VEPEMB in elderly Hodgkin’s lymphoma patients. Results from an Intergruppo Italiano Linfomi (IIL) study

A. Levis1,*, A. P. Anselmo2, A. Ambrosetti3, F. Adamo4, M. Bertini5, E. Cavalieri2, P. Gavarotti6, A. Genua7, M. Liberati7, V. Pavone8, D. Pietrasanta1, M. M. Ricetti3, D. R. Scalabrini9, F. Salvi1, U. Vitolo5, E. Angelucci4, M. Boccadoro6, E. Gallo5 and F. Mandelli2

1 Haematology Division of the Ospedale SS Antonio e Biagio, Alessandria; 2 Haematology Division of the University La Sapienza, Roma; 3 Haematology Division of the University of Verona; 4 Haematology Division of the Ospedale Businco, Cagliari; 5 Haematology Division of the Ospedale S Giovanni Battista, Torino; 6 Haematology Division of the University of Torino; 7 Internal Medicine Division of the University of Perugia; 8 Haematology Division of the University of Bari; 9 Institute of Research Against Cancer, Candiolo, Italy

Received 26 March 2003; revised 2 July 2003; accepted 18 August 2003


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

In advanced age the prognosis of Hodgkin’s lymphoma (HL) is poor, but, as a consequence of the low incidence of HL in the elderly, prospective studies are lacking and the best treatment strategy is difficult to define.

Patients and methods:

One-hundred and five HL patients over 65 years of age were treated homogeneously with an original reduced-intensity regimen designed for HL in the elderly containing vinblastine, cyclophosphamide, procarbazine, etoposide, mitoxantrone and bleomycin (VEPEMB). Forty-eight early stage (IA–IIA) patients received three courses of VEPEMB followed by involved field irradiation. Fifty-seven advanced stage (IIB–IV) patients received six courses followed by radiotherapy limited to the areas of bulky disease.

Results:

Mean age was 71 years (range 66–83). Co-morbidities were present in 39 patients (37%). A treatment plan modification for poor tolerance or toxicity was needed in 18 patients. Results were satisfactory, even if they were better in early rather than in advanced stage disease: complete response rate 98% versus 58% (P <0.01); 5-year failure-free survival 79% versus 34% (P <0.01). The results were affected by advanced stage, systemic symptoms and co-morbidity but they were not influenced by age itself.

Conclusions:

VEPEMB is an effective and low toxic regimen for HL in the elderly. Co-morbidity is a prognostic factor more important than age itself.

Key words: chemotherapy, co-morbidity, elderly, Hodgkin’s lymphoma, prognosis


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
For many years advanced age has been considered an unfavourable prognostic factor for Hodgkin’s lymphoma (HL) [111]. This has been confirmed from both single institution [16] and registry-based studies [711]. Moreover, defining the best treatment strategy for elderly HL patients is difficult, mainly because the disease is infrequent in advanced age [12] and there is so far only limited information from prospective trials [13, 14].

Three different groups of factors influencing the unfavourable outcome in the elderly have been proposed. First, a peculiar biology of the disease in the elderly, characterised by a more aggressive behaviour, as demonstrated by the higher proportion of patients with MC histology [14, 710], infra-diaphragmatic presentation [4, 10], and advanced stage [7]. Second, the advanced age itself and other age related variables, such as co-morbidity [8]. Third, the low compliance and the high percentage of toxic events secondary to conventional therapies [2, 3, 911]. As a consequence of the last two points the efficacy of the best treatment is unbalanced by toxicity and the planned therapy is difficult to follow.

The question arises if a conventional treatment, or a less toxic strategy devised for elderly people is better. Our previous experience with the low-dose chlorambucil, vinblastine, procarbazine, cyclophosphamide, etoposide and bleomycin (CVP/CEB) regimen [13] has shown in a small group of patients that a high drug dose reduction is useful to decrease toxicity but it implies an increased relapse rate. In order to focus on this problem, in 1995, the Intergruppo Italiano Linfomi (IIL) started a prospective study to test the efficacy of VEPEMB (vinblastine, cyclophosphamide, procarbazine, etoposide, mitoxantrone and bleomycin), an original low aggressive chemotherapy regimen, devised for HL elderly patients. The results obtained in 105 elderly patients treated according to VEPEMB schedule are herein analysed.


