Clin Transl Oncol DOI 10.1007/s12094-015-1345-4
RESEARCH ARTICLE
Pemetrexed for primary central nervous system lymphoma in the elderly S. Han1 • M. Wang2 • B. Liu1 • J. Yu1
Received: 4 February 2015 / Accepted: 1 July 2015 Ó Federacio´n de Sociedades Espan˜olas de Oncologı´a (FESEO) 2015
Abstract Objective The aim of this study was to evaluate the efficacy and safety of a consecutive series of elderly patients with primary central nervous system lymphoma (PCNSL) treated with single-agent pemetrexed without radiotherapy or intrathecal chemotherapy. Methods Twelve histologically confirmed newly diagnosed PCNSL patients older than 65 years were studied between 2008 and 2013. An induction chemotherapy was initially given (pemetrexed 600 mg/m2 on day 1, every 3 weeks). Patients achieving a complete, partial response or stable disease proceeded to a maintenance phase (up to 6 cycles). Patients with progressive/recurrent disease (PD) were treated with whole brain radiotherapy on an individual basis. Results Four patients presented complete response, six patients showed partial response and two patients presented progressive disease. The median progression-free survival (PFS) was 9.0 months [95 % confidence interval (CI) 2.0–45.3] and the median overall survival was 19.5 months (95 % CI 5.0–45.3). Adverse events included leukocytopenia, anemia, fatigue, rash and vomiting. No neurotoxicity or treatment-related death was observed. The estimated 1-year and 2-year survival rate was 66.7 and 41.7 %, respectively.
& J. Yu [email protected] 1
The Department of Oncology, Shandong Cancer Hospital and Institute, Shandong University, No. 440 of Jiyan Road, Jinan 250117, Shandong, People’s Republic of China
2
The Department of Oncology, Jiaozhou Central Hospital of Qingdao, No. 29 of Xuzhou Road, Jiaozhou, Qingdao 266300, Shandong, People’s Republic of China
Conclusions Our efficacy results demonstrate that the single-agent pemetrexed was feasible, active and well tolerated in elderly patients with PCNSL. Furthermore, this single-agent regimen results in higher response rates and less toxicity comparable with other chemotherapy or radiotherapy regimens. Prospectively, controlled studies are warranted to confirm such results. Keywords Chemotherapy Elderly Primary central nervous system lymphoma Pemetrexed
Introduction Primary central nervous system lymphoma (PCNSL) is a rare variant of non-Hodgkin lymphoma confined to the brain, spinal cord, leptomeninges, cerebrospinal fluid (CSF), or the eyes, with a median age of 60 years at diagnosis. Although it accounts for less than 5 % of all primary brain tumors, the age-adjusted incidence of PCNSL has increased substantially over the past 30 years [1]. Previous studies revealed that older age was an independent negative prognostic marker in patients with PCNSL [2–4]. Between 2004 and 2006, nearly half of all cases of PCNSL occur among patients older than 60 years, and 20 % of those affected are 80 years or older in the United States [5]. PCNSL developing in the elderly is associated with lower response rates, earlier relapse, and higher incidence of acute and late-delayed toxicities as compared to younger patients [6]. Currently, high-dose methotrexate (HD-MTX)-based chemotherapy is the standard therapy for patients with PCNSL. However, HD-MTX ([3.5 g/m2) is a hospitalbased regimen requiring aggressive fluid management and may not be as well tolerated in elderly patients with an
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increased prevalence of comorbid illnesses [7]. According to a population-based Medicare study of 579 patients diagnosed with PCNSL, age was inversely correlated with the chance of treatment with MTX, and up to 82 % of patients 80 years or older received either radiotherapy alone or no treatment at all [7]. But radiation-induced neurotoxicity is a particularly feared complication of treatment, as it may affect up to 80 % of elderly patients treated with combined methotrexate (MTX)-based chemotherapy and radiotherapy [8–10]. Kasenda et al. reported that exceedingly high MTX area under the curve (AUC) levels can have a negative impact on progressionfree and overall survivals in elderly PCNSL patients [11]. Zhu et al. observed the toxicity of 31 patients diagnosed with PCNSL at age [70 years who were treated with highdose MTX. Grade I–IV toxicities were observed in 27 of 31 patients and included gastrointestinal disturbances in 58 %, hematological complications in 80.6 %, and renal toxicity in 29 % [12]. Pemetrexed has antifolate activity, similar to methotrexate in its ability to penetrate the CNS, but with the advantage of targeting [1 site in folate metabolism. It interrupts purine synthesis via thymidylate synthase and dihydrofolate reductase inhibition, and pyrimidine synthesis via glycinamide ribonucleotide formyltransferase and aminoimidazole carboxamide for methyltransferase inhibition [13]. Raizer et al. assessed the antitumor activity and safety of pemetrexed in recurrent PCNSL [14]. Eleven patients, with a median age of 69.8 years, were treated with pemetrexed 900 mg/m2 every 3 weeks with low-dose dexamethasone, folate, and B12 supplementation. The overall response rate was 55 % and disease control rate was 91 %. The 6-month progression-free survival (PFS) was 45 %, median PFS was 5.7 months, and median overall survival was 10.1 months. Toxicities were primarily hematologic and infectious. But the results of safety and antitumor activity of pemetrexed in PCNSL were rare. This retrospective study was aimed to evaluate the efficacy and safety of pemetrexed in the treatment of initially diagnosed PCNSL in elderly patients.
