial progression-free survival was 34 months. Two patients experienced grade 3/4 toxicity with the first dose; one patient was removed from treatment. No cumulative or additional toxicities were seen with maintenance courses.
CONCLUSION: Rituximab is highly active and extremely well tolerated as first-line single-agent therapy for indolent NHL. First-line treatment with scheduled maintenance at 6-month intervals produces high overall and complete response rates and a longer progression-free survival (34 months) than has been reported with a standard 4-week treatment.
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INTRODUCTION
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ALTHOUGH A NUMBER of standard chemotherapeutic agents are active in the treatment of patients with indolent non-Hodgkin’s lymphoma (NHL), the large majority of these patients remain incurable. Most patients with indolent NHL receive a series of systemic treatments that often begin with low-dose and relatively well-tolerated oral agents. However, remission duration becomes shorter with successive treatments, and the disease is eventually fatal in most patients.
In the relatively brief interval since its introduction, rituximab has become a standard part of therapy for patients with indolent NHL. In patients with relapsed or refractory follicular lymphoma, treatment with four doses of rituximab, administered at weekly intervals, produced a response rate of 60% with a median response duration of 12 months.1 Treatment-related toxicity is usually mild and limited to infusion-related symptoms such as fever, chills, and flushing. Unlike chemotherapeutic agents, rituximab is well tolerated regardless of age or performance status.1,2 Although treatment results are impressive in patients with refractory indolent NHL, the optimal use of rituximab including dose, schedule, duration of therapy, and use in combination regimens remains undefined.
Two observations from the rituximab pivotal trial led to the design of this trial evaluating rituximab as first-line and maintenance therapy for indolent NHL. First, retrospective analysis suggested that patients who received rituximab as second-line therapy had a higher response rate than did patients who had received three or more previous regimens (56% v 38%, respectively).1 Second, re-treatment studies in patients who had an initial response to rituximab therapy demonstrated a second objective response in 40% of patients.3 Furthermore, the median duration of the second response to rituximab exceeded the duration of the first response (18 v 12 months, respectively). Based on these observations, we investigated the use of rituximab as first-line therapy for patients with indolent NHL. After a standard 4-week course of rituximab, patients with objective response or stable disease received scheduled maintenance courses of rituximab at 6-month intervals for a maximum of four courses in an attempt to improve the initial therapeutic response and prolong duration of remission. We have previously published a preliminary report documenting the high initial response rate to first-line rituximab therapy.4 This follow-up report contains response data in a larger number of patients. In addition, all patients have now completed maintenance rituximab therapy with a minimum follow-up of 24 months.
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PATIENTS AND METHODS
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Accrual to this phase II trial began in March 1998. This trial was conducted in the Minnie Pearl Cancer Research Network, a multicenter, community-based collaborative clinical trials group (see Appendix, online at www.jco.org).
Patient Eligibility
Eligible patients were required to have biopsy-proven indolent B-cell NHL with one of the following histologies as defined by the revised European-American lymphoma classification: follicular small cleaved-cell, follicular mixed small cleaved- and large-cell, follicular large-cell, plasmacytoid, and small lymphocytic lymphoma (SLL). Patients with stage II, III, or IV lymphoma at the time of diagnosis were eligible, as were patients with early-stage disease (stage I or II) who had relapsed or progressed after previous radiation therapy. No previous chemotherapy or monoclonal antibody therapy was permitted. Additional eligibility requirements included measurable or assessable disease, Eastern Cooperative Oncology Group performance status of 0, 1, or 2, age more than 18 years old, WBC count  3,000/µL, platelet count 100,000/µL, and adequate liver and kidney function. Patients who had severe lymphoma-related symptoms requiring a rapid response to therapy (eg, respiratory compromise because of large effusions or airway obstruction, bowel obstruction, ureteral obstruction, and chylous ascites) were not eligible; standard combination chemotherapy was recommended for this patient subset. Patients with CNS involvement were ineligible. All patients were required to provide written informed consent before entering this clinical trial. This study was approved by the institutional review board at Centennial Medical Center and by the institutional review boards of participating network sites.
