Primary central nervous system lymphoma: The role of consolidation treatment after a complete response to high-dose methotrexate-based chemotherapy

Abstract

BACKGROUND.

The most effective treatment for a new diagnosis of primary central nervous system lymphoma is high-dose methotrexate (MTX)-based chemotherapy followed by whole-brain radiation therapy (WBRT). However, this combined modality treatment carries an increased risk of delayed neurotoxicity. For patients who achieve a complete response (CR) after induction that uses high-dose MTX-based chemotherapy, it is not clear if consolidation treatment is necessary. Therefore, a retrospective study was conducted to assess the impact of consolidation treatment after a CR to initial induction chemotherapy on disease control and survival.

METHODS.

The authors retrospectively analyzed 122 patients who achieved a CR after initial MTX-based chemotherapy. The benefit of consolidation WBRT, high-dose cytarabine (HDAC), or both on failure-free (FFS) and overall survival (OS) was assessed.

RESULTS.

With a median follow-up of 60 months, FFS was longer in patients who received WBRT plus HDAC as consolidation treatment (P = .03 by univariate analysis); there was no difference in OS observed among patients who received no consolidation treatment, HDAC alone, WBRT plus HDAC, or WBRT alone. Age and Karnofsky performance scale (KPS) were the only independent prognostic factors. Patients who received WBRT alone or in combination with HDAC had higher rates of neurotoxicity.

CONCLUSIONS.

Consolidation treatment with WBRT, HDAC, or both does not appear to improve survival in patients who achieved a CR with induction MTX-based therapy. Age, KPS, and risk of delayed neurotoxicity must be considered in the choice of consolidation regimens. Cancer 2008. © 2008 American Cancer Society.

The optimal management of primary central nervous system lymphoma (PCNSL) is poorly defined. Excellent survival results have been reported with a wide variety of methotrexate (MTX)-based treatment regimens; however, disease control with these regimens is variable, and in many instances the reported overall survival heavily reflects the efficacy of salvage therapies. Although it appears intuitive that intensive induction and consolidation treatment strategies might improve disease control and survival, this has not been studied carefully. Moreover, it is critical to consider the relative acute and chronic treatment-related toxicities of induction and consolidation therapies.

In the past, whole-brain radiation therapy (WBRT) was considered the standard treatment for PCNSL. Although greater than half of patients achieved a complete response (CR) with WBRT alone, recurrences were frequent, and overall survival was only 12 to 18 months.1, 2 The introduction of combined modality treatment with high-dose MTX-based chemotherapy followed by WBRT increased CR rates to as high as 86% but, more importantly, resulted in improved survivals of 32 to 51 months.3-8 However, delayed neurotoxicity resulting from the combined effects of high-dose MTX and WBRT is an unacceptable side effect of this approach. Symptoms of neurotoxicity may be progressive, functionally devastating, and an important cause of death in these patients. In patients aged older than 60 years, virtually all long-term survivors develop delayed neurotoxicity after combined treatment.3, 9

Because of the high-risk of delayed neurotoxicity, multiple phase 2 trials have examined the efficacy of chemotherapy alone; these studies reported CR rates of 30% to 79% and median overall survivals of 14 to 50 months.10-15 However, each study differed with regard to baseline patient characteristics, the number of chemotherapy cycles, and types of chemotherapeutic agents combined with high-dose MTX. Moreover, the overall and failure-free survival analyses included all patients on an intent-to-treat basis, and WBRT was often used for patients who had partial responses and progressive or recurrent PCNSL, strongly influencing survival data.

For patients who achieve a CR after induction high-dose MTX-based chemotherapy, it is not clear whether consolidation treatment improves disease control or survival. In 1 series, we demonstrated that WBRT after a CR in older patients did not prolong overall survival, because of the high risk of death from neurotoxicity in this population.3, 5 However, because PCNSL is a rare disease, prospective randomized trials to address the treatment questions that remain unanswered may not be feasible. Therefore, we conducted a retrospective study to assess the impact of consolidation treatment on outcome after a CR to the initial high-dose MTX-based chemotherapy.

