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Annals of Oncology Advance Access originally published online on March 15, 2007
Annals of Oncology 2007 18(6):1085-1089; doi:10.1093/annonc/mdm073
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© 2007 European Society for Medical Oncology

hematologic malignancies

Central nervous system occurrence in elderly patients with aggressive lymphoma and a long-term follow-up

M Björkholm1,*, H Hagberg2, H Holte3, S Kvaloy3, L Teerenhovi4,{dagger}, H Anderson5, E Cavallin-Ståhl6, J Myhre7, H Pertovaara8, Å Öst9,10, B Nilsson11 and E Ösby1

1 Department of Medicine, Karolinska University Hospital, Stockholm
2 Department of Oncology, Uppsala Academic Hospital, Uppsala, Sweden
3 Rikshospitalet-Radiumhospitalet, Medical Center, Oslo, Norway
4 Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland
5 Department of Cancer Epidemiology, Lund University, Lund
6 Department of Oncology, University Hospital, Lund, Sweden
7 Department of Hematology, the Finsen Center, Rigshospitalet, Copenhagen, Denmark
8 Department of Oncology, Tampere University Hospital, Tampere, Finland
9 Department of Clinical Pathology, Medilab, Täby
10 Karolinska Institutet, Stockholm
11 Unit of Cancer Epidemiology, Karolinska University Hospital and Institutet, Stockholm, Sweden

* Correspondence to: Dr M. Björkholm, Department of Medicine, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. Tel: +46-8-51774198; Fax: +46-8-318264; E-mail: magnus.bjorkholm{at}karolinska.se


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 Appendix
 References
 
Background: Secondary central nervous system (CNS) involvement by aggressive lymphoma is a well-known and dreadful clinical complication. The incidence and risk factors for CNS manifestation were studied in a large cohort of elderly (>60 years) patients with aggressive lymphoma.

Patients and methods: In all, 444 previously untreated patients were randomized to receive 3-weekly combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone or cyclophosphamide, mitoxantrone, vincristine and prednisone (CNOP) (doxorubicin substituted by mitoxantrone) chemotherapy with or without filgrastim. Prophylactic intrathecal methotrexate was given to patients with lymphoma involvement of bone marrow, testis and CNS near sites.

Results: In all 29 of 444 (6.5%) developed CNS disease after a median observation time of 115 months. CNS was the only site of progression/relapse in 13 patients while part of a systemic disease manifestation in 16 patients. In univariate risk factor analysis, CNS occurrence was associated with extranodal involvement of testis (P = 0.002), advanced clinical stage (P = 0.005) and increased age-adjusted International Prognostic Index score (aaIPI; P = 0.035). In multivariate analysis, initial involvement of testis remained significant and clinical stage was of borderline significance. The median survival time was 2 months after presentation of CNS disease.

Conclusion: A significant proportion of elderly patients with advanced aggressive lymphoma will develop CNS disease. CNS occurrence is related to testis involvement, advanced clinical stage and high aaIPI and the prognosis is dismal.

Key words: aggressive non-Hodgkin's lymphoma, central nervous system, CHOP, CNOP, elderly, G-CSF


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 Appendix
 References
 
The vast majority of patients diagnosed with aggressive non-Hodgkin's lymphoma (NHL) are >60 years of age, and increasing age is associated with a worse prognosis [1]. In the elderly, complete remission (CR) is achieved in 60%–65% of patients following combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy given every 3 weeks [2–4] and with CHOP every two weeks or the addition of rituximab the CR rate is raised to 75% [2, 4]. Thus, a substantial proportion of patients >60 years will never reach a CR, which in combination with a rather high relapse rate leads to an overall 5-year survival of ~50%. Patients with occurrence of central nervous system (CNS) manifestation on therapy or after achieving a CR carry a particularly dismal prognosis [5]. The overall incidence of CNS disease in aggressive NHL excluding Burkitt's and lymphoblastic lymphoma is ~5% [6–11]. Prophylactic CNS disease treatment is quite heterogeneous in the elderly. In some centers no such treatment is given and in others certain high-risk patients receive intrathecal (IT) and possibly systemic CNS chemotherapy prophylaxis. This reflects the fact that there is no general consensus about which subgroup among elderly patients should be given prophylactic treatment and no clear data demonstrating efficacy of CNS prophylaxis in the elderly [12–13]. Accordingly, apt predictors of patients at high risk for later CNS disease in relation to prophylactic treatment need to be defined. In order to elucidate these issues, we have analyzed the incidence and risk factors of CNS manifestations in a large series of elderly patients with aggressive lymphoma. Thus, we took advantage of a prospective randomized trial allocating elderly patients to receive CHOP or cyclophosphamide, mitoxantrone, vincristine and prednisone (CNOP) (doxorubicin substituted for mitoxantrone) chemotherapy with or without the addition of granulocyte colony-stimulating factor (G-CSF). IT prophylaxis was given to a predefined subgroup of patients [3].


