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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Lymphoma Trials Office at the CRC and UCL
Cancer Trials Office, London, United Kingdom.
A prospective, multicenter, randomized trial was undertaken to
compare the efficacy and toxicity of adriamycin with mitoxantrone within a 6-drug combination chemotherapy regimen for elderly patients (older than 60 years) with high-grade non-Hodgkin lymphoma (HGL) given
for a minimum of 8 weeks. A total of 516 previously untreated patients
aged older than 60 years were randomized to receive 1 of 2 anthracycline-containing regimens: adriamycin, 35 mg/m2
intravenously (IV) on day 1 (n = 259), or mitoxantrone, 7 mg/m2 IV on day 1 (n = 257); with prednisolone, 50 mg
orally on days 1 to 14; cyclophosphamide, 300 mg/m2 IV on
day 1; etoposide, 150 mg/m2 IV on day 1; vincristine, 1.4 mg/m2 IV on day 8; and bleomycin, 10 mg/m2 IV
on day 8. Each 2-week cycle was administered for a minimum of 8 weeks
in the absence of progression. Forty-three patients were ineligible for
analysis. The overall and complete remission rates were 78% and 60%
for patients receiving PMitCEBO and 69% and 52% for patients
receiving PAdriaCEBO (P = .05, P = .12,
respectively). Overall survival was significantly better with PMitCEBO
than PAdriaCEBO (P = .0067). However, relapse-free
survival was not significantly different (P = .16). At 4 years, 28% of PAdriaCEBO patients and 50% of PMitCEBO patients were
alive (P = .0001). Ann Arbor stage III/IV, World Health
Organization performance status 2-4, and elevated lactate dehydrogenase
negatively influenced overall survival from diagnosis. In conclusion,
the PMitCEBO 8-week combination chemotherapy regimen offers high
response rates, durable remissions, and acceptable toxicity in elderly
patients with HGL.
(Blood. 2001;97:2991-2997) The incidence of non-Hodgkin lymphoma (NHL)
increases exponentially with age, and most patients are 60 years of age
or older at diagnosis.1-3 A dramatic increase in the
incidence of NHL is occurring that is not fully explained by advances
in diagnosis, changes in pathological classification systems, and the
impact of acquired immunodeficiency syndrome. The rate of increase in adults in the United Kingdom, Europe, and the United States is approximately 3% to 4% per year, with mortality rates from NHL increasing at approximately 2% per year.3-6 The largest
increase in incidence has occurred in the elderly,3 and a
recent review has estimated that at least a doubling in the number of
new lymphoma patients over 65 years of age will occur over the next 20 to 25 years concomitant with improvements in supportive care and the aging of Western populations.7
High-grade and aggressive histologies constitute most NHL diagnosed in
the elderly. However, there is no consistent evidence for a difference
in the distribution of main histologic subgroups between patients aged
less than or more than 60.7 In the past, age limits for
inclusion in clinical trials conducted in patients with NHL have meant
that few randomized trials have specifically addressed the questions of
therapeutic efficacy and toxicity in the elderly
population,8 despite evidence that the prognostic impact
of age occurs in conjunction with other factors.9-13
Several hypotheses have been generated and examined to explain these
results, including lymphoma biology itself, reduction in delivery
of total dose and/or dose intensity, reduced treatment toxicity
tolerance, and concomitant medical issues.14-16
During the 1980s, second- and third-generation combination chemotherapy
regimens adapted for the elderly suggested similar outcomes with
reduced toxicity in comparison to regimens for younger patients with
similar histologies.17-25 In the prednisolone, adriamycin, cyclophosphamide, etoposide, bleomycin, oncovin (vincristine), methotrexate (PACEBOM) alternating, weekly, combination chemotherapy regimen, the major toxicity problem was mucositis, which could be
markedly reduced by the omission of methotrexate.26 In
this modified regimen, PAdriaCEBO, the greatest contributor to toxicity is adriamycin. The addition of an anthracycline significantly increases
the complete remission (CR) rate, the median time to treatment
failure, and the 5-year overall survival rate in elderly patients with
aggressive NHL.17 The possibly reduced toxicity, and
excellent activity of mitoxantrone in aggressive NHL led to the
establishment of several randomized trials comparing adriamycin with
mitoxantrone in multiagent regimens.24,27-30 This study
was undertaken to establish the response rates, overall survival, and
disease-specific survival obtained with an 8-week, 6-drug regimen and
to compare the efficacy and toxicity of PAdriaCEBO with PMitCEBO in
elderly patients with high-grade NHL.
