High-dose methotrexate toxicity in elderly patients with primary central nervous system lymphoma

Annals of Oncology 16: 445 – 449, 2005 doi:10.1093/annonc/mdi075 Published online 14 January 2005

Original article

High-dose methotrexate toxicity in elderly patients with primary central nervous system lymphoma K. Jahnke1*, A. Korfel1, P. Martus2, M. Weller3, U. Herrlinger3, A. Schmittel1, L. Fischer1 & E. Thiel1 On behalf of the German Primary Central Nervous System Lymphoma Study Group (G-PCNSL-SG) Departments of 1Hematology, Oncology and Transfusion Medicine, and 2Medical Informatics, Biometry and Epidemiology, Charite´-Universita¨tsmedizin Berlin, Campus Benjamin Franklin, Berlin; 3Department of General Neurology, Center for Neurology, University of Tu¨bingen, Tu¨bingen, Germany Received 20 July 2004; revised 28 September 2004; accepted 29 September 2004

Introduction Primary central nervous system lymphoma (PCNSL) is defined as a non-Hodgkin’s lymphoma that arises within, and at the time of diagnosis is confined to, the central nervous system [1]. Most cases of PCNSL occur in elderly patients, the median age at diagnosis in immunocompetent patients being
55 years old [1]. Age >60 years is associated with a poor prognosis [2]. The prognosis of PCNSL was markedly enhanced by the addition of high-dose methotrexate (HDMTX) to whole-brain irradiation (WBI), while chemotherapy protocols effective in extracerebral lymphoma did not improve survival compared with WBI alone [3,4]. Cerebrospinal fluid (CSF) permeation by MTX is dose-dependent, i.e. the percentage of courses with cytostatic CSF levels varies from 0% to 100% with doses between 0.5 and 6 g/m2 [5 –7].

*Correspondence to: Dr K. Jahnke, Department of Hematology, Oncology and Transfusion Medicine, Charite´-Universita¨tsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. Tel: +49-30-8445-2337; Fax: +49-30-8445-4468; E-mail: [email protected] q 2005 European Society for Medical Oncology

HDMTX is also used to treat other malignancies such as acute lymphoblastic leukemia and osteosarcoma, but since these diseases usually affect younger people, few data are available on toxicity in older patients. This patient population is particularly at high risk for acute toxicity such as impaired renal and hepatic function. Thus, the MTX dose is often primarily reduced in elderly patients, resulting in a reduced treatment efficacy and a less favorable outcome in this population with an already poor prognosis [2]. In an ongoing prospective multicenter study in PCNSL patients, we evaluated the incidence and severity of HDMTXrelated toxicity with special regard to age distribution.

Patients and methods Patients All patients were included in a multicenter phase IV study to evaluate the role of adjuvant WBI in the primary treatment of PCNSL (German Primary CNS Lymphoma Study Group 1) (Figure 1). Initial treatment consisted of HDMTX in all patients. Ethics committee approval was obtained for this study. Patients were then randomized according to remission status. Those with complete remission (CR) either received immediate WBI,

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Background: The dose of high-dose methotrexate (HDMTX) in elderly patients often has to be reduced, resulting in a loss of treatment efficacy. We evaluated HDMTX-related toxicity with special regard to age distribution in patients with primary central nervous system lymphoma (PCNSL) in a phase IV multicenter trial. Patients and methods: One hundred and fifty-four patients (median age 61 years; 89 patients >60 years old, 21 patients >70 years old) received 619 HDMTX cycles. Toxicity was evaluated prospectively using the WHO classification. Unless a reduced dose was required after calculating a decreased glomerular filtration rate (GFR), the patients received 4 g/m2 HDMTX followed by leucovorin rescue. _ 3 usually <10%. The differResults: Toxicity was generally mild with toxicities of WHO grade > ences in the incidence and severity of toxicity were not statistically significant between patients >60 _ 60 years old. The same was true for therapy termination owing to MTX toxicity and for years and < _ 60 years and delayed serum MTX clearance. Dose reduction significantly differed between patients < those >60 years old (18% versus 44%; P = 0.001). Conclusions: HDMTX is a safe treatment for PCNSL patients regardless of age, with adherence to dose reduction determined by calculating the GFR before each treatment cycle. Key words: elderly, glomerular filtration rate, methotrexate, toxicity

446 Table 1. Patient characteristics No. of patients (%) Gender Male

89 (57.8)

Female

65 (42.2)

Age (years) Median Range

Figure 1. Design of the German Primary CNS Lymphoma Study Group 1. MTX, methotrexate; CR, complete remission; WBI, whole-brain irradiation; AraC, cytarabine.

