Central Nervous System Cancers

Central Nervous System Cancers

Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced health care team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are provided only to supplement the latest treatment strategies.


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These Guidelines are a work in progress that may be refined as often as new significant data become available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Note: All recommendations are category 2A unless otherwise indicated.

▶Adult Glioma: WHO Grade 11

REGIMEN

DOSING

Adjuvant Treatment

Useful in Certain Circumstances (No Preferred or Other Recommended Regimens)

Dabrafenib/Trametinib

(for PA, PXA, ganglioglioma if BRAF V600E mutation positive)2-5,a

Days 1-28: Dabrafenib 150mg orally twice daily.

Days 1-28: Trametinib 2mg orally once daily.

Repeat cycle every 4 weeks.

Everolimus (for SEGA)6-9,a

Days 1-28: Everolimus 4.5mg/m2 orally once daily (titrated to achieve blood trough concentration 5-15ng/mL).

Repeat cycle every 4 weeks.

Vemurafenib/Cobimetinib

(for PA, PXA, ganglioglioma if BRAFV600E mutation positive)10-14,a

Days 1-21: Cobimetinib 60mg orally once daily

Days 1-28: Vemurafenib 960mg orally twice daily.

Repeat cycle every 4 weeks.

Recurrent or Progressive Diseased

Other Recommended Regimens (No Preferred Regimens)

Carmustine15-18,b

Days 1-3: Carmustine 80mg/m2 IV over 2 hours daily.

Repeat cycle every 8 weeks or until reaching a lifetime cumulative carmustine dose for a maximum of 6 cycles.

OR

Day 1: Carmustine 150-200mg/m2 IV over 2 hours daily.

Repeat cycle every 8 weeks or until reaching a lifetime cumulative carmustine dose.

Lomustine19-21,b

Day 1: Lomustine 100-130mg/m2 orally once daily.

Repeat cycle every 6 weeks or until reaching a lifetime cumulative lomustine dose.

PCV

(Procarbazine/Lomustine/Vincristine) 19,22-27,a-c

Day 1: Lomustine 110-130mg/m2 orally once daily

Days 8-21: Procarbazine 60-75mg/m2 orally once daily

Days 8,29: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle every 6-8 weeks until disease progression or reaching a lifetime cumulative dose of Lomustine.

RT + adjuvant PCV

(Procarbazine/Lomustine/Vincristine) 19,22,23,28-32,a-c

Day 1: Lomustine 110mg/m2 orally once daily

Days 8-21: Procarbazine 60mg/m2 orally once daily

Days 8,29: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle every 6-8 weeks until disease progression or reaching a lifetime dose of Lomustine.

RT + adjuvant TMZ33-36,a

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) orally once daily.

Repeat cycle every 4 weeks for 6-12 cycles.

RT + concurrent and adjuvant TMZ33,34,36,37,a

Days 1-42: Temozolomide 75mg/m2 orally once daily.

Repeat cycle every 6 weeks with RT, followed by:

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) once orally daily.

Repeat cycle every 4 weeks for 6-12 cycles starting 4 weeks after the completion of concurrent Temozolomide and RT.

TMZ33,38-43,a,e

Days 1-5: Temozolomide 150-200mg/m2 orally once daily.

Repeat cycle every 4 weeks for 12 cycles.

OR

Days 1-28: Temozolomide 50mg/m2 orally.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

Useful in Certain Circumstances

Carboplatin

(for pilocytic astrocytoma)44-46

Day 1: Carboplatin AUC 4-6 IV over 30 minutes.

Repeat cycle every 4 weeks.

OR

Day 1: Carboplatin 560mg/m2 IV over 1 hour.

Repeat cycle every 4 weeks.

Carboplatin/Vincristine

(for pilocytic astrocytoma) (Category 2B)1

See NCCN Central Nervous System Guidelines1

Cisplatin/Etoposide

(for pilocytic astrocytoma)47-49,f

Days 1-3: Cisplatin 25mg/m2 IV over 1 hour daily.

