- Email: [email protected]
A single centre study of the treatment of relapsed primary central nervous system lymphoma (PCNSL) with single agent temozolomide
Journal of Clinical Neuroscience 19 (2012) 1501–1505
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
A single centre study of the treatment of relapsed primary central nervous system lymphoma (PCNSL) with single agent temozolomide S.F. Wong a, H.K. Gan a,b, L. Cher a,⇑ a b
Department of Medical Oncology, Austin Health, 145 Studley Road, Melbourne, Victoria 3084, Australia Ludwig Institute for Cancer Research, Austin Health, Melbourne, Victoria, Australia
a r t i c l e
i n f o
Article history: Received 11 January 2012 Accepted 1 April 2012
Keywords: Central nervous system Lymphoma Salvage therapy Temozolomide
a b s t r a c t Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. Although recommendations for first-line treatment usually incorporate high-dose methotrexate, there is substantial heterogeneity in the types of salvage therapies used at relapse. Phase II data supported the use of temozolomide as a well-tolerated treatment modality in this setting. Therefore, we reviewed the treatment and outcomes of patients with relapsed PCNSL who were treated with salvage temozolomide at our institution. Seven patients were treated with salvage temozolomide between January 2000 and May 2011. The objective response rate was 14%. Progression-free survival was 2 months (95% confidence interval [CI]: 0–5.9) and median overall survival was 4 months (95% CI: 0–13). Toxicity was mild, with one episode of grade 3 neutropenia during 25 cycles of chemotherapy. Although these results are consistent with previous phase II results, the outcomes for these patients remain extremely poor. The low toxicity of temozolomide raises the possibility of combining temozolomide with other chemotherapeutic agents or targeted agents in future clinical trials. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin’s lymphoma (NHL) and accounts for only 4% of all primary brain tumours.1 PCNSL typically affects patients over the age of 60 years in the immunocompetent population.2 It is also seen in immunocompromised patients, including those with acquired immunodeficiency syndrome,3 and can affect a younger population with a median age of 35 years. Although the incidence of PCNSL has been reported to be as high as 10% in autopsy series, the introduction of highly active anti-retroviral therapy has now substantially reduced this.4,5 High dose methotrexate generally forms the backbone of firstline treatment for PCNSL.6,7 There are data suggesting that methotrexate in combination with cytarabine-based regimes8 have superior response rates (RR) compared to methotrexate alone (RR of 69% compared to 40%), with a non-significant 3-year overall survival (OS) of 46% compared to 32%. However, combination therapy is associated with a higher rate of treatment-related toxicities and up to 8% mortality. As such, these regimes have not been universally adopted. Other chemotherapeutic agents, including those used in extra-cranial NHL, are not widely utilised as there are con-
⇑ Corresponding author. Tel.: +61 3 9496 5000; fax: +61 3 9457 6698. E-mail address: [email protected] (L. Cher). 0967-5868/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2012.04.001
cerns about their ability to cross the blood brain barrier and their toxicities in this population.9 Progression after first-line methotrexate is common, with 10% to 15% of patients having primary resistance and 35% to 60% of patients relapsing after an initial response.10,11 The optimal salvage therapy is unclear. Many patients are re-challenged with high dose methotrexate, with one multi-institutional review showing a RR > 91% in both the first and second-line salvage settings,12 and this accords with our experience. Salvage whole brain radiotherapy (WBRT) is also efficacious, with RR of 60% to 74%.13 However, WBRT is associated with significant neurotoxicity, occurring at rates of 4% to 36%, with patients older than 60 years of age being particularly vulnerable.14 Radiotherapy does remain a valid option in many instances as the neurotoxicity is often delayed with a median time of 7 months.15 Less frequently used salvage therapies include high-dose chemotherapy with autologous stem-cell rescue, combination procarbazine, lomustine, and vincristine; and topotecan.16 Temozolomide, an oral second-generation alkylating agent, has attracted interest as a potential therapy for PCNSL based on its low toxicity profile, its activity in other primary CNS malignancies, ability to effectively penetrate the blood brain barrier as well as in vitro additive cytotoxic activity when combined with radiotherapy.11 Patients with relapsed PCNSL were recruited into a phase II trial of temozolomide for relapsed PCNSL17,18 to receive temozolomide at 150 mg/m2 on day 1 to day 5 every 4 weeks. The objective RR
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S.F. Wong et al. / Journal of Clinical Neuroscience 19 (2012) 1501–1505
Fig. 1. Flowchart of patient selection of patients with relapsed primary central nervous system lymphoma (PCNSL) with single agent temozolomide.
was 31%, median progression-free survival (PFS) was 2.8 months and median OS was 3.9 months. Although encouraging, the efficacy of temozolomide has not been documented outside the confines of small clinical trials with highly selected patients. As such, we report on our experience in utilising single agent salvage temozolomide for patients with relapsed PCNSL in a tertiary centre specialising in PCNSL.
