Randomized trial of 8-week versus 12-week VNCOP-B plus G-CSF regimens as front-line treatment in elderly aggressive non-Hodgkin’s lymphoma patients

P. L. Zinzani1,+, F. Gherlinzoni1, S. Storti2, A. Zaccaria3, E. Pavone4, L. Moretti5, P. Gentilini6, L. Guardigni7, A. De Renzo8, P. P. Fattori9, B. Falini10, V. M. Lauta11, D. Mannina12, F. Zaja13, P. Mazza14, E. Volpe15, F. Lauria16, E. Aitini17, F. Ciccone18, M. Tani1, V. Stefoni1, L. Alinari1, M. Baccarani1 and S. Tura1

1 Institute of Hematology ‘Seràgnoli’, University of Bologna, Bologna; 2 Chair of Hematology, ‘Cattolica’ University of Roma, Roma; 3 Hematology Division, Ravenna Hospital, Ravenna; 4 Chair of Hematology, University of Bari, Bari; 5 Hematology Division, Pesaro Hospital, Pesaro; 6 Oncology Division, Forlì Hospital, Forlì; 7 Hematology Unit, Cesena Hospital, Cesena; 8 Division of Hematology, Federico II University, Napoli; 9 Oncology Division, Rimini Hospital, Rimini; 10 Chair of Hematology, University of Perugia, Perugia; 11 Chair of Medicine, University of Bari, Bari; 12 Hematology Division, Messina Hospital, Messina; 13 Chair of Hematology, University of Udine, Udine; 14 Hematology Division, Taranto Hospital, Taranto; 15 Department of Hematology, Avellino Hospital, Avellino; 16 Department of Hematology, University of Siena, Siena; 17 Oncology Division, Mantova Hospital, Mantova; 18 Hematology Division, Latina Hospital, Latina, Italy

Received 22 January 2002; accepted 5 March 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Among the third-generation chemotherapy regimens specifically adapted in the last decade for elderly aggressive non-Hodgkin’s lymphoma (NHL) patients, we designed an 8-week cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin and prednisone (VNCOP-B) plus granulocyte colony-stimulating factor (G-CSF) regimen which, in a national multicenter trial, induced good complete response (CR) and relapse-free survival rates with only moderate toxic effects. Here we report a prospective, multicenter, randomized trial comparing the efficacy and toxicity of 8- and 12-week regimens of VNCOP-B plus G-CSF.

Patients and methods:

From February 1996 to June 2001, 306 consecutive previously untreated stage II–IV aggressive NHL patients >=60 years of age were enrolled from 12 Italian cooperative institutions. Of the 297 evaluable patients, 149 and 148 received 8- and 12-week regimens, respectively, of VNCOP-B.

Results:

The CR rates were 63% and 56% in the 8- and 12-week groups; at a median of 32 months (range 3–62 months), relapse-free survival rates were 59% and 55%, respectively. Hematological and non-hematological toxicities were similar in both treatment groups.

Conclusions:

Our data show that extending induction treatment with the VNCOP-B plus G-CSF regimen from 8 to 12 weeks does not raise the CR rate or provide a more durable remission.

Key words: aggressive non-Hodgkin’s lymphoma, elderly patients, granulocyte colony-stimulating factor, VNCOP-B regimen


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The incidence of non-Hodgkin’s lymphomas (NHL) has rapidly increased in recent years in both the USA and Europe [1, 2]. In various published series, a significant proportion of patients were ‘elderly’ at diagnosis [36], although the age categories were defined using different cut-off points (i.e. 60, 65 or 70 years of age). Whatever the definition of elderly patients, the incidence of lymphoma between the ages of 20 and 80 years increases exponentially. The literature strongly hints that the lymphomas seen in the elderly differ intrinsically from those found in the younger population. The available data indicate that a clinically relevant shift to more aggressive subtypes of NHL occurs with advancing age. A possible indicator of altered histology is the more frequent involvement of extranodal sites in the elderly. It seems reasonable to suppose that in the elderly NHL does have a different biology, based on the observations that the more aggressive histological subtypes are more frequently encountered and extranodal disease is more common.