Days 1-3: Etoposide 100mg/m2 IV over 1 hour daily.

Repeat cycle every 4 weeks for a maximum of 10 cycles.

Dabrafenib/Trametinib

(if BRAF V600E mutation positive)6-9

Days 1-28: Dabrafenib 150mg orally twice daily.

Days 1-28: Trametinib 2 mg orally once daily.

Repeat cycle every 4 weeks.

Entrectinib

(if NTRK gene fusion positive)50-52

Days 1-28: Entrectinib 600mg orally once daily.
Repeat cycle every 4 weeks.

Larotrectinib

(for NTRK gene fusion tumors)53-56

Days 1-28: Larotrectinib 100 mg orally twice daily.

Repeat cycle every 4 weeks.

Selumetinib

(for PA with BRAF fusion or BRAF V600E activation mutation)57,58

Days 1-28: Selumetinib 25mg/m2 orally twice daily.

Repeat cycle every 4 weeks.

Thioguanine + PCV

(for pilocytic astrocytoma) (Category 2B)1,a,c

See NCCN Central Nervous System Guidelines1

Vemurafenib/Cobimetinib

(if BRAF V600E mutation positive)10-14

Days 1-21: Cobimetinib 60mg orally daily

Days 1-28: Vemurafenib 960mg orally twice daily.

Repeat cycle every 4 weeks.

▶Adult Gliomas: Oligodendroglioma (IDH-Mutant, 1p19q Codeleted)1

Adjuvant Treatment WHO Grade 2 (KPS ≥60)a

Preferred Regimens

RT with adjuvant PCV
(Procarbazine/Lomustine/Vincristine) (Category 1)19,22,23,28-32,a,c

Day 1: Lomustine 110mg/m2 orally once daily

Days 8-21: Procarbazine 60mg/m2 orally once daily

Days 8,29: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle every 6-8 weeks for 6 cycles.

RT + adjuvant TMZ33-36,a

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) orally once daily.

Repeat cycle every 4 weeks for 6-12 cycles.

RT + concurrent and adjuvant TMZ33,34,36,37,a

Days 1-42: Temozolomide 75mg/m2 orally once daily.

Repeat cycle every 6 weeks with RT, followed by:

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) once orally daily.

Repeat cycle every 4 weeks for 6-12 cycles starting 4 weeks after the completion of concurrent Temozolomide and RT.

Other Recommended Regimens

PCV19,22-27,a,c

Day 1: Lomustine 110-130mg/m2 orally

Days 8-21: Procarbazine 60-75mg/m2 orally daily

Days 8,29: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle every 6-8 weeks for 6 cycles.

TMZ33,59-61,a

Days 1-21: Temozolomide 75mg/m2 orally daily

Repeat cycle every 4 weeks for a maximum of 12 cycles.

Adjuvant Treatment WHO Grade 3 (KPS ≥60)a

Preferred Regimens

RT + adjuvant PCV
(Category 1)19,22,23,28-32,a,c,g

Day 1: Lomustine 110mg/m2 orally once daily

Days 8-21: Procarbazine 60mg/m2 orally once daily

Days 8,29: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle every 6-8 weeks for 6 cycles.

RT + neoadjuvant PCV
(Category 1) 19,22,23,28-32,a,c,g

Day 1: Lomustine 110mg/m2 orally once daily

Days 8-21: Procarbazine 60mg/m2 orally once daily

Days 8,29: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle every 6-8 weeks for 6 cycles.

Other Recommended Regimens

RT + adjuvant TMZ33-36,a

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) orally once daily.

Repeat cycle every 4 weeks for 6-12 cycles.

RT + concurrent and adjuvant TMZ33,34,36,37,a

Days 1-42: Temozolomide 75mg/m2 orally once daily.

Repeat cycle every 6 weeks with RT, followed by:

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) once orally daily.

Repeat cycle every 4 weeks for 6-12 cycles starting 4 weeks after the completion of concurrent Temozolomide and RT.

