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Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 33-38
Elderly Aggressive-Histology Non-Hodgkin's Lymphoma: First-Line
VNCOP-B Regimen Experience on 350 Patients
By
Pier Luigi Zinzani,
Sergio Storti,
Alfonso Zaccaria,
Luciano Moretti,
Massimo Magagnoli,
Enzo Pavone,
Patrizia Gentilini,
Luciano Guardigni,
Marco Gobbi,
Pier Paolo Fattori,
Brunangelo Falini,
Vito
Michele Lauta,
Maurizio Bendandi,
Filippo Gherlinzoni,
Amalia De Renzo,
Francesco Zaja,
Patrizio Mazza,
Ettore Volpe,
Monica Bocchia,
Enrico Aitini,
Maurizio Tabanelli,
Giuseppe Leone, and
Sante Tura
From the Institute of Hematology "Seràgnoli," University
of Bologna, Bologna; the Department of Hematology,
"Cattolica" University of Roma, Roma; the Hematology Division,
Ravenna Hospital, Ravenna; the Hematology Division, Pesaro Hospital,
Pesaro; the Department of Hematology, University of Bari, Bari; the
Oncology Division, Forlì Hospital, Forlì; Hematology
Unit, Cesena Hospital, Cesena; the Department of Hematology, University
of Genova, Genova; the Oncology Division, Rimini Hospital, Rimini; the
Department of Hematology, University of Perugia, Perugia; the
Department of Medicine, University of Bari, Bari; the Department of
Hematology, University of Napoli, Napoli; the Department of Hematology,
University of Udine, Udine; the Hematology Division, Taranto Hospital,
Taranto; the Division of Hematology, Avellino Hospital; the Department
of Hematology, Siena Hospital, Siena; the Oncology Division, Mantova
Hospital, Mantova; the Hematology Unit, Lugo Hospital, Lugo, Italy.
 |
ABSTRACT |
Age is a risk factor and a prognostic parameter in elderly
aggressive-histology non-Hodgkin's lymphoma (NHL) patients. Several adapted chemotherapeutic regimens have recently been designed and
tested on elderly patients. Several of these trials have shown that
older aggressive-histology NHL patients can benefit from specific and
adequate treatment capable of curing a percentage of these patients.
Between January 1992 and September 1997, 350 previously untreated
aggressive-histology NHL patients greater than 60 years of age were
treated with a combination therapy including cyclophosphamide,
mitoxantrone, vincristine, etoposide, bleomycin, and prednisone
(VNCOP-B). Complete remission (CR) was achieved by 202 (58%) patients
and partial remission (PR) by 87 (25%), whereas the remaining 61 (17%) patients were nonresponders. The overall response rate (CR + PR) was 83%. Clinical and hematologic toxicities were modest, because
71% of the patients received granulocyte colony-stimulating factor
(G-CSF). The CR rates for the three age groups (60 to 69, 70 to 79, and
 80 years) were similar: 61%, 59%, and 56%, respectively. At 5 years, the relapse-free survival rate was 65%, the overall survival
rate was 49%, and the failure-free survival rate was 33%. In the
multivariate analysis, prognostic factors associated with longer
survival or longer relapse-free survival turned out to be localized
disease stage (P = .001) and good performance status
(P = .0002). Application of the International Prognostic
Factor Index was significantly associated with outcome (P
= .001). These data confirm on a large cohort of patients that the VNCOP-B regimen is effective in inducing good CR and relapse-free survival rates with only moderate toxic effects in elderly
aggressive-histology NHL.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
AMONG THE VARIOUS CLASSES of malignant
disease, lymphomas have one of the most rapidly increasing
incidences.1-3 In this group, aggressive-histology
non-Hodgkin's lymphoma (NHL) presents a peak incidence in the age
subset greater than 60 years. In addition, in line with the findings of
large randomized trials that have shown constant cure rates for
aggressive-histology NHL, but no further increase in cure rates with
more intensive therapy during the last decades,4,5
mortality rates have remained unchanged for younger people but have
increased in elderly patients, the highest being observed in males
older than 75 years.
Thus, in the last years, age has emerged as an important risk factor
for aggressive-histology NHL.6-8 This observation could be
explained by the fact that therapy is more toxic and the biology of the
disease more aggressive in the elderly, and by the greater reluctance
to diagnose and treat an elderly patient. Since the induction of
primary complete remission (CR) has been successful in equivalent
percentages of elderly and younger patients, it would seem that these
two subgroups do not differ as regards tumor biology per se and
chemosensitivity. In studies composed of nonselected patients, the
worse outcomes for elderly patients could apparently be explained by
higher toxicity of full-dose chemotherapy, age-associated comorbidity,
and a lower response rate after relapse.9-11 Numerous attempts have been made to analyze the contribution to the age-related worsening of prognosis of factors, such as the biology of the disease,
age-specific comorbidity (hypertension, depression, respiratory disease, diabetes, etc), and the degree of cytotoxicity (substantial alterations in pharmacokinetics of the drugs) with increased
cardiotoxicity, pulmonary toxicity, and mucositis.