Methods Twelve patients with pathologically confirmed PCNSL who were 65 years or older at the time of diagnosis in our institution from January 2008 to June 2013 were reviewed. Patients were required to have a neuropathological diagnosis of PCNSL. Pretreatment evaluation included contrast-enhanced magnetic resonance imaging (MRI) of the brain, while systemic NHL was ruled out by contrast-enhanced computed tomography total-body scans and bone marrow biopsy and aspirate. Other exclusion criteria were
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human immunodeficiency virus seropositivity, systemic lymphoma manifestation, inadequate bone marrow function (defined as neutrophils \2 9 109/l, platelets \100 9 109/l), heart or kidney failure (defined as ejection fraction \50 %, creatinine clearance \50 ml/min), Karnofsky performance score (KPS) B40, and severe non-compensated pulmonary or liver disease [15]. All patients were treated with pemetrexed 600 mg/m2 on day 1 at the induction phase every 3 weeks until a complete response (CR) was obtained or a maximum of six induction cycles was reached. Patients not responding to therapy [stable disease (SD) without clinical improvement or progressive disease (PD)] or relapse were offered to undergo WBRT, on the basis of age, performance, and comorbidity. Response to salvage therapy after PD was not taken into account since agents and strategies varied strongly.
Evaluation and statistical analysis Baseline MRI was obtained in all patients before initiating therapy. According to Response Evaluation Criteria in Solid Tumors (RECIST), tumor response was assessed by MRI after two chemotherapy cycles. Based on the RECIST guideline, complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) were determined. Progression-free survival (PFS) was defined as time between start of treatment and date of progression, death, or start of a new treatment for PCNSL. Overall survival (OS) was measured from the treatment until death or the last follow-up. The Kaplan–Meier method was utilized to construct the PFS and OS curves. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE, version 3.0).
Results Patient characteristics Among the 12 patients, 9 patients (75 %) were men and 3 patients (25 %) were women, with a median age of 73.9 (range 65–84 years); median KPS was 70 (range 40–90). The diagnosis was established by brain biopsy in ten patients, by CSF cytology in two patients. No ocular involvement was involved. All patients received two cycle treatment at least (2–6 cycles, median 4.8). The characteristic of patients is presented in Table 1. Treatment, response and survival Treatment modifications consisted of delays (defined as more than 1 week) in two patients. Four patients
Clin Transl Oncol Table 1 Patient characteristics, treatment outcome with primary central nervous system lymphoma treated with pemetrexed Patient no.
Age at diagnosis, gender
Dose (mg/m2/d), no. of cycles
Response to pemetrexed
PFS (months)
Further therapy at relapse
OS (months)
1
69, M
600, 6
PR
10.0
WBRT
14.0
2
75, M
600, 6
CR
45?
Still in CR
45?
3
71, F
600, 2
PD
2.0
WBRT
5.0
4
80, M
600, 4
CR
30
None
42?
5
68, F
600, 6
PR
20
WBRT
28?
6
74, M
600, 4
PR
6.0
None
10.0
7 8
76, M 84, M
600, 6 600, 4
CR PD
36? 3.0
Still in CR WBRT(CR)
36? 18.0
9
65, F
600, 6
PR
5.0
WBRT
9.0
10
78, M
600, 4
CR
14.0
None
25.0
11
70, M
600, 4
PR
4.0
WBRT
12.0
12
77, M
600, 6
PR
8.0
None
21.0
M male, F female, PFS progression-free survival, OS overall survival, CR complete response, PR partial response, PD progressive disease, WBRT whole brain radiotherapy
Fig. 1 Kaplan–Meier estimates are shown for a progression-free survival (median, 9 months) in 12 elderly patients with primary central nervous system lymphoma treated with first-line pemetrexed chemotherapy
(33.3 %) showed a complete response (CR), six patients (50 %) had a partial response (PR), two patients (16.7 %) had progression diseases (PD), no patient showed stable diseases (SD) in this trial. Two of four patients in CR were alive without disease more than 3 years after treatment (Patient No. 2 and No. 7). The response rate was 83.3 % and disease control rate (PR plus CR) was 83.3 %. The median progression-free survival (PFS) was 9.0 months (95 % CI 2.0–45.3) (Table 1; Fig. 1). The median overall survival (OS) for the entire population was 19.5 months (95 % CI 5.0–45.3) (Table 1; Fig. 2). The median follow-up time was 19.5 months (range 5.0–46). The estimated 1-year and 2-year survival rate was 75 and 41.7 %, respectively. In three patients, progression-free survival (PFS)
Fig. 2 Kaplan–Meier estimates are shown for an overall survival (median, 19.5 months) in these 12 elderly patients
after second-line WBRT was longer than PFS after primary pemetrexed chemotherapy (Table 1). Six patients died of lymphoma, one patient death was due to a cardiac arrest likely unrelated to treatment and in another one patient the cause of death was unknown. No treatment-related death was observed in this study. Adverse events All patients were considered evaluable for adverse events. Adverse events in this trial included anemia, leukopenia, fatigue, rash and vomiting. Only one patient developed grade III anemia. No patient had grade IV adverse events. No neurotoxicity had been observed in this study. After 1 or 2 week rest, all patients were recovered from these adverse events after symptomatic treatment (Table 2).