2. Materials and methods Patients with PCNSL treated with temozolomide between January 2000 and May 2011 were identified by examining our institution’s health information, pharmacy and anatomical pathology records. Patients were excluded if they did not have PCNSL, had never received temozolomide, had a history of extra-cranial systemic lymphoma that preceded their diagnosis of PCNSL or were missing required data from their patient records. The required data were extracted by a single author (S.F. Wong) and comprised the following: patient demographics at the time of initial diagnosis (age, gender, risk factors, performance status), initial disease symptomatology, initial staging investigations (neuroimaging, cerebrospinal fluid sampling, bone marrow assessments), all treatments given (treatment types, treatment dates, doses administered), treatment responses and subsequent relapses. The treatment response was assessed by serial contrast-enhanced MRI using the MacDonald response criteria (1990).19 Data regarding best treatment response and end-of-treatment response were recorded. The objective response rate was defined as the proportion of patients with complete responses (CR) or partial responses (PR). The clinical benefit rate was defined as the proportion of patients experiencing an objective response or stable disease (SD). Descriptive statistics (mean or median, range, 95% confidence interval [CI]) are provided as appropriate to summarise patient characteristics and outcomes. PFS and OS were assessed using Kaplan–Meier curves. PFS was defined as the time from start of treatment until documented progression after that treatment. OS post treatment was calculated from the start of that treatment until
the date of death. Patients who were lost to follow-up before disease progression or death were censored at the date of last follow-up for progression and death respectively. Data were collected only up to 31 October 2011. Adverse events were reviewed and graded according to the Common Terminology Criteria for Adverse Events version 3. Statistics were performed using the Statistical Package for the Social Sciences version 19 (SPSS, Chicago, IL, USA). 3. Results 3.1. Patient characteristics and treatment at initial diagnoses Between January 2000 and May 2011, 46 patients with a diagnosis of PCNSL were identified from our institutional records. Of these, 39 patients were excluded from this review because they did not have PCNSL, had a pre-existing diagnosis of extracranial NHL, had not received temozolomide or had incomplete patient records (Fig. 1). The remaining seven patients were included in this analysis. Their characteristics at the time of diagnosis are shown in Table 1.
Table 1 Characteristics of patients with primary central nervous system lymphoma at initial diagnosis Patient no.
Age (years)
Gender
Immunosuppression
ECOG
Histology
1
75
F
N
0
2 3 4 5 6 7
72 44 74 41 58 51
F M M M M M
N N N N YA YB
2 2 2 2 2 2
Non-Hodgkin’s large cell lymphoma Large B-cell NHL Large B-cell NHL Large B-cell NHL Large B-cell NHL Large B-cell NHL T-cell NHL
F = female, M = male, N = no, NHL = non-Hodgkin’s lymphoma, Y = yes. A Exposure to hydroxyurea and anagrelide for polycythaemia rubra vera. B Exposure to cyclosporine and mycophenolate for liver transplantation.
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S.F. Wong et al. / Journal of Clinical Neuroscience 19 (2012) 1501–1505 Table 2 Characteristics of patients with primary central nervous system lymphoma at first treatment with temozolomide Patient Age No. lines of Prior chemotherapy no. (years) chemotherapy
Best radiological ECOG No. of cycles Dose of of temozolomide temozolomide response (mg/m2)
PFS (months)
Survival (months)
1
76
1
HD Mtx + rituximab
1
1
150
Lost to follow up after cycle 1
Lost to follow up after cycle 1
2
74
2
2
150
PD after cycle 2
2
3 4
45 75
1 2
5 1
200 200
PR after cycle 2 PD after cycle 1
4.5 1
7 4
5
41
1
HD Mtx, second line HD 3 Mtx + rituximab HD Mtx + rituximab 1 HD Mtx + rituximab, second line 1 HD Mtx + rituximab HD Mtx 1
Lost to follow up after cycle 1 4
1
200
60
2
3
2
200
Died with clinical progression after cycle 1 1.5
0.13
6
Died with clinical progression after cycle 1 SD after cycle 2
7
51
1
2
13
200
SD after cycle 2
14
16
HD Mtx, second line HD Mtx + intrathecal cytarabine/ methotrexate HD Mtx
2
HD Mtx – High dose methotrexate; PD – progressive disease; PR – partial response; SD – stable disease; PFS – progression free survival.