Adjuvant Treatment, KPS <60a

Other Recommended Regimens (No Preferred Regimens)

RT + concurrent and adjuvant TMZ33,34,36,37,a

Days 1-42: Temozolomide 75mg/m2 orally once daily.

Repeat cycle every 6 weeks with RT, followed by:

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) once orally daily.

Repeat cycle every 4 weeks for 6-12 cycles starting 4 weeks after the completion of concurrent Temozolomide and RT.

TMZ (Category 2B)33,59-61,a,h

Days 1-21: Temozolomide 75mg/m2 orally daily

Repeat cycle every 4 weeks for a maximum of 12 cycles.

Recurrent or Progressive Disease WHO Grade 2, KPS ≥60d

Other Recommended Regimens (No Preferred Regimens)

Carmustine15-18,b

Days 1-3: Carmustine 80mg/m2 IV over 2 hours daily.

Repeat cycle every 8 weeks or until reaching a lifetime cumulative carmustine dose for a maximum of 6 cycles.

OR

Day 1: Carmustine 150-200mg/m2 IV over 2 hours daily.

Repeat cycle every 8 weeks or until reaching a lifetime cumulative carmustine dose.

Lomustine19-21,b

Day 1: Lomustine 100-130mg/m2 orally once daily.

Repeat cycle every 6 weeks or until reaching a lifetime cumulative lomustine dose.

PCV19,22-27,a,c

Day 1: Lomustine 110-130mg/m2 orally

Days 8-21: Procarbazine 60-75mg/m2 orally daily

Days 8,29: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle every 6-8 weeks until disease progression or reaching a lifetime cumulative lomustine dose.

RT + adjuvant PCV19,22,23,28-32,a,c

Day 1: Lomustine 110mg/m2 orally once daily

Days 8-21: Procarbazine 60mg/m2 orally once daily

Days 8,29: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle every 6-8 weeks until disease progression or reaching a lifetime dose of Lomustine.

RT + adjuvant TMZ33-36,a

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) orally once daily.

Repeat cycle every 4 weeks for 6-12 cycles.

RT + concurrent and adjuvant TMZ33,34,36,37,a

Days 1-42: Temozolomide 75mg/m2 orally once daily.

Repeat cycle every 6 weeks with RT, followed by:

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) once orally daily.

Repeat cycle every 4 weeks for 6-12 cycles starting 4 weeks after the completion of concurrent Temozolomide and RT.

TMZ33,38-43,a,e

Days 1-5: Temozolomide 150-200mg/m2 orally once daily.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

OR

Days 1-28: Temozolomide 50mg/m2 orally.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

Useful in Certain Circumstances

Dabrafenib/Trametinib

(for PA, PXA, ganglioglioma
if BRAF V600E mutation positive)2-5,a

Days 1-28: Dabrafenib 150mg orally twice daily

Days 1-28: Trametinib 2mg orally once daily.

Repeat cycle every 4 weeks.

Entrectinib

(if NTRK gene fusion positive)50-52

Days 1-28: Entrectinib 600mg orally once daily.
Repeat cycle every 4 weeks.

Larotrectinib

(for NTRK gene fusion tumors)53-56

Days 1-28: Larotrectinib 100 mg orally twice daily.

Repeat cycle every 4 weeks.

Vemurafenib/Cobimetinib

(for PA, PXA, ganglioglioma
if BRAF V600E mutation positive)10-14,a

Days 1-21: Cobimetinib 60mg orally once daily

Days 1-28: Vemurafenib 960mg orally twice daily.

Repeat cycle every 4 weeks.

Recurrent Disease WHO Grade 3, KPS ≥60a,i

Preferred Regimens

Bevacizumab62-68,j,k

Day 1: Bevacizumab 10mg/kg IV.

Repeat cycle every 2 weeks.

OR

Day 1: Bevacizumab 5-15mg/kg IV.

Repeat cycle every 3 weeks.

Carmustine15-18,b

Days 1-3: Carmustine 80mg/m2 IV over 2 hours daily.

