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Keywords:

  • aggressive non-Hodgkin lymphoma;
  • central nervous system;
  • prophylaxis;
  • methotrexate

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Central nervous system (CNS) recurrence is almost invariably fatal in patients with aggressive non-Hodgkin lymphoma (NHL). Although some protocols are intended to prevent CNS disease, the value of CNS prophylaxis in patients with aggressive NHL remains to be determined.

METHODS

We retrospectively analyzed a cohort of 68 adults with NHL who had been treated uniformly with systemic chemotherapy and had attained complete remission (CR) of disease. Patients ranged in age from 15 to 77 years (median, 56 years). Median follow-up after CR was 40 months. After CR was attained, 29 patients (Group A) received CNS prophylaxis consisting of four doses of intrathecal methotrexate 10 mg/m2 and hydrocortisone 15 mg/m2 as soon as they could tolerate it. The other 39 patients (Group B) did not receive CNS prophylaxis.

RESULTS

Although bulky mass (45% vs. 21%, P = 0.03) was more frequent in Group A than in Group B, none of the patients in Group A experienced CNS recurrence (0%), whereas CNS recurrence occurred in six patients in Group B (15%). This difference was significant (P = 0.03). Multivariate logistic regression analysis for CNS recurrence identified no CNS prophylaxis (P = 0.01) and bone marrow involvement (P = 0.02) as independent predictors. Among patients without CNS disease, systemic recurrence occurred in 5 patients in Group A and in 11 patients in Group B (P = 0.12). The 5-year overall survival rate from CR was 80% in Group A and 58% in Group B (P = 0.05). The 5-year recurrence-free survival rate from CR was 85% in Group A and 51% in Group B (P = 0.01).

CONCLUSIONS

Prophylactic intrathecal methotrexate and hydrocortisone injection reduces the incidence of CNS recurrence following CR in patients with aggressive NHL and improves the chance of long-term survival. Cancer 2002;95:576–80. © 2002 American Cancer Society.

DOI 10.1002/cncr.10699

Central nervous system (CNS) recurrence of non-Hodgkin lymphoma (NHL) is almost always fatal with a rapid progression of disease. Although CNS recurrence is rare in patients with low-grade NHL, patients with lymphoblastic lymphoma and small noncleaved cell lymphoma often are threatened with this type of recurrence.1, 2 Neoplasia classified according to the working formulation3 (WF) as aggressive lymphoma of intermediate grade or large cell immunoblastic lymphoma shows an incidence of CNS recurrence of approximately 5% when no CNS prophylaxis is added to systemic chemotherapy. Several risk factors for CNS recurrence in patients with complete remission (CR) of disease have been identified and efforts are underway to define patient subgroups for whom CNS prophylaxis is warranted.4–7 However, the effectiveness of CNS prophylaxis remains to be clarified. Although recent progress in systemic chemotherapy has raised the CR rate and reduced systemic recurrences, control of CNS recurrence remains important for improving the results of chemotherapy. We retrospectively analyzed therapeutic outcome in aggressive NHL patients with or without CNS prophylaxis using intrathecal methotrexate (MTX) and hydrocortisone injection.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The subjects of this study were 68 adult patients with aggressive NHL diagnosed between 1991 and 2000 at our institution and affiliated hospitals. Human immunodeficiency virus lymphoma was not included in the study. Patients' age ranged from 15 to 77 years (median, 56). Median follow-up after CR was 40 months. Histologic specimens were evaluated by expert pathologists at each institution according to the WF classification. Tumor categories included diffuse small cleaved cell, diffuse mixed cell, diffuse large cell, and large cell immunoblastic lymphoma. For convenience, a few cases of anaplastic large cell lymphomas were grouped with difffuse large cell lymphoma. Clinical staging was performed according to the Ann Arbor system,8 based on a physical examination, computed tomography (CT) scan of the chest, abdomen, and pelvis, a gallium scintigram, endoscopic examination of the upper gastrointestinal tract, and bone marrow aspiration and biopsy. Patients with initial CNS involvement were excluded from study.

All patients had received two or more courses of an ACOMP-B induction regimen9 (MACOP-B-modified regimen) and achieved CR of disease. In general, two courses of ACOMP-B and sequential consolidative treatment including nine drugs10 (ML-Y9) were added after CR of disease was achieved. The ACOMP-B regimen was given every 4 weeks as follows: doxorubicin, 40 mg/m2 on Days 1 and 15; cyclophosphamide, 600 mg/m2 on Days 1 and 15; vincristine, 1.4 mg/m2 (maximum, 2.0 mg) on Days 1 and 15; MTX, 400 mg/m2 on Day 8 followed by leucovorin rescue; prednisolone, 40 mg/m2 on Days 1–7; and bleomycin, 8 mg/m2 on Day 1. All drugs were given by intravenous injection except for prednisolone, which was given orally. In patients who initially had a bulky tumor mass, local irradiation (40 Gy) was added after CR.

