286

ORIGINAL
Continued-Maintenance Therapy with High-dose Methotrexate
Improves Overall Survival of Patients with Primary Central
Nervous System Lymphoma
Kohei Nakajima, MD, PhD, Yoshifumi Mizobuchi, MD, PhD, Toshitaka Fujihara, MD, PhD, Mai Azumi, MD,
and Yasushi Takagi, MD, PhD
Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan, Tokushima, 770-8503,
Japan

Abstract : Background. PCNSL is mainly treated with HD-MTX-based chemotherapy with or without WBRT.
However, As WBRT is associated with delayed neurotoxicity leading to dementia in the elderly, many institutes
reported benefits of intensive chemotherapy or high-dose chemotherapy with ASCT. We investigated whether
treatment with HD-MTX and rituximab, followed by continued-maintenance HD-MTX monotherapy (3.5g / m2),
improves overall survival (OS). Methods. In this retrospective, single-center trial 52 immunocompetent patientswith newly diagnosed PCNSL were included. All were treated between January 2005 and December 2017. The
controls were 18 patients who, between 2005 and 2011, had received 3 cycles of HD-MTX and then adjuvant
treatment with WBRT. In 2011 we started HD-MTX continued-maintenance therapy to treat 34 PCNSL patients.
In the induction phase, these patients received HD-MTX every 14 days until a complete response (CR) was observed. When CR was obtained, maintenance therapy with HD-MTX (3.5g / m2) was delivered every three months.
Results. In 3-year overall survival (OS) there was a statistically significant difference between the two groups[controls : 33.1% (95%, CI 12.4 - 55.7%) ; maintenance group : 74.9% (95%, CI 55.6 - 86.7%) (p < 0.02)]. Conclusion : The
induction of HD-MTX based chemotherapy followed by continued-maintenance HD-MTX monotherapy improved
OS compared with chemoradiotherapy consisting of HD-MTX followed by WBRT. J. Med. Invest. 68 : 286-291, August, 2021
Keywords : malignant lymphoma, methotrexate, maintenance therapy, whole-brain radiotherapy

INTRODUCTION
Primary central nervous system lymphomas (PCNSLs) are
1 - 4% of all brain tumors(1, 2) ; their incidence is increased in
the elderly. No standard of care for patients with PCNSL has
been defined. In most institutions, PCNSL is mainly treated byhigh-dose methotrexate (HD-MTX)-based chemotherapy withor without subsequent whole-brain radiotherapy (WBRT) ; theoverall response rate exceeded 50% (1). However, WBRT is associated with delayed neurotoxicity leading to dementia, especiallyin the elderly (3). Therefore, to defer or avoid WBRT, intensive
and high-dose chemotherapy with autologous stem cell support
has been delivered (1, 2, 4, 5). However, as these therapies may
elicit severe side effects in the elderly, maintenance therapy has
been suggested as an alternative (2, 6).
Rituximab, a humanized anti-CD20 monoclonal antibody, iseffective in a variety of systemic B-cell lymphomas. Although its
efficacy in patients with PCNSL is incompletely understood, it
has been added to PCNSL treatment protocols (1, 7).
We investigated whether the induction with HD-MTX andrituximab chemotherapy, followed by continued-maintenance
HD-MTX monotherapy improves the overall survival (OS) of
PCNSL patients and whether deferring WBRT helps to avoid
deterioration in the Karnofsky performance score (KPS).

Received for publication March 17, 2021 ; accepted May 14, 2021.
Address correspondence and reprint requests to Kohei Nakajima,
Department of Neurosurgery, Institute of Biomedical Sciences
Tokushima University Graduate School, Japan, 3-18-15, Kuramoto-cho,
Tokushima, 770-8503, Japan and Fax : +81-88-632-9464.

PATIENTS AND METHODSPatients

Between January 2005 and December 2017, we encountered
59 patients with PCNSL. After excluding 7 patients with HIV
infection, a creatinine clearance < 60, and lymphoma outside
the central nervous system, our study population consisted of
52 immunocompetent patients with newly diagnosed PCNSL.
They underwent stereotactic surgery or tumor resection under
craniotomy. The diagnosis was based on histological and immunohistochemical findings.
This study was approved by the institutional review board,
and written informed consent was waived because of the retrospective design.