Six of seven patients had diffuse large B-cell NHL whereas the seventh patient had a T-cell NHL. At the time of initial diagnosis, 85% of patients were of intermediate fitness (performance status 2). The median age of patients was 58 years. All patients were staged with an MRI scan, with some also having examinations of their cerebrospinal fluid (CSF) (57%) and bone marrow (71%). Staging showed that five patients had bilateral disease (71%), multiple lesions (71%) or involvement of deep structures (71%). No patient had evidence of raised lactate dehydrogenase or extracranial disease. All were treated up-front with high dose intravenous methotrexate, with 42% also receiving concomitant rituximab. The RR after first line treatment was 70% with five PR and one SD. All patients who received combined methotrexate and rituximab had a PR. The median PFS was 6 months (range: 0–16 months). Three patients were re-treated with methotrexate-based chemotherapy at progression, with two receiving concurrent rituximab whereas the third received concurrent intrathecal cytarabine and methotrexate. No patient had an objective response (two SD and one PD) and the median PFS was 10 months (range: 2–12 months). 3.2. Temozolomide salvage therapy Temozolomide was given as second-line chemotherapy in four patients and third-line in three patients. Their characteristics at the time of temozolomide treatment are shown in Table 2. The median age at the time of treatment with temozolomide was 60 years (range: 41–75 years). Approximately half (57%) had a good performance status (ECOG 1), with the rest having an intermediate to poor performance status (ECOG 2–3). A total of 42% of patients were found to have bilateral CNS relapse and one had nonenhancing tumour progression. A total of 25 cycles of temozolomide were administered in this study (median of two cycles per patient). All patients were treated with temozolomide at a daily dose of 150–200 mg/m2 on day 1 to day 5 every 4 weeks, until progression of disease, unacceptable toxicities or patient refusal. Temozolomide was generally well tolerated. One patient experienced Grade 2 thrombocytopenia and one patient experienced Grade 3 neutropenia. They received a dose reduction of 15% and 28% respectively at the discretion of the physician. One patient developed a non-neutropenic infection after the second cycle of chemotherapy for which he was being treated with intravenous antibiotics. After initially responding to treatment, the patient deteriorated acutely and died. The death was presumed to be unrelated to temozolomide.
Fig. 2. Kaplan–Meier curves showing (A) progression-free survival (PFS) from time of temozolomide treatment in months; and (B) overall survival from time of temozolomide treatment in months for patients with relapsed primary central nervous system lymphoma with single agent temozolomide.
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Response data are available for all patients except one patient who died during cycle one of treatment and a second patient who was lost to follow up after the first cycle of temozolomide. (These patients are regarded as having progressive disease for the purposes of response evaluation.) Overall, one of seven patients had a PR to temozolomide treatment for an objective RR of 14%. A further two patients experienced SD for an overall clinical benefit of 42%. Duration of response was brief with the median PFS being 2 months (95% CI: 0–5.9 months) (Fig. 2). Median survival from the time of commencing temozolomide treatment was only 4 months (95% CI: 0–13 months) (Fig. 2). Four patients (57%) died while being treated with temozolomide, after one cycle (n = 1), two cycles (n = 2) and 13 cycles (n = 1) of temozolomide respectively. Two patients died with confirmed radiological progression, one patient died presumably from PD and one died from likely pulmonary emboli. Two patients (28%) received radiotherapy as salvage after progression with temozolomide treatment, and died at 3 months and 4 months respectively post cessation of temozolomide.
