1 Department of Medical Oncology and Radiotherapy, The Norwegian Radium Hospital, Oslo; 2 Norwegian Medicines Agency, Oslo, Norway
Received 28 September 2001; revised 10 January 2002; accepted 11 February 2002
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Abstract |
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To determine the incidence and risk factors for central nervous system (CNS) relapse in patients with non-Hodgkins lymphoma (NHL).
Patients and methods:
Patient records were registered prospectively in successive patients with NHL admitted to the Norwegian Radium Hospital from 1980 to 1996. A total of 2514 patients had no CNS involvement at diagnosis and were treated according to standard protocols. The incidence and risk factors for CNS progression or relapse were examined retrospectively.
Results:
In low-grade (L)-NHL, the risk of CNS involvement was low (2.8%). In high-grade (H)-NHL, lymphoblastic and Burkitts NHL patients had a high risk of CNS recurrence (24.4%) at 5 years, and prophylaxis seemed to reduce this risk. For the other patients with H-NHL, the proportion with CNS involvement at 5 years was 5.2%. Multivariate analysis identified five independent risk factors, each present in >5% of patients: elevated serum lactate dehydrogenase, serum albumin <35 g/l, <60 years of age, retroperitoneal lymph node involvement and involvement of more than one extranodal site. If four or five of these risk factors were present, the risk of CNS recurrence was in excess of 25% at 5 years.
Conclusions:
The risk of CNS involvement in this study is comparable with the results from other large series. CNS prophylaxis is not recommended in any subgroup of L-NHL. The risk of CNS involvement among patients with either Burkitts or lymphoblastic lymphomas is considerable and these patients should therefore receive intensive chemotherapy including systemic and intrathecal methotrexate. Patients with other types of H-NHL should receive adequate CNS prophylaxis if at least four of the five risk factors identified are present.
Key words: central nervous system involvement, central nervous system prophylaxis, non-Hodgkins lymphoma, risk factors
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Introduction |
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It is well established that patients with lymphoblastic or Burkitts lymphomas have an increased risk of CNS relapse [3, 811], which is to some extent prevented by CNS prophylactic treatment [11, 12]. At some centers, CNS prophylaxis is also administered to patients with other high-grade lymphomas at sites presumed to be associated with CNS recurrence, such as the bone marrow, skeleton, testicles and paranasal sinuses [8, 10, 13, 14]. However, definite proof that CNS prophylaxis prevents CNS recurrence in these histological groups is, lacking. Central nervous system recurrence is considered rare in low-grade lymphomas [10, 15, 16]; however, only a few studies have examined its incidence in these types of lymphoma.
Whether CNS prophylaxis should include both systemic CNS-active and intraspinal chemotherapy is unclear, although lessons learnt from the treatment of lymphoblastic leukemia [17] favor the use of both lines of treatment, although the risk of neurotoxicity may increase [3, 18].
Numerous studies [7, 10, 16, 1923] have examined risk factors associated with CNS involvement, but some of the results are contradictory. The main objective of this study was to identify the risk factors for developing CNS involvement during primary treatment or at relapse, and to establish a risk model that can guide clinicians in the identification of high-risk patients and decide when CNS prophylaxis should be given.
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Patients and methods |
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Among these 2514 patients with NHL, 106 patients (4.2%) developed CNS involvement during primary treatment (n = 36) or at relapse (n = 70). The percentage CNS recurrence according to the Kiel classification [24] were as follows: low grade, n = 33 (2.8%); high grade, n = 52 (4.3%); lymphoblastic or Burkitts lymphoma, n = 20 (24.4%). One patient with unclassified lymphoma relapsed in the CNS. Standard staging procedures were performed. Examinations of the cerebrospinal fluid (CSF) was performed on all patients given CNS prophylactic chemotherapy (see section on Treatment). The prevalence of HIV positivity in Norway during the 19801990s was extremely low. HIV positivity was routinely assessed from 1990.
Clinical stage at presentation was classified according to the Ann Arbor system [25]. More than half of the patients had stage IV disease [1396 patients (56%)], whereas 259 patients (10%) were in stage III, 362 patients (14%) in stage II and 497 patients (20%) in stage I. Performance status was assessed according to the Eastern Cooperative Oncology Group (ECOG) scale.