>60

89

>70

21

Comorbidities Cardiovascular disease Renal disease

Exclusion criteria were a creatinine clearance of <50 ml/min, positive HIV serology, active infection, a Karnofsky performance status (KPS) <50% for reasons not related to PCNSL and <30% for PCNSL-related reasons, concomitant malignant disease, concomitant immunosuppression, pregnancy, no effective contraception, breast feeding in women with child-bearing potential, and treatment with salicylates, non-steroidal antiinflammatory drugs, sulfonamides or penicillins within 1 week prior to HDMTX. One hundred and fifty-four patients from 42 institutions were enrolled at the time of this analysis (Table 1). HDMTX toxicity was evaluated prospectively. KPS before treatment was available for 80 patients. The median KPS was 70% for all patients (range 30% to 100%), as well as for those >60 years (range 35% to 100%) and >70 years old (range 40% to 80%).

Treatment HDMTX doses were adapted to the creatinine clearance determined prior to each HDMTX cycle. The glomerular filtration rate (GFR) was calculated as follows: GFR ¼ ½CrU ðmg=dlÞ=CrS ðmg=dlÞ £ ½UV ðmlÞ=1440 min; where CrU is the urinary creatinine concentration in a 24-h urine sample, CrS is the serum creatinine concentration and UV is the urine volume in 24 h. The MTX dose was reduced according to the decrease of the GFR relative to 100 ml/min. For example, if the GFR was beyond 100 ml/min, the dose was not reduced; if the GFR was 80 ml/min, the MTX dose was reduced by 20%. Unless a dose reduction was required, all patients received a HDMTX dose of 4 g/m2 intravenously (i.v.) over 4 h per cycle, repeated every 2 weeks up to a maximum of six cycles. The dose of 4 g/m2 was chosen based on the promising results published by GuhaThakurta et al. [8]. In addition, 8 mg of oral dexamethasone was administered thrice daily over 10 consecutive days during cycle 1. Serum MTX concentrations were measured 24, 42 and 68 h after the beginning of the infusion. All patients received i.v. hydration with 2 l of 5% glucose over 24 h with 120 mval of sodium bicarbonate beginning on day 1, as well as 25 mg of leucovorin i.v. every 6 h starting 24 h after the beginning of the

43 (29.5) 9 (6.3)

Hepatic disease

3 (2.1)

Pulmonary disease

2 (1.4)

Neurological symptoms at diagnosis Psychosyndrome

61 (39.6)

Hemiparesis

53 (34.4)

Headache

47 (30.5)

Cerebral nerve palsy

26 (16.9)

Cerebellar syndrome

19 (12.3)

Epilepsy

19 (12.3)

Elevated intracranial pressure

6 (3.9)

Diagnosis confirmed by Stereotactic biopsy

91 (59.1)

Total resection

20 (13)

Partial resection

19 (12.3)

Open biopsy

18 (11.7)

Cerebrospinal fluid evaluation

1 (0.6)

Unknown

5 (3.2)

Histology Diffuse large B cell Small lymphocytic B cell T cell Unknown

124 (80.5) 8 (5.2) 4 (2.6) 18 (11.7)

MTX infusion. Leucovorin and i.v. hydration were continued until the serum MTX serum levels had dropped below 0.1 mM. Intensified leucovorin rescue was performed in patients with serum MTX levels >150, >1 and >0.1 mM at 24, 42 and 68 h, respectively. Urine pH was evaluated after each micturition and kept above pH 7 with oral potassium sodium hydrogen citrate or additional sodium bicarbonate infusions until the serum MTX concentration had dropped below 0.1 mM. Toxicity was evaluated according to the WHO criteria [9]. Treatment termination was mandatory for the following reasons: patient’s desire, progressive leukencephalopathy, a serum creatinine >1.5 the normal value for 1 week, grade 4 toxicity (excluding alopecia and hematotoxicity) or repeated grade 3 toxicity, persisting myelosuppression (ANC <1500/ml or platelets <100 000/ml) or persistence of toxicity other than alopecia for >2 weeks after the next scheduled HDMTX cycle, severe protocol violation, and progressive disease under HDMTX.

