BRAIN CANCER TREATMENT REGIMENS (Part 1 of 5)

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1 BRAIN CANCER TREATMENT REGIMENS (Part 1 of 5) The selection, dosing, and administration of anticancer agents and the management of associated toxicities are complex. Drug dose modifications and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and because of individual patient variability, prior treatment, and comorbidities. Thus, the optimal delivery of anticancer agents requires a healthcare delivery team experienced in the use of such agents and the management of associated toxicities in patients with cancer. The cancer treatment regimens below may include both FDA-approved and unapproved uses/regimens and are provided as references only to the latest treatment strategies. Clinicians must choose and verify treatment options based on the individual patient. NOTE: GREY SHADED BOXES CONTAIN UPDATED REGIMENS. REGIMEN Adult Low-Grade Infiltrative Supratentorial Astrocytoma/Oligodendroglioma (Excluding Pilocytic Astrocytoma) Temozolomide (Temodar; TMZ) 1 3 Temozolomide 75mg/m 2 orally daily from the first day of radiotherapy until the last day of radiotherapy, but for no longer than 49 days followed by a 4 week break, then followed by Days 1 5: Temozolomide 150mg/m 2 orally for the first cycle then, barring any hematologic toxicities, temozolomide 200mg/m 2 orally beginning with the second cycle. Repeat cycle every 4 weeks for up to 6 cycles. Days 1 49: Temozolomide 75mg/m 2 orally. Repeat cycle every 11 weeks. Recurrent or Progressive Low-Grade Disease Temozolomide 1,3 Days 1 49: Temozolomide 75mg/m 2 orally daily. Repeat cycle every 11 weeks. Cisplatin (Platinol) + etoposide Days 1 3: Cisplatin 25mg/m 2 /day IV + etoposide 100mg/m 2 /day IV. (Toposar, VePesid, Etopophos; Repeat cycle every 4 weeks for first 3 cycles, VP-16) 1,4 then repeat every 5 weeks for next 3 cycles, then repeat every 6 weeks for the last 3 cycles; total 10 cycles over approximately months (total dose 750mg/m 2 cisplatin and 3,000mg/m 2 etoposide). Carboplatin (Paraplatin) 1,5 Carboplatin 560mg/m 2 IV at 4-week intervals; until disease progression, unacceptable toxicity, or for 12 additional courses after achieving maximal response. PCV (Procarbazine [Matulane] + lomustine [CeeNU; CCNU] + vincristine [Oncovin; Vincasar PFS]) 1,6 Anaplastic Gliomas Temozolomide 1,7 PCV with deferred RT 1,8 Days 1 5: Temozolomide 200mg/m 2 /day orally. Repeat cycle every 4 weeks until disease progression or for up to 24 cycles. Recurrent/Salvage Treatment Temozolomide 1,9 Temozolomide 50mg/m 2 daily for up to 1 year or until disease progression. Bevacizumab (Avastin) + irinotecan (Camptosar; CPT-11) 1,10 Cyclophosphamide (Cytoxan) 1,11 PCV 1,6 Etoposide 1,12 Day 1: Bevacizumab 10mg/kg IV in combination with irinotecan 125mg/m 2, 340mg/m 2 IV in patients receiving enzyme inducing antiepileptics. Repeat once every 2 weeks. Days 1 2: Cyclophosphamide 750mg/m 2 IV. Days 8 & 29: Vincristine 1.4mg/m 2 (maximum 2mg) IV. Etoposide 50mg daily.