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 Appendix
 References
 
Between May 1992 and January 1997, 458 previously untreated patients >60 years entered this Nordic Lymphoma Group trial [3]. They had histologically diagnosed high-grade NHL according to the updated Kiel classification, clinical stage II–IV disease and World Health Organization performance status of three or less. All histology was reviewed by a central panel. Exclusion criteria included human immunodeficiency virus (HIV) infection, history of low-grade lymphoma, overt CNS disease, congestive heart failure [CHF; New York Heart Association (NYHA) classification III–IV], history of neoplasm, aminotransferases and alkaline phosphatase >2.5 times the upper limit of normal, bilirubin >50 µM, serum creatinine >300 µM and any serious medical or psychiatric illness that would prevent informed consent or completion of protocol-prescribed treatment and follow-up.

Details of clinical investigations, treatment regimens, tumor response evaluation, end points and statistics are previously published [3]. Briefly, three patients were excluded due to cerebrospinal fluid dissemination (n = 2) and HIV infection (n = 1). Among the remaining 455 patients (median age 71 years; range 60–86 years), 47 patients previously hospitalized for class I–II CHF (NYHA) were randomized to receive CNOP with or without G-CSF. Four-hundred and eight patients were randomized in a bifactorial design to receive either CHOP (doxorubicin 50 mg/m2) or CNOP (mitoxantrone 10 mg/m2) with or without G-CSF (5 µg/kg) from day 2 until day 10–14 of each cycle given every 3 weeks; eight cycles. Ethics committee approval was obtained in all participating centers.

central nervous system disease
Thus, patients with manifest (clinical and/or laboratory) CNS disease at diagnosis were excluded from the trial. Lumbar puncture and cerebrospinal fluid analysis were carried out in patients fulfilling criteria for prophylaxis treatment and in patients with a clinical suspicion of CNS disease. Six instillations of IT methotrexate, 12 mg, were given as CNS prophylaxis to patients with lymphoma bone marrow involvement and with testicular, orbital and other CNS near sites of lymphoma presentation.

statistical analyses
Comparisons among groups were analyzed by the Wilcoxon (Gehan) exact test (accounting for censored observations). Pretreatment characteristics and type of chemotherapy, treatment with G-CSF or not and response to treatment were included in univariate analysis of their ability to predict CNS occurrence. A second multivariate Cox regression analysis was carried out including factors that were significant in univariate analyses. Actuarial risk of CNS manifestations was calculated by the Kaplan–Meier method.


   results
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 Abstract
 introduction
 patients and methods
 results
discussion
 Appendix
 References
 
In the first report of this study the median follow-up time was 57 months, which presently has been extended to 115 months (range 18–151 months) in surviving patients. Eleven patients were lost to follow-up. In all, 367 of 444 remaining patients (82.7%) had deceased. Initial distribution of patient and disease characteristics and outcome are shown in Table 1. The large majority of patients had diffuse large B-cell lymphoma and only a few patients with lymphoblastic lymphoma were included. Less than 10% of the patients had on pathology review low-grade NHL or Hodgkin's lymphoma, or a diagnosis based on cytology. The outcome results have been presented elsewhere [3], in short, patients receiving CHOP fared better than those given CNOP chemotherapy, and concomitant G-CSF did not improve the CR rate or overall survival.


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  		Table 1. Distribution of patient and disease characteristics