Initial Staging Evaluation
Before rituximab therapy, all patients underwent staging procedures including history, physical examination, complete blood counts, chemistry profile, computed tomography of the chest and abdomen, and bone marrow aspiration/biopsy. All areas of lymphoma involvement were documented. In patients with multiple measurable lymph nodes and/or tumor masses, at least three of the largest lesions were measured bidimensionally and followed serially to determine response to therapy. Polymerase chain reaction to detect the presence of bcl-2 gene rearrangements was not a routine part of the initial evaluation or the restaging of patients in this trial.
Initial Treatment
All patients were treated with rituximab 375 mg/m2 administered intravenously (IV) at weekly intervals for 4 consecutive weeks. Rituximab was administered by slow IV infusion following standard guidelines. Premedication with oral acetaminophen 650 mg and diphenhydramine 50 mg was administered 30 minutes before rituximab infusion. Dexamethasone or other steroids were not routinely administered as premedication.
Infusion-related events were expected to be the most common toxicities in this trial. Rituximab infusion was stopped if serious infusion-related toxicity occurred (ie, hypotension, angioedema, or bronchospasm) and then restarted at slow infusion rates after the toxicity had resolved. After the infusion was restarted, the rate of rituximab infusion was again escalated as tolerated using standard guidelines. Treatment of infusion-related symptoms was at the discretion of the treating physician but could include additional diphenhydramine (25 to 50 mg IV), bronchodilators, IV saline, or meperidine (25 to 50 mg IV) for severe chills or rigors. Patients were withdrawn from the study if severe hypersensitivity reactions continued or recurred after maximum premedication and slowing of the rituximab infusion rate.
Myelosuppression was not expected to be a common treatment-related toxicity. However, the following parameters for myelosuppression-related dose reductions were observed: (1) if WBC count 2,000/µL and platelet count 75,000/µL, full-dose rituximab was administered and (2) if WBC count less than 2,000/µL or platelet count less than 75,000/µL, rituximab was withheld. Blood counts were repeated after 1 week, and full dose was resumed if WBC count was 2,000/µL and platelet count was 75,000/µL. For other grade 3 or 4 nonhematologic toxicities, rituximab was held for 1 week or until the toxicity had decreased to grade 2 or less. Rituximab was then reinstituted at full dose. All courses of rituximab consisted of four doses whether or not treatment delays were necessary.
Determination of Response
Patients were evaluated for response 2 weeks after completing the 4-week course of rituximab. Initial restaging included physical examination, complete blood counts, chemistry profile, and computed tomography of the chest and abdomen. Additional radiologic and/or endoscopic procedures were performed if necessary to re-evaluate sites of known lymph node involvement. Patients with bone marrow involvement at study entry had repeat bone marrow aspiration and biopsy if necessary to confirm complete remission. Radiology and bone marrow reports for all patients treated at network sites were reviewed centrally; however, actual scans and bone marrow slides were not reviewed.
All patients were assigned an initial response category at the time of the first restaging at 6 weeks. Radiology reports were required to contain objective measurement of indicator lesions, and all reports were reviewed centrally. Response categories were assigned using traditional definitions of response. Complete response required the total disappearance of clinically and radiologically detectable disease for at least 4 weeks. Any residual adenopathy detected by computed tomography scanning was required to be less than 1.5 cm (or < 1 cm if nodes were 1.1 to 1.5 cm pretreatment). In addition, patients with initial bone marrow involvement were required to have clearing (as determined by repeat aspiration and biopsy) to be categorized as complete responders. Partial response required at least a 50% reduction in the size of measurable lesions, as measured by the sum of products of perpendicular diameters of the greatest dimensions of measurable lesions, with no new lesions appearing. For patients with assessable disease, partial response required objective improvement in the assessable lesions with accompanying symptomatic improvement. Stable disease was defined as a reduction of less than 50% or an increase of less than 25% in the size of measurable lesions, with no new lesions appearing. For patients with assessable disease, stable disease required no change in assessable lesions, no worsening of objective symptoms, and no new lesions appearing. Progressive disease was defined as an increase of more than 25% in the size of any measurable or assessable lesions or the appearance of any new lesions.
