Reduced cycles of high-dose methotrexate prior to whole brain irradiation for PCNSL

On 17 February 2019, Hiroyuki Kobayashi from Hokkaido University School of Medicine, Sapporo, JP and colleagues, published in the Journal of Chemotherapy the results of a retrospective study investigating the long-term efficacy of a reduced number of high-dose methotrexate (HD-MTX) in combination with whole brain radiotherapy (WBRT) for primary central nervous system lymphoma (PCNSL).

Singe agent HD-MTX together with WBRT are one of the most common regimens used for the treatment of PCNSL. The aim of this study was to assess whether a moderate HD-MTX dose and a reduced number of cycles (up to three) prior to WBRT lead to a survival benefit in PCNSL patients. The main endpoints of the study were overall survival (OS), response rates, and progression-free survival (PFS).

Study design & baseline characteristics

• N = 54 PCNSL patients
• Median patient age (range): 60.5 (31–78) years
• Median Karnofsky performance status (range): 80 (50–100)
• Males: 50% of patients
• Dosing:
  • HD-MTX:5 g/m² intravenously for three hours every 14 days (on Days 1, 15, and 29)
    • Leucovorin rescue treatment: 15 mg intravenously for four hours was initiated 24 hours after MTX infusion until serum MTX levels were < 0.05 µM
  • WBRT: 30 Gy/15 fractions administered five times per week, 14–20 days following HD-MTX completion
    • Additional 10–20 Gy localized boost was given to patients that had lesion remnants under MRI
  • Treatment response assessment was performed by magnetic resonance imaging (MRI) through comparing baseline MRI (one week prior treatment) with MRIs 1–3 days before each treatment cycle
  • During the follow-up, patients were evaluated by MRI every 2–3 months for the first three years and every six months thereafter

Key results

• ORR: 80%
• Response rates prior to WBRT (n = 54):
  • Complete response (CR): 35% (n = 19)
  • Partial response (PR): 44% (n = 24)
  • Stable disease (SD): n = 4 patients
  • Disease progression (PD): n = 7 patients
• Response rates after WBRT (n = 54):
  • CR: n = 49 patients
  • PR: n = 4 patients
  • PD: n = 1
• Median follow-up for censored cases: 79.4 months
• Median OS: 58.4 months
• Two-year OS: 74% (95% CI, 60–84)
• Five-year OS: 50% (95% CI, 36–62)
• Median PFS: 42.5 months
• Two-year PFS: 66% (95% CI, 52–77)
• Five-year PFS: 40% (95% CI, 27–53)
• Survival analysis based on responders (CR + PR) versus non-responders (SD + PD), revealed:
  • Median OS: not reached versus8 months (P < 0.001)
• At the end of observation:
  • 54% of patients had died (n = 29)
    • No deaths were related to toxicity
  • 70% of patients experienced progression or relapse (n = 38)
• Patients receiving second line chemotherapy: n = 22
  • Three patients received myeloablative chemotherapy followed by autologous stem cell transplantation
  • Patients with CNS recurrence were treated with AraC- or platinum-based chemotherapy

Safety

• Patients receiving various HD-MTX treatment cycles:
  • Three cycles: n = 45
  • Two cycles: n = 5
  • One cycle: n = 4
• HD-MTX dose reduction was necessary in n = 2 patients (Grade 3 renal impairment)
• The most common Grade 4 hematological adverse events (AEs) observed were:
  • Neutropenia: n = 2
  • Thrombocytopenia: n = 2
• No Grade 4 non-hematological toxicities occurred
• The most common Grade ≤ 3 non-hematological AEs was:
  • Interstitial pneumonia: n = 2 (Grade 3)
• No deaths related to treatment toxicity were observed
• Twenty-two patients received WBRT alone. Localized 10 Gy boost was administered in 32 cases

Conclusions

• A maximum of three HD-MTX treatment cycles can be efficacious in combination with WBRT for PCNSL patients
• Such treatment (minimized cycles) will decrease the risk of toxicity in PCNSL patients and should be considered after further validation of these retrospective results