Aggressive NHL can potentially be cured by intensive cytotoxic chemotherapy if a complete remission (CR) is achieved. However, such chemotherapy may cause severe and even life-threatening toxicity in older individuals. Combination chemotherapy in elderly aggressive NHL patients consisted, initially, in the use of the same regimens employed in younger adults and, more recently, in the development of regimens specifically designed to decrease toxicity without losing therapeutic activity [718]. The goals of these studies were to use different chemotherapeutic drugs to reduce toxicity with respect to the gold-standard cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimen. The hope was to deliver an effective regimen while maintaining quality of life by ameliorating side effects. Mitoxantrone has often been used to minimize cardiac toxicity, nausea, vomiting, mucositis and alopecia. Oral etoposide, prednimustine and other drugs have been incorporated to minimize side effects. Comparisons among trials are difficult because of the different entry requirements, including vast differences in age ranges (and median ages) of the patients. The 2-year disease-free survival rate ranges from 15% to 55%. Results from the three available randomized trials [1921] suggest that CHOP should be considered the standard for good performance status patients. These studies also emphasized that lymphoma failure, rather than comorbid illness, is the most important factor for the overall survival of older patients.

Since 1992, we have performed prospective studies on elderly aggressive-histology NHL patients using an 8-week pilot regimen, the VNCOP-B (cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin and prednisone) protocol, developed at our institute. Employing moderate doses of this MACOP-like regimen chemotherapy at frequent dosing intervals, a good remission rate was achieved [22]. We then performed a national multicenter randomized trial comparing VNCOP-B with and without granulocyte colony-stimulating factor (G-CSF) to determine whether toxicity can be further reduced without sacrificing efficacy [23]. We subsequently reported our entire experience with the VNCOP-B regimen in 350 previously untreated elderly aggressive-histology NHL patients, and were able to confirm that the regimen is effective in inducing good CR and relapse-free survival rates with only moderate toxic effects [24]. To evaluate the role of the quantity of chemotherapy in terms of CR and relapse-free survival rates, we have now undertaken a national multicenter randomized trial comparing 8-week VNCOP-B plus G-CSF with 12-week VNCOP-B plus G-CSF. In this report we summarize the data of this trial on 306 previously untreated aggressive-histology NHL patients.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
From February 1996 to June 2001, 306 consecutive previously untreated patients with aggressive NHL and >=60 years of age from 12 Italian cooperative institutions were registered for the study. Diagnostic specimens of all patients were reviewed and classified according to the REAL classification [25]. Eligibility criteria were as follows: confirmed diagnosis of aggressive-histology NHL (Burkitt’s lymphomas and lymphoblastic lymphomas were excluded from this study); stage II–IV as outlined by the Ann Arbor Conference [26]; performance status 0 to 2 according to the Eastern Cooperative Oncology Group (ECOG) [27]; HIV negative; normal hepatic, cardiac and renal functions. Staging evaluation included initial hematological and chemical survey, in addition to chest X-rays, abdominal ultrasonography, computed tomography of the chest and abdomen and bone marrow biopsy in all patients. Bulky disease was defined as a tumor mass >=6 cm.

Of the 306 patients enrolled, 297 patients (149 in the 8-week VNCOP-B plus G-CSF arm and 148 in the 12-week VNCOP-B plus G-CSF arm) fulfilled the criteria for entry. Nine patients were excluded because of incorrect diagnosis (two patients), loss to follow-up (five patients) or protocol violations (two patients with discordant lymphoma). All patients gave written informed consent (provided according to the Declaration of Helsinki). Randomization was done according to a 1:1 ratio. The characteristics of the 297 patients are shown in Table 1. The age-adjusted index according to the International Prognostic Factor Index (IPI) [28] was used; because all of the patients were >60 years of age, the age parameter of the complete index was irrelevant. Table 2 summarizes the stratification of patients in the two different therapeutic arms according to this index.