    Patients and methods
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patients
From January 1995 to December 2001, 111 HL patients aged ≥66 years were treated with VEPEMB. Inclusion criteria were age ≥66 years, diagnosis of HL documented histologically, no previous treatment for HL, absence of other neoplastic diseases or HIV infection and informed consent. Concomitant age-related diseases were not a reason for excluding the patients, except for the presence of severe organ failures. Co-morbidity was defined as the presence of a concomitant disease, requiring specific treatment. Adequate follow-up data with a minimum follow-up of 1 year for censored patients is so far available for 105 patients who are the object of the present report.

Staging and treatment
All patients were clinically staged with full blood tests, thoracic and abdominal computed tomography (CT) scan and bone marrow biopsy. A mass of >10 cm on the CT scan or physical examination and/or a mediastinal mass larger than one-third of the thoracic diameter were defined as bulky disease.

Patients were subdivided according to stage and systemic symptoms: early stage: IA and IIA; advanced stage, from IIB to IV. Forty-eight early stage patients received three courses of VEPEMB followed by involved field radiotherapy at 30 Gy, while 57 advanced stage patients entered a program of six courses of VEPEMB plus radiotherapy limited to bulky or non-responding areas.

The VEPEMB regimen was scheduled as follows: vinblastine 6 mg/m2 intravenously (i.v.) on day 1, cyclophosphamide 500 mg/m2 i.v. on day 1, procarbazine 100 mg/m2 per os (p.o.) on days 1–5, prednisone 30 mg/m2 p.o. on days 1–5, etoposide 60 mg/m2 p.o. on days 15–19, mitoxantrone 6 mg/m2 i.v. on day 15, bleomycin 10 mg/m2 i.v. on day 15. Each course was repeated every 28 days. Granulocyte colony-stimulating factor (G-CSF) was not preliminary scheduled as prophylaxis, but it was used in subsequent cycles if the absolute neutrophil count was <0.5 x 109/l, mainly during infectious complications. Erythropoietin was not used, for the drug was not yet available in Italy for this indication at the time of the study.

Statistical methods
The actual dose intensity of each drug after three and six courses of chemotherapy was calculated as mg/m2/week according to the method of Hryniuk [15]. The relative drug dose intensities of each drug were calculated as the ratio between actual and projected dose intensity. The arithmetic means of the relative dose intensities after three (RDI3) and six (RDI6) courses of chemotherapy were used as an indicator of drug delivery adequacy [15].

Early deaths were included in the evaluation of both final complete remission (CR) and overall survival (OS) as failure. OS data include all patients, and an event was the death of a patient whatever the cause; OS duration was measured from the beginning of treatment to date of death or last follow-up evaluation. In the disease-specific survival (DSS) curves, only deaths due to HL or acute early toxicity were considered as an event, while deaths from other causes non-related to lymphoma were treated as censored. The relapse-free survival (RFS) curves were plotted only for patients who achieved CR; the duration was calculated from the time of CR assessment to the date of relapse or last follow-up evaluation with the patients free of disease; patients dying while in CR of causes unrelated to HL were considered as censored in computing RFS. The failure-free survival curves (FFS) were calculated for all patients, and any type of HL-related events, such as failure to achieve CR, relapse and toxic death were considered a failure.

All curves were plotted according to the Kaplan–Meier method [16]. Differences between curves were assessed for significance with the Wilcoxon generalised method [17]. Multivariate analyses of prognostic factors were undertaken according to the Cox proportional hazards regression models [18].


    Results
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
The mean age of the 105 evaluable patients was 71 years (range 66–83). Forty-eight patients (46%) were aged between 66 and 70 years and only 18 patients (17%) were >75 years. Co-morbidities were present in 39 patients (37%). Clinical features at diagnosis are summarised in Table 1, while information on toxicity and adherence to the initial plan are shown in Table 2.