Between January 1993 and February 1997, the British National
Lymphoma Investigation (BNLI) conducted a randomized, multicenter trial
in elderly patients with HGL comparing the multiagent PAdriaCEBO chemotherapy regimen with the PMitCEBO regimen. Eligibility criteria included age between 60 and 85 years; previously untreated high-grade lymphoma defined as large cell lymphoma and diffuse large-cell lymphoma, including immunoblastic lymphoma and diffuse mixed-cell lymphoma and excluding lymphoblastic and Burkitt lymphoma
(intermediate- and/or high-grade malignancy, groups D through H
according to the Working Formulation31); stage IB-IV
disease; and normal renal, hepatic, and cardiac function.
Patients with prior low-grade lymphoma, severe intercurrent illness,
positive human immunodeficiency virus serology, or previous malignancy
were excluded. A central BNLI panel reviewed all histology, and all
staging was performed according to the Ann Arbor classification.
Diagnostic and staging procedures at entry included, as a minimum, a
full blood count; liver function tests; measurement of erythrocyte
sedimentation rate, serum electrolytes, and calcium, phosphate, and
serum lactate dehydrogenase (LDH) levels; chest x-ray, computed
tomography scan of the abdomen and pelvis, bone marrow aspiration, and
trephine. Examination of the cerebrospinal fluid was not
performed unless clinically indicated. Randomization was performed
centrally through the BNLI office for patients to receive either
PAdriaCEBO or PMitCEBO. Ethics committee approval was obtained in all
participating centers.
Treatment regimens
Response
Statistical analysis
The demographic characteristics of the 473 eligible patients
enrolled in this study are presented in Table
1. Both treatment groups were well
balanced regarding baseline characteristics. There were no statistical
differences in the age-adjusted prognostic factors. Forty-three
patients (8%) were found to be incorrectly enrolled, 6% (16 of 259)
were ineligible in the PAdriaCEBO arm and 11% (27 of 257) in the
PMitCEBO arm (P = ns). After central pathology review, 40 patients had their histologic diagnosis changed from HGL and 3 patients
were ineligible for other reasons: 1 because the patient was too young
and the other 2 because they were too old. In addition, a further 7 eligible patients were lost to follow-up for the survival
analyses.
Response Response rates for assessable patients in both treatment arms are outlined in Table 2. For patients receiving PMitCEBO the CR rate was 60% (138 of 230), and 52% (126 of 243) patients receiving PAdriaCEBO had a CR to therapy (P = .12). Partial response rates were not significantly different; however, overall response rates were significantly in favor of treatment with PMitCEBO, 78% versus 69% ( 2 = 4.53, P = .05). Three patients are
not evaluable for response; 1 patient refused treatment, and 2 patients
were lost to follow-up.
Survival The median follow-up time is 20 months for all patients and 26 months for complete responders. Survival curves are illustrated in Figures 2 to 4, demonstrating overall, relapse-free, and lymphoma-specific survival. There was a significant overall survival advantage for patients receiving PMitCEBO (P = .0067), with a trend for improved cause-specific survival (P = .06). The 4-year cause-specific survival was 35% for patients receiving PAdriaCEBO and 59% for patients receiving PMitCEBO (P < .001), and the 4-year overall survival was significantly inferior for patients receiving PAdriaCEBO (28%) compared with those receiving PMitCEBO (50%) (P < .001). Relapse-free survival was not significantly different between the 2 arms of the trial (P = .16). Overall and cause-specific survival were negatively influenced by treatment, age, stage at presentation, and performance status. LDH was not routinely performed by some centers and was not included in these analyses; however, LDH significantly influenced overall and progression-free survival (P = .03 and P = .04, respectively). After multivariate analysis, these factors continued to carry prognostic value (Table 3).