Repeat cycle every 8 weeks or until reaching a lifetime cumulative carmustine dose for a maximum of 6 cycles.

OR

Day 1: Carmustine 150-200mg/m2 IV over 2 hours daily.

Repeat cycle every 8 weeks or until reaching a lifetime cumulative carmustine dose.

Lomustine19-21,b

Day 1: Lomustine 100-130mg/m2 orally once daily.

Repeat cycle every 6 weeks or until reaching a lifetime cumulative lomustine dose.

PCV19,22,27,a,c

Day 1: Lomustine 110-130mg/m2 orally

Days 8-21: Procarbazine 60-75mg/m2 orally daily

Days 8,29: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle every 6-8 weeks until disease progression or reaching a lifetime cumulative dose of Lomustine.

TMZ33,38-43,a

Days 1-5: Temozolomide 150-200mg/m2 orally once daily.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

OR

Days 1-28: Temozolomide 50mg/m2 orally.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

Other Recommended Regimens

Carmustine + Bevacizumab15,17,62,63,69,b,j-l

Days 1-3: Carmustine 80mg/m2 IV over 2 hours daily

Days 1,15,29,43: Bevacizumab 5-10mg/kg IV.

Repeat cycle every 6-8 weeks or until reaching a lifetime cumulative Carmustine dose.

OR

Days 1: Carmustine 150-200mg/m2 IV over 2 hours daily

Days 1,15,29,43: Bevacizumab 5-10mg/kg IV.

Repeat cycle every 6-8 weeks or until reaching a lifetime cumulative Carmustine dose.

Lomustine + Bevacizumab19,20,62,70,b,j-l

Day 1: Lomustine 90-110mg/m2 orally

Days 1,15,29: Bevacizumab 5-10mg/kg IV.

Repeat cycle every 6 weeks or until reaching a lifetime cumulative Lomustine dose.

TMZ + Bevacizumab33,62,71,72,a,j-l

Days 1,15: Bevacizumab 5-10mg/kg IV

Days 1-28: Temozolomide 50mg/m2 orally daily.

Repeat cycle every 4 weeks.

Useful in Certain Circumstances

Carboplatin

(if failure or intolerance to the preferred or other recommended regimens) (Category 3)44-46

Day 1: Carboplatin AUC 4-6 IV over 30 minutes.

Repeat cycle every 4 weeks.

OR

Day 1: Carboplatin 560mg/m2 IV over 1 hour.

Repeat cycle every 4 weeks.

Cisplatin

(if failure or intolerance to the preferred or other recommended regimens) (Category 3)47,73,74,210,211,f

Day 1: Cisplatin 60mg/m2 IV over 1 hour daily.

Repeat cycle every 3 or 4 weeks.

Dabrafenib + Trametinib

(if BRAF V600E mutation positive)2-5

Days 1-28: Dabrafenib 150mg orally twice daily.

Days 1-28: Trametinib 2mg orally once daily.

Repeat cycle every 4 weeks.

Entrectinib

(for NTRK gene fusion tumors)50-52

Days 1-28: Entrectinib 600mg orally once daily.
Repeat cycle every 4 weeks

Etoposide

(if failure or intolerance to the preferred or other recommended regimens) (Category 2B)49,75-79

Days 1-21: Etoposide 50mg/m2 orally daily.

Repeat cycle every 4-5 weeks.

Larotrectinib

(for NTRK gene fusion tumors)53-56

Days 1-28: Larotrectinib 100mg orally twice daily.

Repeat cycle every 4 weeks.

Vemurafenib + Cobimetinib
(if BRAF V600E mutation positive)10-14

Days 1-21: Cobimetinib 60mg orally once daily

Days 1-28: Vemurafenib 960mg orally twice daily.

Repeat cycle every 4 weeks.

▶Adult Glioma: IDH-Mutant Astrocytoma

Adjuvant Treatment WHO Grade 2, KPS >60a

Preferred Regimens

RT with adjuvant PCV

(Procarbazine/Lomustine/Vincristine) (Category 1)19,22,23,28-32,a,c

Day 1: Lomustine 110mg/m2 orally once daily

Days 8-21: Procarbazine 60mg/m2 orally once daily

Days 8,29: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle every 6-8 weeks for 6 cycles.