4. Discussion This study is a retrospective review of the small subset of patients at our institution, a major Australian neuro-oncology unit, who received salvage temozolomide for relapsed PCNSL. The review aimed to compare outcomes for salvage treatment with temozolomide in the community setting, compared to the published literature from phase II trials. All patients initially received a high dose methotrexate-based treatment in the first line setting (RR of 70% and median PFS of 6 months) and 42% were re-challenged with high dose methotrexate at the time of first relapse (RR 0% but 67% of patients had SD). The results of our patients re-challenged with methotrexate appear inferior to the published results with salvage methotrexate.12 The published retrospective review included a study population who achieved CR after initial methotrexate-based treatment or received methotrexate after gross total resection or interstitial radiation. In contrast, our study included patients with no CR and only one PR after first-line methotrexate. Additionally, no patients received whole brain radiotherapy before proceeding to methotrexate-based treatment. Differences in patient selection may account for the variation in results. Patients who achieve CR after first line chemotherapy are chemosensitive, and more likely to respond to salvage chemotherapy than those who achieved PR or are non-responders. As expected, temozolomide treatment was generally well tolerated. Toxicities were mainly asymptomatic haematological abnormalities. However, although toxicity was mild as expected, objective RR was lower than published data. Only one patient had PR with an objective RR of 14% and 28% of patients had SD. Progressive disease while on treatment was seen in 85% of patients. Survival was also disappointing (PFS of 2 months and median OS of 4 months), although similar to the published phase II data. Patients in the phase II study were similar to our study population with the same median age of 60 years, and a similar proportion having intermediate to poor fitness (56% compared to 42% respectively). However, about 80% of patients in the published study had only received one line of treatment before receiving salvage temozolomide. This is in comparison to our series where 43% of patients had received more than one line of treatment prior to salvage temozolomide. Overall, these data suggest that the use of temozolomide for PCNSL needs to be carefully considered on a case-by-case basis, but in our opinion, its use is best confined to clinical trials at this time. Potential applications of temozolomide in future trials include combination therapy with proven agents for PCNSL or potentially as a radiosensitising agent. For example, one retrospective series found that temozolomide in combination
with rituximab appeared to be efficacious, with an objective RR of 53%, median OS of 14 months and median PFS of 7.7 months.20 The question of what salvage therapy to administer to patients with PCNSL at relapse remains difficult. In our institution, re-treatment with methotrexate or use of WBRT is most commonly used. It is important to stress that WBRT is a highly efficacious treatment for patients where further chemotherapy is not thought likely to be of benefit. Whilst it is true that there is a significantly increased risk of neurotoxicity, these are usually delayed and must be weighed up against the aggressive nature of relapsed PCNSL. The choice between chemotherapy or radiotherapy for patients with relapsed PCNSL depends on several factors including age and medical comorbidities of patients, achievement of CR to first line chemotherapy, time to progression after chemotherapy and tolerance to previous chemotherapy treatments. In conclusion, our data are broadly similar to the published data from clinical trials with temozolomide for patients with relapsed PCNSL, although outcomes remain poor in these patients generally. The low toxicity of temozolomide makes it a reasonable candidate for further studies, particularly in combination with other active agents for PCNSL.
Conflicts of interest/disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
References 1. Ferreri AJM, Abrey LE, Blay J-Y, et al. Summary statement on primary central nervous system lymphomas from the Eighth International Conference on Malignant Lymphoma, Lugano, Switzerland, June 12 to 15, 2002. J Clin Oncol 2003;21:2407–14. 2. Schabet M. Epidemiology of primary CNS lymphoma. J Neurooncol 1999;43:199–201. 3. Olson JE, Janney CA, Rao RD, et al. The continuing increase in the incidence of primary central nervous system non-Hodgkin lymphoma: a surveillance, epidemiology, and end results analysis. Cancer 2002;95:1504–10. 4. Besson C, Goubar A, Gabarre J, et al. Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy. Blood 2001;98:2339–44. 5. Skiest DJ, Crosby C. Survival is prolonged by highly active antiretroviral therapy in AIDS patients with primary central nervous system lymphoma. AIDS 2003;17:1787–93. 6. Ferreri AJ, Reni M, Pasini F, et al. A multicenter study of treatment of primary CNS lymphoma. Neurology 2002;58:1513–20. 7. Joerger M, Huitema AD, Krahenbuhl S, et al. Methotrexate area under the curve is an important outcome predictor in patients with primary CNS lymphoma: a pharmacokinetic-pharmacodynamic analysis from the IELSG no. 20 trial. Br J Cancer 2010;102:673–7. 8. Ferreri AJ, Reni M, Foppoli M, et al. High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet 2009;374:1512–20. 9. Schultz C, Scott C, Sherman W, et al. Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS lymphomas: initial report of radiation therapy oncology group protocol 88-06. J Clin Oncol 1996;14:556–64. 10. Deangelis LM, Iwamoto FM. An update on therapy of primary central nervous system lymphoma. Hematology (Am Soc Hematol Educ Program). 2006:311–6. 11. Wedge S, Porteous J, Newlands E. Temozolomide: a candidate for combination with locoregional radiotherapy. Br J Cancer. 1996;73(Suppl. 26):43. 12. Plotkin SR, Betensky RA, Hochberg FH, et al. Treatment of relapsed central nervous system lymphoma with high-dose methotrexate. Clin Cancer Res 2004;10:5643–6. 13. Nelson DF, Martz KL, Bonner H, et al. Non-Hodgkin’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. 14. Abrey LE, DeAngelis LM, Yahalom J. Long-term survival in primary CNS lymphoma. J Clin Oncol 1998;16:859–63. 15. Hottinger AF, DeAngelis LM, Yahalom J, et al. Salvage whole brain radiotherapy for recurrent or refractory primary CNS lymphoma. Neurology 2007;69:1178–82. 16. Fischer L, Thiel E, Klasen HA, et al. Response of relapsed or refractory primary central nervous system lymphoma (PCNSL) to topotecan. Neurology 2004;62:1885–7.