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Clin Transl Oncol Table 2 Adverse events in this study Adverse events
NCICTCAE grade I
Leukopenia Fatigue
II
IV
1 2
Anemia Rash
III
1 1
Vomiting
1 1
Peripheral neuritis
1
Total
4
3
1
Discussion Age has been recognized as an important prognostic factor in PCNSL, and profoundly influences treatment choices in routine clinical practice [3, 4]. Previous studies demonstrated that approximately 50 % of patients with PCNSL were more than 65 years old. A study from the Surveillance, Epidemiology, and End Results (SEER) cancer registry reported that only 80 % of newly diagnosed patients aged 65 years or older were treated. Thirty-six percent of patients were treated with whole brain radiotherapy (WBRT) alone and 22 % received chemotherapy alone [16]. PCNSL developing in the elderly is associated with lower response rates, earlier relapses, and higher incidence of acute and late-delayed toxicities as compared to younger patients (Table 3). Minimizing toxicity in elderly patients is particularly challenging and suboptimal therapy remains a problem. Previous studies revealed that the WBRT may not be appropriate for the PCNSL in the elderly patients because of the increased risk of late neurotoxicity and its shortly median survival time. In a prospective RTOG study evaluating the use of 40-Gy irradiation with a 20-Gy boost to the tumor, median survival in elderly patients treated with WBRT alone was reported to be only 7.6 months. Therefore, the reporters considered that radiation alone was likely inadequate therapy for the elderly patients of PCNSL [17]. High-dose methotrexate (HD-MTX)-based chemotherapy is the standard therapy for patients with primary CNS lymphoma (PCNSL). Multiple studies have reported that elderly patients can tolerate MTX-containing regimens with good response rates [12, 15, 18, 19]. But HD-MTX can also be applied to elderly patients without substantial toxicity as long as organ functions, especially renal function, are adequate [7]. Some elderly patients, however, cannot receive HDMTX because of more markedly impaired renal function (creatinine clearance/50 ml/min) or other comorbidities. Roth et al. (G-PCNSL-SG-1) reported the outcomes of 126 patients who were aged 70 or more. The rate of complete
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and partial responses (CR?PR) to HD-MTX-based chemotherapy was 44 %. Toxicity was age-independent except for a 34 % of grade III/IV leukopenia. Death on therapy was more frequent (18 %), and PFS was 4.0 months and overall survival was 12.5 months. The authors concluded that lower response rate and higher mortality on HD-MTX-based chemotherapy as well as lower PFS of CR patients and less salvage therapy contribute to the poor prognosis of elderly patients with PCNSL [20]. Welch et al. performed a retrospective review of all PCNSL patients aged 80 years or older treated at Memorial Sloan-Kettering Cancer Center from 1993 to 2011 [21]. Twenty-three of 24 patients were treated with chemotherapy (92 % with high-dose MTX, typically in combination with vincristine and procarbazine). Response to treatment was noted in 62.5 % of patients. Median overall survival was 7.9 months, and median progression-free survival was 6.5 months. Although this study shows that high-dose MTX is safe among the oldest patients, the median overall survival and median progression-free survival are lower. This warrants the search for effective and mild therapies for these patients. In this study, we tried to use pemetrexed for induction therapy for the PCNSL to assess the efficacy of pemetrexed in PCNSL in the elderly. Pemetrexed’s similarity to methotrexate but ability to target [1 aspect of folate metabolism led us to hypothesize that this agent might also be active in PCNSL with lower toxicity. Twelve newly diagnosed as PCNSL in the elderly patients underwent pemetrexed for induction therapy in this study. All patients were treated with pemetrexed 600 mg/m2 on day 1 at the induction phase every 3 weeks and a maximum of six induction cycles was applied. In this study, the clinical response rate with pemetrexed was not less than HD-MTX or other single. Clinical activity was seen with an overall response rate (CR?PR) of 83.3 %. Our median progression-free survival (PFS) was 9.0 months and the median overall survival (OS) for the entire population was 19.5 months. The estimated 1-year and 2-year survival rate was 75 and 41.7 %, respectively. This was comparable to other chemotherapeutic agents used in the PCNSL setting. A retrospective series explored temozolomide monotherapy in elderly patients with PCNSL and severe comorbidities. In 17 patients (62–90 years old), the complete response rate was 47 %, median progression-free survival was 5 months, and median overall survival was 21 months. Five of 17 patients (29.4 %) had prolonged responses for at least 12 months and survived for more than 24 months [22]. The rate of adverse event was lower than that reported in the previous studies treating with single-agent chemotherapy. In view of toxicity, one patient experienced grade 3 anemia. In
31
24
23
35
10
174
38
17
50
28
Zhu et al. [12]
Welch et al. [21]
Omuro et al. [9]
Olivier et al. [23]
Ng et al. [19]
Ney et al. [25]
Lee et al. [24]
Kurzwelly et al. [22]
Hoang Xuan et al. [6]
Fritsch et al. [15]
75
72
75
69
72
73
65
68
82
74
70
Median age
HD-MTX, CCNU, PCB, IT-MTX, steroids R, HD-MTX, CCNU, PCB
TMZ
HD-MTX, RANIMST, PCB, steroids
HD-MTX, WBRT
HD-MTX
HD-MTX, VIND, IDA, steroids
HD-MTX, TMZ
MVP
HD-MTX
HD-MTX, PCB, CCNU
Regimens
Chemotherapy
Chemotherapy
Chemotherapy WBRT
Chemotherapy WBRT
Chemotherapy WBRT
Chemotherapy
Chemotherapy
Chemotherapy
Chemotherapy
Chemotherapy
Chemotherapy WBRT
Type of treatment
82 (64)
48 (42)
53 (47)
74 (42)
76 (n.r.)
90 (60)
51 (17)
70 (55)
63 (58)
96 (60)
90 (45)
Response rate (CR) %
18 %
6%
6%
32 %
n.r.
30 %
34 %
0
4%
37 %
26 %
PR
7%
24 %
47 %
21 %
n.r.
