Monotherapy with = methotrexate for primary central nervous lymphoma has single agent = activity in the absence of radiotherapy: a single institution = cohort

Methods

Cohort ascertainment

The Massachusetts = General=20 Hospital Cancer Registry since 1946 records all newly confirmed = malignant=20 tumors diagnosed. These data are archived in an IRB-approved = database and=20 an electronic medical record system. We queried this database for = records=20 of patients with PCNSL treated at the Massachusetts General = Hospital (MGH)=20 between January 1, 1980 and August 1, 2007. We included = non-Hodgkin=E2=80=99s=20 lymphoma (=E2=80=9CLarge-cell lymphoma=E2=80=9D, = =E2=80=9Cimmunoblastic lymphoma=E2=80=9D and =E2=80=9CNHL of=20 nervous system=E2=80=9D) [15] of the central nervous system confirmed by = pathologic=20 examination. Pathologic diagnoses were not re-confirmed. All = patients had=20 mass lesions (MRI) of brain, ventricles or meninges in the setting = of=20 pathologic confirmation of lymphoma of brain parenchyma, CSF, = nerve roots=20 and/or spinal cord, or clonal immunoglobulin gene rearrangement = [16], flow cytometry, or cytologic = (=E2=80=9Catypical=E2=80=9D or=20 =E2=80=9Csuspicious=E2=80=9D or =E2=80=9Cmalignant=E2=80=9D) = abnormalities of cells from CSF or vitreous.=20 We included patients with confirmed involvement of brain, CSF, = nerve or=20 spinal cord, in the setting of previous intraocular lymphoma = (PIOL), as=20 well as PCNSL patients who later relapsed in brain or CSF. We = excluded=20 patients lacking histologic confirmation. immunocompromised = patients;=20 those with HIV positivity or recipients of organ transplant, those = with=20 CNS low-grade lymphoma or acute leukemia, systemic lymphoma (NHL) = with=20 spread to the central nervous system. We recorded=20 comorbidities.

Treatment

Of 209 PCNSL = patients we=20 selected 121 whose first therapy was HD-MTX every = ten-14 days) [11, 17]. Of these 67 have been the subject of reports = [7, 9, 11]. We excluded those with multi-drug = chemotherapy that=20 was MTX-based; recipients of >5=20 standard fractions of whole-brain irradiation (WBXRT) or = recipients of=20 alternative dosing schedules of MTX. Prior to 1995, MTX was = provided to=20 nine patients at dose level 3.5 g/sq.m. Thereafter dosing was = 8 g/sq.m. every ten to fourteen days until disease = progression or CR.=20 A subgroup of CR patients continued to receive MTX every month for = three=20 cycles and then every three months thereafter = (=E2=80=9Cmaintenance=E2=80=9D). MTX dosing=20 for all patients was adjusted to pre-treatment calculated or = measured=20 glomerular filtration rate. Leucovorin calcium rescue (25 mg = every=20 6 h) was initiated 24 h after the start of MTX infusion = and=20 continued until 24 h after MTX levels fell below <.25 = mcM/l.=20 No complete responder received further = corticosteroids.

Outcome measures

We sought to = determine the=20 benefit of MTX therapy for PCNSL of brain. We defined the date of=20 progression as the date (after CR or PR) of provision of the next = form of=20 systemic chemotherapy. These treatments at recurrence included = retreatment=20 with MTX (systemic MTX, or alternative route MTX: intrathecal,=20 intravitreal, =E2=80=9Cintraocular=E2=80=9D), drugs other than = MTX, radiation therapy (to=20 whole brain or localized radiosurgery [SRS] or spine). All 121 = patients=20 had radiographic measurable disease. Case ascertainment is = depicted in=20 Fig. 1.