S.F. Wong et al. / Journal of Clinical Neuroscience 19 (2012) 1501–1505 17. Reni M, Mason W, Zaja F, et al. Salvage chemotherapy with temozolomide in primary CNS lymphomas: preliminary results of a phase II trial. Eur J Cancer 2004;40:162–8. 18. Reni M, Zaja F, Mason W, et al. Temozolomide as salvage treatment in primary brain lymphomas. Br J Cancer 2007;96:864–7.
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19. Macdonald DR, Cascino TL, Schold SC, et al. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8:1277–80. 20. Enting RH, Demopoulos A, DeAngelis LM, et al. Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Neurology 2004;63:901–3.
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
A single centre study of the treatment of relapsed primary central nervous system lymphoma (PCNSL) with single agent temozolomide S.F. Wong a, H.K. Gan a,b, L. Cher a,⇑ a b
Department of Medical Oncology, Austin Health, 145 Studley Road, Melbourne, Victoria 3084, Australia Ludwig Institute for Cancer Research, Austin Health, Melbourne, Victoria, Australia
a r t i c l e
i n f o
Article history: Received 11 January 2012 Accepted 1 April 2012
Keywords: Central nervous system Lymphoma Salvage therapy Temozolomide
a b s t r a c t Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. Although recommendations for first-line treatment usually incorporate high-dose methotrexate, there is substantial heterogeneity in the types of salvage therapies used at relapse. Phase II data supported the use of temozolomide as a well-tolerated treatment modality in this setting. Therefore, we reviewed the treatment and outcomes of patients with relapsed PCNSL who were treated with salvage temozolomide at our institution. Seven patients were treated with salvage temozolomide between January 2000 and May 2011. The objective response rate was 14%. Progression-free survival was 2 months (95% confidence interval [CI]: 0–5.9) and median overall survival was 4 months (95% CI: 0–13). Toxicity was mild, with one episode of grade 3 neutropenia during 25 cycles of chemotherapy. Although these results are consistent with previous phase II results, the outcomes for these patients remain extremely poor. The low toxicity of temozolomide raises the possibility of combining temozolomide with other chemotherapeutic agents or targeted agents in future clinical trials. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin’s lymphoma (NHL) and accounts for only 4% of all primary brain tumours.1 PCNSL typically affects patients over the age of 60 years in the immunocompetent population.2 It is also seen in immunocompromised patients, including those with acquired immunodeficiency syndrome,3 and can affect a younger population with a median age of 35 years. Although the incidence of PCNSL has been reported to be as high as 10% in autopsy series, the introduction of highly active anti-retroviral therapy has now substantially reduced this.4,5 High dose methotrexate generally forms the backbone of firstline treatment for PCNSL.6,7 There are data suggesting that methotrexate in combination with cytarabine-based regimes8 have superior response rates (RR) compared to methotrexate alone (RR of 69% compared to 40%), with a non-significant 3-year overall survival (OS) of 46% compared to 32%. However, combination therapy is associated with a higher rate of treatment-related toxicities and up to 8% mortality. As such, these regimes have not been universally adopted. Other chemotherapeutic agents, including those used in extra-cranial NHL, are not widely utilised as there are con-
⇑ Corresponding author. Tel.: +61 3 9496 5000; fax: +61 3 9457 6698. E-mail address: [email protected] (L. Cher). 0967-5868/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2012.04.001
cerns about their ability to cross the blood brain barrier and their toxicities in this population.9 Progression after first-line methotrexate is common, with 10% to 15% of patients having primary resistance and 35% to 60% of patients relapsing after an initial response.10,11 The optimal salvage therapy is unclear. Many patients are re-challenged with high dose methotrexate, with one multi-institutional review showing a RR > 91% in both the first and second-line salvage settings,12 and this accords with our experience. Salvage whole brain radiotherapy (WBRT) is also efficacious, with RR of 60% to 74%.13 However, WBRT is associated with significant neurotoxicity, occurring