Treatment protocols
Between 2005 and 2011, 18 patients (control, group 1) weretreated with 3 cycles of HD-MTX [3.5 g / m2 intravenously (iv)over 3 hr every 2 weeks] ; thereafter they underwent adjuvant
WBRT (total dose 40~50Gy). If progressive disesase (PD) was
observed, the protocol was stopped and WBRT was performed.
(Figure 1)
In 2011 we started HD-MTX continued-maintenance therapy (group 2, n = 34). In the induction phase these patients received HD-MTX therapy every 14 days until complete response(CR) was observed. Then, maintenance therapy with HD-MTX(3.5g / m2) was delivered every 3 months. If PD was observed
during any treatment phase, the protocol was stopped and
WBRT was performed. In 2013 we added rituximab (375 mg / m2)
on day 1 of the induction phase. Patient with relapse in the maintenance phase were treated with rituximab and HD-MTX again.
When re-challenge chemotherapy was effective, it was continued

The Journal of Medical Investigation Vol. 68 2021

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The Journal of Medical Investigation Vol. 68 August 2021

Medical University, Saitama, Japan), a graphical user interface
for R (The R Foundation for Statistical Computing, Vienna,
Austria) and a modified version of R commander designed to add
statistical functions frequently used in biostatistics.

RESULTS

Patient characteristics

Figure 1. Flow chart summarizing the number of patients in the

two treatment groups.
Abbreviations : HD-MTX, high-dose methotrexate ; R-MTX, rituximab
plus HD-MTX ; WBRT, whole-brain radiation therapy ; CR, complete
response ; PD, progressive disease

Between 2005 and 2017 we encountered 59 patients with
B-cell PCNSL ; of these, 52 were entered in our study. Excluded
were 7 patients ; 4 due to kidney disturbance, 2 with massive
intratumoral hematoma receiving supportive care only, and one
with thrombocytopenia.
Of the 52 patients, 18 received HD-MTX and WBRT until
2010 ; they were the control (group 1). The other 34 underwent
HD-MTX maintenance therapy ; their treatment was started in2011 (group 2). In 25 patients of this group, rituximab was added
to HD-MTX at the induction phase. As shown in Table 1, themedian age, gender, number of lesions, and the KPS at the startof chemotherapy were similar in all 52 patients.
Table 1. Patient demographic and clinical characteristics

until CR was obtained. Maintenance chemotherapy was continued until it failed to elicit a response (Figure 1).
In HD-MTX chemotherapy, leucovorin rescue (15 mg, x 6 / day)
was administered iv 24 hr after HD-MTX administration. Adequate hydration was maintained. Their urine was alkalized
by the iv injection of NaHCO3 and its pH was monitored. These
supportive treatments were continued until their plasma MTX
level fell to < 0.1 μmol / l.
We defined “protocol-achieved population” as patients obtained CR after three cycles of HD-MTX therapy and WBRTin group 1, and same as patients who obtained CR during theinduction phase in group 2.

Response evaluation, toxicity, and performance status
The treatment response was evaluated after each cycle bycontrast-enhanced magnetic resonance imaging (CE-MRI). CR
was defined as the total disappearance of all enhancing lesions
on MRI scans, treatment failure as progressive disease (PD)with an increase of more than 25% in the tumor volume, theobservation of new lesions on MRI scans, death, or discontinuation of chemotherapy due to complications. Acute toxicity wasevaluated based on the National Cancer Institute’s Common
Terminology Criteria for Adverse Events. In all patients, theKPS pre-treatment and every 6-months post-treatment wasrecorded for 2 years.

Statistical analysis
The patient characteristics were compared using Fisher’s
exact- or the unpaired t -test, as appropriate. Progression freesurvival (PFS) was defined as the interval between the histological diagnosis and tumor progression, overall survival (OS)as the time between the histological diagnosis and death or last
follow-up. The Kaplan-Meier method was used for univariate
analysis of survival ; differences were assessed with the log-rank
test. The Cox proportional hazards regression model was applied to calculate the hazard ratio (HR) and the 95% confidence
interval (CI) to investigate prognostic factors for OS. Prognostic
candidates were selected with reference to previous studies.
A p value < 0.05 was considered to indicate statistical significance performed with EZR (Saitama Medical Center, Jichi

