Treatment approaches for primary CNS lymphomas

Figures & data

Box 1. Biology of PCNSL in immunocompetent patients.

Mostly Epstein–Barr-virus (EBV)-negative, diffuse large B-cell lymphomas in immunocompetent patients. Tumour cells seem to be derived from a germinal centre exit B cell. Notably, most PCNSL in HIV-infected patients in the pre-HAART (highly active anti-retroviral activity) era were EBV associated.

Chromosomal translocations, gains and losses of genetic material, ongoing aberrant somatic hypermutation (SHM), tumour suppressor genes mutations, gene inactivation by DNA methylation and NF-κB activation are events implicated in transformation.

Analysis of site-specific genomic aberrations suggests that two major groups of genes – one involved in the immune response, including regulation of HLA expression, and the other involved in apoptosis, including the p53 pathway – could be implicated in PCNSL pathogenesis

The existence of specific interactions between PCNSL cells and the CNS microenvironment has been postulated given the selective manifestation of PCNSL in the CNS and the observation that extra-cerebral relapses are extremely rare. However, it is not yet known whether B cells enter the CNS as non-malignant or malignant B cells.

CD4 and CD8 T cells, non-malignant B cells, and macrophages/microglia are often involved in the characteristic infiltrate of these tumours. It has been suggested that the tumour cells of PCNSL might down-regulate the intracerebral immune response by anti-inflammatory cytokines such as interleukin (IL)-4 and IL-10, and thus may escape immune surveillance. The high frequency of human leucocyte antigen (HLA) loss reported in these tumours supports this hypothesis.

A preferential usage of the IGHV4 – 34 gene segment has been reported in these tumours. Nevertheless, there is no clear evidence in favour of an antigen-driven proliferation for these tumours.

Box 2. Epidemiology and clinical presentation of PCNSL.

Rare form of extra-nodal B cell neoplasm that accounts for 4% of all primary brain tumours.

Propensity for elderly populations with a median age at diagnosis of 60 years.

Patients typically present with symptoms that are suggestive of focal neurologic dysfunction that depend on the location of the tumour.

Common symptoms and signs include: i) cognitive, behavioural, and personality changes; ii) headaches, hydrocephalus or other signs of increased intracranial pressure; and iii) acute onset of weakness, aphasia, or sensory disturbances. Seizures are uncommon.

Prognostic factors include: i) age; ii) Eastern Cooperative Oncology Group performance status; iii) serum lactate dehydrogenase level; iv) cerebrospinal fluid (CSF) protein level; and v) tumour location. These five parameters together compose the elements of a prognostic score, confirmed by the International Extranodal Lymphoma Study Group (IELSG), which divides patients into three risk groups.

Gadolinium-enhanced magnetic resonance imaging (MRI) of the brain tends to demonstrate a supratentorial mass that is commonly deep or peri-ventricular in location. The most common locations are the cerebral hemispheres, basal ganglia and corpus callosum.

On MRI, PCNSL are usually hypo-intense on T1 images and hypo- to iso-intense on T2 images. Contrast enhancement is diffuse and relatively homogeneous.

Table 1. Published prospective trials on PCNSL in immunocompetent patients treated with chemotherapy alone or combined treatment.