at rates of 4% to 36%, with patients older than 60 years of age being particularly vulnerable.14 Radiotherapy does remain a valid option in many instances as the neurotoxicity is often delayed with a median time of 7 months.15 Less frequently used salvage therapies include high-dose chemotherapy with autologous stem-cell rescue, combination procarbazine, lomustine, and vincristine; and topotecan.16 Temozolomide, an oral second-generation alkylating agent, has attracted interest as a potential therapy for PCNSL based on its low toxicity profile, its activity in other primary CNS malignancies, ability to effectively penetrate the blood brain barrier as well as in vitro additive cytotoxic activity when combined with radiotherapy.11 Patients with relapsed PCNSL were recruited into a phase II trial of temozolomide for relapsed PCNSL17,18 to receive temozolomide at 150 mg/m2 on day 1 to day 5 every 4 weeks. The objective RR
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S.F. Wong et al. / Journal of Clinical Neuroscience 19 (2012) 1501–1505
Fig. 1. Flowchart of patient selection of patients with relapsed primary central nervous system lymphoma (PCNSL) with single agent temozolomide.
was 31%, median progression-free survival (PFS) was 2.8 months and median OS was 3.9 months. Although encouraging, the efficacy of temozolomide has not been documented outside the confines of small clinical trials with highly selected patients. As such, we report on our experience in utilising single agent salvage temozolomide for patients with relapsed PCNSL in a tertiary centre specialising in PCNSL.
2. Materials and methods Patients with PCNSL treated with temozolomide between January 2000 and May 2011 were identified by examining our institution’s health information, pharmacy and anatomical pathology records. Patients were excluded if they did not have PCNSL, had never received temozolomide, had a history of extra-cranial systemic lymphoma that preceded their diagnosis of PCNSL or were missing required data from their patient records. The required data were extracted by a single author (S.F. Wong) and comprised the following: patient demographics at the time of initial diagnosis (age, gender, risk factors, performance status), initial disease symptomatology, initial staging investigations (neuroimaging, cerebrospinal fluid sampling, bone marrow assessments), all treatments given (treatment types, treatment dates, doses administered), treatment responses and subsequent relapses. The treatment response was assessed by serial contrast-enhanced MRI using the MacDonald response criteria (1990).19 Data regarding best treatment response and end-of-treatment response were recorded. The objective response rate was defined as the proportion of patients with complete responses (CR) or partial responses (PR). The clinical benefit rate was defined as the proportion of patients experiencing an objective response or stable disease (SD). Descriptive statistics (mean or median, range, 95% confidence interval [CI]) are provided as appropriate to summarise patient characteristics and outcomes. PFS and OS were assessed using Kaplan–Meier curves. PFS was defined as the time from start of treatment until documented progression after that treatment. OS post treatment was calculated from the start of that treatment until
the date of death. Patients who were lost to follow-up before disease progression or death were censored at the date of last follow-up for progression and death respectively. Data were collected only up to 31 October 2011. Adverse events were reviewed and graded according to the Common Terminology Criteria for Adverse Events version 3. Statistics were performed using the Statistical Package for the Social Sciences version 19 (SPSS, Chicago, IL, USA). 3. Results 3.1. Patient characteristics and treatment at initial diagnoses Between January 2000 and May 2011, 46 patients with a diagnosis of PCNSL were identified from our institutional records. Of these, 39 patients were excluded from this review because they did not have PCNSL, had a pre-existing diagnosis of extracranial NHL, had not received temozolomide or had incomplete patient records (Fig. 1). The remaining seven patients were included in this analysis. Their characteristics at the time of diagnosis are shown in Table 1.
Table 1 Characteristics of patients with primary central nervous system lymphoma at initial diagnosis Patient no.