Toxicity

We recorded = adverse events=20 that resulted in delay, reduction or cessation of MTX therapy. = These=20 included >grade 2 CTC toxicities (NCI toxicity criteria),=20 leukoencephalopathy (in the absence of gadolinium-enhancing = tumor);=20 leukopenia (White blood cell count =E2=89=A43,000 or = ANC =E2=89=A41,500);=20 thrombocytopenia (Platelet counts =E2=89=A475,000); azotemia=20 (Creatinine =E2=89=A51.5 =C3=97 ULN); anaphylactic = reaction or=20 generalized eruption; hepatic dysfunction (SGOT or Alkaline = phosphatase=20 elevation >2.5 =C3=97 ULN); or newly appearing = changes in=20 cognition or sensation. We defined = leukoencephalopathy >grade 2=20 (moderate increase in subarachnoid space (SAS); and/or moderate=20 ventriculomegaly; and/or focal flair or T2 hyperintensities = extending into=20 centrum ovale; or involving 1/3 to 2/3 of susceptible areas of = cerebrum)=20 and identified patients with 10% decrement in Mini-mental status = exam as=20 performed every two weeks prior to CR and every two months=20 thereafter).

Response to therapy

Response to = therapy, based=20 upon two-dimensional measurements of gadolinium enhancing mass(es) = on MRI=20 or CT (if MRI contraindicated) at bi-monthly intervals included: = Complete=20 response ([CR]=E2=80=94complete absence of gadolinium enhancing = mass(es)), Partial=20 response ([PR]=E2=80=94less than complete reduction of enhancing = mass(es)), Mixed=20 response ([MR]=E2=80=94variable change of multiple masses = including progression=20 with concomitant PR or CR), Stable disease ([SD]=E2=80=94No change = in size of a=20 mass), Progressive disease ([PD]=E2=80=94increased diameter of = enhancing=20 gadolinium mass(es)). Persisting enhancement at the prior biopsy = site was=20 not viewed as progression. We recorded the date of best response = after=20 start of MTX as well as the sites of failure.

Data analysis

We recorded = patient age,=20 gender, annualized risk of PCNSL, patient comorbidities, drug = toxicities=20 and response to therapy. Patients were not contacted and thus we = recorded=20 the interval from diagnosis to last follow-up. Patients lost to = follow-up=20 after Cycle 1 MTX, were assigned survival of = =E2=80=9Czero=E2=80=9D months. Their toxicity=20 data were recorded. We calculated progression-free survival (PFS) = and=20 overall survival (OS) for all patients.

Results

209 patients were = diagnosed with=20 primary central nervous system lymphoma between January 1, 1980 = and August=20 1, 2007. The case-incidence peak occurred 1996=E2=80=932000. One = hundred=20 twenty-one patients received MTX monotherapy, of whom 117 had data = for=20 survival evaluation (Fig. 2).

Fig. 1

Schematic = of case=20 ascertainment. NHL non-Hodgkin lymphoma, = dx=20 diagnosis, IOL intra-ocular lymphoma, = PCNSL=20 primary central nervous system lymphoma, CHT = chemotherapy,=20 MTX methotrexate, WBXRT whole-brain = radiation=20 therapy

Demographics

The median age of = the 121=20 patients was 63 years (range 23=E2=80=9386 years). Males = predominated=20 (53%). Brain parenchymal involvement was most common (94%) = including 11%=20 with brain and another nervous system site. Six percent of patient = had CSF=20 involvement with nodular measurable disease. Comorbidity included: = lupus=20 erythematosus prior MTX therapy (one for =E2=80=9Cbreast = cancer=E2=80=9D and one for=20 unconfirmed =E2=80=9Cocular lymphoma=E2=80=9D), renal = insufficiency (2), idiopathic=20 thrombocytopenic purpura (2), polyglandular autoimmune syndrome E = type 1=20 (1), steroid use (10), non-brain radiation therapy for systemic = malignancy=20 (3) and ocular lymphoma [4]), prior chemotherapy (7) and Lyme = disease=20 (2).