Ref.	N°	TS*	Primary Chemotherapy^‡			ORR^§	CRR^¶	Median follow-up	OS		Neuro toxicity
			Drugs	M dose	it CHT				2-years	5-years
Series treated with CHT alone
[28]	31	C	M	8 g/m^2/14 d	-	100%		31 mo.	63%	NR	0%
[20]	50	C	M L P MP	1 g/m^2/10 d	M	48%	42%	36 mo.	45%	NR	8%
[19]	25	C	M	8 g/m^2/14 d	-	74%	52%	23 mo.	70%	NR	5%
[25]	65	C	M V I C A	5 g/m^2/28 d	ivM/a	71%	61%	26 mo.	69%	43%	3%
[24]	37	C	M	8 g/m^2/14 d	-	35%	30%	56 mo.	51%	25%	20%
Series treated with HD-MTX plus RT
[29]	25	CR	M	3.5 g/m^2/21 d	-	88-92%	56%-88%	60 mo.	58%	38%	8%
[30]	46	CR	M	1 g/m^2/7 d	a*	NR - 95%	NR - 82%	36 mo.	62%	37%	22%#
[14]	31	CRC	M	1 g/m^2/7 d	M	64-87%	NR - 87%	97 mo.	72%	22%	32%
Series treated with HD-MTX-containing CHT plus RT
[31]	25	CR	A a C M O P	3 g/m^2/21 d	M/a/P	72 – 72%	67%-78%	24 mo.	70%	56%	0%
[17]	57	CRC	a Bn M O ± CHOP	1.5 – 3 g/m^2/14 d	-	68 – 71%	62%-64%	59 mo.	60%	36%	NS
[32]	56	CR	Bn M N P	1.5 g/m^2/28 d	M	71% – 100%	54%-61%	8 mo.	86%	NS	29%
[33]	31	CR	A B C M O P	2 g/m^2/15 d	M/a/P*	89 – 67%		24 mo.	48%	36%	7%
[16]	52	CRC	M N O	3.5 g/m^2/7 d	M	90 – 94%	56%-87%	60 mo.	75%	40%	25%
[7]	102	CR	M N O	2.5 g/m^2/14 d	M	94 – NR	58%- NR	56 mo.	64%	32%	15%
[26]	52	CR	Bn M O P	3 g/m^2/14 d	M	NR – 81%	33%-69%	27 mo.	69%	NR	12%
[34]	41	CR	A I M T	3.5 g/m^2/21 d	-	76 – 83%	44%-56%	49 mo.	50%	41%	NR
[15]	30	CRC	M N O R	3.5 g/m^2/14 d	M*	93%-NR	44%-77%	37 mo.	67%	NR	NR

Published in lancet 2009;374: 1512 – 1520 and reproduced under kind permission by Elsevier.

Only trials on 25 patients or more and published as original articles are considered. Trials on high-dose chemotherapy supported by autologous stem cell transplant are excluded. N: Number of enrolled patients.

*Treatment sequence: C: Chemotherapy alone; CR: Chemotherapy followed by radiotherapy; CRC: Chemotherapy followed by radiotherapy and further chemotherapy.

^‡Primary chemotherapy: A or H: Adriamycin; a: Cytarabine; B: Bleomycin; Bn: BCNU; C: Cyclophosphamide; Cn: CCNU; E: Etoposide; M: Methotrexate; m: Nitrogen mustard; N: Procarbazine; O: Vincristine; P: Prednisone or other corticoids; R: Rituximab; T: Thiotepa; V: Teniposide. Series using intrathecal chemotherapy (it CHT) exclusively in patients with positive CSF cytology at diagnosis are marked with an asterisk.

^§ORR: Overall response rate; in series treated with combined modality, response rate after chemotherapy and (-) after the entire planned treatment is reported.

^¶CRR: Complete remission rate; in series treated with combined modality, response rate after chemotherapy and (-) after the entire planned treatment is reported.

NS: not specified; NR: not reported. # 5-year risk rate.

Table 2. Main features of reported studies on the role of HDC/ASCT in PCNSL.