Deaths There were significantly fewer deaths in the mitoxantrone-containing arm (107 of 230 vs 137 of 243;2 = 4.21, P = .04), with 100 deaths
occurring from NHL for patients receiving PAdriaCEBO and 84 deaths for
patients receiving PMitCEBO (P = .45). The causes of death
in both treatment groups are listed in Table
4. There was a trend for an increase in
risk of treatment-related deaths in the PAdriaCEBO arm (22 of 243 vs
11/230, respectively; 2 = 2.70, P = .10).
There were no differences in cardiac deaths, with 8 in each
arm.
Treatment received Patients receiving PMitCEBO received significantly more treatment than patients receiving PAdriaCEBO (Table 5).
Toxicity Toxicities graded according to the common toxicity criteria are listed in Tables 6 and 7. There was significantly more leucopenia and thrombocytopenia in the patients receiving PAdriaCEBO (P = 0.02 and P = 0.008, respectively); however, clinically significant infections were not different. There were no other clinically significant differences in toxicity between the 2 groups.
The management of elderly patients with HGL requires special consideration because of the increased risk of toxicity and death from treatment and disease. Initiatives to improve cytotoxic delivery without compromising benefit have led investigators to develop weekly, multiagent chemotherapy regimens.20-23,25,36-55 Improvements in supportive care enable the delivery of chemotherapy at standard doses and intensity to deliver maximum benefit to patients.56 The minimum age of entry of 60 was chosen because patients younger than this were eligible for high-dose regimens and because this age carried prognostic significance in the international prognostic index (IPI) analyses. In the BNLI randomized trial conducted in patients of all ages with stage II-IV HGL, treatment with PACEBOM was comparable with the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen: CR rate of 64% (vs CHOP, 57%; P = ns) and an actuarial overall survival at 4 years of 61% (vs CHOP, 54%; P = ns).26 The current trial was designed to compare response rates, disease-free survival, overall survival, and toxicity between adriamycin and mitoxantrone in the PACEBOM regimen modified for elderly patients. The ratio of mitoxantrone to doxorubicin dose was based on the interim analyses of concurrent trials examining the same issue.24,27-30 In this study, the overall response rates were superior for elderly patients with HGL receiving PMitCEBO compared with PAdriaCEBO (Table 2). Both rates compare favorably with other randomized studies in elderly patients as well as the standard CHOP chemotherapy regimen.24,27,29,57-59 The data from this trial confirm the finding from The International Non-Hodgkin's Lymphoma Prognostic Factors Project (IPI) that patients older than 60 years had CR rates that were similar to those observed in younger patients.12 Patients in the mitoxantrone arm had significantly better overall survival and trend for improved cause-specific survival, reflecting durable remissions after chemotherapy in this group (Figures 2-4). The IPI retrospective analysis reported that the prognostic factors impacted on lower rates of complete responses and higher rates of relapse.12 Relapse rates at 2 years are 64% and 69% for PAdriaCEBO and PMitCEBO, respectively, and at 4 years are 38% and 58% for PAdriaCEBO and PMitCEBO, respectively. These rates compare favorably with those seen in the Dutch Hemato-Oncology Study Group trial of mitoxantrone substitution for adriamycin in elderly patients with HGL.24 Partial and NPPR rates were similar between the 2 arms, excluding slow responses as a cause for poorer prognosis.60 The age for inclusion in this trial was chosen in order to maintain consistency with trials examining the role of high-dose chemotherapy in younger patients with poor prognostic features and because this was the discriminating value reported in the IPI study. The multivariate model based on tumor stage, serum LDH, and performance status was not significantly different between the 2 treatment groups in this trial. Gómez and colleagues retrospectively analyzed a cohort of elderly (older than 60 years) patients with aggressive NHL who received treatment with adriamycin-based chemotherapy. They reported that the risk of treatment-related death was