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Table 1. Clinical features at diagnosis
 

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Table 2. Toxicity and adherence to initial treatment plan according to stage
 
RDI3 was 0.85 (range 0.53–1.1), and only 16% of the patients showed a RDI3 <0.70. Among the patients that ended six courses of chemotherapy, RDI6 was 0.79 (range 0.49–1.0), while 24% of patients showed a RDI6 <0.70.

Among the 48 early stage patients, 42 (87%) regularly ended their treatment in an outpatient setting. Only three patients out of this group needed an interruption of their chemotherapy plan. The first for an acute autoimmune thrombocytopenia that required a shift to prednisone treatment during the second course of VEPEMB; the second for left leg acute arterial occlusive disease; the last one for pneumonia. Only one patient experienced grade 4 anaemia and required transfusion support. Three patients needed admission to hospital for co-morbidities independent of HL, but none of them died of these complications.

Among the 57 advanced stage patients only 34 (60%) regularly ended their chemotherapy in an outpatient setting without complications. All of them experienced at least one episode of grade 3–4 neutropenia and required G-CSF administration from course four to six. An infectious episode was reported in eight patients (14%). Transfusion support, for grade 3–4 anaemia, was needed in 10 patients (18%). Fifteen patients (26%) needed a chemotherapy plan interruption and/or modification, mainly from course four to six, for the following reasons: nine (16%) for haematological toxicity, infections or poor treatment compliance; two for heart failure; one for chronic obstructive lung disease; three for HL progression. During the chemotherapy, hospitalisation was needed by 12 patients (21%) for the following reasons: toxicity-related problems in nine cases (16%); other age-related problems independent of HL or VEPEMB chemotherapy in three cases. Two patients died during the treatment induction. The first was a male aged 75 years in stage IIB who died of a stroke; the second was a female aged 66 years in stage IIIA with a long history of rheumatic disease and prednisone treatment who died of sepsis.

The outcome is summarised in Table 3. The final CR rate was 76%, the 5-year RFS rate of patients entering CR was 82%, the 5-year actuarial OS and DSS rates were, respectively, 64% and 69%, the 5-year FFS rate was 56%. So far 31 patients have died: 25 of HL or acute toxicity-related problems, one of secondary leukaemia and five of unrelated causes. The better results of early as compared to advanced stage disease are detailed in Table 3.


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Table 3. Results for all patients and for patients subdivided according to stage group
 
In univariate analysis the achievement of CR was influenced by systemic symptoms, stage and co-morbidity. The RFS of patients entering CR was negatively affected by male gender, LD histology, advanced stage and bulky disease. OS, DSS and FFS were all negatively affected by advanced stage, systemic symptoms and co-morbidity, while they were not influenced by age itself. FFS curves according to age and co-morbidity are shown in Figures 1 and 2, respectively. The influence of conventional prognostic features on the outcome is summarised in Table 4.



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Figure 1. Failure-free survival (FFS) according to age (n.s., not significant).

 


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Figure 2. Failure-free survival (FFS) according to the presence of co-morbidity.

 

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Table 4. Role of conventional prognostic features in univariate analysis
 
In multivariate analysis, stage, systemic symptoms and co-morbidity maintained their independent value in affecting OS, DSS and FFS.


    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
The poor prognosis of HL in the elderly is highly dependent on the difficulty of achieving CR. However, authors agree that elderly patients entering CR with a conventional adequate treatment show the same RFS as younger patients [610]. Unfortunately, many elderly patients cannot be conventionally treated because of their poor performance status or age-related co-morbidities, as demonstrated by two different retrospective studies [9, 10]. In both these studies patients treated with less than adequate strategies showed an OS or a RFS poorer than those treated with conventional strategies. Moreover, even if selected patients with good performance status are sometimes treated successfully with conventional regimens [6, 8], elderly people are vulnerable to chemotherapy and the risk of toxic events is a major problem [7, 9, 13].

On the other hand, there are only two studies on small groups of patients treated with low-dose regimens. Both have shown that a significant drug dose reduction is useful in minimising toxicity, but unfortunately this advantage is associated with a high failure rate. The CVP/CEB regimen was well tolerated and it induced a high CR rate, but these results were counterbalanced by a high relapse rate [13]. The VBM (vinblastine, bleomycin, methotrexate) schedule, proposed by Stanford for early stage patients, was also well tolerated in the elderly, but the CR rate obtained in stage III and IV was as low as 33% [14].