10 %
29 %
45 %
38 %
3 %
30 %
PD
16
7
5
18
24
18
13
8
7
7.1
6
Mean PFS (Mo)
18
14
21
43
25
36
19
35
8
37
15
Mean OS (Mo)
Neutropenias 64 %
Neutropenia 19 %
Leukopenia 12 %
Thrombocytopenia 42 %
Anemia 37 %
Neutropenia 69 %
Nephrotoxicity 9 %
Nausea 10 %
Thrombocytopenia 5 %
Neutropenia 52 %
Hematotoxicity 21.7 %
Infection 18.5 % Nephrotoxicity 13.0 %
Anemia 14 %
Leukopenia 32 %
Cardiac 3.2 %
Hematological 6.5 %
Anemia 32 %
Thrombocytopenia 29 %
Neutropenia 64 %
Grade (III/IV) toxicity
CCNU lomustine, CR complete response, CTX chemotherapy, HD-MTX high-dose methotrexate, IDA idarubicin, IT intrathecal, mo months, MVP high-dose methotrexate–vincristine– procarbazine, n.r. not reported, PCB procarbazine, PR partial response, Pts patients, RANIMST ranimustine, R rituximab, TMZ temozolomide, VIND vindesine, WBRT whole brain radiotherapy
30
No. of Pts
Illerhaus et al. [18]
References
Table 3 The relevant studies of CNS lymphoma in the elderly in recent years
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this study, the toxicity included anemia, leukopenia, fatigue, rash and vomiting. No patient had grade IV adverse events. No neurotoxicity and treatment-related death had been observed in this study. But in the G-PCNSL-SG-1 trial, toxicity with HD-MTX was age-independent except for a 34 % of grade III/ IV leukopenia and death on therapy was as high as 18 % [21]. The pemetrexed is relatively easy to administer to patients, unlike methotrexate, which requires hospitalization for continuous hydration. The current study has several limitations. First, the data of this study were collected retrospectively and there might have introduced some patient selection bias. Second, the relatively small sample size limited our power to detect potentially important associations between patient characteristics and clinical outcomes of interest. Therefore, a prospective study of a large number of patients will be needed to verify the results of this study in the future. Third, the retrospective nature of this study means that relevant patient characteristics such as nutritional status, comorbidities, precise steroid dosing, detailed neurocognitive evaluations, and geriatric assessments were unavailable. Fourth, the dose of pemetrexed was less compared to Jeffrey’s 900 mg/m2, maybe higher dose could bring better result. In conclusion, this study demonstrated that the singleagent pemetrexed was feasible, active and well tolerated in elderly patients with PCNSL. Furthermore, this singleagent regimen results in high response rates and less toxicity comparable with other chemotherapy or radiotherapy regimens. The single-agent pemetrexed offers effective and safe therapy for elderly patients with PCNSL. This is a meaningful trial for treatment of elderly patients with PCNSL. The further larger studies will be warranted to confirm such results in the future. Compliance with ethical standards Conflict of interest
The authors declare no conflict of interest.
References 1. Olson JE, Janney CA, Rao RD, Cerhan JR, Kurtin PJ, Schiff D, et al. The continuing increase in the incidence of primary central nervous system nonHodgkin lymphoma: a surveillance, epidemiology, and end results analysis. Cancer. 2002;95:1504–10. 2. Ferreri AJ, Reni M, Pasini F, Calderoni A, Tirelli U, Pivnik A, et al. A multicenter study of treatment of primary CNS lymphoma. Neurology. 2002;58:1513–20. 3. Ferreri AJ, Blay JY, Reni M, Pasini F, Spina M, Ambrosetti A, et al. Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol. 2003;21:266–72.
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4. Abrey LE, Ben-Porat L, Panageas KS, Yahalom J, Berkey B, Curran W, et al. Primary central nervous system lymphoma: the Memorial Sloan-Kettering Cancer Center prognostic model. J Clin Oncol. 2006;24:5711–5. 5. CBTRUS. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004–2006. Hinsdale, IL: Central Brain Tumor Registry of the United States. 2010. www.cbtrus.org. 6. Hoang-Xuan K, Taillandier L, Chinot O, Soubeyran P, Bogdhan U, Hildebrand J, et al. Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol. 2003;21:2726–31. 7. Jahnke K, Korfel A, Martus P, Weller M, Herrlinger U, Schmittel A, et al. Highdose methotrexate toxicity in elderly patients with primary central nervous system lymphoma. Ann Oncol. 2005;16:445–9. 8. Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000;18:3144–50. 9. Omuro AM, Taillandier L, Chinot O, Carnin C, Barrie M, Hoang-Xuan K. Temozolomide and methotrexate for primary central nervous system lymphoma in the elderly. J Neurooncol. 2007;85:207–11. 