Current Status and Future of Relapsed Primary Central Nervous System Lymphoma (PCNSL)

Abstract

The treatment of primary central nervous system lymphoma (PCNSL) has centered around high-dose methotrexate and radiotherapy (RT). Methotrexate administered intra-arterially (IA) with blood-brain barrier disruption (BBBD) and without RT, has been a highly effective treatment with a 5 year survival of 42% without cognitive loss. The purpose of this analysis is to determine responses for patients with relapsed PCNSL treated with second line IA carboplatin-based chemotherapy with BBBD. Between February 1991 and April 2000, 37 relapsed PCNSL patients, most who failed front line therapy with methotrexate based chemotherapy, were treated at Oregon Health & Science University (OHSU) and Hadassah Hebrew University Hospital (HHUH) with IA carboplatin-based chemotherapy with BBBD. Nine patients had prior RT. The mean age was 57.5 years, and all but 1 patient were treated within 8 months after relapse. The median time for survival from first IA carboplatin/BBBD treatment was 6.8 months;however, 7 out of 37 patients survived > or = 27 months. Nine patients had radiographic complete response (CR), 4 patients had radiographic partial response (PR), 12 had stable disease (SD), 10 had progressive disease (PD), and 2 were non-evaluable. The median time to failure for patients with CR and PR was 9.1 months. One long-term survivor is alive at 91.0 months from first carboplatin/BBBD treatment. In conclusion, we show that relapsed PCNSL has shown sensitivity to second line IA carboplatin-based chemotherapy with BBBD. We have developed a new protocol using i.v. rituximab prior to BBBD with IA carboplatin, i.v. cyclophosphamide and i.v. etoposide phosphate. The long-term program goal is to consolidate dose-intensive chemotherapy with monoclonal antibody directed radiation. Because patients with recurrent PCNSL commonly continue to relapse even after obtaining a complete response to enhanced chemotherapy treatment, patients w ho complete or fail the above carboplatin/BBBD treatment regimen will be offered consolidation with radioimmunotherapy using zevalin (Ibritumomab tiuxetan), IDEC-2B8 conjugated with yttrium-90 (90Y).

Temozolomide as salvage treatment in primary brain lymphomas

“…These results suggest that temozolomide is an active agent against PCNSL. Recent reports of outcomes for recurrent PCNSL using combined chemotherapy (Arellano-Rodrigo et al, 2003;Tyson et al, 2003), single agent topotecan (Fischer et al, 2006) or combined chemo-immunotherapy (Enting et al, 2004) have observed responses similar to those we observed with temozolomide. In these studies, reported response rates were 33 -53% and 1-year survivals were 25 -58% (Arellano-Rodrigo et al, 2003;Tyson et al, 2003;Enting et al, 2004;Fischer et al, 2006) with better results observed in the smallest retrospective series, which included almost exclusively (93%) recurrent patients (Enting et al, 2004).…”

“…Recent reports of outcomes for recurrent PCNSL using combined chemotherapy (Arellano-Rodrigo et al, 2003;Tyson et al, 2003), single agent topotecan (Fischer et al, 2006) or combined chemo-immunotherapy (Enting et al, 2004) have observed responses similar to those we observed with temozolomide. In these studies, reported response rates were 33 -53% and 1-year survivals were 25 -58% (Arellano-Rodrigo et al, 2003;Tyson et al, 2003;Enting et al, 2004;Fischer et al, 2006) with better results observed in the smallest retrospective series, which included almost exclusively (93%) recurrent patients (Enting et al, 2004). The conclusions one can draw from these series are limited because in most cases less than 20 patients were reported (Arellano-Rodrigo et al, 2003;Enting et al, 2004), most series were retrospective (Tyson et al, 2003;Enting et al, 2004), used heterogeneous salvage treatment (Tyson et al, 2003), heterogeneous drug dose and schedule (Enting et al, 2004) or included patients with systemic recurrence (Fischer et al, 2006).…”

“…In these studies, reported response rates were 33 -53% and 1-year survivals were 25 -58% (Arellano-Rodrigo et al, 2003;Tyson et al, 2003;Enting et al, 2004;Fischer et al, 2006) with better results observed in the smallest retrospective series, which included almost exclusively (93%) recurrent patients (Enting et al, 2004). The conclusions one can draw from these series are limited because in most cases less than 20 patients were reported (Arellano-Rodrigo et al, 2003;Enting et al, 2004), most series were retrospective (Tyson et al, 2003;Enting et al, 2004), used heterogeneous salvage treatment (Tyson et al, 2003), heterogeneous drug dose and schedule (Enting et al, 2004) or included patients with systemic recurrence (Fischer et al, 2006). Furthermore, the series that presented response and survival data superior to those reported here included more patients with favourable prognostic factors (younger age, better PS) or had many patients who had been treated with chemotherapy alone.…”

Phase II Trial of Temsirolimus for Relapsed/Refractory Primary CNS Lymphoma

“…Response rate in the present trial is in the upper range of responses in other studies on refractory/relapsed PCNSL, [6][7][8][9][10][11][12][13][14][15] which is remarkable considering the accumulation of negative prognostic factors such as relatively old age, poor Memorial Sloan Kettering Cancer Center score, heavy pretreatment (including HD-ASCTand WBRT), and short interval since last pretreatment. Comparison of studies on refractory/relapsed PCNSL is, however, difficult due to use of different response criteria, wide spectrum of patients' ages, heterogeneous pretreatment, and a frequent lack of detailed information on the potentially confounding use of steroids.…”

Primary CNS Lymphoma in Immunocompetent Patients

“…As discussed above, the most promising results have been reported with ICT-ASCT. Conventional second-line chemotherapy, such as temozolomide (TMZ) [104], topotecan [112], intra-arterial carboplatin [113], and high-dose cytarabine combined with etoposide and ifosfamide [102], has been also shown to be potentially active in relapsed PCNSL. These latter treatments achieved objective response rates of 26%-37%, 1-year PFS rates of 13%-22%, and 1-year OS rates of 25%-41%.…”