As soon as possible after CR was attained, 29 patients (Group A) received CNS prophylaxis consisting of four intrathecal doses of MTX (10 mg/m2) and hydrocortisone (15 mg/m2), ordinarily given twice a week for 2 weeks. Systemic chemotherapy was given simultaneously or sequentially. The other 39 patients (Group B) did not receive CNS prophylaxis. The decision for giving CNS prophylactic chemotherapy or no prophylaxis was not randomized, but depended on the decision of each attending physician. Specifically, we began to use CNS prophylaxis in 1992, mainly for patients who initially had an advanced stage of disease. Therefore, most patients who received CNS prophylaxis in this study had advanced disease.

Factors examined to compare patient background between the two groups included gender, histology, phenotype, age (older than 60 vs. 60 years old and younger), serum lactate dehydrogenase (LDH) concentration (greater than the upper limit of normal vs. equal to or less than normal), performance status (2–4 vs. 0–1), clinical stage according to the Ann Arbor classification (III or IV vs. I or II), number of sites of extra lymph node involvement (two or more vs. fewer), the international prognostic index11 (IPI), presence versus absence of bone marrow involvement, and presence or absence of a bulky mass, defined as a tumor 10 cm or more in diameter. Received dose intensity12 for each drug was calculated through the period of ACOMP-B therapy in the two groups.

CNS recurrence was diagnosed when malignant cells were detected in cytocentrifuged preparations of cerebrospinal fluid or when an intracranial mass was detected by CT scan or magnetic resonance imaging. Epidural spinal cord compression was not considered to be CNS recurrence in this study. Patients with symptoms suggesting CNS disease but no other evidence were not regarded as having CNS recurrence.

Statistical Analysis

The Fisher exact test, the chi-square test, and the two-group Student t tests for unpaired data were used to determine statistically significant differences between groups. The Mann–Whitney U test was used between ordered groups. Multivariate logistic regression analysis was used to identify risk factors for CNS recurrence. A survival curve was constructed using Kaplan–Meier methods and groups were compared by the Wilcoxon test. P < 0.05 indicated significance.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

There were more female patients (P = 0.02) and patients with a bulky mass (P = 0.03) in Group A than in Group B (Table 1). Although serum LDH concentration and clinical stage were higher in Group A, the differences were not statistically significant. Received dose intensity of each drug included in the ACOMP-B regimen showed no difference between the two groups (Table 2).

Table 1. Patient Characteristics
 CNS prophylaxisP valuea
Group A (+)Group B (−)
  • CNS: central nervous system; DSC: diffuse small cleaved cell; DM: diffuse mixed cell; DL: diffuse large cell; IBL: large cell immunoblastic; NS: not significant; LDH: lactate dehydrogenase; EN: number of extra lymph node sites; BM: bone marrow involvement.

  • a

    Fisher exact test.

  • b

    Chi-square test.

  • c

    Mann–Whitney U test.

Gender   
 Male1227 
 Female17120.02
Histology   
 DSC36 
 DM31 
 DL1929 
 IBL43NSb
Phenotype   
 B1422 
 T/NK69 
 ND98NS
Age (yrs)   
 > 60715 
 ≤ 602224NS
LDH   
 Above normal2121 
 Normal or less than normal8180.10
Performance status   
 2–41212 
 0–11727NS
Stage   
 III, IV2526 
 I, II4130.06
EN   
 ≥ 2811 
 ≤ 12128NS
International index   
 Low710 
 Low-intermediate913 
 High-intermediate512 
 High84NSc
BM   
 Positive65 
 Negative2334NS
Bulky mass   
 Positive138 
 Negative16310.03
Table 2. Received Dose Intensity of Each Drug (mg/m2/week)a
 CNS prophylaxisP Valueb
Group A (+)Group B (−)
  • CNS: central nervous system; ADR: doxorubicin; CPA: cyclophosphamide; VCR: vincristine; MTX: methotrexate; BLM: bleomycin.

  • a

    Received dose intensity of each drug indicated as mean ± SD.

  • b

    Student t test for unpaired data.

ADR17.0 ± 2.917.0 ± 3.1NS
CPA255.1 ± 42.2250.3 ± 47.2NS
VCR0.54 ± 0.090.55 ± 0.12NS
MTX79.1 ± 16.478.6 ± 23.9NS
BLM1.65 ± 0.681.55 ± 0.57NS

None of the patients in Group A developed CNS recurrence compared with six patients in Group B (Table 3); this difference was significant (P = 0.03). In one patient in Group B, CNS recurrence was associated with simultaneous systemic recurrence; this case was considered CNS rather than systemic recurrence in the data analysis. Recurrence in the other five patients was limited to the CNS. In the six patients with CNS recurrence, the phenotype of lymphoma cell was B in three patients, T/NK in one patient, and not determined in two patients. The initial IPI was low in one patient, low–intermediate in two patients, high–intermediate in two patients, and high in one patient. Times from CR to CNS recurrence were 1, 1, 2, 5, 13, and 56 months. Median survival from CNS recurrence in these six patients was 6.5 months. Multivariate logistic regression analysis for risk factors of CNS recurrence identified absence of CNS prophylaxis (P = 0.01) and presence of bone marrow involvement (P = 0.02) as independent predictors (Table 4).

Table 3. CNS and Systemic Recurrence
 CNS prophylaxisP valuea
Group A (+)Group B (−)
  • CNS: central nervous system.