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or WBI was deferred until relapse. Patients without CR were randomized to either receive immediate WBI or cytarabine. Inclusion criteria were histologically and/or cytologically/immunocytologically (in CSF) confirmed PCNSL without prior cytostatic treatment, written informed consent, age > _ 18 years, an absolute neutrophil count (ANC) of > _ 1500/ml, platelets > _ 100 000/ml, normal total bilirubin, transaminases < _ 3 the normal value _ 50 ml/min. and a creatinine clearance of >

61 19– 83

447 Statistics _ 60 years and in those >60 Toxicity was analyzed separately in patients < years and >70 years old with respect to the number of HDMTX cycles and patients. Differences in the incidence and severity of toxicity between _ 60 and those >60 years old were compared using the x2-test for patients < linear association. Moreover, the incidence of grade 3–4 toxicity, grade 4 toxicity, premature HDMTX termination and delayed serum MTX clearance rates were analyzed using Fisher’s exact test. With 154 patients and toxicity frequencies ranging from 25% to 75%, differences in toxicities of
24% would have been detectable with a power of 80%. _ 70 years and those >70 years old were Differences between patients < only analyzed descriptively owing to the small number of patients >70 years old. The level of significance was 0.05 (two-sided) for all analyses. No adjustment was made for multiplicity. All analyses were performed using the software package SPSSWIN (release 11.5).

No interim efficacy analysis has been planned in this trial.

Results Tables 2 and 3 show a summary of all toxicities.

Hematological toxicity and infections Of 69 patients evaluable for toxicity before treatment, five patients (7%) had grade 1 anemia, one had grade 2 neutropenia and one had a grade 2 infection. When comparing the different grades of anemia, thrombopenia, leucopenia and infections, no significant differences in the severity and fre_ 60 and >60 years old, nor quency were found in patients < were they found for the comparison of all toxicity grades

Non-hematological toxicity Serum creatinine levels were elevated before treatment in six patients (9%). Prior to chemotherapy, grade 1 mucositis and pulmonary impairment were found in one patient each, while grade 2 pulmonary impairment was seen in two patients. Comparing the different grades of gastrointestinal toxicity, pulmon_ 60 and >60 years old, ary toxicity and alopecia in patients < no significant differences in the severity and frequency were found, nor were they found for the comparison of all toxicity grades (grade 0–4, x2-test for linear association) together or for the subgroup analysis of severe toxicity (grade 3–4 versus grade 0–2 and grade 4 versus grade 0–3, Fisher’s exact test). Elevation of transaminases (grade 1–3), creatinine elevation (grade 1–2), nausea (grade 1) and mucositis (grade 1–2) were most frequently seen. No acute HDMTX-related neurotoxicity was observed. On follow-up, 30 patients (19.5%) had evidence of leukencephalopathy on brain magnetic resonance imaging, and 11 patients (7.1%) demonstrated clinical evidence of late neurotoxicity.

MTX dose reduction, treatment termination and delayed MTX clearance Owing to a reduced GFR, the MTX dose was reduced in 11 _ 60 years, in 36 (44%) >60 years, and in 14 (18%) patients <

Table 2. High-dose methotrexate (HDMTX)-associated hematological toxicity and infections in primary central nervous system lymphoma patients, _ 60/>60 and >70 years olda analyzed separately for treated patients, applied HDMTX cycles, and patients < Toxicity WHO grade 1 < _ 60 years

>60 years

Patients (%)

14 (22)

18 (20)

Cycles (%)

55 (18)

Patients (%) Cycles (%)

Toxicity WHO grade 2

Toxicity WHO grade 3

Toxicity WHO grade 4

< _ 60 years

>60 years

>70 years

< _ 60 years

>60 years

>70 years

< _ 60 years

>60 years

>70 years

6 (29)

13 (20)

20 (23)

5 (24)

7 (11)

13 (15)

4 (19)

0

0

0

59 (19)

18 (35)

25 (8)

35 (12)

8 (15)

8 (3)

13 (4)

4 (8)

0

0

0

9 (14)

16 (18)

9 (43)

10 (15)

7 (8)

1 (5)

3 (5)

7 (8)

1 (5)

2 (3)

6 (7)

0

32 (10)

27 (9)

7 (14)

16 (5)

16 (5)

3 (6)

3 (1)

10 (3)

2 (4)

3 (1)

6 (2)

2 (4)

>70 years

Hemoglobin

Leukocytes

Granulocytes (neutrophils) Patients (%)

5 (8)

2 (3)

1 (5)

2 (3)

0

0

1 (2)

2 (3)

1 (5)

0

2 (3)

1 (5)

Cycles (%)

10 (4)

2 (1)

1 (2)

5 (2)

0

0

1 (0)

2 (1)

1 (2)

0

2 (1)

1 (2)

Thrombocytes Patients (%)