Control group(group 1)

Patient
characteristics

Maintenance group(group 2)

all

Protocolachieved
population

allProtocolachieved
population

18

10

34

18

Male

12

5

15

6

Female

6

5

19

12

Median

64.5

62.2

68.5

64.8

Range

44 - 77

44-72

38 - 86

38-79

Single

6

2

16

7

Multiple

12

8

18

11

≧ 70

5

4

12

7

  < 70

13

6

22

11

No. of patientsSex

Age (years)

Number of lesions

KPS at diagnosis

Response and survival
Three cycles of HD-MTX therapy and WBRT were completed
by 10 of 18 (55.6%) group 1 patients. In 8, HD-MTX treatment
was stopped due to PD (n = 7) and they underwent WBRT ; theother patient developed severe myelosuppression after cycle 3
and died of pneumonia (Figure 1).
Among group 2, 18 of 34 patients (52.9%) who underwent induction- and maintenance therapy obtained CR in the induction
phase. The other 16 (47.1%) manifested PD during the induction
phase ; 11 received WBRT, 2 suffered rapid tumor progression
and did not undergo radiotherapy, 2 were treated with alternative chemotherapy (temozolomide), and one died of pulmonary
embolism. Median number of cycles with HD-MTX was 8.8 ingroup 2, same as in group 1 was 2.9. As shown in Figure 1, 9 of
the 34 group 2 patients (26%) manifested PD during the maintenance phase ; 2 underwent WBRT and 7 were re-treated with

K. Nakajima, et al. Continued-Maintenance Therapy for PCNSL

288

HD-MTX plus rituximab. CR was obtained in 5 of the re-challenged patients.
The median follow-up period was 35.6 months (range 3.6- 140.8 months) in group 1 and 7.9 months (range 0.3 - 87.7
months) in group 2. For group 1, one- and 3-year PFS was 22.9%(95%, CI 6.2 - 45.6%) and 15.2% (95%, CI 2.7 - 37.6%), respectively ; for group 2 it was 39.4% (95%, CI 23.1 - 55.4%) and 32.3%(95%, CI 17.0 - 48.5%), respectively. The inter-group difference
was not statistically significant (p = 0.07) (Figure. 2).
In all population of group 1, the rate of one- and 3-year OS was
77.8% (95%, CI 51.1 -91.0%) and 33.1% (95%, CI 12.4 - 55.7%), respectively ; it was 88.1% (95%, CI 71.4 - 95.4%) and 74.9% (95%,
CI 55.6 - 86.7%), respectively, in the same population of group 2.
As the treatment in group 2 was started in 2011, the follow-up
period at the time of analysis (2019) was too short to obtain
median survival data. There was a statistically significant difference between the groups in OS (log-rank test p = 0.02) (Figure3A) ; in the protocol-achieved population of group 1, 3-year OS
was 20.0% (95%, CI 3.1 - 47.5%) ; in the same population of group
2 it was 94.1% (95%, CI 65.0 - 99.1%) (log-rank test p = 0.0001)(Figure 3B). Multivariate analysis revealed Receiving maintenance therapy was an independent factor related to OS (HR0.39 ; 95% CI, 0.17 - 0.90 ; p = 0.027). In our study population,
well-established prognostic factors such as the patient age and
KPS were not associated with OS (Table 2).

Figure 2. Progression-free survival

Kaplan-Meier curve showing progression-free survival in all patients.
Solid line : control group; dashed line : maintenance group

Figure 3. Overall survival(A) Kaplan-Meier curve showing overall survival in all patients.
(B) Kaplan-Meier curve showing overall survival in protocol-achieved population.
Solid line : control group ; dashed line: maintenance group

Table 2. Univariate and multivariate analyses for overall survival
Univariate analysis

Multivariate analysis

Hazard ratio (95%CI)

p value

Hazard ratio (95%CI)

p valueAge

1.32 (0.51-3.38)

0.558

1.28 (0.49-3.33)

0.62

KPS

0.72 (0.16-3.12)

0.66

0.68 (0.15-3.02)

0.62

Maintenancetherapy

0.39 (0.17-0.92)

0.03

0.39 (0.17-0.90)