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Table 1. Clinical characteristics of 297 elderly patients with aggressive non-Hodgkin’s lymphoma
 

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Table 2. Age-adjusted International Prognostic Factor Index (IPI) in 8- and 12-week VNCOP-B regimen groups
 
Treatment protocol
VNCOP-B is a methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin (MACOP-B)-like regimen [29] with several distinctive features: treatment is completed in 8 or 12 weeks and includes mitoxantrone and etoposide instead of doxorubicin and methotrexate, respectively. We selected these replacements with the aim of reducing 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 schedules of the VNCOP-B programs (8- and 12-week) are listed in Table 3. G-CSF administration was 5 µg/kg/day subcutaneously throughout treatment, starting on day 3 of every week for five consecutive days. All patients received Pneumocystis carinii prophylaxis with cotrimoxazole (two consecutive days per week) during the entire course of therapy. All patients with bulky disease at the time of diagnosis or with local residual disease received radiation therapy at a dose of 30–36 Gy.


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Table 3. Drug doses and treatment schedule for 8- and 12-week VNCOP-B
 
Response
All patients were restaged after completion of chemotherapy. Clinical and pathological evaluations were made by repeating radiographic investigations and bone marrow and/or liver biopsies if previous results had been positive. Complete response 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 a 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 [27].

Statistical methods
Overall survival 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. Overall and relapse-free survival curves were calculated according to the method of Kaplan and Meier [30]. Deaths from lymphoma, secondary to lymphoma treatment or to any disease (related or unrelated) were considered an event. Analyses of prognostic factors were performed with log-rank tests, Cox’s analysis [31] and logistic regression analysis.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
As can be seen from Table 1, the two groups of patients, randomized for the 8-week arm (149 patients) versus the 12-week arm (148 patients), are fully comparable in their main clinical and pathological features, without any statistically significant difference. Except for lactate dehydrogenase (LDH) level, the data monitoring committee observed no difference between the two arms such as to suggest interrupting the trial for ethical reasons.

Response to treatment
The clinical results are summarized in Table 4. In 8-week VNCOP-B, the rate of CR was 63% (94 of 149) as against 56% (83 of 148) in the 12-week group. There were 19 (13%) and 23 (16%) non-responders in the 8- and 12-week VNCOP-B groups, respectively. With regard to the relapse-free interval, 30 of 94 (32%) patients who achieved CR after 8-week VNCOP-B had a relapse within 36 months, as compared with 34 of 83 (41%) patients from the 12-week group.


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Table 4. Clinical results
 
Overall, the relapse-free survival rate for the 177 patients with CR was 57% at 60 months (median 32, range 3–62). No significant difference was observed at 60 months between the two treatment arms: 59 and 55% for 8- and 12-week VNCOP-B, respectively (Figure 1). Overall survival at 60 months was 52 and 37% after 8- and 12-week VNCOP-B, respectively (Figure 2) (P = 0.01). This last statistically significant result is related to the different percentage of patients with elevated LDH level in the two groups (29% and 45% for 8- and 12-week VNCOP-B, respectively). In fact, the comparison of overall survival curves in patients with normal LDH levels do not show any statistically significant difference.



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Figure 1. Relapse-free survival curves of 8- and 12-week cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin and prednisone (VNCOP-B) groups.

 


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Figure 2. Overall survival curves of 8- and 12-week cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin and prednisone (VNCOP-B) groups.

 
Toxic effects
Neutropenia grade III–IV occurred in 32% of patients treated with 8-week VNCOP-B and in 30% of patients from the 12-week VNCOP-B group. The incidence of anemia and thrombocytopenia grade III–IV was similar in the two subsets of patients (<=5%). Clinically relevant infections (grade III–IV) were recorded in 3% and 5% of the 8- and 12-week VNCOP-B groups, respectively (P = n.s.). No instance of severe cardiac, liver or renal problems was observed. The causes of death in the two treatment groups are listed in Table 5.


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Table 5. Causes of death
 
Statistical analysis
In keeping with our previous report [24], among the nine factors (age, sex, presence/absence of bulky disease, presence/absence of B symptoms, stage, LDH level, extranodal sites, histological subtype and performance status) investigated by Cox multivariate analysis, those most significantly associated with longer overall or relapse-free survival were localized disease stage (P = 0.001) and good performance status (P = 0.001). The IPI [28] was associated significantly with outcome (P <0.0000) (Figure 3).



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Figure 3. Overall survival curves (all patients) according to International Prognostic Factor Index (IPI).