Our original VEPEMB study is the first prospective experience applied to a large number of elderly HL patients. Both tolerance and efficacy of the VEPEMB regimen are satisfactory, if compared to our previous experience with elderly patients treated with conventional chemotherapy [10]. In early stages, three courses of VEPEMB followed by involved field radiotherapy produced excellent results.

Advanced stage patients who entered a plan of six courses of chemotherapy, showed a higher percentage of toxic events and, as expected, the results were less satisfactory. The number of early deaths compares favourably with a value as high as 23% of early toxic deaths evidenced in our retrospective analysis of patients treated with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or ABVD-like regimens [10]. Only 60% of advanced stage patients ended their plan of six courses of VEPEMB in an outpatients setting without significant toxic events. This figure is difficult to comment upon because of the lack of similar information from published studies, on the basis of an intention-to-treat analysis. The fact that a protocol violation for toxicity or poor patient compliance was evidenced in about one-fourth of the patients stresses the difficulty of applying even reduced intensity chemotherapy in a non-selected group of elderly patients. The systematic use of G-CSF allowed a percentage of infective complications as low as 14%. In contrast the 18% of patients requiring transfusion support, which is usually unnecessary for HL treatment, was higher than expected. This is indicative of the reduced erythropoiesis in older people, and suggests the benefit of a systematic use of erythropoietin support, as for other haematological malignancies [19].

The results obtained in advanced stage in terms of CR rate (58%) and 5-year FFS rate (34%) can be considered satisfactory, even if they are lower than those obtained in younger people. From the analysis of prognostic factors it seems evident that, besides stage and symptoms, the only factor that influenced the outcome in terms of both OS and DSS was the presence of co-morbidity, while there was no role for age itself. The prognostic role of co-morbidity suggests that the evaluation of the patient frailness is more important than age itself in predicting the tolerance of the treatment and the clinical outcome [2022]. In our experience the largest contributions to mortality remain both the inability to control the lymphoma and the toxicity of the treatment.

Major improvements in the outcome of advanced stage HL have recently been obtained with both standard and escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) regimens [23], which are presently under discussion as the new standard therapy for advanced stage HL [24]. Escalated BEACOPP is considered too toxic in patients aged >60 years [25]. Moreover, in the elderly, even the baseline version of BEACOPP is more toxic than other conventional regimens [26], and there is not so far any experience with a reduced-dose BEACOPP. It is difficult to say if, in a selected group of elderly patients with good performance status, conventional treatments such as ABVD and baseline BEACOPP or a reduced intensity regimen like VEPEMB are better. The Nebraska Lymphoma Study Group has shown better results with the anthracycline-containing regimen ChlVPP/ABV (chlorambucil, vinblastine, procarbazine, prednisone, doxorubicin, bleomycin and vincristine) than with the less aggressive ChlVPP schedule (chlorambucil, vinblastine, procarbazine and prednisone) in a small number of elderly patients [27]. The authors suggest that the inclusion of doxorubicin should be a key component of HL treatment in the elderly. However, the Nebraska study was not a randomised study and the choice of the attending physician to treat the individual patient with the doxorubicin-containing regimen could be based on a favourable patient selection. Moreover, the cut-off to define the ‘older patient’ in this study was only 60 years and the percentage of patients >70 years and/or with co-morbidity treated with ChlVPP/ABV are not reported. In our study anthracyclines were avoided, but mitoxantrone was included and VEPEMB results seem acceptable. There is of course an agreement on the fact that an anthracycline-containing regimen is useful, but the crucial point remains the difficulty of predicting those patients that can tolerate it without significant toxicity.