MATERIALS AND METHODS

The records of all immunocompetent patients with a new diagnosis of PCNSL treated at Memorial Sloan-Kettering Cancer Center from January 1983 to December 2005 were reviewed to identify those patients with a CR to the initial high-dose MTX-based chemotherapy. Patients underwent a staging evaluation that included lumbar puncture for cerebrospinal fluid (CSF) cytology unless medically contraindicated, ophthalmologic examination including slit-lamp, abdominal computed tomographic (CT) scan, CT scan or x-ray of the chest, bone marrow biopsy, and human immunodeficiency virus type-1 serology. An Ommaya reservoir was placed for intrathecal (IT) MTX administration in patients with positive CSF cytology or according to requirements of specific clinical trials. A creatinine clearance of ≥50 mL/min was required before the initiation of high-dose MTX.

All patients received a MTX-based regimen with doses between 1 and 3.5 g/m²; other drugs used in combination with high-dose MTX included procarbazine, vincristine, rituximab, and IT-MTX. After the initial chemotherapy, consolidation strategies were categorized as: 1) no consolidation treatment, 2) high-dose cytarabine (HDAC) alone, 3) WBRT plus HDAC, and 4) WBRT alone.

Response to treatment was assessed with follow-up cranial magnetic resonance imaging (MRI) or cranial CT scans. CR was defined as resolution of all enhancing tumor in patients not receiving corticosteroids. Patients with a complete resolution of all enhancing tumor, but who remained on corticosteroid treatment, were labeled as uncertain CR. In addition, patients with CSF or eye involvement at the time of diagnosis had to have complete resolution of disease in these compartments to qualify for a CR.

Patients were followed by serial cranial MRI/CT scans and repeat neurologic examinations 3 or 4 times a year. Cognitive impairment was identified by clinical examination; extensive neuropsychologic tests were not performed routinely. Neurotoxicity was defined clinically as neurologic decline after treatment for PCNSL that was not caused by tumor recurrence or another identifiable cause.

Statistical Analysis

The differences in categoric variables between treatment groups were assessed by the chi-square test. The differences in median age and Karnofsky performance scale (KPS) were evaluated by K-sample equality of median test. Failure-free survival (FFS) was calculated from the date of initial CR to date of disease recurrence, progression, death or last follow-up. Overall survival (OS) was calculated from the date of initial CR to death or last follow-up. Survival curves were estimated using the Kaplan-Meier product limit method, and the survival time among different groups was compared using the log-rank test. Multivariate analyses were performed with the Cox proportional-hazards regression model to identify variables that were independently predictive of outcome. Factors with P ≤ .2 on univariate analyses were entered as candidate variables, and multivariate analysis was performed. Time to neurotoxicity was calculated from date of CR to date of neurotoxicity or last follow-up. Because a large number of patients died before developing neurotoxicity, we accounted for death as a competing risk when estimating the incidence of neurotoxicity.16 The estimates of the incidence of neurotoxicity for various groups were compared using a modified chi-square test.17 Two-sided P values ≤.05 were considered statistically significant. Calculations were performed using STATA (version 8.0; StataCorp College Station, Tex).

RESULTS

Patient Characteristics

A total of 122 patients who achieved a CR after induction high-dose MTX-based chemotherapy were identified. Seventy (57%) patients were men; the median age was 60 years, and the median KPS at the time of diagnosis was 70. Histologic diagnosis was diffuse large B-cell lymphoma in 101 (83%) patients. Sixteen (13%) patients had ocular and 33 (27%) had CSF involvement.

Eighty patients underwent consolidation treatment (37 with HDAC, 29 with WBRT plus HDAC, and 14 with WBRT alone), and 42 did not receive any consolidation regimen. Patients in the WBRT and the WBRT plus HDAC groups were younger than the other groups (P < .001). Other baseline characteristics were similar across the 4 groups (Table 1).