11 (12)

3 (14)

3 (5)

3 (3)

1 (5)

0

7 (8)

3 (14)

3 (5)

3 (3)

1 (5)

12 (4)

12 (4)

3 (6)

4 (1)

4 (1)

1 (2)

0

9 (3)

3 (6)

3 (1)

3 (1)

1 (2)

Patients (%)

1 (2)

5 (6)

3 (14)

9 (14)

11 (12)

4 (19)

8 (12)

9 (10)

3 (14)

1 (2)

3 (3)

0

Cycles (%)

7 (2)

8 (3)

5 (10)

16 (5)

6 (11)

9 (3)

3 (6)

1 (0)

3 (1)

0

Cycles (%)

9 (14)

Infection

a

13 (4)

_ 60 and >60 years. No statistically significant differences were observed between patients <

10 (3)

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Late neurotoxicity was defined as a dementia syndrome in absence of cerebral lymphoma manifestations.

(grade 0–4, x2-test for linear association) together or for the analysis of severe toxicity (grade 3–4 and grade 4 alone versus grade 0–2 and 0–3, respectively, Fisher’s exact test). There was a tendency towards higher frequency of grade 1–3 anemia and grade 1–2 infections in older patients.

448 Table 3. Non-hematological high-dose methotrexate (HDMTX) toxicity in primary central nervous system lymphoma patients, analyzed separately for _ 60/>60 and >70 years olda treated patients, applied HDMTX cycles, and patients < Toxicity WHO grade 1

Toxicity WHO grade 2

< _ 60 years

>60 years

Patients (%)

15 (23)

15 (17)

5 (24)

2 (3)

7 (8)

4 (19)

1 (2)

Cycles (%)

24 (8)

31 (10)

10 (19)

5 (2)

12 (4)

4 (8)

1 (0)

Patients (%)

10 (16)

28 (33)

5 (24)

Cycles (%)

45 (15)

51 (18)

7 (14)

>70 years

< _ 60 years

Toxicity WHO grade 3

>60 years

>70 years

< _ 60 years

Toxicity WHO grade 4 >70 years

< _ 60 years

>60 years

>70 years

5 (6)

0

0

1 (1)

1 (5)

5 (2)

0

0

1 (0)

1 (2)

9 (11)

1 (5)

5 (8)

4 (5)

1 (5)

1 (2)

6 (2)

4 (1)

1 (2)

>60 years

Creatinine

Transaminases 6 (7)

3 (14)

12 (19)

18 (6)

6 (10)

15 (5)

6 (12)

20 (7)

10 (4)

Alkaline phosphatase 6 (9)

5 (6)

0

1 (2)

3 (4)

0

0

0

0

0

0

0

Cycles (%)

7 (2)

8 (3)

0

2 (1)

3 (1)

0

0

0

0

0

0

0

Patients (%)

2 (3)

5 (6)

2 (10)

0

3 (4)

1 (5)

0

1 (1)

1 (5)

0

1 (1)

0

Cycles (%)

5 (2)

6 (2)

2 (4)

0

3 (1)

1 (2)

0

1 (0)

1 (2)

0

1 (0)

0

9 (10)

Bilirubin

Mucositis Patients (%)

2 (10)

5 (8)

10 (12)

2 (10)

1 (2)

4 (5)

0

0

0

0

12 (4)

16 (5)

2 (4)

9 (3)

15 (5)

3 (6)

1 (0)

4 (1)

0

0

0

0

Patients (%)

11 (17)

13 (15)

5 (24)

4 (6)

3 (3)

2 (10)

2 (3)

2 (2)

1 (5)

0

0

0

Cycles (%)

23 (7)

28 (9)

9 (17)

7 (2)

4 (1)

2 (4)

2 (1)

5 (2)

1 (2)

0

0

0

Patients (%)

4 (6)

5 (6)

3 (14)

3 (5)

1 (1)

0

3 (5)

0

0

0

0

0

Cycles (%)

8 (3)

7 (2)

4 (8)

4 (1)

2 (1)

0

3 (1)

0

0

0

0

0

Patients (%)

5 (8)

8 (10)

2 (10)

3 (5)

4 (5)

1 (5)

2 (3)

5 (6)

1 (5)

0

0

0

Cycles (%)

11 (4)

14 (5)

2 (4)

4 (1)

6 (2)

1 (2)

9 (3)

7 (3)

1 (2)

0

0

0

Patients (%)

3 (5)

1 (1)

1 (5)

2 (3)

4 (5)

2 (10)

1 (2)

2 (2)