10. Omuro AM, Ben-Porat LS, Panageas KS, Kim AK, Correa DD, Yahalom J, et al. Delayed neurotoxicity in primary central nervous system lymphoma. Arch Neurol. 2005;62:1595–600. 11. Kasenda B, Rehberg M, Thurmann P, Franzem M, Veelken H, Fritsch K, et al. The prognostic value of serum methotrexate area under curve in elderly primary CNS lymphoma patients. Ann Hematol. 2012;91:1257–64. 12. Zhu JJ, Gerstner ER, Engler DA, Mrugala MM, Nugent W, Nierenberg K, et al. High-dose methotrexate for elderly patients with primary CNS lymphoma. Neuro Oncol. 2009;11:211–5. 13. Shih C, Chen VJ, Gossett LS, Gates SB, MacKellar WC, Habeck LL, et al. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res. 1997;57:1116–23. 14. Raizer JJ, Rademaker A, Evens AM, Rice L, Schwartz M, Chandler JP, et al. Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma. Cancer. 2012;118:3743–8. 15. Fritsch K, Kasenda B, Hader C, Nikkhah G, Prinz M, Haug V, et al. Immunochemotherapy with rituximab, methotrexate, procarbazine, and lomustine for primary CNS lymphoma (PCNSL) in the elderly. Ann Oncol. 2011;22:2080–5. 16. Panageas KS, Elkin EB, Ben-Porat L, Deangelis LM, Abrey LE. Patterns of treatment in older adults with primary central nervous system lymphoma. Cancer. 2007;110:1338–44. 17. Nelson DF, Martz KL, Bonner H, Nelson JS, Newall J, Kerman HD, et al. NonHodgkin’s lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys. 1992;23:9–17. 18. Illerhaus G, Marks R, Muller F, Ihorst G, Feuerhake F, Deckert M, et al. Highdose methotrexate combined with procarbazine and CCNU for primary CNS lymphoma in the elderly: results of a prospective pilot and phase II study. Ann Oncol. 2009;20:319–25. 19. Ng S, Rosenthal MA, Ashley D, Cher L. High-dose methotrexate for primary CNS lymphoma in the elderly. Neuro Oncol. 2000;2:40–4. 20. Roth P, Martus P, Kiewe P, Mohle R, Klasen H, Rauch M, et al. Outcome of elderly patients with primary CNS lymphoma in the G-PCNSL-SG-1 trial. Neurology. 2012;79:890–6. 21. Welch MR, Omuro A, Deangelis LM. Outcomes of the oldest patients with primary CNS lymphoma treated at Memorial Sloan-Kettering Cancer Center. Neuro Oncol. 2012;14:1304–11. 22. Kurzwelly D, Glas M, Roth P, Weimann E, Lohner H, Waha A, et al. Primary CNS lymphoma in the elderly: temozolomide therapy and MGMT status. J Neurooncol. 2010;97:389–92. 23. Olivier G, Clavert A, Lacotte-Thierry L, Gardembas M, Escoffre-Barbe M, Brion A, et al. A phase 1 dose escalation study of idarubicin combined with methotrexate, vindesine, and prednisolone for untreated elderly patients with primary central nervous system lymphoma. The GOELAMS LCP 99 trial. Am J Hematol. 2014;89:1024–9. 24. Lee SY, Okoshi Y, Kurita N, Seki M, Yokoyama Y, Maie K, et al. Prognosis factors in Japanese elderly patients with primary central nervous system lymphoma treated with a nonradiation, intermediate-dose methotrexate-containing regimen. Oncol Res Treat. 2014;37:378–83. 25. Ney DE, Reiner AS, Panageas KS, Brown HS, DeAngelis LM, Abrey LE. Characteristics and outcomes of elderly patients with primary central nervous system lymphoma: the Memorial Sloan-Kettering Cancer Center experience. Cancer. 2010;116:4605–12.
RESEARCH ARTICLE
Pemetrexed for primary central nervous system lymphoma in the elderly S. Han1 • M. Wang2 • B. Liu1 • J. Yu1
Received: 4 February 2015 / Accepted: 1 July 2015 Ó Federacio´n de Sociedades Espan˜olas de Oncologı´a (FESEO) 2015
Abstract Objective The aim of this study was to evaluate the efficacy and safety of a consecutive series of elderly patients with primary central nervous system lymphoma (PCNSL) treated with single-agent pemetrexed without radiotherapy or intrathecal chemotherapy. Methods Twelve histologically confirmed newly diagnosed PCNSL patients older than 65 years were studied between 2008 and 2013. An induction chemotherapy was initially given (pemetrexed 600 mg/m2 on day 1, every 3 weeks). Patients achieving a complete, partial response or stable disease proceeded to a maintenance phase (up to 6 cycles). Patients with progressive/recurrent disease (PD) were treated with whole brain radiotherapy on an individual basis. Results Four patients presented complete response, six patients showed partial response and two patients presented progressive disease. The median progression-free survival (PFS) was 9.0 months [95 % confidence interval (CI) 2.0–45.3] and the median overall survival was 19.5 months (95 % CI 5.0–45.3). Adverse events included leukocytopenia, anemia, fatigue, rash and vomiting. No neurotoxicity or treatment-related death was observed. The estimated 1-year and 2-year survival rate was 66.7 and 41.7 %, respectively.