Table 1. Patient Characteristics

Characteristic	No Consolidation (n=42)	HDAC (n=37)	WBRT + HDAC (n=29)	WBRT (n=14)	Total (n=122)	P
HDAC indicates high-dose cytarabine; WBRT, whole-brain radiation therapy; KPS, Karnofsky performance scale; NA, not available; CSF, cerebrospinal fluid.
Gender
Men, No. (%)	20 (48)	25 (68)	16 (55)	9 (64)	70 (57)	.3
Women, No. (%)	22 (52)	12 (32)	13 (45)	5 (36)	52 (43)
Age, y
Median	68	64	51	56	60	<.001
(Range)	(19-84)	(22-79)	(28-68)	(41-89)	(19-89)
KPS
Median	70	70	70	60	70	.4
(Range)	(40-100)	(40-100)	(50-90)	(30-100)	(30-100)
Ocular involvement
Yes, No. (%)	6 (14)	3 (8)	6 (21)	1 (7)	16 (13)	.4
No, No. (%)	33 (79)	33 (89)	23 (79)	13 (93)	102 (84)
NA, No. (%)	3 (7)	1 (3)	0 (0)	0 (0)	4 (3)
CSF involvement
Yes, No. (%)	10 (24)	7 (19)	10 (34)	6 (43)	33 (27)	.4
No, No. (%)	25 (60)	27 (73)	17 (59)	8 (57)	77 (63)
NA, No. (%)	7 (16)	3 (8)	2 (7)	0 (0)	12 (10)
Histology
Large B cell, No. (%)	36 (86)	35 (95)	24 (73)	8 (57)	103 (85)	.1
Other, No. (%)	1 (2)	0 (0)	2 (7)	2 (14)	5 (4)
Type not specified, No. (%)	5 (12)	2 (5)	3 (10)	4 (29)	14 (11)

The median dose of radiation was 4770 centigrays (cGy) (range, 2340 cGy–5580 cGy) for the group who received WBRT alone and 4500 cGy (range, 2340 cGy–5440 cGy) for the group that received WBRT plus HDAC.

Failure-free and Overall Survival

The median follow-up of surviving patients was 60 months (range, 8 months–235 months); there were no differences in median follow-up time among the 4 groups (P = 0.2). Ninety-two (75%) patients had failure events, and the median FFS for all 122 patients was 24 months (95% confidence interval [CI], 15 months–31 months). Seventy-five (61%) patients had died at the time of last follow–up, and the median OS for all 122 patients was 53 months (95% CI, 36 months-61 months). The most frequent causes of death were recurrent PCNSL (61%) and neurotoxicity (16%) (Table 2).

Table 2. Causes of Death

Cause of Death	No Consolidation (n=29/42), No. (%)	HDAC (n=20/37), No. (%)	WBRT + HDAC (n=14/29), No. (%)	WBRT (n=12/14), No. (%)	All Patients (n=75/122), No. (%)
HDAC indicates high-dose cytarabine; WBRT, whole-brain radiation therapy; PCNSL, primary central nervous system lymphoma.
PCNSL	16 (55)	15 (75)	9 (65)	6 (50)	46 (61)
Acute toxicity	1 (3)	0	1 (7)	0	2 (3)
Neurotoxicity	6 (21)	0	3 (21)	3 (25)	12 (16)
Unrelated	4 (14)	5 (25)	1 (7)	2 (17)	12 (16)
Unknown	2 (7)	0	0	1 (8)	3 (4)

FFS was longer in patients who received WBRT plus HDAC when compared with other groups (P = .03) (Fig. 1A). OS was not different among the 4 groups (P = .16) (Fig. 1B). Table 3 shows the median FFS and OS for each consolidation treatment group.

Figure 1. (A) Failure-free survival and (B) overall survival according to the type of consolidation treatment. HDAC indicates high-dose cytarabine; WBRT, whole-brain radiation therapy.

Table 3. Failure-free and Overall Survival

	No Consolidation (n=42)	HDAC (n=37)	WBRT + HDAC (n=29)	WBRT (n=14)	P
HDAC indicates high-dose cytarabine; WBRT, whole-brain radiation therapy; FFS, failure-free survival; 95% CI, 95% confidence interval; NR, not reached; OS, overall survival.
Median FFS, mo (95% CI)	15 (7-27)	18 (13-31)	42 (25-NR)	22 (8-74)	.03
5-year FFS, % (95% CI)	17 (7-32)	23 (11-38)	48 (28-65)	36 (13-59)
Median OS, mo (95% CI)	39 (20-58)	60 (32-NR)	71 (37-NR)	31 (8-61)	.16
5-year OS, % (95% CI)	32 (17-47)	51 (33-66)	59 (38-75)	34 (12-59)

Long-term Outcome

Sixty-seven (55%) patients developed recurrent lymphoma during the follow-up period. Chemotherapy was the most commonly used salvage strategy, independent of the initial consolidation treatment. Eight (29) patients in the no consolidation group and 7 (29%) patients in the HDAC group received salvage WBRT alone or in combination with chemotherapy. Forty (60%) patients achieved an objective radiographic response to the salvage treatment: 20 (74%) in the no consolidation group, 15 (63%) in the HDAC group, 3 (25%) in the WBRT plus HDAC group, and 2 (50%) in the WBRT group.