Response to therapy

Of 121 patients, 106 = (87.6%)=20 initially received MTX at a dose of 8 g/m² and = fifteen=20 (12.4%) received doses of 3.5 g/m² or less. = Response was=20 not evaluable in four patients due to: missing MRI (1 patient), = lost to=20 follow-up (1), cessation of MTX prior to response evaluation (2). = An=20 additional patient, evaluable for response, died of progressive = lymphoma=20 prior to MTX therapy. The overall response rate to Methotrexate = induction=20 was 85% (100/117). CR occurred in 58% (58.5% of patients treated = at MTX=20 8 g/m² and 50% at MTX 3.5 g/m²). = CR was=20 achieved after a median of 6 cycles of therapy over an elapsed = time of=20 3 months. Twenty-seven percent of patients had PR, 7% PD, 5% = SD, and=20 3% MR. Patients who did not achieve a CR rapidly progressed. = Twenty-seven=20 of the 41 patients who achieved PR, SD or MR, progressed after two = more=20 cycles of MTX (one month) (Fig. 2).

Six PCNSL patients had MRI = measurable tumor=20 in the setting of CSF with =E2=80=9Catypical=E2=80=9D or = =E2=80=9Csuspicious=E2=80=9D cells. Five of these=20 achieved CR (2=E2=80=939 cycles MTX), and one progressed (1 = cycle). Three=20 patients additionally received at least one cycle of intrathecal = therapy=20 and five received intravitreal therapy.

The median overall survival (53 = deaths and 68=20 censored) was 7 years (95% CI of 4.6, 12.8). The survival = rates at=20 1, >5 and 10 years were 86, 58 and 44% respectively=20 (Fig. 3,=20 OS). For patients achieving CR, the median progression-free = survival was=20 3.14 years (95% CI of 2.48, 5.18) (Fig. 4,=20 PFS). Thirty percent of the entire cohort progressed during = therapy with=20 MTX (Table = 1). Forty = additional=20 patients (59% of those with CR) recurred 14 months (IQR 6.75, = 32.5)=20 after complete response. Patients in CR who continued MTX at least = one=20 year further fared better than those who stopped within two cycles = of CR.=20 Progression-free survival for the former was 3.48 years (95% = CI of=20 2.16, 5.8; Fig. 4), versus = 2.86 years=20 (95% CI of 1.32 and upper bound not reached; Fig. 4)=20 for the latter. Recurrences occurred in brain (68%), vitreous (5), = systemic sites (5), nerve root (2) and CSF (1). Of sixty-three = deaths=20 (through August 1, 2007), 63% resulted from PCNSL. No deaths were=20 attributable to drug toxicity.

Fig. 2

Responses = to MTX=20 monotherapy. CR complete response, PD = progressive=20 disease, PR partial response, MR mixed = response,=20 SD stable disease

Fig. 3

Overall = survival of=20 cohort (n =3D 121). Of 121 patients in = the cohort,=20 53 patients died and 68 survived. The median OS was = 7 years=20 with 95% CI 4.6, 12. The 1, 5 and 10 year OS rates were = 86, 58=20 and 44% respectively. TTP time=20 (more ...)

Fig. 4

Progression-free=20 survival. a PFS of CR patients=20 (n =3D 68)=E2=80=94Of 68 patients = achieving CR, forty=20 progressed, while 28 (censored) remained progression-free. = The=20 median PFS was 3.14 years with 95% CI of (2.48, 5.18). = The 1,=20 5=20 (more ...)

Of CR patients, 40 ultimately = recurred=20 including twenty patients with one recurrence, fourteen with two=20 sequential recurrences, and six with three recurrences. Twenty-six = patients with relapsed PCNSL were treated again with MTX = monotherapy.=20 Eighteen (69%) again achieved CR and one achieved PR.