2 Glioblastoma Adjuvant treatment Temozolomide 1,2 BRAIN CANCER TREATMENT REGIMENS (Part 2 of 5) Concurrent with radiotherapy Temozolomide 75mg/m 2 /day orally. Post-radiotherapy Days 1 5: Temozolomide mg/m 2 orally. Recurrent/Salvage Treatment Bevacizumab + irinotecan 1,13 Initial therapy Day 1: Bevacizumab 10mg/kg IV. Repeat every 2 weeks until disease progression. After tumor progression Day 1: Bevacizumab 10mg/kg IV + irinotecan 125mg/m 2, 340mg/m 2 IV in patients receiving enzyme inducing antiepileptics. Repeat once every 2 weeks. Cyclophosphamide 1,11 Days 1 2: Cyclophosphamide 750mg/m 2 IV. Nitrosourea wafer (Gliadel Place up to 8 wafers in resection cavity. [polifeprosan 20 with carmustine implant]) 1,14,15 PCV 1,6 Bevacizumab 1,16 Meningioma Alpha-interferon (α-ifn) 1,17 Primary CNS Lymphoma Primary Treatment High-dose methotrexate (MTX) 8g/m 2 combination therapy + deferred RT 1,18 Rituximab [Rituxan] 1,19 Rituximab + temozolomide 1,20 Day 1: Bevacizumab 10mg/kg. Repeat every 2 weeks. α-ifn 10 million Units/m 2 SC every other day for 4 weeks. Induction therapy MTX 8g/m 2 IV administered every 2 weeks until complete response achieved or max of 8 cycles reached. Consolidation MTX 8g/m 2 IV administered every 2 weeks for 2 cycles. MTX 8g/m 2 IV administered every 4 weeks for 11 cycles. Rituximab Day 1: Rituximab 375mg/m 2 IV. Rituximab + temozolomide Induction therapy Day 1: Rituximab 375mg/m 2 IV, followed by Days 1 5: Temozolomide mg/m 2 orally daily, after rituximab infusion. Days 1 5: Temozolomide mg/m 2 orally daily. Repeat cycle every 4 weeks for 8 cycles.

3 BRAIN CANCER TREATMENT REGIMENS (Part 3 of 5) Primary CNS Lymphoma () Primary Treatment High-dose methotrexate (MTX) High-dose methotrexate (MTX) 3.5g/m 2 combination therapy + RT. 3.5g/m 2 combination therapy + RT Cytarabine (Cytosar-U; ARA-C) 1,21 R-MPV (Rituximab + MTX + leucovorin + procarbazine + vincristine 1,22,23 MPV (MTX + leucovorin + procarbazine + vincristine) 1,21,24 Ifosfamide 1,25 Cytarabine Day 1: MTX 3.5g/m 2 IV, followed by Days 2 and 3: Cytarabine 2g/m 2 IV twice daily. Repeat cycle every 3 weeks for 4 cycles and follow with whole-brain irradiation. R-MPV Day 1: Rituximab (Rituxan) 500mg/m 2 IV. Day 2: MTX 3.5g/m 2 IV, followed by leucovorin 20 25mg every 6 hrs starting 24 hrs after MTX infusion for 72 hrs or until serum MTX level <1 x 10 8 mg/dl. Increase leucovorin to 40mg every 4 hrs if MTX level >1 x 10 5 mg/dl at 48 hours, or >1 x 10 8 mg/dl at 72 hrs. Day 2: Vincristine 1.4mg/m 2 (max 2.8mg) IV. Days 1 7: Procarbazine 100mg/m 2 orally once daily of odd-numbered cycles only. Use along with growth factor supplementation for 3 5 days starting 24 hrs after the last dose of procarbazine during odd-numbered cycles, and starting 96 hrs after MTX infusion or when MTX levels <1 x 10-8 mg/dl during even-numbered cycles. If positive CSF cytology: MTX 12mg intra-ommaya between days 5 and 12 of each cycle. Repeat cycle every 2 weeks for 5 cycles. If CR, begin whole-brain radiotherapy (WBRT) 3 5 weeks after R-MPV. If PR, 2 more additional cycles of R-MPV. If CR after 7 cycles of R-MPV, WBRT beginning 3 5 weeks after the completion of R-MPV. If persistent disease after 7 cycles of R-MPV, WBRT beginning 3 5 weeks after the completion of R-MPV. If stable disease or progressive disease after 5 cycles of R-MPV, WBRT beginning 3 5 weeks after the completion of R-MPV. 3 weeks after completion of WBRT, consolidation cytarabine 3g/m 2 /day (max 6g) IV for 2 days. Use along with growth factor supplementation for 10 days starting 48 hrs after completion of cytarabine. A second cycle of cytarabine given 1 month later. MPV Day 1: MTX 3.5g/m 2 IV. Day 2: Leucovorin 10mg every 6 hrs for 12 doses starting 24 hrs after MTX infusion. Day 1: Vincristine 1.4mg/m 2 (max 2.8mg) IV. Days 1 7: Procarbazine 100mg/m 2 orally once daily cycles 1, 3, and 5 only. Repeat every 2 weeks for 5 cycles. MTX 12mg intra-ommaya on alternate weeks after systemic MTX. Leucovorin 10mg every 6 hrs for 8 doses starting 24 hrs after intra-ommaya MTX. 3 5 weeks after MPV, WBRT for patients <60 years. 3 weeks after WBRT, consolidation cytarabine 3g/m 2 /day IV for 2 days. A second cycle of cytarabine given 1 month later. Ifosfamide Day 1: MTX 4gm/m 2 IV, followed by leucovorin 20 25mg IV every 6 hrs starting 24 hrs after MTX for 72 hrs or until serum MTX level <1 x 10 8 mg/dl. Increase leucovorin to 40mg every 4 hrs if MTX level >1 x 10 5 mg/dl at 48 hours or >1 x 10 8 mg/dl at 72 hrs. Days 3 5: Ifosfamide 1.5gm/m 2 IV + mesna 400mg IV before ifosfamide, then 4 hrs and 8 hrs after.