0.027

The Journal of Medical Investigation Vol. 68 August 2021
KPS
In all population of group 1, the mean KPS before the startof chemotherapy was 56.7 ; it was 58.3 at 6-, 47.8 at 12-, 46.7 at
18-, and 42.8 at 24 months from the start of chemotherapy. At
all time point the range was 0 - 90. In the same population ofgroup 2, the mean KPS before the start of chemotherapy was
57.6 (range 20 - 90) ; it was 64.7 at 6-, 62.6 at 12-, 57.1 at 18-,
and 57.1 at 24 months and the range was 0 - 90 at all these time
points (Figure 4A).
In the protocol-achieved population of group 2, the KPS
was improved 6 months after the start of chemotherapy andremained stable throughout the 24-month observation period.
On the other hand, in the same population of group 1, the KPS
deteriorated gradually. Although there was no statisticallysignificant inter-group difference, group 2 did not manifest adeterioration in the KPS (Figure 4B).

Toxicity
The rate of toxic effects of grade 3 or higher was 22.2% in group
1 and 14.7% in group 2 ; there was no significant inter-groupdifference in the toxicity of chemotherapy. One group 1 patientdeveloped severe myelosuppression and died of pneumonia, and3 developed liver dysfunction reversible without specific therapy.
In group 2, one patient died of pulmonary embolism, anotherdeveloped a wound infection, 2 manifested grade 3 neutropenia,
and another 2 developed liver dysfunction.

DISCUSSION
Our findings show that OS in patients who underwent induction with HD-MTX and rituximab chemotherapy, followed bycontinued-maintenance HD-MTX monotherapy, was superior
to OS in patients treated by chemoradiotherapy consisting of
3 cycles of HD-MTX followed by WBRT. Multivariate analysis
revealed maintenance therapy as the independent factor for OS
and that this treatment avoided KPS deterioration.
No standard of care has been established for PCNSL patients.
In the past, PCNSL was treated with WBRT only. In addition
to the lack of durable responses, PCNSL patients older than 60

289

years who received radiotherapy manifested delayed neurotoxicity and deterioration of their KPS (8-10). WBRT alone is nolonger initial treatment for most patients with PCNSL.
Recently, PCNSL is mainly treated with HD-MTX based
chemotherapy with or without WBRT. Thiel et al. (11) performeda phase 3 randomized trial that included 551 PCNSL patients toassess whether HD-MTX-based chemotherapy without WBRT
was inferior to the same treatment with WBRT. Patients treatedwith chemotherapy plus WBRT achieved prolonged PFS but noimprovement in OS. Treatment-related neurotoxicity was morecommon in patients receiving WBRT. Subsequently, various
studies have been attempted to defer or avoid WBRT by delivering intensive chemotherapy and high-dose chemotherapy plus
autologous stem cell support. In the multicenter phase 2 studies
administered multi-agent chemotherapy that included rituximab, MTX, vincristine, and procarbazine for induction therapy
that was followed by reduced-dose WBRT and cytarabine asconsolidation chemotherapy, intensive chemotherapy was associated with high response rates, long-term disease control, andminimal neurotoxicity (12, 13). In the International Extranodal
Lymphoma Study Group-32 trial, an international randomized
phase 2 study, patients who reached CR by multi-agent chemotherapy with rituximab, MTX, cytarabine and thiotepa, wererandomized into a group that received high-dose chemotherapy
supported by autologous stem-cell transplantation (ASCT) anda group treated with HD-MTX followed by WBRT. This study
appeared WBRT and ASCT were both feasible and effective as
consolidation therapies in patients aged 70 years or younger.
However, the incidence of hematologic toxicity was higher in patients who had undergone high-dose chemotherapy supported by
ASCT (14). In our study, the incidence of grade 3 and higher toxic
effects was 22.2% in the control- and 14.7% in the maintenancegroup, and those were fewer than intensive chemotherapy.
The effectiveness of HD-MTX continued-maintenance therapy
in PCNSL patients has also been evaluated by others (15, 16).
Chamberlain et al. (17) treated 40 patients with HD-MTX maintenance therapy. They reported a median OS was 33.5 months
for 28 patients who completed maintenance therapy. In ourmaintenance group, OS at 1- and 3 years was 88.1% and 74.9%,
respectively. These outcomes were similar to patients who received multi-agent chemotherapy in earlier studies (Table 3).