Maintenance Therapy and Follow-Up
Patients with objective response or stable disease at the time of initial re-evaluation remained on the study and received maintenance rituximab therapy. Patients with progressive lymphoma at re-evaluation were removed from the study, and further treatment was at the discretion of the treating physician.
Maintenance courses of rituximab were administered at 6-month intervals until progression of lymphoma was documented or for a maximum of four rituximab courses. Maintenance courses of rituximab were identical to the induction course (375 mg/m2 IV administered weekly for 4 consecutive weeks).
During maintenance treatment with rituximab, patients were seen and examined by their physicians at least every 3 months. Complete restaging was performed at 6-month intervals before each scheduled maintenance course of rituximab. Restaging included physical examination, complete blood counts, chemistry profile, and repeat computed tomography scanning of all areas of previous lymphoma involvement. Repeat bone marrow aspiration/biopsy was not performed at each restaging unless it was necessary to document complete remission.
After completion of maintenance therapy, patients continued to be seen at 3-month intervals and restaged (as above) at 6-month intervals.
Patients who had an objective response or stable disease at the time of the first or any subsequent re-evaluation but progressed before the next scheduled course of rituximab were eligible to receive the next course of rituximab before the scheduled 6-month interval. This decision was made by the treating physician based on the patient’s initial response and perceived benefit from rituximab therapy. However, the interval between courses of rituximab could never be less than 4 months, and patients progressing earlier than 4 months were removed from the study.
Statistical Methods
All patients who completed the first 4-week course of rituximab were considered assessable for response. All patients were included in the toxicity analyses. Time-to-progression was calculated from the first day of treatment until the date of documented lymphoma progression. Actuarial survival curves were constructed using the method of Kaplan and Meier.5 Comparisons of survival for various subsets of patients were accomplished using two-sided log-rank analysis.6
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RESULTS
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Patient Characteristics
Between March 1998 and May 1999, 62 patients were entered onto this multicenter phase II trial. Patient characteristics are listed in Table 1. The median patient age was 65 years, typical of the population of patients with indolent NHL. Thirty-eight patients (61%) had follicular lymphomas; the remainder had SLL. Although guidelines for initiation of treatment in patients with indolent NHL vary among physicians, 48 (77%) of 62 patients were thought by their treating physicians to require some form of therapy versus observation alone when they entered onto this clinical trial.
A number of additional prognostic factors (ie, tumor bulk, extranodal disease, lactate dehydrogenase levels, or B symptoms) pertinent to this patient population were also assessed (Table 1). Forty-nine patients (79%) had either stage III or IV disease at the time of treatment. Patients were also grouped into four risk categories according to the International Prognostic Index.7,8 To determine the risk category, five prognostic features (age, performance status, stage, extranodal involvement, and lactate dehydrogenase level) were assessed, and patients were categorized according to the number of adverse factors. Forty-nine of 52 patients could be categorized; 21 patients (35%) in this trial had high-intermediate or high-risk disease, and 17 patients (29%) had low-risk disease.
Treatment Received
Sixty (97%) of 62 patients completed the first 4-week course of rituximab and were assessable for response. One patient, an elderly women with known coronary artery disease, developed flushing, dyspnea, and ischemic chest pain during the first infusion. She was admitted to the hospital for observation, and all symptoms subsequently resolved; however, she was not rechallenged with further rituximab. The second unassessable patient, an 89-year-old man, was moved to a nursing facility by his family immediately after completing the first 4-week course of rituximab and was not available for re-evaluation or continuation of treatment.
At present, all patients have completed rituximab treatment and have either experienced lymphoma progression or are being followed in continuing remission. Forty-six (74%) of 62 patients received at least one maintenance course of rituximab. The total number of rituximab courses received by the patients on this study was one course for 16 patients, two courses for eight patients, three courses for two patients, and four courses for 36 patients.