RT +adjuvant TMZ33-36,a

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) orally once daily.

Repeat cycle every 4 weeks for 6-12 cycles.

RT + concurrent and adjuvant TMZ33,34,36,37,a

Days 1-42: Temozolomide 75mg/m2 orally once daily.

Repeat cycle every 6 weeks with RT, followed by:

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) once orally daily.

Repeat cycle every 4 weeks for 6-12 cycles starting 4 weeks after the completion of concurrent Temozolomide and RT.

Other Recommended Regimens

PCV19,22-27,a,c

Day 1: Lomustine 110-130mg/m2 orally

Days 8-21: Procarbazine 60-75mg/m2 orally daily

Days 8,29: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle every 6-8 weeks for 6 cycles.

TMZ33,59-61,a

Days 1-21: Temozolomide 75mg/m2 orally daily

Repeat cycle every 4 weeks for a maximum of 12 cycles.

Adjuvant Treatment WHO Grade 3 or 4, KPS ≥60a

Preferred Regimens

RT + adjuvant TMZ (12 cycles)33-36,a

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) orally once daily.

Repeat cycle every 4 weeks for 12 cycles.

RT + concurrent and adjuvant TMZ33,34,36,37,a

Days 1-42: Temozolomide 75mg/m2 orally once daily.

Repeat cycle every 6 weeks with RT, followed by:

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) once orally daily.

Repeat cycle every 4 weeks for 6-12 cycles starting 4 weeks after the completion of concurrent Temozolomide and RT.

Adjuvant Treatment, KPS <60a

Other Recommended Regimens (No Preferred Regimens)

RT + adjuvant TMZ33-36,a

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) orally once daily.

Repeat cycle every 4 weeks for 6-12 cycles.

RT + concurrent and adjuvant TMZ33,34,36,37,a

Days 1-42: Temozolomide 75mg/m2 orally once daily.

Repeat cycle every 6 weeks with RT, followed by:

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) once orally daily.

Repeat cycle every 4 weeks for 6-12 cycles starting 4 weeks after the completion of concurrent Temozolomide and RT.

Recurrent or Progressive Disease WHO Grade 2, KPS ≥60a,d

Other Recommended Regimens (No Preferred Regimens)

Carmustine15-18,b

Days 1-3: Carmustine 80mg/m2 IV over 2 hours daily.

Repeat cycle every 8 weeks or until reaching a lifetime cumulative Carmustine dose for a maximum of 6 cycles.

OR

Day 1: Carmustine 150-200mg/m2 IV over 2 hours daily.

Repeat cycle every 8 weeks or until reaching a lifetime cumulative Carmustine dose.

Lomustine19-21,b

Day 1: Lomustine 100-130mg/m2 orally once daily.

Repeat cycle every 6 weeks or until reaching a lifetime cumulative Lomustine dose.

PCV19,22-27,a,c

Day 1: Lomustine 110-130mg/m2 orally

Days 8-21: Procarbazine 60-75mg/m2 orally daily

Days 8,29: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle every 6-8 weeks until disease progression or reaching a lifetime cumulative Lomustine dose.

RT + adjuvant PCV19,22,23,28-32,a,c

Day 1: Lomustine 110mg/m2 orally once daily

Days 8-21: Procarbazine 60mg/m2 orally once daily

Days 8,29: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle every 6-8 weeks until disease progression or reaching a lifetime dose of Lomustine.

RT + adjuvant TMZ33-36,a

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) orally once daily.

Repeat cycle every 4 weeks for 6-12 cycles.

RT + concurrent and adjuvant TMZ33,34,36,37,a

Days 1-42: Temozolomide 75mg/m2 orally once daily.

Repeat cycle every 6 weeks with RT, followed by:

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) once orally daily.