Recently, age-adapted treatment regimens, from first to third
generation, have been designed and tested for their feasibility and
efficacy in elderly aggressive-histology NHL patients.12-22 In addition, progress has been made in defining maximally tolerated doses of the cytotoxic drugs and specifically testing anthracyclines with reduced cardiotoxicity,23-26 as well as in
investigating the advantages of applying hematopoietic growth factors
in this older population.
Since 1992, we have performed prospective studies on elderly
aggressive-histology NHL patients using a treatment protocol developed
at the "Seràgnoli" Institute in Bologna: an 8-week pilot
regimen, the VNCOP-B protocol, using moderate doses of chemotherapy at
frequent dosing intervals, obtained a good remission
rate.27 Subsequently, we performed a multicenter randomized
trial that included granulocyte colony-stimulating factor (G-CSF) as a
further component of treatment to determine whether toxicity can be
further reduced without sacrificing efficacy.28 In
this report, we summarize the data concerning our entire experience
with VNCOP-B regimen on 350 previously untreated elderly
aggressive-histology NHL patients.
| |
PATIENTS AND METHODS |
The present study regards 350 consecutive, previously untreated
aggressive-histology NHL patients older than 60 years of age diagnosed
between January 1992 and September 1997. It should be noted that 149 of
these patients were previously presented in a randomized trial on the
role of G-CSF.28 Eligibility criteria included a confirmed
histologic diagnosis of aggressive-histology NHL according to the
updated Kiel classification (Burkitt's lymphomas and lymphoblastic
lymphomas were excluded from this study)29; disease stage
II to IV according to the Ann Arbor staging system30; Eastern Cooperative Oncology Group (ECOG)31 performance
status less than 3; human immunodeficiency virus-negative; and normal renal, hepatic, and cardiac functions. The diagnosis was reviewed by a
panel of pathologists during the study period, and patients who did not
fulfill all of the inclusion criteria were excluded from the final evaluation.
Staging evaluation included initial hematologic and chemical survey, in
addition to chest x-rays, abdominal ultrasonography, computerized
tomography of the chest and abdomen, and bone marrow biopsy in all
patients. Other studies included lymphography, and liver biopsy when
appropriate; no patient underwent staging laparotomy. Bulky disease was
defined as a tumor mass 6 cm. Approval was obtained from the
Institutional Review Board for these studies. Informed consent was
provided according to the Declaration of Helsinki.
Patient characteristics.
Characteristics of the 350 patients are listed in Table
1. The median age was 69 years (range, 60 to 87); 55 (16%) patients were older than 80 years, and 12 (3.5%)
were 85 years. A considerable percentage of patients had clinically
aggressive disease: in particular, 65% had stage III or IV disease,
28% had a bulky disease, 25% had two or more extranodal sites, 18%
had bone marrow involvement, and 35% had increased values of serum
lactic dehydrogenase (LDH). The age-adjusted index, according to the
International Prognostic Factor Index,6 was used, because
all of the patients were older than 60 and, thus, the age parameter of
the complete index was irrelevant. According to this index, 63 (18%)
patients had no adverse factors, 137 (39%) had one factor, 109 (31%)
had two factors, and 41 (12%) had three adverse parameters.
Treatment protocol.
The VNCOP-B is a MACOP-B (methotrexate, doxorubicin, cyclophosphamide,
vincristine, prednisone, bleomycin)-like regimen32 with
several distinctive features: treatment is completed in 8 weeks and
includes mitoxantrone and etoposide instead of doxorubicin and
methotrexate, respectively. We selected these replacements with the aim
to reduce the incidence of mucositis and cardiac side effects. Drug
doses, including prednisone (intramuscular or oral administration),
were reduced by one third; all treatment was given on an outpatient
basis. Doses and schedule of the VNCOP-B program are listed in Table
2. The single-day dosing schedule of
etoposide was chosen for logistic reasons. The G-CSF administration was
5 µg/kg/d subcutaneously throughout treatment, starting on day 3 of
every week for 5 consecutive days. All patients received bacterial and
Pneumocystis carinii prophylaxis with cotrimoxazole (2 consecutive days per week) during the entire course of therapy.