& J. Yu [email protected] 1
The Department of Oncology, Shandong Cancer Hospital and Institute, Shandong University, No. 440 of Jiyan Road, Jinan 250117, Shandong, People’s Republic of China
2
The Department of Oncology, Jiaozhou Central Hospital of Qingdao, No. 29 of Xuzhou Road, Jiaozhou, Qingdao 266300, Shandong, People’s Republic of China
Conclusions Our efficacy results demonstrate that the single-agent pemetrexed was feasible, active and well tolerated in elderly patients with PCNSL. Furthermore, this single-agent regimen results in higher response rates and less toxicity comparable with other chemotherapy or radiotherapy regimens. Prospectively, controlled studies are warranted to confirm such results. Keywords Chemotherapy Elderly Primary central nervous system lymphoma Pemetrexed
Introduction Primary central nervous system lymphoma (PCNSL) is a rare variant of non-Hodgkin lymphoma confined to the brain, spinal cord, leptomeninges, cerebrospinal fluid (CSF), or the eyes, with a median age of 60 years at diagnosis. Although it accounts for less than 5 % of all primary brain tumors, the age-adjusted incidence of PCNSL has increased substantially over the past 30 years [1]. Previous studies revealed that older age was an independent negative prognostic marker in patients with PCNSL [2–4]. Between 2004 and 2006, nearly half of all cases of PCNSL occur among patients older than 60 years, and 20 % of those affected are 80 years or older in the United States [5]. PCNSL developing in the elderly is associated with lower response rates, earlier relapse, and higher incidence of acute and late-delayed toxicities as compared to younger patients [6]. Currently, high-dose methotrexate (HD-MTX)-based chemotherapy is the standard therapy for patients with PCNSL. However, HD-MTX ([3.5 g/m2) is a hospitalbased regimen requiring aggressive fluid management and may not be as well tolerated in elderly patients with an
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increased prevalence of comorbid illnesses [7]. According to a population-based Medicare study of 579 patients diagnosed with PCNSL, age was inversely correlated with the chance of treatment with MTX, and up to 82 % of patients 80 years or older received either radiotherapy alone or no treatment at all [7]. But radiation-induced neurotoxicity is a particularly feared complication of treatment, as it may affect up to 80 % of elderly patients treated with combined methotrexate (MTX)-based chemotherapy and radiotherapy [8–10]. Kasenda et al. reported that exceedingly high MTX area under the curve (AUC) levels can have a negative impact on progressionfree and overall survivals in elderly PCNSL patients [11]. Zhu et al. observed the toxicity of 31 patients diagnosed with PCNSL at age [70 years who were treated with highdose MTX. Grade I–IV toxicities were observed in 27 of 31 patients and included gastrointestinal disturbances in 58 %, hematological complications in 80.6 %, and renal toxicity in 29 % [12]. Pemetrexed has antifolate activity, similar to methotrexate in its ability to penetrate the CNS, but with the advantage of targeting [1 site in folate metabolism. It interrupts purine synthesis via thymidylate synthase and dihydrofolate reductase inhibition, and pyrimidine synthesis via glycinamide ribonucleotide formyltransferase and aminoimidazole carboxamide for methyltransferase inhibition [13]. Raizer et al. assessed the antitumor activity and safety of pemetrexed in recurrent PCNSL [14]. Eleven patients, with a median age of 69.8 years, were treated with pemetrexed 900 mg/m2 every 3 weeks with low-dose dexamethasone, folate, and B12 supplementation. The overall response rate was 55 % and disease control rate was 91 %. The 6-month progression-free survival (PFS) was 45 %, median PFS was 5.7 months, and median overall survival was 10.1 months. Toxicities were primarily hematologic and infectious. But the results of safety and antitumor activity of pemetrexed in PCNSL were rare. This retrospective study was aimed to evaluate the efficacy and safety of pemetrexed in the treatment of initially diagnosed PCNSL in elderly patients.
Methods Twelve patients with pathologically confirmed PCNSL who were 65 years or older at the time of diagnosis in our institution from January 2008 to June 2013 were reviewed. Patients were required to have a neuropathological diagnosis of PCNSL. Pretreatment evaluation included contrast-enhanced magnetic resonance imaging (MRI) of the brain, while systemic NHL was ruled out by contrast-enhanced computed tomography total-body scans and bone marrow biopsy and aspirate. Other exclusion criteria were
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human immunodeficiency virus seropositivity, systemic lymphoma manifestation, inadequate bone marrow function (defined as neutrophils \2 9 109/l, platelets \100 9 109/l), heart or kidney failure (defined as ejection fraction \50 %, creatinine clearance \50 ml/min), Karnofsky performance score (KPS) B40, and severe non-compensated pulmonary or liver disease [15]. All patients were treated with pemetrexed 600 mg/m2 on day 1 at the induction phase every 3 weeks until a complete response (CR) was obtained or a maximum of six induction cycles was reached. Patients not responding to therapy [stable disease (SD) without clinical improvement or progressive disease (PD)] or relapse were offered to undergo WBRT, on the basis of age, performance, and comorbidity. Response to salvage therapy after PD was not taken into account since agents and strategies varied strongly.
Evaluation and statistical analysis Baseline MRI was obtained in all patients before initiating therapy. According to Response Evaluation Criteria in Solid Tumors (RECIST), tumor response was assessed by MRI after two chemotherapy cycles. Based on the RECIST guideline, complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) were determined. Progression-free survival (PFS) was defined as time between start of treatment and date of progression, death, or start of a new treatment for PCNSL. Overall survival (OS) was measured from the treatment until death or the last follow-up. The Kaplan–Meier method was utilized to construct the PFS and OS curves. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE, version 3.0).
Results Patient characteristics Among the 12 patients, 9 patients (75 %) were men and 3 patients (25 %) were women, with a median age of 73.9 (range 65–84 years); median KPS was 70 (range 40–90). The diagnosis was established by brain biopsy in ten patients, by CSF cytology in two patients. No ocular involvement was involved. All patients received two cycle treatment at least (2–6 cycles, median 4.8). The characteristic of patients is presented in Table 1. Treatment, response and survival Treatment modifications consisted of delays (defined as more than 1 week) in two patients. Four patients
Clin Transl Oncol Table 1 Patient characteristics, treatment outcome with primary central nervous system lymphoma treated with pemetrexed Patient no.
Age at diagnosis, gender
Dose (mg/m2/d), no. of cycles
Response to pemetrexed
PFS (months)
Further therapy at relapse
OS (months)
1
69, M
600, 6
PR
10.0
WBRT
14.0
2
75, M
600, 6
CR
45?
Still in CR
45?
3
71, F
600, 2
PD
2.0
WBRT
5.0
4
80, M
600, 4
CR
30
None
42?
5
68, F
600, 6
PR
20
WBRT
28?