Ref.	N° pts	Median age (range)	Treatment line	Therapy (induction → intensification)	ASCT conditioning	WBRT	Outcome	Neuro toxicity	Median f-up (months)	TRM
[38]	22	53 (27 – 64)	Salvage	araC + VP16	TT/Bu/Cy	No	3-y OS 64%	32%	41	4%
[39]	43	52 (23 – 65)	Salvage	araC + VP16	TT/Bu/Cy	No	2-y OS 45%	5%	36	7%
[40]	6	53 (30 – 66)	First-line	MBVP → IFO + araC	BEAM	Yes	2-y OS 40%	33%	41	0%
[41]	25	52 (21 – 60)	First-line	MBVP → IFO + araC	BEAM	Yes	4-y OS 64%	8%	34	4%
[42]	30	54 (27 – 64)	First-line	HD-MTX → araC + TT	BCNU/TT	Yes	5-y OS 69%	17%	63	3%
[43]	13	54 (38 – 67)	First-line	HD-MTX → araC + TT	BCNU/TT	Yes‡	3-y OS 77%	0%	23	0%
[44]	23	55 (18 – 69)	First-line	HD-MTX → -	Bu/TT	Yes‡	2-y OS 48%	39%	15	13%
[22]	28	53 (25 – 71)	First-line	HD-MTX → araC	BEAM	No	2-y OS 55%	0%	28	4%
[45]	7	56 (41 – 64)	First-line*	HD-MTX → araC	TT/Bu/Cy	No	3-y OS 50%	0%	28	14%

Published in Leukemia and Lymphoma 2008;49:11, 2042 – 2047 and reproduced under kind permission.

araC: Cytarabine; ASCT: Autologous stem cell transplantation; BCNU: Carmustine; BEAM (regimen): Carmustine, etoposide, cytarabine, and melphalan; Bu: Busulfan; Cy: Cyclophosphamide; IFO: Ifosfamide; MBVP (regimen): Methotrexate, carmustine, etoposide, and methylprednisolone; OS: Overall survival; TRM: treatment-related mortality; TT: thiotepa; VP16: Etoposide; WBRT: Whole-brain irradiation.

*One patient received the treatment as salvage therapy.

‡Only for patients not achieving a complete remission.

Table 3. Salvage therapies for PCNSL.

Treatment	Study	N°	mAge	Prior RT	PS 0 – 1	CR + PR	mPFS	mOS	1-yr OS	N	PLT	Other tox
Topotecan [73]	prospective	27	51	52%	60%	19 + 14%	2.0	8.4	39%	26%	15%	11%
Temozolomide [37,74]	prospective	36	60	86%	28%	25 + 6%	2.8	4.0	31%	6%	3%	3%
Methotrexate [75]	retrospective	22	58	14%	-	73 + 19%	26	26	70%	5%	5%	36%
Temozolomide + Rituximab [68]	retrospective	15	69	13%	67%	40 + 13%	2.2	10.5	58%	7%	27%	7%
VP16 + Ifosfamide + AraC [67]	retrospective	16	54	100%	37%	37 + 0%	4.5	6.0	41%	69%	50%	37%
i.a. Carboplatin ± VP16 ± CTX ± RT [76]	retrospective	37	57	24%	76%	24 + 11%	3.0	6.8	25%	22%	19%	> 30%
Radiotherapy [66]	retrospective	27	67	-	-	37 + 37%	9.7	10.9	49%	-	-	15% neuro
Radiotherapy [65]	retrospective	48	-	-	-	58 + 21%	10.0	16.0	54%	-	-	58% neuro
AraC + VP16→TTP + Busulfan + CTX [39]	prospective	43	52	33%	-	50 + 0%	-	18	-	-	-	TRM: 14%
Intrathecal Rituximab [59]	Phase I	10	56	80%	-	0 + 60%	-	5.2	30%

mAge: Median age; RT: Radiotherapy; PS: Performance status; CR: Complete response; PR: Partial response; mPFS: Median progression-free survival; mOS: Median overall survival; 1-yr OS: One-year overall survival; N: Grade 3 – 4 neutropenia; PLT: Grade 3 – 4 thrombocytopenia; tox: Toxicity; i.a.: intra-arterial; VP16: Etoposide; HD-AraC: High-dose cytarabine; TTP: Thiotepa; CTX: Cyclophosphamide.

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