Central nervous system involvement was diagnosed by the patients history and by clinical examination, computed tomography (CT) scan or magnetic resonance imaging (MRI) and/or CSF examination. The meninges were considered to be involved if MRI of the meninges showed infiltration and/or if the CSF showed positive cytology. Patients with CNS-related symptoms and a white blood cell count >20 x 106/l in the CSF were also considered to have meningeal involvement. Among the 22 patients with intracerebral involvement, a biopsy to confirm the lymphoma diagnosis was only performed in one patient. Patients with CNS-related symptoms, but whose results from MRI of the meninges and CSF examinations were normal or inconclusive, were regarded as clinically diagnosed CNS lymphoma. Other explanations such as CNS-associated infection, hemorrhage or infarction were excluded.
Histology
All the biopsies were classified according to the Kiel classification [24] in low-grade NHL (L-NHL) or high-grade NHL (H-NHL). Distribution of the various histological subtypes amongst the 2514 patients is shown in Table 1. Histological diagnosis was not reviewed specifically for this analysis, but the great majority of cases were diagnosed by one of two experienced hematopathologists.
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One hundred and nineteen of the 141 patients receiving CNS prophylaxis were <60 years of age. Intrathecal CNS prophylaxis with MTX 12 mg was after 1990 given to most patients with H-NHL with involvement of the bone marrow, epidural space, skeleton, testicles or paranasal sinuses. In addition, the latter group received high-dose MTX with folic acid rescue.
Analysis of potential risk factors
The following factors were registered as potential risk factors for CNS involvement and entered into univariate analysis.
Statistics
Statistical analyses were performed by using SPSS for Windows (Release 8.0; SPSS, Chicago, IL, USA). The KaplanMeier method was used for estimating the probability of CNS involvement during primary treatment or at relapse [29], and the time to CNS recurrence for different groups were compared by the log-rank test [30]. Time to CNS involvement was from the date of NHL diagnosis to the date of CNS recurrence. Patients with no CNS recurrence were treated as censored. Coxs proportional hazards model was used to analyze several prognostic factors simultaneously [31]. Due to a large number of possible prognostic factors, P <0.01 was considered as statistically significant in the univariate analysis and were included in the Cox model. Only variables maintaining a statistically significant effect were kept in the model.
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Results |
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The description of the patients according to their histology is listed in Table 2.
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For the patients with H-NHL, CNS progression occurred in 19 patients during primary treatment and 33 at relapse. The risk of isolated or systemic CNS involvement was similar, but isolated CNS recurrence seemed to take place somewhat earlier.
In lymphoblastic and Burkitts lymphoma, there was a significant effect of CNS active treatment on CNS recurrence after 5 years. Nineteen per cent [95% confidence interval (CI) 9% to 30%] of the 68 patients who received CNS prophylaxis had a CNS recurrence versus 78% (95% CI 52% to 100%) of those 14 who were not given CNS prophylaxis (P <0.0001).
Risk factors for CNS involvement in the different histological groups
Low-grade histology
A total of 33 (2.8%) of 1163 patients developed CNS involvement. In multivariate analysis, B-symptoms, involvement of the bone marrow or skin were independent prognostic factors, and the relative risk of CNS involvement was 2.8 (P <0.007), 2.8 (P <0.007) and 3.7 (P <0.01), respectively. Patients with two of the three factors had a risk of CNS involvement of ~7% within 5 years in multivariate analysis. Only three patients had all three risk factors; one of these three developed CNS involvement. Analysis of the different low-grade histologies did not reveal any difference in the risk of developing CNS involvement. However, five patients with aggressive centrocytic (mantle cell lymphoma according to the WHO classification) received CNS prophylaxis.
High-grade histology (lymphoblastic and Burkitts lymphomas excluded)
A total of 52 (4.3%) of 1220 patients developed CNS involvement (Table 2). The time to CNS involvement was 250 months. The KaplanMeier estimate for the probability of CNS recurrence within 5 years of diagnosis was 5.6% (95% CI 4% to 7%). The majority of patients [35 (67%) of 52] had their CNS involvement during the first year after NHL diagnosis.
Univariate analyses of risk factors significantly associated with CNS recurrence for the 1220 patients with H-NHL are listed in Table 3.
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Risk factors from the univariate analyses were entered into the Cox regression model, by both forward selection and backward elimination, and the same prognostic factors were found to be important by all modeling strategies. Five variablesage, LDH, albumin, retroperitoneal glands and number of extranodal siteswere shown to have an independent impact on subsequent CNS involvement. The five variables had relative risk (RR), 95% CI for RR and P value as follows: number of extranodal sites >1 versus 1, RR = 3.0 (1.75.4), P <0.001; age >60 years versus
60 years, RR = 2.8 (1.55.4), P = 0.002; albumin <35 g/l versus
35 g/l, RR = 2.5 (1.34.6), P = 0.005; LDH
450 U/l versus <450 U/l, RR = 2.1 (1.04.4), P = 0.049; retroperitoneal glands yes versus no, RR = 1.9 (1.03.5), P = 0.037.