6
74, M
600, 4
PR
6.0
None
10.0
7 8
76, M 84, M
600, 6 600, 4
CR PD
36? 3.0
Still in CR WBRT(CR)
36? 18.0
9
65, F
600, 6
PR
5.0
WBRT
9.0
10
78, M
600, 4
CR
14.0
None
25.0
11
70, M
600, 4
PR
4.0
WBRT
12.0
12
77, M
600, 6
PR
8.0
None
21.0
M male, F female, PFS progression-free survival, OS overall survival, CR complete response, PR partial response, PD progressive disease, WBRT whole brain radiotherapy
Fig. 1 Kaplan–Meier estimates are shown for a progression-free survival (median, 9 months) in 12 elderly patients with primary central nervous system lymphoma treated with first-line pemetrexed chemotherapy
(33.3 %) showed a complete response (CR), six patients (50 %) had a partial response (PR), two patients (16.7 %) had progression diseases (PD), no patient showed stable diseases (SD) in this trial. Two of four patients in CR were alive without disease more than 3 years after treatment (Patient No. 2 and No. 7). The response rate was 83.3 % and disease control rate (PR plus CR) was 83.3 %. The median progression-free survival (PFS) was 9.0 months (95 % CI 2.0–45.3) (Table 1; Fig. 1). The median overall survival (OS) for the entire population was 19.5 months (95 % CI 5.0–45.3) (Table 1; Fig. 2). The median follow-up time was 19.5 months (range 5.0–46). The estimated 1-year and 2-year survival rate was 75 and 41.7 %, respectively. In three patients, progression-free survival (PFS)
Fig. 2 Kaplan–Meier estimates are shown for an overall survival (median, 19.5 months) in these 12 elderly patients
after second-line WBRT was longer than PFS after primary pemetrexed chemotherapy (Table 1). Six patients died of lymphoma, one patient death was due to a cardiac arrest likely unrelated to treatment and in another one patient the cause of death was unknown. No treatment-related death was observed in this study. Adverse events All patients were considered evaluable for adverse events. Adverse events in this trial included anemia, leukopenia, fatigue, rash and vomiting. Only one patient developed grade III anemia. No patient had grade IV adverse events. No neurotoxicity had been observed in this study. After 1 or 2 week rest, all patients were recovered from these adverse events after symptomatic treatment (Table 2).
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Clin Transl Oncol Table 2 Adverse events in this study Adverse events
NCICTCAE grade I
Leukopenia Fatigue
II
IV
1 2
Anemia Rash
III
1 1
Vomiting
1 1
Peripheral neuritis
1
Total
4
3
1
Discussion Age has been recognized as an important prognostic factor in PCNSL, and profoundly influences treatment choices in routine clinical practice [3, 4]. Previous studies demonstrated that approximately 50 % of patients with PCNSL were more than 65 years old. A study from the Surveillance, Epidemiology, and End Results (SEER) cancer registry reported that only 80 % of newly diagnosed patients aged 65 years or older were treated. Thirty-six percent of patients were treated with whole brain radiotherapy (WBRT) alone and 22 % received chemotherapy alone [16]. PCNSL developing in the elderly is associated with lower response rates, earlier relapses, and higher incidence of acute and late-delayed toxicities as compared to younger patients (Table 3). Minimizing toxicity in elderly patients is particularly challenging and suboptimal therapy remains a problem. Previous studies revealed that the WBRT may not be appropriate for the PCNSL in the elderly patients because of the increased risk of late neurotoxicity and its shortly median survival time. In a prospective RTOG study evaluating the use of 40-Gy irradiation with a 20-Gy boost to the tumor, median survival in elderly patients treated with WBRT alone was reported to be only 7.6 months. Therefore, the reporters considered that radiation alone was likely inadequate therapy for the elderly patients of PCNSL [17]. High-dose methotrexate (HD-MTX)-based chemotherapy is the standard therapy for patients with primary CNS lymphoma (PCNSL). Multiple studies have reported that elderly patients can tolerate MTX-containing regimens with good response rates [12, 15, 18, 19]. But HD-MTX can also be applied to elderly patients without substantial toxicity as long as organ functions, especially renal function, are adequate [7]. Some elderly patients, however, cannot receive HDMTX because of more markedly impaired renal function (creatinine clearance/50 ml/min) or other comorbidities. Roth et al. (G-PCNSL-SG-1) reported the outcomes of 126 patients who were aged 70 or more. The rate of complete
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and partial responses (CR?PR) to HD-MTX-based chemotherapy was 44 %. Toxicity was age-independent except for a 34 % of grade III/IV leukopenia. Death on therapy was more frequent (18 %), and PFS was 4.0 months and overall survival was 12.5 months. The authors concluded that lower response rate and higher mortality on HD-MTX-based chemotherapy as well as lower PFS of CR patients and less salvage therapy contribute to the poor prognosis of elderly patients with PCNSL [20]. Welch et al. performed a retrospective review of all PCNSL patients aged 80 years or older treated at Memorial Sloan-Kettering Cancer Center from 1993 to 2011 [21]. Twenty-three of 24 patients were treated with chemotherapy (92 % with high-dose MTX, typically in combination with vincristine and procarbazine). Response to treatment was noted in 62.5 % of patients. Median overall survival was 7.9 months, and median progression-free survival was 6.5 months. Although this study shows that high-dose MTX is safe among the oldest patients, the median overall