Response.
All patients were restaged after completion of chemotherapy. Clinical
and pathologic evaluations were made by repeating radiographic investigations and bone marrow and/or liver biopsies if previous results had been positive. CR was defined as the total disappearance of
signs and symptoms due to disease, as well as the normalization of all
previous abnormal findings. Partial remission (PR) was defined as the
reduction of at least 50% of known disease with disappearance of the
systemic manifestations. No response (NR) was anything less than a PR.
Standard ECOG toxicity criteria were used.31
Statistical methods.
The survival curve was measured from the time of entry into the
protocol until death; the relapse-free interval was calculated from the
date of response until relapse or death. Survival, relapse-free survival, and failure-free survival curves were calculated according to
the method of Kaplan and Meier.33
Deaths from lymphoma, secondary to lymphoma treatment, or to a possibly
related or unrelated disease were considered an event. Analyses of
prognostic factors were performed with log-rank tests, Cox's
analysis,34 and logistic regression analysis.
| |
RESULTS |
Treatment outcome is summarized in Table 1. A CR was achieved by 202 of
350 (58%) patients, and PR by 87 (25%) patients, while the remaining
61 patients had NR. The overall response rate (CR + PR) was 83%. The
CR rates for the three age groups (60 to 69, 70 to 79, and 80 years)
were similar: 61%, 59%, and 56%, respectively.
Among the 202 patients who achieved CR, 48 (24%) relapsed. The overall
rate of relapse-free survival for the 202 patients with CR was 65% at
69 months (median, 36 months; range, 9 to 72) (Fig 1).
The majority of relapses was observed within the first 24 months: 43 of
48 (90%). After 2 years, only five patients showed a relapse. The
overall survival rate at 69 months was 49% (Fig 2). The overall survival rates
of the three age groups (60 to 69, 70 to 79, and 80 years) were
similar: 53%, 51%, and 47%, respectively. At 69 months, the
failure-free survival rate was 33% (Fig 3).
Toxic effects.
With regard to hematologic toxicity, the incidence of anemia and
thrombocytopenia was less than 10% and transfusions were not required.
Neutropenia less than 0.5 × 109/L occurred in 103 of
350 (29%) patients. These data are underestimated because in 248 of
350 (71%) patients, we used G-CSF with a subcutaneous administration
throughout the treatment, starting on day 3 of every week for 5 consecutive days. The same consideration has to be made for the
frequency of clinically relevant infections: in fact, patients who
received G-CSF showed a significantly lower incidence of neutropenia
with the reduction of the number of infections. Globally, clinically
relevant infections were recorded in 39 of 350 (11%) patients.
Nonhematologic toxicity was minimal. Mild mucositis was observed in a
few patients. Cardiac, liver, and renal problems were not observed.
There were only four (1%) fatalities due to drug side effects during
the treatment period (two from sepsis, one gastric hemorrhage, and one
P carinii infection). Four patients died of solid neoplasms
(one liver, one pancreas, one meningioma, and one melanoma).
Statistical analysis.
To evaluate whether any covariate prognostic factor could influence the
outcome of CR, adjustment for the prognostic factors was performed by
the linear logistic model. Information on nine prognostic factors (age,
sex, presence or absence of B symptoms, stage, LDH level, presence or
absence of bulky disease, extranodal sites, histologic subtype, and
performance status) was associated with the outcome of all of the
patients (Table 3). Lower CR
rate was correlated to the presence of bulky disease (P = .02),
poor performance status (P = .01), and advanced stage
(P = .01). The prognostic factors associated with longer
relapse-free survival in univariate analyses (log-rank test) were
localized disease stage (P = .001 and P = .002, respectively), good performance status (P = .0001 and P = .0001), and normal LDH level (P = .03 and P = .01).
In a Cox multivariate analysis, the prognostic factors most
significantly associated with longer survival or longer relapse-free survival were localized disease stage (P = .001) and good
performance status (P = .0002). The International Prognostic
Factor Index6 was significantly associated with outcome
(P = .001) (Fig 4).
| |
DISCUSSION |
During the last several years it has become clear that the treatment of
elderly aggressive-histology NHL patients has been underevaluated, with
confounding factors being caused not only by prejudice on the part of
patients, but sometimes also by the attitudes of specialists. The
increasing efforts in analyzing the contribution of these factors to
the inferior treatment outcome of older aggressive-histology NHL
patients is therefore a major prerequisite in a more scientific
approach to developing treatment protocols specifically adapted to the
situations of elderly subjects. In this context, scientifically
reproducible (rather than individualized) estimations of a patient's
comorbidity, fitness, and natural life expectancy are required. In
addition, ways of determining the quality of life of a given subject
that move from the patient's and not the physician's viewpoints will
have to be developed.