Efficacy
The initial treatment response (assessed at 6 weeks) and the subsequent best response to treatment are summarized in Table 2. When evaluated at 6 weeks, objective responses were documented in 28 (47%) of 60 assessable patients. However, only five patients (8%) had tumor progression and were removed from treatment, whereas the remaining 27 patients (45%) had stable disease. With further follow-up, usually after the first maintenance course, the overall response rate and the complete response rate improved substantially. With continued therapy, 16 (59%) of 27 patients who initially had stable disease achieved an objective response. Of these 16 late responders, eight had response documented after the second rituximab course, six after the third course, and two after all four rituximab courses were completed. Currently, 22 patients (37%) have achieved complete response, and the overall response rate is 73%. Overall, 25 patients (42%) improved their response category after their initial evaluation at 6 weeks.
The response rate to treatment with single-agent rituximab was compared in several patient subgroups. Patients with follicular NHL had a similar response rate when compared with patients with SLL (76% v 70%, respectively). Patients with stage IV lymphoma had a lower overall response rate (56%) than did patients with earlier stages (88%). However, response rates of patients in the low/low-intermediate versus high-intermediate/high International Prognostic Index risk groups were similar (79% v 63%, respectively).
The progression-free survival for the entire group of patients is shown in Fig 1. With a minimum follow-up of 24 months and a median follow-up of 30 months, the median actuarial progression-free survival was 34 months. The actual progression-free survival rates at 1 and 2 years were 69% and 64%, respectively; actuarial 3-year progression-free survival rate was 49%. At present, 31 patients are alive and progression-free; 19 of these patients (61%) are in complete remission. Of the 22 patients who achieved complete remission, 19 (86%) remain in complete remission, two have progressed, and one patient died of cardiovascular problems while in complete remission. Twelve (36%) of 33 patients who had less than a complete response to treatment remain progression-free.
Survival comparisons of patient subsets are shown in Fig 2. Progression-free survival in patients with follicular lymphoma and SLL were not significantly different. However, all seven patients who have progressed after remissions of at least 18 months had SLL. Therefore, further follow-up is necessary before final comparisons of these two subgroups can be made. Patients with stage IV lymphoma had 1- and 2-year progression-free survival rates of 51% and 47%, respectively, as compared with 1- and 2-year progression-free survival rates of 80% and 77%, respectively, for patients with stages II and III (P = .02).
Fifty-one (82%) of 62 patients remain alive, whereas 11 patients have died. Eight of these 11 patients died of complications related to progressive lymphoma, whereas three patients died of intercurrent illnesses.
Toxicity
Rituximab therapy was well tolerated. The adverse events encountered during the first treatment course are listed in Table 3. Sixty-two patients received a total of 245 rituximab doses. Only two patients had grade 3 or 4 adverse events. One patient, previously mentioned, had flushing, dyspnea, and ischemic chest pain. This was the only patient removed from therapy because of treatment-related toxicity. One additional patient had severe chills and rigors with the first dose of rituximab but was able to continue treatment without further episodes. The most common grade 1 or 2 toxicities were fever (18%), chills/rigors (26%), and nausea (21%). Almost all of the adverse events occurred during the first rituximab infusion. Eight patients (13%) had circulating malignant lymphocyte counts more than 10,000/µL when treatment was initiated. Four of these eight patients experienced grade 1 or 2 infusion-related toxicity during the first dose of rituximab, but none experienced grade 3 or 4 toxicity. The incidence of toxicity in patients older than 70 years was not different than toxicity in younger patients.
Toxicity observed during subsequent maintenance courses was less common than with the first course of rituximab. There were no additional episodes of grade 3 or 4 toxicity of any kind. There were no cumulative toxicities observed. No patient in this trial has had grade 3 or 4 myelosuppression, and there have been no opportunistic infections. Patients have not been assessed serologically for human antichimeric antibody reactions; however, there have been no clinical episodes to suggest sensitization.