0

1 (2)

4 (5)

0

Cycles (%)

5 (2)

1 (0)

1 (2)

3 (1)

7 (2)

2 (4)

1 (0)

3 (1)

0

1 (0)

4 (1)

0

Cycles (%)

7 (11)

Nausea/emesis

Diarrhea

Alopecia

Lungs

a

_ 60 and >60 years. No statistically significant differences were observed between patients <

_ 60 years old differed signifi(70%) >70 years old. Patients < cantly from those >60 years (P = 0.001). The mean amount of MTX dose reduction required in dose-reduced patients was 15.6% (range 1.3% to 80%). HDMTX was stopped prematurely due to toxicity in three _ 60 years versus seven patients (8%) >60 years patients (5%) < old (P = 0.52). The main reason was nephrotoxicity in two _ 60 years old and in six patients (7%) >60 patients (3%) < years old (P = 0.469). Delayed MTX clearance was observed in two patients (3%) < _ 60 years old versus nine patients (11%) >60 years old (P = 0.116).

Discussion Provided that renal function is adequate, current evidence suggests that HDMTX can be tolerated without life-threatening

toxicity as long as dose escalation is accompanied by hydration, urine alkalinization and adequate leucovorin rescue guided by monitoring of serum MTX concentrations [8, 10 –13]. This is the first report on a prospective multicenter evaluation of age-dependent HDMTX toxicity in a uniformly treated representative patient population. The toxicity observed was transient and reversible in all patients and usually of minor clinical importance. Hematological toxicity (especially anemia) was most frequently seen. It was demonstrated for the first time that the incidence and severity of the toxicities do not significantly differ between older and younger patients; however, there was a tendency towards higher rates of anemia, infections, nephrotoxicity and total bilirubin elevation in older patients. The HDMTX dose was reduced much more frequently in the elderly, suggesting that HDMTX dose reduction according to the pretreatment GFR probably plays a critical

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Patients (%)

449 function prior to and during treatment should be the rule in these patients, rather than therapeutic nihilism.

Acknowledgements This study was supported by the German Cancer Council (Deutsche Krebshilfe, project number 70-2838).

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role for the prevention of toxicity in elderly patients, especially nephrotoxicity. Five small studies with single-agent HDMTX at a dose of 3.5–8 g/m2 are available for comparison with our study [8,10–13]. The reported overall acute and subacute toxicity was mild, which supports the data from our study. In a study with 25 patients (median age 61 years, 13 patients > _ 60 years old, median KPS 60%), there were three occurrences of mucositis, one of chest and back pain associated with dyspnea, nausea and vomiting, two of deep venous thrombosis, and one each of pulmonary embolism, transient encephalopathy, isolated nausea, acute renal failure (rapidly reversed) and skin rash, out of a total of 79 HDMTX cycles. Agranulocytosis and thrombocytopenia were seen in one patient in the setting of an ileus and presumed malabsorption of oral leucovorin [10]. In a prospective multicenter phase II trial with 25 patients (mean age 60 years, median KPS 80%) and 287 treatment courses, 12 patients had 18 episodes (6%) of unspecified grade 3 or 4 toxicity [11]. In two prospective studies, primary dose reduction was performed based on the pretreatment creatinine clearance. In one of the prospective single-center studies, which included 31 patients (median age 63 years, median KPS 40%), the dose was reduced in 139 of 375 cycles (37%). Grade 3 mucositis was seen in six courses (2%) and transient renal failure in three courses (1%) [8]. In the other prospective study, with 37 patients (median age 60 years, median KPS 70%), WHO grade 3 and 4 toxicity was observed in 19 of 179 courses (11%). One patient with WHO grade 4 leukopenia died of septicemia, accounting for the toxic death rate of 2.7% [12]. Data concerning HDMTX toxicity in elderly patients are rare, and there are no studies comparing toxicity rates and grades with those in younger patients. In a retrospective study, grade 3 nausea was found in one, grade 2 mucositis in two, and grade 2 elevation of transaminases in two of 10 elderly patients (median age 72.5 years, eight patients >70 years, six patients with Eastern Cooperative Oncology Group performance score 2 or higher) [13]. In conclusion, single-agent HDMTX is a safe treatment regardless of age when dose reduction schedules based on the GFR calculated before each treatment cycle are implemented. Reducing the MTX dose simply according to the patient’s age is not justified, especially considering the poor prognosis of elderly patients with a malignant disease. Life expectancy for elderly tumor patients is usually determined by the malignant disease. Thus, careful monitoring and assessment of organ