Back in the days of first-generation chemotherapeutic regimens, when in
a Southwest Oncology Group (SWOG) study CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy was reduced by
50% in patients over 65 years of age, CR rates declined.35 However, in a small subset of patients over 65 years of age who received full doses, the CR rate approximated that of younger patients.
Fisher et al4 subsequently indicated that the gold-standard regimen for elderly aggressive-histology NHL patients was CHOP. However, at full dosage, the percentage of toxic deaths increased, while the CR rate decreased when the doses were reduced. Recently, three prospective, randomized studies36-38 have shown that
the standard CHOP regimen can be given in sufficient doses to elderly aggressive lymphomas obtaining CR rates of 45%,38
49%,37 or 68%.36 In these studies, the
treatment-related mortality rate was between 0% and 15%.
Pirarubicin, an anthracycline supposed to display reduced
cardiotoxicity, has also been used in place of doxorubicin. As shown by
the data of the randomized Groupe d'Etude des Lymphomes de l'Adulte
(GELA) study,23 the pirarubicin-containing CTVP regimen was
superior to CVP (cyclophosphamide, vincristine, and
prednisone), despite its higher level of toxicity. CTVP
produced a CR rate of 47% with a treatment-related mortality rate of
15%.
Full dosage second- and third-generation protocols appear to be too
intensive to be administered to elderly aggressive-histology NHL
patients without significantly escalating toxicity. Nevertheless, new
protocols specifically tailored to the tolerance and the biologic (rather than calendar) age of patients have been reported to produce functional lymphoma therapy in the elderly.11-22 All of
these regimens were characterized by a shorter duration and by the use
of doxorubicin-free protocols to reduce the incidence of
cardiotoxicity. Among these adapted regimens, the CR rate ranged
between 45% and 75%. In particular, third-generation protocols
usually combine myelosuppressive and nonmyelotoxic medications in rapid
alternation with the aim of reducing the risk of cross-reactivity
together with the length of treatment while maintaining or enhancing
dose-intensity.
In 1993, we reported that VNCOP-B (a MACOP-B-like methotrexate-and
doxorubicin-free regimen) was generally well tolerated, with 85% of
patients able to complete all courses of therapy at the full dose; the
overall response rate was 93% with a CR rate of 76%.27
Following this, we have set out to confirm these preliminary data in a
multicenter prospective study and to evaluate the role of G-CSF in this
protocol in a randomized trial. In 1997, we reported that the VNCOP-B
CR rate was 59% and that G-CSF turned out to be effective in reducing
the neutropenia and infection rates.28 Other reports have
shown that hematopoietic growth factors can reduce hematologic toxicity
in this subset of patients.39-41
The present global evaluation of all 350 elderly aggressive-histology
NHL patients who received the VNCOP-B regimen as first therapy showed a
CR rate of 58% without statistically significant modifications of the
CR rate among the different age subgroups (60 to 69, 70 to 79, and 80
years). The 5-year relapse-free rate was 65%, with a median of 36 months, and the 5-year overall survival rate was 49%, with a
failure-free survival rate of 33%. The drug-related death rate was
only 1%. The International Prognostic Factor Index6 was
significantly associated with outcome.
On the basis of these data on a large cohort of patients, some
observations are apparent: (1) the VNCOP-B regimen is effective in
elderly patients with advanced aggressive-histology NHL, with a CR rate
only slightly lower than that obtained in younger aggressive-histology NHL patients; (2) the complete responders have a good probability of a
long-term survival; and (3) considering the few cases of clinical
toxicity, VNCOP-B treatment is well tolerated (with the inclusion of
G-CSF) and there is no evidence of severe or permanent toxic effects.
With the aim of reducing the gap between the older and younger
aggressive-histology NHL and also among the different prognostic
subgroups of elderly patients, we have recently started a prospective
comparative study between 8-week VNCOP-B and 12-week VNCOP-B (with the
inclusion of G-CSF in both protocols) in order to evaluate CR, overall
survival, and relapse-free survival rates.
| |
ACKNOWLEDGMENT |
The authors thank Robin M.T. Cooke for language editing.
| |
FOOTNOTES |
Submitted November 30, 1998; accepted March 1, 1999.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Pier Luigi Zinzani, MD, Istituto di
Ematologia e Oncologia Medica "Seràgnoli," Policlinico S. Orsola, Via Massarenti 9 40138 Bologna, Italy.
| |
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ABSTRACT
INTRODUCTION