MTX-toxicities included = eighty-one=20 events. Sixteen of these led to drug cessation and 14 to MTX dose=20 reduction or delay. Toxicities included leukoencephalopathy (8) = (including=20 full-scale IQ decrement by 30 points which led to MTX cessation);=20 reversible azotemia (21 patients) (of which four led to MTX = cessation and=20 three to dose delay or reduction). MTX was continued in four = patients=20 despite elevated liver enzymes (LFT) including one MTX delay. The = 18=20 occurrences of leukopenia led to drug cessation (1) dose delays = (2) while=20 thrombocytopenia (16) did not. Sixteen cutaneous drug reactions, = included=20 a fixed drug reaction, did not require discontinuation; but one=20 anaphylactic reaction led to drug cessation. Nine patients ceased = MTX=20 therapy as a result of sepsis (2), renal failure (2), mucositis = (2),=20 pulmonary emboli, clostridium gastroenteritis and drug-resistant=20 tachycardia.

Discussion

We report a single-site = cohort=20 provided MTX monotherapy for PCNSL. The therapy provided CR or PR = response=20 in 85% and PFS of 3.14 years. The overall survivals of 86% at = one=20 year, 58% at five years and 44% at 10 years- are likely low = as we=20 assumed death to have occurred on the date of last follow-up. = These data=20 will well serve investigators describing the benefits to PCNSL = patients of=20 novel immunologic or stem cell therapies. Despite initial MTX = responses=20 (CR, PR, MR, SD); 30% of the 117 patients progressed within=20 15 months. We were unable to establish, as has been reported = by=20 Ferreri [18], a metric to separate eventual responders = from=20 non-responders despite evaluating (unpublished) the prognostic = roles of=20 demography, number and volume of brain lesions, pre-therapy = performance=20 status and MTX pharmacokinetics. Recent studies [19] suggest correlates of MTX efficacy and = toxicity=20 including pharmacogenomic analyses as well as assays of the = expression of=20 folate carrier channels [20, 21].

Toxicities of MTX were rare and = reversible.=20 Sixty-eight percent of recipients experienced no toxicity; but = seven=20 MTX-related toxic events led to MTX cessation. These included:=20 leukoencephalopathy, azotemia, leucopenia, anaphylaxis, sepsis, = and=20 mucositis. This low rate reflects care provided by neurologic and=20 chemotherapy nurses with experience in the provision of hydration = in the=20 setting of brain edema, the knowledge of drug-MTX interactions and = experience in the provision of =E2=80=9Caccelerated=E2=80=9D = calcium leucovorin emerging=20 during azotemia or the release of MTX from = =E2=80=9Cthird-spaces=E2=80=9D. These=20 toxicities have been well documented [22].

Our CR rate of 58% is similar to = other=20 reports (Table = 2) including = Watanabe [23] (CR =3D 50%) and Ng [14] (CR6/10); but unlike that of Herrlinger [13] (CR =3D 30%). Uncertain is whether = differences=20 reflect the comorbidity of patients or intricacies of MTX=20 administration.

<= /DIV>

= Table 1

Recurrence after=20 MTX therapy (n =3D 117)

Three months after starting MTX = therapy=20 patients can be declared =E2=80=9Cresponders=E2=80=9D or = =E2=80=9Cnon-responders=E2=80=9D. By this=20 evaluation (6 cycles MTX) CR was identified in 58% of patients; PD = was=20 declared somewhat earlier (2 months). Thus 3 months of = MTX=20 therapy represents a baseline against which investigators may = evaluate the=20 efficacy of adding other agents. MTX=E2=80=94monotherapy is not = curative.=20 Progression of disease was seen in sixty-six percent of patients = with PR,=20 MR or SD and in 59% of those with CR. Uncertain is whether = continuation of=20 MTX-monotherapy prolongs PFS. The PFS for CR patients who = continued MTX=20 every three months was 3.48 years in comparison to = 2.86 years=20 for those who ceased MTX within the first year and similar = patients=20 reported by others [12, 14]. These recurrences do not reflect resistance = to MTX; as=20 CR followed MTX-monotherapy retreatment in eighteen of 26 PCNSL = patients=20 who had relapsed. Although MTX-based multi-drug/irradiation = therapies=20 (Table = 3) are associated = with PFS=20 rates ranging from 5.6 months [24] (Cytarabine, Carmustine, etoposide, melphalan = with stem=20 cell rescue) to 11 months [25] (Lomustine, procarbazine, Cytarabine and=20 methylprednisolone) to 77.4 months [26] (receiving steroids, cyclophosamide or = etoposide and=20 procarbazine) it is unlikely that these approaches will be the = subject of=20 randomized trials in comparison to MTX-monotherapy. The multi-drug = therapies [24=E2=80=9337] overall survivals are 60 months [5, 27] 50 months [31] 7 months [26] similar to those we report.