  • a

    Fisher exact test.

  • b

    Five isolated and one associated with simultaneous systemic recurrence.

  • c

    Patients with CNS recurrence were excluded from the examination.

CNS recurrence (+)06b 
CNS recurrence (−)29330.03
Systemic recurrence (+)511 
Systemic recurrence (−)24220.12c
Table 4. Covariates Associated with CNS Recurrence in Multivariate Logistic Regression Analysis
 P valueRelative risk (95% confidence interval)
  1. CNS: central nervous system; BM: bone marrow.

CNS prophylaxis (+)0.010.0000006 (0–∞)
BM involvement (+)0.0260.9 (1.02–3645)

In the 62 patients without CNS recurrence, 16 systemic recurrences were seen (5 in Group A and 11 in Group B). The difference between the two groups did not reach statistical significance (Table 3).

Overall survival from CR in Group A was significantly better than in Group B (P = 0.05; Fig. 1A). The 5-year overall survival rate was 80% in Group A and 58% in Group B. The difference was even greater for recurrence-free survival (P = 0.01; Fig. 1B). The 5-year recurrence-free survival rate was 85% in Group A and 51% in Group B. The end-point was the first recurrence, whether CNS or systemic.

thumbnail image

Figure 1. Kaplan–Meier curves for overall survival (A) and recurrence-free survival (B) in patients with aggressive non-Hodgkin lymphoma who received or did not receive central nervous system prophylaxis with intrathecal methotrexate and hydrocortisone.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The role of CNS prophylaxis in patients with aggressive NHL is still uncertain. Although many reports have described CNS involvement and initial risk factors in patients with aggressive NHL, subjects generally included not only those with CNS recurrence during systemic CR but also CNS involvement in the presence of active systemic disease. Analysis of the efficacy of CNS prophylaxis must be limited to patients with CR of disease. We found four reports describing circumstances of CNS recurrence in patients with CR of aggressive NHL. Van Besien et al.4 identified an elevated serum LDH concentration and involvement of more than one extra lymph node site as independent risk factors for CNS recurrence. Zinzani et al.5 found only advanced stage to be a risk factor for CNS recurrence. Bos et al.6 could not find a subgroup for which CNS prophylactic treatment might be expected to provide substantial benefit. The patients in these three studies did not receive any CNS prophylaxis. Haioun et al.7 reported a large cohort of 974 patients with CR of disease who had been treated uniformly with the same systemic chemotherapeutic regimen, including intravenous high-dose MTX and CNS prophylaxis by intrathecal injection of MTX. Occurrence of isolated CNS recurrence according to IPI was 0.6% in low and low–intermediate patients but 4.1% in high–intermediate and high patients. Haioun et al. concluded that the prophylaxis notably reduced the risk of CNS recurrence in higher-risk patients (high–intermediate and high) compared with the reported rates for patients who did not receive prophylaxis.4–6

In the current study, we retrospectively analyzed therapeutic outcome in patients with aggressive NHL with or without CNS prophylaxis using intrathecal MTX and hydrocortisone. All patients had been treated uniformly with systemic chemotherapy using the ACOMP-B regimen and had attained CR of disease. CNS prophylactic chemotherapy or no prophylaxis depended on the decision of each attending physician. However, most patients receiving CNS prophylaxis in this study had initial advanced stage, because we considered intrathecal prophylactic chemotherapy particularly important for these patients. We also considered the dose intensity of each drug given in ACOMP-B therapy and found it similarly distributed in the two groups. Although ACOMP-B induction included 400 mg/m2 of intravenous MTX per cycle, this dose probably was too low for adequate CNS prophylaxis.13 As for the background variables, female gender was overrepresented among the 29 patients with CNS prophylaxis, as was a bulky tumor, which usually is considered to be a risk factor for CNS involvement. In spite of this, all six CNS recurrences occurred among patients without CNS prophylaxis, representing a significant difference. Moreover, multivariate analysis showed lack of CNS prophylaxis to be the strongest independent predictor of CNS recurrence, followed by bone marrow involvement. This indicates that CNS prophylaxis is beneficial for patients with aggressive NHL. The overall survival and recurrence-free survival curves showed better outcomes in the patient group with CNS prophylaxis. When the six patients with CNS recurrence were censored from the curves at the time of recurrence, the difference between the two groups was no longer statistically significant for both overall and recurrence-free survival rates (data not shown), indicating that the survival benefits were the result of CNS prophylaxis. As for timing, CNS prophylaxis should be considered as soon as possible after patients achieve CR of disease because four of the six CNS recurrences in our study occurred within 5 months from CR. We also examined the possibility that intrathecal MTX injection for CNS prophylaxis might penetrate the blood–brain barrier and reduce systemic recurrence, but no significant prevention of systemic recurrence was evident in the 62 patients without CNS recurrence.

We conclude that prophylactic intrathecal MTX and hydrocortisone injection reduce the incidence of CNS recurrence following CR in patients with aggressive NHL and improves survival rates. Further randomized controlled studies are warranted to define subgroups with particular survival benefit from CNS prophylaxis.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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