Repeat cycle every 4 weeks for 6-12 cycles starting 4 weeks after the completion of concurrent Temozolomide and RT.

TMZ33,38-43,a,e

Days 1-5: Temozolomide 150-200mg/m2 orally once daily.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

OR

Days 1-28: Temozolomide 50mg/m2 orally.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

Useful in Certain Circumstances

Dabrafenib/Trametinib

(if BRAF V600E mutation positive)2-5

Days 1-28: Dabrafenib 150 mg orally twice daily

Days 1-28: Trametinib 2mg orally once daily.

Repeat cycle every 4 weeks.

Entrectinib

(if NTRK gene fusion positive)50-52

Days 1-28: Entrectinib 600mg orally once daily.
Repeat cycle every 4 weeks.

Larotrectinib

(for NTRK gene fusion tumors)53-56

Days 1-28: Larotrectinib 100mg orally twice daily.

Repeat cycle every 4 weeks.

Vemurafenib/Cobimetinib (if BRAF V600E mutation positive)10-14

Days 1-21: Cobimetinib 60mg orally once daily

Days 1-28: Vemurafenib 960mg orally twice daily.

Repeat cycle every 4 weeks.

Recurrent or Progressive Disease, WHO Grade 3 or 4, KPS ≥60a,d,i

Preferred Regimens

Bevacizumab62-68,j,k

Day 1: Bevacizumab 10mg/kg IV.

Repeat cycle every 2 weeks.

OR

Day 1: Bevacizumab 5-15mg/kg IV.

Repeat cycle every 3 weeks.

Carmustine15-18,b

Days 1-3: Carmustine 80mg/m2 IV over 2 hours daily.

Repeat cycle every 8 weeks or until reaching a lifetime cumulative carmustine dose for a maximum of 6 cycles.

OR

Day 1: Carmustine 150-200mg/m2 IV over 2 hours daily.

Repeat cycle every 8 weeks or until reaching a lifetime cumulative carmustine dose.

Lomustine19-21,b

Day 1: Lomustine 100-130mg/m2 orally once daily.

Repeat cycle every 6 weeks or until reaching a lifetime cumulative lomustine dose.

PCV19,22-27,a,c

Day 1: Lomustine 110-130mg/m2 orally

Days 8-21: Procarbazine 60-75mg/m2 orally daily

Days 8,29: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle every 6-8 weeks until disease progression or reaching a lifetime cumulative Lomustine dose.

TMZ33,38-43,a

Days 1-5: Temozolomide 150-200mg/m2 orally once daily.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

OR

Days 1-28: Temozolomide 50mg/m2 orally.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

Other Recommended Regimens

Carmustine + Bevacizumab15,17,62,63,69,b,j-l

Days 1-3: Carmustine 80mg/m2 IV over 2 hours daily

Days 1,15,29,43: Bevacizumab 5-10mg/kg IV.

Repeat cycle every 6-8 weeks or until reaching a lifetime cumulative Carmustine dose.

OR

Days 1: Carmustine 150-200mg/m2 IV over 2 hours daily

Days 1,15,29,43: Bevacizumab 5-10mg/kg IV.

Repeat cycle every 6-8 weeks or until reaching a lifetime cumulative Carmustine dose.

Lomustine + Bevacizumab19,20,62,70,b,j-l

Day 1: Lomustine 90-110mg/m2 orally

Days 1,15,29: Bevacizumab 5-10mg/kg IV.

Repeat cycle every 6 weeks or until reaching a lifetime cumulative lomustine dose.

TMZ + Bevacizumab33,62,71,72,b,j-l

Days 1,15: Bevacizumab 5-10 mg/kg IV

Days 1-28: Temozolomide 50mg/m2 orally daily.

Repeat cycle every 4 weeks.

Useful in Certain Circumstances

Carboplatin

(if failure or intolerance to the preferred or other recommended regimens) (Category 3)44-46

Day 1: Carboplatin AUC 4-6 IV over 30 minutes.

Repeat cycle every 4 weeks.