The following variables were significant in univariate analysis, but not included in multivariate analysis because they represented <5% of the patients with H-NHL: lungs, pancreas, mammae, gynecological localization and lymphocytes >4.0 x 109/l. IPI score and age-adjusted IPI score, both for patients <61 years of age as well as for all age groups were not significant in this analysis, both when tested against the individual five risk factors and against our risk model as one set of factors (P >0.6).
Figure 1 shows KaplanMeier estimates for the risk of CNS involvement in groups representing the number of the five risk factors (age, LDH, albumin, retroperitoneal lymph node involvement, more than one extranodal site) present at diagnosis. As the estimated hazard ratios are not identical, the curves only give a general picture. The probability of CNS recurrence within 5 years is listed in Table 4. Patients with four or five risk factors represented 12% of the patients and 54% of those with a subsequent CNS relapse.
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Discussion |
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Why some lymphomas spread to the CNS is not clear. Bloodbrain dissemination from the retroperitoneal glands or bone marrow to the leptomeninges through the intervertebral venous plexa may play a role [2, 8, 14], as may adhesion molecules expressed by tumor cells, since CD56 expression is associated with CNS infiltration in peripheral T-cell lymphomas [32]. Gene expression profiling using microarray techniques [33] may uncover more powerful biological variables for predicting CNS recurrence in the future. However, one should not forget that PCR rearrangement studies of Ig rearrangements in late CNS relapses indicate that they may also represent a second unpredictable de novo neoplasm [34].
The overall risk of CNS dissemination following a primary diagnosis of lymphoma was 4.2% (106 of 2514 patients). Central nervous system recurrence occurred in 96 of 106 patients within 5 years, median time 10 months. The risk is reported to range from 1.6 [35] to 22% [15] with the majority between 3 and 10% [7, 10, 21, 23, 36]. The latency time to CNS involvement varied from 6 to 8 months [7, 21, 23, 36].
Factors previously reported to be associated with increased risk of CNS recurrence include:
Involvement of specific sites were the prominent risk factors in previous studies when analyzed by either univariate or multivariate analyses. However, in more recent studies that include a higher number of patients [7, 20, 35], other risk factors have turned out to be more important (LDH, IPI, number of extranodal sites). Our data are partly in line with these findings, but we did not find IPI to be an independent risk factor. This may be due to an increased risk for CNS recurrence in younger, not older, patients, while the opposite is the case for IPI score. Neither was the age adjusted IPI score for patients <61 years of age nor for all patients an independent risk factor in multivariate analysis. The analysis of IPI scores could, however, be calculated only for the 55% of patients with an ECOG score. Furthermore, we found retroperitoneal lymph node infiltration to be an independent factor, which may be due to the vicinity of these glands (especially when bulky) to the intervertebral venous plexa and thereby to the leptomeninges [2]. A fifth independent risk factor, serum albumin, has not been included as a potential risk factor for CNS recurrence by other investigators. In advanced Hodgkins disease, however, it is found to be a risk factor for a shorter progression-free survival [38].
Many authors recommend CNS prophylaxis for those with bone marrow involvement [1, 2, 16, 1923, 36, 39]. However, recent data have not confirmed the association between bone marrow involvement and CNS disease [7, 35]. This discrepancy may be due to a co-variation with other risk factors, such as IPI and LDH, not previously examined.
Several investigators have evaluated the risk of CNS recurrence in NHL throughout the last 30 years. The few investigations performed in indolent lymphomas describe the risk in general to be low [10, 15, 16]. The few cases of CNS involvement were reported to be associated with a transformation to high-grade malignancy [15]. Montserrat et al. [40] found that five of 22 patients with mantle-cell lymphoma (MCL) developed CNS involvement. Nevertheless, they consider the role of CNS prophylaxis in reducing CNS recurrence as doubtful, because CNS infiltration in MCL is almost invariably part of a disseminated disease or a systemic relapse, and because the prognosis is poor anyway. However, recent attempts to improve the survival in MCL include high-dose MTX/Ara-C given systemically [41].
For the 1163 patients with L-NHL in our study, CNS recurrence occurred in 33 patients (2.8%).