 
In all, 29 of 444 patients (6.5%) developed CNS disease. The diagnosis was based on cytopathology/pathology in nine patients, symptoms and radiological findings (magnetic resonance imaging/computerized tomography) in 15 patients and only on neurological symptoms in the remaining five patients. The actuarial risk (Kaplan–Meier) of developing CNS disease was 12%. The median time from randomization to CNS occurrence was 9 months (range 1–100 months); in 13 patients CNS disease appeared within 6 months and in 19 patients within 24 months after randomization (Figure 1). Six patients developed CNS disease 55 months or later after randomization (Figure 1). Four of these were isolated CNS relapses while two were associated with a systemic disease manifestation. Among CR patients seven developed an isolated CNS relapse and seven as part of a systemic relapse. In 15 patients who did not reach CR, six patients developed isolated CNS progressive disease and nine patients as part of a systemic disease progression. Thus, CNS was the only site of progressions/relapses in 13 patients while part of a systemic disease manifestation in 16 patients. There was no significant difference in time to CNS progression according to type of CNS disease (local or systemic), although isolated CNS progression tended to occur later. In all, 21 of 29 (72%) patients with CNS disease had diffuse large B-cell lymphoma. Patient and disease characteristics according to CNS occurrence are summarized in Table 2. In univariate risk factor analysis, CNS occurrence was associated with extranodal involvement of testis (P = 0.002), advanced clinical stage (P = 0.005) and increased age-adjusted (aa) International Prognostic Index score (IPI) [14] (P = 0.035) (Table 2). The presence of >1 extranodal site, bone marrow involvement, poor performance status, an elevated lactate dehydrogenase (LDH) level, bulky disease or B symptoms were not related to the risk of CNS manifestation. In addition, later development of a CNS lymphoma manifestation was not related to G-CSF therapy. There was a nonsignificant tendency of more CNS disease among CNOP-treated patients (P = 0.089). The median time to CNS recurrence was 12.5 months (range 1–100 months) in the CHOP treatment arm and 9.0 months (range 2–89 months) in the CNOP treatment arm (P = 0.963). In multivariate analyses, initial involvement of testis remained significant (P < 0.001), clinical stage at diagnosis was borderline significant (P = 0.05) but aa IPI score not significant (P = 0.167). Two among the four patients with testicular disease at diagnosis later developed parenchymal CNS disease, the third had a positive cerebrospinal fluid examination and the fourth patient had a diagnosis only on the basis of clinical symptoms. Treatment of patients with CNS disease was quite heterogeneous and therapeutic decisions were left to the discretion of the local physician. The median survival time was 2 months and no patient was alive at follow-up (Figure 2). IT methotrexate had been given prophylactically during the induction treatment in six of 29 patients with a CNS recurrence. All of these had lymphoma bone marrow involvement, testicular, orbital or skeletal sites of lymphoma presentation. Three additional CNS patients fulfilled the indications for IT methotrexate therapy but did not receive this treatment. Two of five patients with lymphoblastic lymphoma had a CNS relapse, one of them received IT prophylaxis. In total, 91 of 444 (20.5%) patients fulfilled criteria for IT prophylaxis according to the study protocol.


Figure 1
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  		Figure 1. Point of time of central nervous system lymphoma manifestation after randomization.

 

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  		Table 2. Risk factors analysis for CNS manifestation

 

Figure 2
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  		Figure 2. Overall survival after diagnosis of central nervous system disease.

 

   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
Appendix
 References
 
The incidence of secondary CNS involvement in aggressive lymphoma (Burkitt's and lymphoblastic lymphoma excluded) has been reported to be ~5% and the extremely poor prognosis makes the management of these patients a great clinical challenge. In the present prospective study, with a noteworthy median follow-up time of close to 10 years, 6.5% of patients developed CNS disease. In the pivotal CHOP ± rituximab study by Groupe d'Etude des Lymphomes de l'Adulte (GELA), CNS occurrences were observed in 20 of 399 (5.0%) patients aged 60–80 years [15]. In that study, prophylaxis of CNS disease was not part of the protocol and the median follow-up was only 24 months. Since 10 of 29 (34%) patients had CNS disease diagnosed 2 years or more after randomization in the present study, it seems likely that with a longer observation period in the French study the incidence will be almost identical in these two large prospective studies. In further support for this is the fact that CNS disease was not related to the use of mitoxantrone and G-CSF (present study) or rituximab [15]. This is in accordance with the poor penetration through the blood–brain barrier of doxorubicin [16], mitoxantrone [17] and rituximab [18]. In both the present and the French study, univariate analysis revealed that CNS occurrences were associated with advanced clinical stage and an increased aa IPI score, but not sex, age, B symptoms or the presence of >1 extranodal site. An elevated LDH was, however, predictive in the GELA study but not in the present study. Conversely, extranodal involvement of testis was associated with a higher risk in the present patient population. In addition, in multivariate analysis, testis involvement and advanced clinical stage remained significant and borderline significant, respectively in this study, while an increased IPI score was the only independent predictor of CNS recurrence in the French study. The above-discussed differences in follow-up time and prophylactic therapy may, at least in part, explain these minor discrepancies. An interesting observation in the present report was that six of 29 (21%) CNS occurrences were observed 55 months or more after randomization. Since the fraction of long-term survivors increases among aggressive lymphoma patients it may be anticipated that more patients will develop CNS disease. This assumption is on the basis of the fact that neither 2-weekly CHOP nor the addition of rituximab will reduce CNS disease [15, 19].