Figure 4. Mean KPS scores in the course of the 2-year follow-up period.
(A) All patients(B) Protocol-achieved population
Solid line : control group; dashed line : maintenance group.

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K. Nakajima, et al. Continued-Maintenance Therapy for PCNSL

Table 3. Comparison of our study with previously reported findings
No. ofpatients

1 yearPFS

2 yearPFS

3 yearPFS

2 yearOS

3 yearOS

WBRT41

MTX + IFOS + WBRT

154

NA

NA

NA

NA

43.5

NA

48

28

NA

NA

NA

NA

MTX + IFOS
MTX + R + PCZ + VCR + dose-reduced WBRTITTgroup

164

NA

30.7

NA

NA

NA

NA

52

65

57

51

85

81

77

MTX + R + PCZ + VCR + dose-reduced WBRT
per-protocol group

43

84

77

71

94

87

84

MTX + Ara-C ± R ± thiotepa + WBRT

55

NA

76

NA

NA

82

NA

MTX + Ara-C ± R ± thiotepa + ASCT58

MTX + BCNU + teniposide + prednisolone

100

NA

75

NA

NA

77

NA

58

NA

NA

79

65

MTX + BCNU + teniposide + prednisolone + R

61

99

65

NA

NA

79

71

58

MTX + WBRT

18

22.9

15.2

15.2

77.8

72.2

33.1

MTX ± R, maintenance MTX

34

39.4

39.4

32.3

88.1

79

74.9

Reference

RegimenNelson, 1992 (8)Thiel, 2010 (11)Morris, 2013 (12)Ferreri, 2017 (14)Bromberg, 2019 (18)Current study

1 yearOS

Abbreviations : WBRT, whole brain radiotherapy ; MTX, methotrexate ; IFOS, ifosfamide; R, rituximab ; PCZ, procarbazine ; VCR, vincristine ; Ara-C, cytarabine ; BCNU, carmustine ; NA, not available

Based on these data, maintenance therapy might be appropriate for the elderly PCNSL patients with a poor KPS and low- or
no tolerance for intensive chemotherapy or high-dose chemotherapy with ASCT. On the other hand, the PFS of our study was
shorter than in earlier investigations. HD-MTX with or without
rituximab might be insufficient as an induction chemotherapy
in patients with newly diagnosed PCNSL. It is a further study
on whether improvement of prognosis is obtained by introducing
intensive chemotherapy for patients aged 70 and younger.
Although the efficacy of rituximab, a humanized anti-CD20
monoclonal antibody, against PCNSL is still incompletely understood, rituximab has been included in many PCNSL treatment
protocols and shown to improve the CR rate and the duration ofOS (18-20). In our study, no significance was found to add rituximab to induction therapy.
Methotrexate and WBRT can each cause cognitive dysfunction due to neurotoxicity, but there is synergistic toxicity whenthese modalities are combined. In PCNSL patients, the addition of WBRT to HD-MTX increases the risk of neurotoxicity
due to leukoencephalopathy. Patients aged > 60 years who
received WBRT were significantly higher risk of delayed neurotoxicity and a reduction of KPS score (7, 10, 11). On the other
hand, Chamberlain et al. (17) reported no cognitive decline
was documented in surviving patients treated with HD-MTX
maintenance therapy. Similarly in our study, KPS score tended
to be maintained in patients achieving CR with HD-MTX
maintenance therapy. However long-term effects of HD-MTX
administration are not clear, longer neuropsychological follow-up
is necessary to evaluate the relationship with neurotoxicity due
to leukoencephalopathy.
This study has some limitations. The population in our retrospective, single center study was small and although bothgroups were similar with respect to their background, we usedhistorical data to obtain a control group. This may have resulted
in bias. Also, the patients in the maintenance group were notfollowed long enough to estimate their median survival at thetime of analysis.
We report that induction therapy with HD-MTX with or without rituximab chemotherapy followed by continued monotherapy
maintenance with HD-MTX improved the overall survival ofpatients with PCNSL. It was superior to chemoradiotherapy
consisting of 3 cycles of HD-MTX followed by WBRT. Receiving
maintenance therapy was an independent good prognostic indicator for the OS and the maintenance protocol avoided KPS
deterioration.

CONFLICT OF INTEREST
We have no sources of financial support and no potential conflicts of interest.

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