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Two long-term trends hold major implications for clinicians caring for elderly patients with malignant lymphoma: (i) the median age of the population is steadily increasing; (ii) the incidence of lymphoma in the elderly is rising rapidly. The management of elderly patients with aggressive NHL requires special consideration because of the increased risk of toxicity and death from treatment and disease. Age has been shown to be a prognostic factor in the treatment of aggressive NHL. Some studies have suggested that patients >65 years of age have greater toxicity, lower CR and decreased survival, and that therapy is often complicated by comorbid medical conditions [32, 33].

Non-randomized studies using standard-dose CHOP for the treatment of elderly patients produced very similar CR rates to those observed in younger patients [34]. While confirming that the gold-standard regimen for elderly aggressive NHL patients was CHOP, Fisher et al. [35] found that the percentage of toxic deaths did increase with age, and that when doses were reduced, the CR rate also decreased. Two prospective, randomized studies [19, 20] have since shown that the standard CHOP regimen can be given in sufficient doses to elderly aggressive NHL patients in such a way as to obtain CR rates between 49% and 68%.

In the last 10 years, third-generation combination chemotherapy regimens specifically designed for elderly aggressive NHL patients have been tested [7–18, 22]. Some of them include adriamycin and cyclophosphamide, administered at different doses and with different schedules. Mitoxantrone, considered less cardiotoxic than the anthracyclines, and etoposide, a drug with an oral formulation that allows treatment on an outpatient basis, have now also been introduced. All these novel regimens have been reported to be active and relatively well tolerated. As in the case of our VNCOP-B protocol, some of these third-generation regimens are short-duration weekly combination chemotherapy protocols [16, 18, 22, 36]. Such regimens have produced CR rates that are only slightly lower than those obtained in younger aggressive NHL; CR, overall survival and relapse-free survival rates were equivalent to those achieved with CHOP or CHOP-like regimens. The specifically designed regimens have the advantage that they are well tolerated, providing no evidence of severe or permanent toxic effects. Furthermore, the protocols take only 8–10 weeks, compared with 18 weeks for CHOP.

Following our encouraging results using the 8-week VNCOP-B regimen with the addition of G-CSF, we undertook the present trial to investigate the possibility of potentiating induction treatment so as to increase the CR rate while also reducing the relapse rate in the first 36 months. In this randomized trial, we compared the 8-week VNCOP-B regimen with an extended 12-week protocol containing a further block of four cycles including two Mitoxantrone administrations. The additional 4 weeks of treatment brought no benefit in terms of CR rate (63% versus 56% for 8- and 12-week VNCOP-B, respectively) or relapse-free survival (59% versus 55%).

On the basis of these data, we can conclude that augmenting induction treatment does not improve the CR rate or reduce the number of relapses in the first 3 years. Nevertheless, it is interesting to note that the specific formulation (in terms of dosages, timing and selection of drugs) for elderly patients of the VNCOP-B plus G-CSF regimen allowed treatment to be prolonged to 12 weeks without any increase in the toxic effects. One way of increasing CR rates, in terms of quantity and quality, and reducing the first 3-year relapse rates could be a strategy where a specifically designed induction regimen (like 8-week VNCOP-B plus G-CSF) is followed by a consolidation phase with non-cross resistant drugs [e.g. NAEPP (navelbine, epirubicin, prednisone) regimen] [37] for two to four courses. An alternative approach involves the use of the anti-CD20 monoclonal antibody following the enthusiastic preliminary results from the Groupe d’Etude des Lymphomes de l’Adulte (GELA) trial where eight cycles of CHOP plus rituximab (R-CHOP) appeared more effective than CHOP alone [38].


    Acknowledgements
 
We are grateful to Robin M. T. Cooke for his editing of the manuscript.


    Footnotes
 
+ Correspondence to: Dr P. L. Zinzani, Istituto di Ematologia e Oncologia Medica ‘L. e A. Seràgnoli’, Policlinico S.Orsola, Via Massarenti 9, 40138 Bologna, Italy. Tel: +39-51-390413; Fax: +39-51-398973; E-mail: plzinzo{at}med.unibo.it Back


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