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DISCUSSION
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The results of this multicenter phase II trial, now with minimum follow-up of 24 months, confirm the high level of activity with single-agent rituximab in the first-line treatment of patients with indolent NHL. The high initial response rate reported in the first 39 patients entering onto this trial4 is confirmed in a larger number of patients and with additional follow-up. We can now make several additional observations regarding this treatment approach. First, the response to first-line rituximab therapy was improved in a substantial percentage of patients by delivering maintenance rituximab courses every 6 months. In this trial, 16 of 27 patients with stable disease at first re-evaluation achieved objective response after the second or subsequent maintenance course of rituximab, and the complete response rate increased from 7% to 37%. Second, median progression-free survival for all patients was 34 months, which is considerably improved when compared with the 12-month median progression-free survival in previously treated patients receiving a single 4-week course of rituximab. Third, response rates and response duration were similar in the subgroups of patients with follicular lymphomas and SLL. Finally, the strategy of maintenance administration of rituximab was well tolerated, and no cumulative toxicities were encountered.
The high activity level of rituximab, when used as first-line treatment for follicular lymphoma, has also been documented by Colombat et al.9 In their trial, 50 patients with follicular lymphoma who fulfilled criteria for a low tumor burden were treated with a standard 4-week course of rituximab and then observed until tumor progression. The response rate, as measured 1 month after completion of rituximab therapy, was 73%, with a 20% complete remission rate. Although this patient population differed in several ways from the patients in our trial (eg, fewer symptomatic patients and patients with SLL were excluded), the response rates in the two trials were identical.
Treatment results with rituximab in patients with refractory SLL have been disappointing; previous reports have documented an overall response rate of approximately 15%.1,10 However, in this first-line rituximab trial, 17 (70%) of 24 patients with SLL had objective response to treatment, and the progression-free survival was similar to patients with follicular lymphoma. Recent reports using rituximab in higher weekly doses or three times weekly have suggested higher response rates in patients with previously treated chronic lymphocytic leukemia (CLL).11,12 In addition, incorporation of rituximab into first-line combination regimens for CLL has suggested improved activity versus chemotherapy alone.13 The mechanism of relative resistance to rituximab in patients with refractory CLL/SLL was initially postulated to be related to the lower density of CD20 expression on the cell membranes.14 More recently, a correlation between expression of cell surface complement inhibitors, such as CD55 and CD59, and resistance to rituximab has been suggested in patients with CLL/SLL.15 However, neither CD20 expression density nor the level of CD55/CD59 expression has correlated with response to rituximab in patients with follicular lymphoma.16 Further experience with rituximab in the first-line treatment of CLL/SLL is important because the documentation of major efficacy differences in the treatment of first-line versus refractory patients would help to define the optimal role of this drug. We are currently performing an identical trial using single-agent rituximab plus maintenance courses in previously untreated patients with CLL/SLL. As part of this trial, CD20 density measured before therapy will be correlated with response to rituximab.
For patients with follicular indolent lymphomas, rituximab is firmly established as part of standard treatment. However, several important questions regarding the most effective use of rituximab in these patients remain unresolved. In the majority of patients with follicular lymphoma who receive a sequence of palliative treatments, the optimal positioning of rituximab in the treatment sequence is undefined. Rituximab is clearly one of the most active agents for the treatment of these lymphomas. Two trials using single-agent rituximab as first-line treatment have demonstrated high response rates (74% and 73%).9 In addition, rituximab has less acute and chronic toxicity than other treatment options, as well as a shorter, more convenient duration of therapy. With the exception of oral chlorambucil, the cost of a 4-week course of rituximab may not be substantially higher than other standard options when all treatment and supportive care costs are included.17 Therefore, use of rituximab early in the sequence of therapy (ie, first- or second-line) seems most consistent with the goal of providing patients with effective, minimally toxic palliative therapy. Strong rationale now exists to administer rituximab as first-line treatment to patients who are elderly, have poor performance status, are hesitant to accept chemotherapy, or are uncomfortable with an observation only strategy.