Twenty-one (17%) patients developed treatment-related neurotoxicity; the risk was higher in patients who received WBRT as part of the consolidation regimen. The 2-year and 5-year incidence of neurotoxicity in patients who received WBRT as part of consolidation treatment was 21% (95% CI, 12%-38%) and 21% (95% CI, 12%-38%), respectively, compared with 4% (95% CI, 1%-12%) and 7% (95% CI, 3%-17%), respectively, for patients who did not receive WBRT as consolidation treatment (P = .07). Two of 15 patients who received WBRT as salvage therapy developed neurotoxicity. The median latency for developing neurotoxicity from the initial CR date was 6 months for patients who received WBRT as consolidation treatment compared with 58 months for patients who did not (P = .02). Median age at diagnosis of patients who developed neurotoxicity was 64 years (range, 22 years–72 years).

Univariate and Multivariate Analyses of Prognosticand Treatment Factors

On the univariate analyses, younger age and a KPS ≥70 were associated with a decreased risk of failure and death. Consolidation treatment with WBRT plus HDAC was associated with decreased failure risk by univariate analysis (Table 4). However, by multivariate analyses, only age and KPS were found to be independent prognostic factors (Table 5).

Table 4. Univariate Analyses of Failure-free and Overall Survival

Variable	No.	%	Failure-free Survival			Overall Survival
			P	Hazards Ratio	95% CI	P	Hazards Ratio	95% CI
95% CI indicates 95% confidence interval; KPS, Karnofsky performance scale; WBRT, whole-brain radiation therapy; HDAC, high-dose cytarabine; CSF, cerebrospinal fluid.
Age	122	100	.004	1.03	1.01-1.04	.001	1.03	1.01-1.05
KPS
≥70	67	62	.03	1.64	1.05-2.57	.003	2.11	1.30-3.44
<70	41	38
Treatment
WBRT+HDAC	29	24	.04	0.42	0.23-0.77	.17	0.58	0.30-1.09
HDAC	37	30		0.92	0.72-1.18		0.80	0.61-1.07
WBRT	14	11		0.75	0.39-1.45		1.11	0.56-2.18
No consolidation	42	34		1.00	—		1.00	—
CSF involvement
No	77	70	.64	1.12	0.70-1.77	.30	1.30	0.79-2.14
Yes	33	30
Ocular involvement
No	102	86	.61	0.85	0.45-1.60	.76	1.11	0.57-2.18
Yes	16	14

Table 5. Multivariate Analyses of Failure-free and Overall Survival

Variable	No.	%	Failure-free Survival			Overall Survival
			P	Hazards Ratio	95% CI	P	Hazards Ratio	95% CI
95% CI indicates 95% confidence interval; KPS, Karnofsky performance scale; WBRT, whole-brain radiation therapy; HDAC, high-dose cytarabine.
Age	122	100	.06	1.02	1.00-1.04	.002	1.03	1.01-1.06
KPS
≥70	67	62	.07	1.55	0.97-2.49	.01	1.83	1.09-3.05
<70	41	38
Treatment
WBRT+HDAC	29	24	.39	0.58	0.29-1.15	.85	0.98	0.45-2.10
HDAC	37	30		1.01	0.76-1.32		0.95	0.70-1.29
WBRT	14	11		0.80	0.39-1.66		1.29	0.59-2.81
No consolidation	42	34		1.00	—		1.00	—