High-grade histology was diagnosed in 1220 patients, of whom 52 (4.3%) had CNS recurrence. A risk model was made of five additional risk factors present in >5% of patients and which were independent risk factors in multivariate analysis: age, albumin, LDH, retroperitoneal lymph node involvement and more than one extranodal site. The patients with H-NHL could be divided in two risk groups: a low risk group comprising patients with less than four risk factors who had a risk of CNS recurrence of 6.2%. A high risk group in which patients possess four or five risk factors (12.3% of patients) who had a risk for CNS recurrence of
25% (comprising 54% of the CNS recurrences). In our view, CNS prophylaxis should be given to patients with at least a two- to three-fold increased risk of CNS recurrence. We thus recommend that the patients in the high-risk group should receive CNS prophylaxis.
We could not confirm a significantly higher risk for CNS recurrence for patients with involvement of the testicles, paranasal sinuses or skeleton in the univariate analyses. Notably, skeletal (80 patients) and testicular (25 patients) involvement with stage IE and IIE disease had a very low risk of CNS involvement in our study [42]. Those with involvement of the bone marrow had a significantly higher risk of CNS recurrence in univariate analysis, but not in multivariate analysis.
Lymphoblastic or Burkitts lymphomas were diagnosed in 82 patients, of whom 20 (24.4%) had CNS recurrence. Our data indicate an effect of CNS prophylaxis; those 68 patients who received CNS prophylaxis had a probability of 19% for CNS involvement within 5 years, versus 78% for those who did not receive any CNS prophylaxis. Reasons for not giving the more intensive chemotherapy regimen including CNS prophylaxis were increased age or poor performance status in most patients, and the groups were therefore not directly comparable. Inclusion of age and performance status in the analysis did not, however, change the effect of prophylaxis. No independent risk factors for developing CNS involvement could be found in these histological groups. There is general agreement that lymphoblastic and Burkitts lymphomas should receive aggressive combination chemotherapy including effective CNS prophylaxis with high dose MTX and/or Ara-C given systemically as well as intrathecal therapy with the same agents [43].
Most patients with CNS recurrence also developed lymphoid recurrence outside the CNS. As indicated from the treatment of childhood leukemias [44] and lymphomas [45], systemic control seems to reduce the likelihood of CNS recurrence. The GELA (Groupe dEtudes des Lymphomes de lAdulte) group has recently reported [46] that a more intensive chemotherapy regimen (ABVCP), including CNS-active consolidation treatment, results in fewer CNS recurrences than ordinary CHOP-like therapy. Prospective randomized studies in which one [10, 47] or several study arms [48] contain CNS-active regimens could have clarified the importance of CNS prophylactic treatment. However, the incidence of CNS recurrence is not reported in any of these studies. Frequencies of CNS recurrence derived from these studies, especially if the data were put together in a meta analysis, might clarify whether CNS-active treatment really protects against CNS involvement.
We found no clear protective effect of our suboptimal CNS prophylaxis treatment, which partly consisted of high-dose systemic MTX and MTX given by i.t. injection, and partly by MTX i.t. alone. As our study was not a randomized intervention study, patients receiving CNS prophylaxis were not comparable to those not receiving prophylaxis, and the effect of prophylaxis could not be estimated. However, based on pharmacological studies and data from the treatment of acute lymphoblastic leukemias and lymphomas, as well as studies from the GELA group, intensive systemic therapy including systemic high-dose MTX and MTX i.t. seems to be justified for those patients with an increased risk of CNS recurrence.
Our study is retrospective in nature, and ideally the results should be confirmed in a prospective study. Given the low number of events (5% CNS recurrences), it would be difficult to recruit a sufficient number of patients prospectively. Alternatively, our results might be confirmed on a different set of patients by using the database of the French GELA group or the population-based registry, Danish Lymphoma Study Group Registry (LYFO) from western Denmark.
In conclusion, this study represents a large single-center analysis on CNS recurrence in patients with NHL. As lymphoblastic and Burkitts lymphoma patients carry a high risk (25%) of CNS recurrence, all these patients should receive prophylactic CNS therapy. In the low-grade malignancy group, the risk of CNS recurrence was too low to recommend CNS prophylaxis. For the non-Burkitts, non-lymphoblastic H-NHLs, five risk factors each present in >5% of the patients were independently associated with CNS recurrence. If four or more of these factors (<60 years of age, elevated LDH, low albumin, retroperitoneal lymph node involvement, involvement of more than one extranodal site) are present, we recommend the use of CNS prophylaxis. In addition, based on literature studies, we recommend that patients with testicular [10, 16, 37] involvement with at least stage IIE disease and patients with involvement of paranasal sinuses [10] also receive CNS prophylaxis.
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Footnotes |
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