Support for a more aggressive prophylactic approach came from the same French group, which prospectively compared conventional CHOP and no CNS prophylaxis with ACVBP chemotherapy (doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone), including four IT methotrexate injections and two courses of i.v. methotrexate (3 g/m2) [20]. Patients (61–69 years) had at least one prognostic factor of the aa IPI. There were 8.3% and 2.8% CNS progressions/relapses in CHOP- and ACVBP-treated patients, respectively (P = 0.004). Only very recently the German High-Grade Non-Hodgkin's Lymphoma Study Group reported 37 cases of CNS relapse or progression among 1693 patients (2.2%) participating in the NHL-A and B1/B2 studies [19]. Intriguingly, only 71 patients (4.2%) received prophylaxis by decision of the treating physician. Etoposide treatment was observed to significantly reduce the risk of CNS failure. Since half of the NHL-B1/2 and all NHL-A patients received etoposide, this may be a major explanation for the low incidence of CNS disease despite no vigorous CNS prophylaxis. In conclusion, CNS progressions/relapses occurred in 6.5% of elderly patients with clinical stage II–IV aggressive NHL. CNS relapses can occur 5 years or more after treatment. In this study, testis involvement, advanced clinical stage and high aa IPI predicted CNS disease, which at present carries a very dismal prognosis. Certainly, we need to find answers to questions such as which high-risk patients should receive CNS prophylaxis and what is the best strategy with today's therapeutic armamentarium. Hopefully, improvements in diagnostics and disease monitoring [21] as well as the introduction of new agents such as liposomal cytarabin [22] will reduce the number of patients to suffer from this devastating clinical condition.


   Appendix
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Appendix
References
 
Additional participants in this Nordic Lymphoma Group Study include the following:

Regional coordinators
Finland: E. Elonen, T. Ruutu, Helsinki; M. Vapaatalo, Hyvinkää; K. Oksanen, Hämeenlinna; M. Pajunen, Jyväskylä; O. Kuittinen, S. Virtanen, Oulu; B. Rask, Porvoo; H. Pertovaara, Tampere; R. Huovinen, Turku.

Norway: O. Mella, Bergen; A. F. Abrahamsen, G. Lauvvang, Oslo; E. Wist, Tromsö; R. Telhaug, Trondheim.

Sweden: A. M. Ekberg, J. H. Svensson, Borås; K. Wallman, Falun; S. Bergström, Gävle; I. Braide, T. Ekman, H. Nilsson-Ehle, Göteborg; L. Hellquist, Halmstad; B. Norberg, Jönköping; L. Nurbo, Karlskrona; S. Fredén, Karlstad; M. Mogensen, Kristianstad; M. Hjort, Lidköping; E. Haapaniemi, Linköping; P. Kjärgaard, Ljungby; C. Myhr-Eriksson, Luleå; A. Johnson, M. Åkerman, Lund; O. Zettervall, Malmö; D. Fors, Piteå; J. Hallgren, Simrishamn; V. Hjalmar, B. Johansson, E. Kimby, R. Lerner, J. Liliemark, K. Merk, M. Merup, Stockholm; M. Hedenus, Sundsvall; P. Johansson, Uddevalla; B. Osterman, Umeå; G. Enblad, A. Killander, C. Sundström, A. Taube, Uppsala; S. Hasselblom, Varberg; T. Kunze, Visby; U. Petterson, Västerås; T. Samuelsson, Växjö; M. Nordström, Örebro; K. Tholin, Östersund.

Pathology review panel
K. Bendix, Århus, Denmark; K. Franssila, Helsinki, Finland; A. Myking, Bergen, R. Langholm, Oslo, Norway; Å. Öst (coordinator), Stockholm, Sweden.

Data management
Cecilia Arnesson, Southern Swedish Regional Tumour Registry, Lund University Hospital, Lund, Sweden.


   Footnotes
 
{dagger} Deceased. Back

Received for publication November 10, 2006. Revision received January 30, 2007. Accepted for publication February 1, 2007.


   References
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 Abstract
 introduction
 patients and methods
 results
 discussion
 Appendix
 References
 
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