DISCUSSION

The results of the current study suggest that intensive consolidation treatment with WBRT and HDAC may provide better disease control without a clear impact on survival in patients with PCNSL. However, longer FFS in this group could be because of more powerful prognostic factors such as age and KPS, as suggested by the multivariate analysis. The decision regarding consolidation treatment was made by the treating physician or guided by clinical trials criteria. As the risk of neurotoxicity in older patients who received WBRT became more established, fewer patients in this age group were irradiated in our institution. In contrast, younger patients may have been more likely to receive intense consolidation treatment because of fewer comorbid conditions and possibly better performance status. Consequently, patients who underwent WBRT and HDAC were younger compared with patients who did not receive WBRT. Although no survival differences were found among the different consolidation strategy groups, the sample size may have limited our ability to detect small but significant survival benefits of more intensive consolidation treatment. As an example, a clinical trial that randomizes patients to WBRT or no consolidation treatment would need to accrue at least 230 patients who achieved a CR after induction chemotherapy to detect a 5-year survival increase from 30% to 45% (2-sided P < .05 and 90% power). Moreover, salvage therapies such as chemotherapy18 or WBRT,19 which can be effective in inducing remission and prolonging survival, could also account for the apparent lack of survival benefit of intensive consolidation treatments.

The role of consolidation treatment with WBRT in PCNSL was studied retrospectively in 54 patients who achieved a CR after high-dose MTX-based chemotherapy; 39 received WBRT and 15 patients did not receive any consolidation treatment. After a median follow-up of 26 months and 12 months for the WBRT and the no consolidation groups, respectively, there was no difference noted with regard to the 2-year probability of FFS and OS.20 Another group of patients, derived from 19 different clinical trials, who achieved a CR after high-dose MTX chemotherapy, received WBRT either as consolidation treatment (n = 73) or at the time of disease recurrence (n = 49), and no difference in disease-free or overall survival was found after a median follow-up of 34 to 40 months.20, 21 In contrast, a subset analysis from a phase 2 clinical trial that included 25 patients aged younger than 60 years who achieved a CR after initial chemotherapy and received either 45 Gy or 30.6 Gy of WBRT as consolidation treatment indicated that higher-dose WBRT was associated with lower 3-year recurrence rates (25% v 83%; P = .01) and better 3-year OS (92% vs 60%; P = .04).22

To our knowledge, consolidation treatment with chemotherapy has not been well studied in PCNSL. Cytarabine is a chemotherapeutic agent that can penetrate into the CSF and brain parenchyma when administered systemically, and has demonstrated efficacy in the treatment of parenchymal brain involvement from systemic lymphoma.23-25 Moreover, in retrospective analyses, PCNSL patients who received HDAC in addition to high-dose MTX had longer OS compared with patients who received only high-dose MTX.20, 21 Consequently, HDAC has been incorporated into high-dose MTX-based chemotherapy regimens14, 22 or given as consolidation treatment.4 Therefore, HDAC may be a more attractive consolidation treatment option in otherwise healthy older patients in whom WBRT carries a high risk of neurotoxicity.

Previous trials using chemotherapy and WBRT reported neurotoxicity rates between 15% and 30%.3-8 Even in a trial that used only chemotherapy, a neurotoxicity rate as high as 22% was reported.11 In the current study, the risk of neurotoxicity was higher in patients treated with WBRT as consolidation treatment, and this group also had a shorter latency for development of neurotoxicity.

The major challenge in the treatment of PCNSL is to improve disease control and survival, while minimizing treatment-related toxicities. Ongoing phase 2 clinical trials are attempting to answer this question by focusing on different strategies. Rituximab, a monoclonal antibody against the CD20 antigen of B-lymphocytes, is being incorporated into initial high-dose MTX-based induction chemotherapy to evaluate feasibility and efficacy of immunochemotherapy. Other studies are examining the efficacy of lower doses of WBRT administered to complete responders to initial MTX-based chemotherapy, in an effort to retain the benefit of WBRT while minimizing the risk of neurotoxicity.26 In addition, other clinical trials are using high-dose chemotherapy with stem cell rescue as a consolidation strategy with or without WBRT.27-32

The role of consolidation therapy for PCNSL patients who achieved a CR after induction chemotherapy with MTX-based chemotherapy is still unclear. Long-term consequences of available consolidation strategies may outweigh the potential benefits, at least in elderly patients. Ideally, patients should be enrolled in available clinical trials that seek to address these issues, such as those being conducted by the Radiation Therapy Oncology Group33 or the Cancer and Leukemia Group B.34 A multidisciplinary group has formed the International Primary CNS Lymphoma Collaborative Group under the sponsorship of the International Extranodal Lymphoma Study Group, with the goal of developing better treatments for patients with PCNSL.

Acknowledgements

We thank Judy Lampron for her expert editorial assistance.