Age (years)
Gender
Immunosuppression
ECOG
Histology
1
75
F
N
0
2 3 4 5 6 7
72 44 74 41 58 51
F M M M M M
N N N N YA YB
2 2 2 2 2 2
Non-Hodgkin’s large cell lymphoma Large B-cell NHL Large B-cell NHL Large B-cell NHL Large B-cell NHL Large B-cell NHL T-cell NHL
F = female, M = male, N = no, NHL = non-Hodgkin’s lymphoma, Y = yes. A Exposure to hydroxyurea and anagrelide for polycythaemia rubra vera. B Exposure to cyclosporine and mycophenolate for liver transplantation.
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S.F. Wong et al. / Journal of Clinical Neuroscience 19 (2012) 1501–1505 Table 2 Characteristics of patients with primary central nervous system lymphoma at first treatment with temozolomide Patient Age No. lines of Prior chemotherapy no. (years) chemotherapy
Best radiological ECOG No. of cycles Dose of of temozolomide temozolomide response (mg/m2)
PFS (months)
Survival (months)
1
76
1
HD Mtx + rituximab
1
1
150
Lost to follow up after cycle 1
Lost to follow up after cycle 1
2
74
2
2
150
PD after cycle 2
2
3 4
45 75
1 2
5 1
200 200
PR after cycle 2 PD after cycle 1
4.5 1
7 4
5
41
1
HD Mtx, second line HD 3 Mtx + rituximab HD Mtx + rituximab 1 HD Mtx + rituximab, second line 1 HD Mtx + rituximab HD Mtx 1
Lost to follow up after cycle 1 4
1
200
60
2
3
2
200
Died with clinical progression after cycle 1 1.5
0.13
6
Died with clinical progression after cycle 1 SD after cycle 2
7
51
1
2
13
200
SD after cycle 2
14
16
HD Mtx, second line HD Mtx + intrathecal cytarabine/ methotrexate HD Mtx
2
HD Mtx – High dose methotrexate; PD – progressive disease; PR – partial response; SD – stable disease; PFS – progression free survival.
Six of seven patients had diffuse large B-cell NHL whereas the seventh patient had a T-cell NHL. At the time of initial diagnosis, 85% of patients were of intermediate fitness (performance status 2). The median age of patients was 58 years. All patients were staged with an MRI scan, with some also having examinations of their cerebrospinal fluid (CSF) (57%) and bone marrow (71%). Staging showed that five patients had bilateral disease (71%), multiple lesions (71%) or involvement of deep structures (71%). No patient had evidence of raised lactate dehydrogenase or extracranial disease. All were treated up-front with high dose intravenous methotrexate, with 42% also receiving concomitant rituximab. The RR after first line treatment was 70% with five PR and one SD. All patients who received combined methotrexate and rituximab had a PR. The median PFS was 6 months (range: 0–16 months). Three patients were re-treated with methotrexate-based chemotherapy at progression, with two receiving concurrent rituximab whereas the third received concurrent intrathecal cytarabine and methotrexate. No patient had an objective response (two SD and one PD) and the median PFS was 10 months (range: 2–12 months). 3.2. Temozolomide salvage therapy Temozolomide was given as second-line chemotherapy in four patients and third-line in three patients. Their characteristics at the time of temozolomide treatment are shown in Table 2. The median age at the time of treatment with temozolomide was 60 years (range: 41–75 years). Approximately half (57%) had a good performance status (ECOG 1), with the rest having an intermediate to poor performance status (ECOG 2–3). A total of 42% of patients were found to have bilateral CNS relapse and one had nonenhancing tumour progression. A total of 25 cycles of temozolomide were administered in this study (median of two cycles per patient). All patients were treated with temozolomide at a daily dose of 150–200 mg/m2 on day 1 to day 5 every 4 weeks, until progression of disease, unacceptable toxicities or patient refusal. Temozolomide was generally well tolerated. One patient experienced Grade 2 thrombocytopenia and one patient experienced Grade 3 neutropenia. They received a dose reduction of 15% and 28% respectively at the discretion of the physician. One patient developed a non-neutropenic infection after the second cycle of chemotherapy for which he was being treated with intravenous antibiotics. After initially responding to treatment, the patient deteriorated acutely and died. The death was presumed to be unrelated to temozolomide.