associated with poor performance status and not with increasing age.61 A recent retrospective analysis of IPI factors using an extension of the Cox proportional hazards model in patients younger than 60 years with aggressive NHL identified performance status as the only predictive factor for survival during the first 3 months of therapy.62 In this trial treatment, age, stage, and performance status carried prognostic significance. Differences in patient characteristics between the 2 trial arms were not seen and therefore cannot account for the superior activity of PMitCEBO. Treatment with either regimen was well tolerated in both groups with acceptable hematologic and nonhematologic toxicities as well as comparable treatment-related death rates. There were no differences in cardiac or infectious complications that may have affected survival in this elderly population. There is no evidence to support increased response rates with weekly mitoxantrone as a single agent63,64; however, several groups have examined its role in combination regimens. Zinzani and colleagues have reported their results of a regimen similar to PMitCEBO, called VNCOP-B, in elderly patients with aggressive NHL. They treated 29 patients with cyclophosphamide, 250 mg/m2, and mitoxantrone, 10 mg/m2, delivered on weeks 1, 3, 5, and 7; vincristine, 2 mg administered on weeks 2, 4, 6, and 8; etoposide, 100 mg/m2 administered on weeks 2 and 6; bleomycin, 8 mg/m2 administered on weeks 4 and 8; and prednisone, 40 mg given intramuscularly daily throughout therapy.46 They reported 22 CRs (76%), an overall response rate of 93% and, after a median of 13 months of follow-up, overall survival of 75%. These results support the use of short-duration weekly combination chemotherapy regimens for elderly patients with HGL. Phase II trials of less aggressive regimens have less toxicity at the expense of reduced response rates.23 Mitoxantrone has been substituted for adriamycin in combination chemotherapy regimens for a variety of malignancies because of good activity and reduced toxicity at equivalent levels of bone marrow suppression and with a milligram-to-milligram ratio of approximately 5:1.65 Several groups have undertaken randomized comparisons of mitoxantrone substituted for adriamycin in patients with HGL. Elderly patients (older than 60 years) receiving CHOP had superior CR rates and lymphoma-specific and overall survival rates compared with patients receiving CNOP.24 In the trial by Bezwoda et al, patients receiving CNOP had faster times to CR and nearly double the median relapse-free survival compared with patients receiving CHOP.59 Other groups have not been able to demonstrate any differences in response rates or survival in their trials, which included patients of all ages.27-29,57,66 A possible reason for an improved drug regimen is that the drugs are better tolerated and a greater proportion of the planned dose intensity is actually given.67-69 In Table 5, it is apparent that significantly more of nearly all drugs were administered in the PMitCEBO arm, but this, of course, is confounded by the fact that the lower response rate with PACEBO led to earlier discontinuation of this therapy. After 4 weeks, for instance, the anthracycline and cyclophosphamide delivered was the same in both arms (data not shown). The issue of dose intensity cannot be accurately addressed because of the way in which the date of chemotherapy administration was recorded. In conclusion, the PMitCEBO arm resulted in a significant improvement in lymphoma control although the reasons for this are not fully clear. If a weekly schedule of combination chemotherapy is used to treat elderly patients with HGL, it is preferable to use an anthracenedione such as mitoxantrone than an anthracycline such as doxorubicin. These results compare favorably with other polychemotherapy regimens used in the elderly.
Submitted April 26, 2000; accepted January 22, 2001.
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.
Reprints: David Cunningham, Royal Marsden Hospital, Downs Rd, Sutton Surrey SM25PT, United Kingdom; e-mail: dcunn{at}icr.ac.uk.
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Abstract
Introduction
a Groupe d'Etude des Lymphomes de l'Adulte study on 453 patients older than 69 years.
J Clin Oncol.
1997;15:2945-2953