<= /DIV>

= Table 2

Literature reports=20 of MTX monotherapy

Promising preliminary = data suggest=20 efficacy of adding to MTX the drugs Temodar [33] and Rituxan [38]; the provision of autologous stem cell = transplantation=20 [39, 40] and low dose brain radiation. These trials = are ongoing.=20 Our data provide a benchmark by which to measure the additive = value of=20 these approaches. Certainly stem cell transplantation appears a = logical=20 addition by which to consolidate the MTX-related CR seen in almost = 60% of=20 our MTX recipients. Our early experience with MTX and Temodar and = Rituxan=20 points to a reduced interval from diagnosis to = CR.

Acknowledgment

We would like to thank Alona = Muzikansky for=20 her help with statistical studies.

Open Access This = article is=20 distributed under the terms of the Creative Commons Attribution=20 Noncommercial License which permits any noncommercial use, = distribution,=20 and reproduction in any medium, provided the original author(s) = and source=20 are credited.

Contributor Information

Julien Cobert, Phone: +908-787-6123, Email:=20 jmcobert/at/gmail.com .

Fred Hochberg, Phone: +617-724-8770, Email:=20 FHochberg/at/partners.org , Email: fhochberg/at/rcn.com .

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39. Illerhaus G, Marks R, Ihorst G, et = al.=20 High-dose chemotherapy with autologous stem-cell transplantation = and=20 hyperfractionated radiotherapy as first-line treatment of primary = CNS=20 lymphoma. J Clin Oncol. = 2006;24:3865=E2=80=933870. doi: = 10.1200/JCO.2006.06.2117.=20 [PubMed]=20 [Cross=20 Ref]

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43. Hiraga S, Arita N, Ohnishi T, et = al. Rapid=20 infusion of high-dose methotrexate resulting in enhanced = penetration into=20 cerebrospinal fluid and intensified tumor response in primary = central=20 nervous system lymphomas. J = Neurosurg.=20 1999;91:221=E2=80=93230. doi:=20 10.3171/jns.1999.91.2.0221. [PubMed]=20 [Cross=20 Ref]

<= /DIV>

= Table 3

Literature reports=20 of PFS/OS for MTX-based multidrug chemotherapy

PubMed articles by these = authors

Cobert,=20 J.
Hochberg,=20 E.
Woldenberg,=20 N.
Hochberg,=20 F.

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ReviewPrimary central nervous system lymphoma: = biological=20 aspects and controversies in management.
Eur J Cancer. 2007 May;=20 43(7):1141-52.
[Eur J Cancer. = 2007]
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[Cancer Res. 1966]
ReviewFolate antagonists.
Annu Rev Med. 1967; = 18():27-34.
[Annu Rev Med. 1967]
ReviewChemotherapy of the non-Hodgkin's = lymphomas.
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[Cancer. 1978]
High-dose=20 methotrexate with folinic acid in the treatment of advanced = non-Hodgkin=20 lymphoma including CNS involvement.
Blood. 1977 Dec; = 50(6):1039-47.
[Blood. 1977]

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Immunoglobulin=20 gene rearrangement analysis in cerebrospinal fluid of patients with=20 lymphoproliferative processes.
J Neurol Sci. 2006 Sep 25;=20 247(2):208-16.
[J Neurol Sci. = 2006]