Fig. 2. Kaplan–Meier curves showing (A) progression-free survival (PFS) from time of temozolomide treatment in months; and (B) overall survival from time of temozolomide treatment in months for patients with relapsed primary central nervous system lymphoma with single agent temozolomide.
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Response data are available for all patients except one patient who died during cycle one of treatment and a second patient who was lost to follow up after the first cycle of temozolomide. (These patients are regarded as having progressive disease for the purposes of response evaluation.) Overall, one of seven patients had a PR to temozolomide treatment for an objective RR of 14%. A further two patients experienced SD for an overall clinical benefit of 42%. Duration of response was brief with the median PFS being 2 months (95% CI: 0–5.9 months) (Fig. 2). Median survival from the time of commencing temozolomide treatment was only 4 months (95% CI: 0–13 months) (Fig. 2). Four patients (57%) died while being treated with temozolomide, after one cycle (n = 1), two cycles (n = 2) and 13 cycles (n = 1) of temozolomide respectively. Two patients died with confirmed radiological progression, one patient died presumably from PD and one died from likely pulmonary emboli. Two patients (28%) received radiotherapy as salvage after progression with temozolomide treatment, and died at 3 months and 4 months respectively post cessation of temozolomide.
4. Discussion This study is a retrospective review of the small subset of patients at our institution, a major Australian neuro-oncology unit, who received salvage temozolomide for relapsed PCNSL. The review aimed to compare outcomes for salvage treatment with temozolomide in the community setting, compared to the published literature from phase II trials. All patients initially received a high dose methotrexate-based treatment in the first line setting (RR of 70% and median PFS of 6 months) and 42% were re-challenged with high dose methotrexate at the time of first relapse (RR 0% but 67% of patients had SD). The results of our patients re-challenged with methotrexate appear inferior to the published results with salvage methotrexate.12 The published retrospective review included a study population who achieved CR after initial methotrexate-based treatment or received methotrexate after gross total resection or interstitial radiation. In contrast, our study included patients with no CR and only one PR after first-line methotrexate. Additionally, no patients received whole brain radiotherapy before proceeding to methotrexate-based treatment. Differences in patient selection may account for the variation in results. Patients who achieve CR after first line chemotherapy are chemosensitive, and more likely to respond to salvage chemotherapy than those who achieved PR or are non-responders. As expected, temozolomide treatment was generally well tolerated. Toxicities were mainly asymptomatic haematological abnormalities. However, although toxicity was mild as expected, objective RR was lower than published data. Only one patient had PR with an objective RR of 14% and 28% of patients had SD. Progressive disease while on treatment was seen in 85% of patients. Survival was also disappointing (PFS of 2 months and median OS of 4 months), although similar to the published phase II data. Patients in the phase II study were similar to our study population with the same median age of 60 years, and a similar proportion having intermediate to poor fitness (56% compared to 42% respectively). However, about 80% of patients in the published study had only received one line of treatment before receiving salvage temozolomide. This is in comparison to our series where 43% of patients had received more than one line of treatment prior to salvage temozolomide. Overall, these data suggest that the use of temozolomide for PCNSL needs to be carefully considered on a case-by-case basis, but in our opinion, its use is best confined to clinical trials at this time. Potential applications of temozolomide in future trials include combination therapy with proven agents for PCNSL or potentially as a radiosensitising agent. For example, one retrospective series found that temozolomide in combination
with rituximab appeared to be efficacious, with an objective RR of 53%, median OS of 14 months and median PFS of 7.7 months.20 The question of what salvage therapy to administer to patients with PCNSL at relapse remains difficult. In our institution, re-treatment with methotrexate or use of WBRT is most commonly used. It is important to stress that WBRT is a highly efficacious treatment for patients where further chemotherapy is not thought likely to be of benefit. Whilst it is true that there is a significantly increased risk of neurotoxicity, these are usually delayed and must be weighed up against the aggressive nature of relapsed PCNSL. The choice between chemotherapy or radiotherapy for patients with relapsed PCNSL depends on several factors including age and medical comorbidities of patients, achievement of CR to first line chemotherapy, time to progression after chemotherapy and tolerance to previous chemotherapy treatments. In conclusion, our data are broadly similar to the published data from clinical trials with temozolomide for patients with relapsed PCNSL, although outcomes remain poor in these patients generally. The low toxicity of temozolomide makes it a reasonable candidate for further studies, particularly in combination with other active agents for PCNSL.
Conflicts of interest/disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
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