The role of maintenance rituximab therapy is also unclear. In this trial, we have demonstrated the safety of this approach; repeated courses of rituximab were administered with no cumulative toxicity. In fact, the infusion-related toxicity with repeat courses was less frequent than during the first course, possibly because of the lower tumor burden present in most patients. In addition, the long median progression-free survival of 34 months suggests that maintenance rituximab extends the duration of remission when compared with treatment with a single 4-week course. However, the cost of treatment is increased by administering maintenance courses, and the overall benefit of this strategy versus re-treatment of responding patients with rituximab at the time of progression is unknown. Several observations from this trial that may favor a maintenance strategy versus re-treatment at progression include the following: (1) conversion of stable disease to objective response after maintenance courses, (2) an increased complete response rate, and (3) probable decreased toxicity of maintenance while in remission versus at relapse. Although the relative merits of maintenance versus re-treatment at progression are unresolved, it is clear that a substantial percentage of patients benefit from receiving more than a single 4-week course of rituximab. All patients who have an initial response to rituximab lasting more than 9 months should receive either maintenance treatment or re-treatment at the time of progression. Ongoing randomized trials should clarify this issue.
It seems likely that the addition of rituximab and/or other new agents to current chemotherapy regimens will ultimately prolong survival in patients with indolent lymphoma. Although randomized trials comparing standard chemotherapy versus chemotherapy/rituximab combinations have not been completed, results of several phase II trials have demonstrated high complete response rates and long response duration with chemotherapy plus rituximab.18-21 In addition to clinical complete response, the frequency of molecular complete remissions has been higher with rituximab-containing combinations.18,20,21 Eradication of clonal chromosomal changes has correlated with longer remission duration and improved cure rate in other hematologic malignancies. Although this correlation has not yet been proven in indolent NHL, it seems likely that the quality of complete remission is being improved by the addition of rituximab. As various rituximab-containing combination regimens are evaluated, the results of this trial with front-line, single-agent rituximab will provide a useful benchmark to evaluate the impact of additional agents.
APPENDIX
Minnie Pearl Cancer Research Network Participating Sites
The following sites participate in the Minnie Pearl Cancer Research Network:Tennessee Oncology, PLLC, Nashville, TN; Northwest Georgia Oncology Centers, P.C., Marietta, GA; Upstate Carolina CCOP, Spartanburg, SC; Jackson Oncology Associates, Jackson, MS; Atlanta Cancer Care, Atlanta, GA; Consultants in Blood Disorders and Cancer, Louisville, KY; Graves-Gilbert Clinic, Bowling Green, KY; Mary Bird Perkins Cancer Center, Baton Rouge, LA; Louisiana Oncology Associates, Lafayette, LA; Grand Rapids CCOP, Grand Rapids, MI; The Medical Oncology Group, PA, Gulfport, MS; Greenview Regional Hospital, Bowling Green, KY; King’s Daughters’ Medical Center, Ashland, KY; Northeast Alabama Regional Medical Center, Anniston, AL; Oncology and Hematology Associates of Southwest Virginia, Inc, Roanoke, VA; Hattiesburg Clinic, Hattiesburg, MS; Pasco Hernando Oncology Associates, PA, New Port Richie, FL; Hematology and Oncology Services, New Orleans, LA; Cancer Outreach Associates, PC, Abingdon, VA; Thompson Oncology Group, Knoxville, TN; Northeast Arkansas Clinic, Jonesboro, AR; and Providence Cancer Center, Mobile, AL.
The appendix listing Minnie Pearl Cancer Research Network participating sites is available online at www.jco.org.
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ACKNOWLEDGMENTS
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Supported in part by grant no. U0824n from Genentech, Inc, South San Francisco, CA, and a grant from The Minnie Pearl Foundation, Nashville, TN.
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Submitted August 9, 2001;
accepted June 27, 2002.
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TOP
ABSTRACT
INTRODUCTION