In order to successfully balance effectiveness and low toxicity, treatment personalisation is needed, but it should be based on an objective evaluation of the individual patients frailness. Treatment personalisation is one of the most important problems yet to be solved in geriatric oncology, due to the difficulty of predicting how co-morbidities and functional limitations reduce the ability to tolerate conventional chemotherapy. The most efficient tool for evaluating the clinical importance of co-morbid conditions and functional limitations is provided by the Comprehensive Geriatric Assessment, which is based on standardised interviews and validated scales [28]. Several scales and indexes for evaluating co-morbidity, such as, for instance, the ‘Charlson Co-morbidity Index’, the ‘Cumulative Illness Rating Scale’ or the ‘Kaplan–Fenstein Index’ have been proposed recently in measuring co-morbidity in older cancer patients [29]. These indexes together with the measures of functional status such as the ‘Activities of Daily Living (ADL)’ and the ‘Instrumental Activities of Daily Living (IADL)’ scales can be considered the best tool for studying objectively the vulnerability to chemotherapy in different groups of older patients [30, 31].

In order to focus on the problem of the best treatment strategy for HL in the elderly, a large cooperative prospective study, that includes an initial comprehensive geriatric evaluation and then compares in a random way a reduced intensity regimen like VEPEMB to a conventional regimen such as ABVD or baseline BEACOPP, should be useful.


    Acknowledgements
 
This work was supported in part by the no-profit ‘Comitato Gigi Ghirotti’ and ‘Alessandria AIL’ foundations. The principal investigators and participating centres involved in this study are as follows. A. Levis, E. D’Andrea, D. Pietrasanta, F. Salvi: UOA Ematologia, Ospedale SS Antonio e Biagio Alessandria; A. P. Anselmo, E. Cavalieri, F. Mandelli: Cattedra di Ematologia, Università La Sapienza, Roma; M. Liberati, Istituto Medicina Interna e Scienze Oncologiche, Policlinico Monteluce, Perugia; E. Gallo, M. Bertini, B. Botto, U. Vitolo: UOA Ematologia, Ospedale San Giovanni Battista, Torino; C. Tarella, P. Gavarotti: Cattedra di Ematologia, Università di Torino; V. Liso, V. Pavone: Cattedra di Ematologia Università di Bari; M. Aglietta, D. R. Scalabrini: UOA Oncologia, IRCC Candiolo; G. Pizzolo, A. Ambrosetti, M. M. Ricetti: Cattedra di Ematologia, Università di Verona; E. Angelucci, F. Adamo: UOA Ematologia, Ospedale Businco, Cagliari; A. Tonso: UOA Medicina B, Ospedale degli Infermi, Biella; L. Gugliotta, F. Merli: UOA Ematologia, Reggio Emilia; E. Vivaldi: UOA Medicina, Trento; F. Ficara: UOA Medicina, Ospedale SS Annunziata, Savigliano; M. C. Bertoncelli: UOA Medicina, Ospedale Civile, Novara; L. Mairone: UOA Medicina, Ospedale Evangelico Valdese, Torino; G. Cametti: UOA di Medicina, Ospedale Civile, Chieri; Scaramucci: UOA Medicina, Ospedale Civile, Montefiascone; Nalli, UOA Medicina, Ospedale Civile, Lodi; A. Novarino: UOA Oncologia, Ospedale S Giovanni Battista, Torino; L. Griso: UOA Medicina, Ospedale Agnelli, Pinerolo; V. Infelise: UOA Medicina, Ospedale Civile, Borgomanero; F. Di Vito: UOA Oncologia, Ospedale Civile, Aosta; G. Saglio, T. Guglielmelli: Clinica Medica, Ospedale san Luigi Gonzaga, Orbassano; M. Galliano: UOA Medicina, Ospedale Civile, Nizza Monferrato; Giachetti: Cattedra di Ematologia, Università di Parma; F. Ricciuti, A. Pizzuti: UOA Ematologia, Ospedale Civile, Potenza; M. Spriano, UOA Ematologia, Ospedale san Martino, Genova.


    FOOTNOTES
 
* Correspondence to: A. Levis, Department of Haematology, SS Antonio e Biagio Hospital, Via Venezia 18, 15100, Alessandria, Italy. Tel: +39-0131-206262; Fax: +39-0131-261029; E-mail: alevis{at}ospedale.al.it Back


    REFERENCES
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
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