4 BRAIN CANCER TREATMENT REGIMENS (Part 4 of 5) Recurrence or Progressive Disease Consider high-dose chemotherapy with autologous stem cell reinfusion in patients who achieve a complete response with conventional doses of salvage chemotherapy or have no residual disease after re-resection. High-dose MTX Retreat (see regimen on previous page). Temozolomide or topotecan (Hycamtin) 1,26 Topotecan Days 1 5: Topotecan 1.5mg/m 2. Repeat every 3 weeks. Rituximab + temozolomide 1,27 Induction therapy Day 1: Rituximab 375mg/m 2 IV, plus Days 1 5: Temozolomide mg/m 2 orally daily, administered after rituximab infusion. Days 1 5: Temozolomide mg/m 2 orally daily, administered after rituximab infusion. Repeat cycle every 4 weeks for 8 cycles. Adult Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumor (PNET) Vincristine + cisplatin + lomustine 1,28 Vincristine + cisplatin + cyclophosphamide 1,28 Recurrence/Salvage Treatment (No Prior Chemotherapy) High-dose cyclophosphamide ± etoposide 1 Carboplatin + etoposide + cyclophosphamide 1 Cisplatin + etoposide + cyclophosphamide 1 During craniospinal radiotherapy (RT) Day 1: Lomustine 75mg/m 2 orally. Day 2: Cisplatin 75mg/m 2 IV. Days 2, 8 and 15: Vincristine 1.5mg/m 2 IV bolus, max 2mg bolus; up to max 8 doses. *Data supporting the use of VCR have been found in pediatric trials only. Omission of VCR during RT or dose modification may be required for adults because they do not tolerate this regimen as well as children. Day 1: Cisplatin 75mg/m 2 IV. Days 2, 8 and 15: Vincristine 1.5mg/m 2 IV bolus, max 2mg bolus. Days 22, 23: Cyclophosphamide 1,000mg/m 2 IV. *Data supporting the use of VCR have been found in pediatric trials only. Omission of VCR during RT or dose modification may be required for adults because they do not tolerate this regimen as well as children. Consider high-dose chemotherapy with autologous stem cell reinfusion in patients who achieve a complete response with conventional doses of salvage chemotherapy or have no residual disease after re-resection. Recurrence/Salvage Treatment (Prior Chemotherapy) Consider high-dose chemotherapy with autologous stem cell reinfusion in patients who achieve a complete response with conventional doses of salvage chemotherapy or have no residual disease after re-resection. High-dose cyclophosphamide ± etoposide 1 Etoposide 1,29,30 Temozolomide 1,31 Days 1 21: Etoposide 50mg daily. Repeat every 4 weeks. Days 1 5: Temozolomide 180mg/m 2 /day (patients with prior craniospinal irradiation [CSI]) 200mg/m 2 /day (patients with no prior CSI). Repeat every cycle every 4 weeks for up to 11 cycles.

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