OR

Day 1: Carboplatin 560mg/m2 IV over 1 hour.

Repeat cycle every 4 weeks.

Cisplatin

(if failure or intolerance to the preferred or other recommended regimens) (Category 3)47,73,74,210,211,f

Day 1: Cisplatin 60mg/m2 IV over 1 hour daily.

Repeat cycle every 3 or 4 weeks.

Dabrafenib + Trametinib

(if BRAF V600E mutation positive)2-5

Days 1-28: Dabrafenib 150mg orally twice daily.

Days 1-28: Trametinib 2mg orally once daily.

Repeat cycle every 4 weeks.

Entrectinib

(for NTRK gene fusion tumors)50-52

Days 1-28: Entrectinib 600mg orally once daily.
Repeat cycle every 4 weeks

Etoposide

(if failure or intolerance to the preferred or other recommended regimens) (Category 2B)49,75-79

Days 1-21: Etoposide 50mg/m2 orally daily.

Repeat cycle every 4-5 weeks.

Larotrectinib

(for NTRK gene fusion tumors)53-56

Days 1-28: Larotrectinib 100mg orally twice daily.

Repeat cycle every 4 weeks.

Vemurafenib + Cobimetinib

(if BRAF V600E mutation positive)10-14

Days 1-21: Cobimetinib 60mg orally once daily

Days 1-28: Vemurafenib 960mg orally twice daily.

Repeat cycle every 4 weeks.

Adjuvant Treatment, KPS ≥60a

Preferred Regimens

RT with concurrent and adjuvant TMZ + TTF33,34,36,37,a

Days 1-42: Temozolomide 75mg/m2 orally daily. Repeat cycle every 6 weeks with RT, followed by:

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) orally daily.

Repeat cycle every 4 weeks for 6-12 cycles starting 4 weeks after the completion of concurrent temozolomide and RT).

Useful in Certain Circumstances

RT + concurrent and adjuvant Lomustine and TMZ

(for patients with MGMT promoter-methylated tumors and age ≤70 years) (Category 2B)19,33,80,a,b,m

Day 1: Lomustine 100mg/m2 orally once daily

Days 2-6: Temozolomide 100mg/m2 orally once daily.

Administer for one 6-week cycle with concurrent RT, followed by:

Day 1: Lomustine 100mg/m2 orally once daily

Days 2-6: Temozolomide 100-200mg/m2 orally once daily.

Repeat cycle for 6 weeks for 5 cycles.

TMZ (for patients with MGMT promoter-methylated tumors and age >70 years)33-36,a

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) orally once daily.

Repeat cycle every 4 weeks for 6-12 cycles.

Adjuvant Treatment, KPS <60a

Useful in Certain Circumstances (No Preferred or Other Recommended Regimens)

RT + concurrent and adjuvant TMZ

(for patients age 70 or younger)33,34,36,37,a

Days 1-42: Temozolomide 75mg/m2 orally once daily.

Repeat cycle every 6 weeks with RT, followed by:

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) once orally daily.

Repeat cycle every 4 weeks for 6-12 cycles starting 4 weeks after the completion of concurrent Temozolomide and RT.

TMZ (for patients with MGMT promoter-methylated tumors)33-36,a

Days 1-5: Temozolomide 150-200mg/m2 (increase as tolerated) orally once daily.

Repeat cycle every 4 weeks for 6-12 cycles.

Recurrence TherapyI,n

Preferred Regimens

Bevacizumab62-68,j,k

Day 1: Bevacizumab 10mg/kg IV.

Repeat cycle every 2 weeks.

OR

Day 1: Bevacizumab 5-15mg/kg IV.

Repeat cycle every 3 weeks.

Carmustine15-18,b

Days 1-3: Carmustine 80mg/m2 IV over 2 hours daily.

Repeat cycle every 8 weeks or until reaching a lifetime cumulative Carmustine dose for a maximum of 6 cycles.

OR

Day 1: Carmustine 150-200mg/m2 IV over 2 hours daily.