survival and median progression-free survival are lower. This warrants the search for effective and mild therapies for these patients. In this study, we tried to use pemetrexed for induction therapy for the PCNSL to assess the efficacy of pemetrexed in PCNSL in the elderly. Pemetrexed’s similarity to methotrexate but ability to target [1 aspect of folate metabolism led us to hypothesize that this agent might also be active in PCNSL with lower toxicity. Twelve newly diagnosed as PCNSL in the elderly patients underwent pemetrexed for induction therapy in this study. All patients were treated with pemetrexed 600 mg/m2 on day 1 at the induction phase every 3 weeks and a maximum of six induction cycles was applied. In this study, the clinical response rate with pemetrexed was not less than HD-MTX or other single. Clinical activity was seen with an overall response rate (CR?PR) of 83.3 %. Our median progression-free survival (PFS) was 9.0 months and the median overall survival (OS) for the entire population was 19.5 months. The estimated 1-year and 2-year survival rate was 75 and 41.7 %, respectively. This was comparable to other chemotherapeutic agents used in the PCNSL setting. A retrospective series explored temozolomide monotherapy in elderly patients with PCNSL and severe comorbidities. In 17 patients (62–90 years old), the complete response rate was 47 %, median progression-free survival was 5 months, and median overall survival was 21 months. Five of 17 patients (29.4 %) had prolonged responses for at least 12 months and survived for more than 24 months [22]. The rate of adverse event was lower than that reported in the previous studies treating with single-agent chemotherapy. In view of toxicity, one patient experienced grade 3 anemia. In
31
24
23
35
10
174
38
17
50
28
Zhu et al. [12]
Welch et al. [21]
Omuro et al. [9]
Olivier et al. [23]
Ng et al. [19]
Ney et al. [25]
Lee et al. [24]
Kurzwelly et al. [22]
Hoang Xuan et al. [6]
Fritsch et al. [15]
75
72
75
69
72
73
65
68
82
74
70
Median age
HD-MTX, CCNU, PCB, IT-MTX, steroids R, HD-MTX, CCNU, PCB
TMZ
HD-MTX, RANIMST, PCB, steroids
HD-MTX, WBRT
HD-MTX
HD-MTX, VIND, IDA, steroids
HD-MTX, TMZ
MVP
HD-MTX
HD-MTX, PCB, CCNU
Regimens
Chemotherapy
Chemotherapy
Chemotherapy WBRT
Chemotherapy WBRT
Chemotherapy WBRT
Chemotherapy
Chemotherapy
Chemotherapy
Chemotherapy
Chemotherapy
Chemotherapy WBRT
Type of treatment
82 (64)
48 (42)
53 (47)
74 (42)
76 (n.r.)
90 (60)
51 (17)
70 (55)
63 (58)
96 (60)
90 (45)
Response rate (CR) %
18 %
6%
6%
32 %
n.r.
30 %
34 %
0
4%
37 %
26 %
PR
7%
24 %
47 %
21 %
n.r.
10 %
29 %
45 %
38 %
3 %
30 %
PD
16
7
5
18
24
18
13
8
7
7.1
6
Mean PFS (Mo)
18
14
21
43
25
36
19
35
8
37
15
Mean OS (Mo)
Neutropenias 64 %
Neutropenia 19 %
Leukopenia 12 %
Thrombocytopenia 42 %
Anemia 37 %
Neutropenia 69 %
Nephrotoxicity 9 %
Nausea 10 %
Thrombocytopenia 5 %
Neutropenia 52 %
Hematotoxicity 21.7 %
Infection 18.5 % Nephrotoxicity 13.0 %
Anemia 14 %
Leukopenia 32 %
Cardiac 3.2 %
Hematological 6.5 %
Anemia 32 %
Thrombocytopenia 29 %
Neutropenia 64 %
Grade (III/IV) toxicity
CCNU lomustine, CR complete response, CTX chemotherapy, HD-MTX high-dose methotrexate, IDA idarubicin, IT intrathecal, mo months, MVP high-dose methotrexate–vincristine– procarbazine, n.r. not reported, PCB procarbazine, PR partial response, Pts patients, RANIMST ranimustine, R rituximab, TMZ temozolomide, VIND vindesine, WBRT whole brain radiotherapy
30
No. of Pts
Illerhaus et al. [18]
References
Table 3 The relevant studies of CNS lymphoma in the elderly in recent years
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Clin Transl Oncol
this study, the toxicity included anemia, leukopenia, fatigue, rash and vomiting. No patient had grade IV adverse events. No neurotoxicity and treatment-related death had been observed in this study. But in the G-PCNSL-SG-1 trial, toxicity with HD-MTX was age-independent except for a 34 % of grade III/ IV leukopenia and death on therapy was as high as 18 % [21]. The pemetrexed is relatively easy to administer to patients, unlike methotrexate, which requires hospitalization for continuous hydration. The current study has several limitations. First, the data of this study were collected retrospectively and there might have introduced some patient selection bias. Second, the relatively small sample size limited our power to detect potentially important associations between patient characteristics and clinical outcomes of interest. Therefore, a prospective study of a large number of patients will be needed to verify the results of this study in the future. Third, the retrospective nature of this study means that relevant patient characteristics such as nutritional status, comorbidities, precise steroid dosing, detailed neurocognitive evaluations, and geriatric assessments were unavailable. Fourth, the dose of pemetrexed was less compared to Jeffrey’s 900 mg/m2, maybe higher dose could bring better result. In conclusion, this study demonstrated that the singleagent pemetrexed was feasible, active and well tolerated in elderly patients with PCNSL. Furthermore, this singleagent regimen results in high response rates and less toxicity comparable with other chemotherapy or radiotherapy regimens. The single-agent pemetrexed offers effective and safe therapy for elderly patients with PCNSL. This is a meaningful trial for treatment of elderly patients with PCNSL. The further larger studies will be warranted to confirm such results in the future. Compliance with ethical standards Conflict of interest
The authors declare no conflict of interest.
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