Repeat cycle every 8 weeks or until reaching a lifetime cumulative Carmustine dose.

Lomustine19-21,b

Day 1: Lomustine 100-130mg/m2 orally once daily.

Repeat cycle every 6 weeks or until reaching a lifetime cumulative Lomustine dose.

PCV (Procarbazine/Lomustine/
Vincristine)19,22-27,a-c

Day 1: Lomustine 110-130mg/m2 orally once daily

Days 8-21: Procarbazine 60-75mg/m2 orally once daily

Days 8 and 29: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle every 6-8 weeks until reaching a lifetime cumulative dose of Lomustine.

Regorafenib81,82

Days 1-21: Regorafenib 160mg orally once daily.

Repeat cycle every 4 weeks.

TMZ33,38-43,59-61,a

Days 1-21: Temozolomide 75mg/m2 orally once daily.

Repeat cycle every 4 weeks for 12 cycles.

OR

Days 1-5: Temozolomide 150-200mg/m2 orally daily.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

OR

Days 1-28: Temozolomide 50mg/m2 orally daily.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

Other Recommended Regimens

Carmustine + Bevacizumab15,17,62,63,69,b,j-l

Days 1-3: Carmustine 80mg/m2 IV over 2 hours daily

Days 1,15,29,43: Bevacizumab 5-10mg/kg IV.

Repeat cycle every 6-8 weeks or until reaching a lifetime cumulative Carmustine dose.

OR

Days 1: Carmustine 150-200mg/m2 IV over 2 hours daily

Days 1,15,29,43: Bevacizumab 5-10mg/kg IV.

Repeat cycle every 6-8 weeks or until reaching a lifetime cumulative Carmustine dose.

Lomustine + Bevacizumab19,20,62,70,b,j-l

Day 1: Lomustine 90-110mg/m2 orally

Days 1,15,29: Bevacizumab 5-10mg/kg IV.

Repeat cycle every 6 weeks or until reaching a lifetime cumulative Lomustine dose.

TMZ + Bevacizumab33,62,71,72,a,j-l

Days 1,15: Bevacizumab 5-10mg/kg IV

Days 1-28: Temozolomide 50mg/m2 orally daily.

Repeat cycle every 4 weeks.

Useful in Certain Circumstances

Carboplatin/Etoposide

(if failure or intolerance to the preferred or other recommended regimens) (Category 3)44,48,49,88,211

Days 1-3: Carboplatin 100mg/m2 IV over 30 minutes daily.

Days 1-3: Etoposide 120mg/m2 over 1 hour daily.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

OR

Day 1: Carboplatin AUC 4-6 IV.

Days 1-3: Etoposide 100-120mg/m2 over 1 hour daily.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

Cisplatin/Etoposide

(if failure or intolerance to the preferred or other recommended regimens) (Category 3)47-49,f

Days 1-3: Cisplatin 25mg/m2 IV over 1 hour daily.

Days 1-3: Etoposide 100mg/m2 IV over 1 hour daily.

Repeat cycle every 4 weeks for a maximum of 10 cycles.

Dabrafenib/Trametinib

(if BRAF V600E mutation positive)2-5

Days 1-28: Dabrafenib 150 mg orally twice daily.

Days 1-28: Trametinib 2 mg orally once daily.

Repeat cycle every 4 weeks.

Entrectinib

(if NTRK gene fusion positive)50-52

Days 1-28: Entrectinib 600mg orally once daily.
Repeat cycle every 4 weeks.

Etoposide

(if failure or intolerance to the preferred or other recommended regimens) (Category 2B)49,75-79

Days 1-21: Etoposide 50mg/m2 orally daily.

Repeat cycle every 4-5 weeks.

Larotrectinib

(for NTRK gene fusion tumors)52-56

Days 1-28: Larotrectinib 100mg orally twice daily.

Repeat cycle every 4 weeks.

Vemurafenib/Cobimetinib

(if BRAF V600E mutation positive)10-14

Days 1-21: Cobimetinib 60mg orally once daily

Days 1-28: Vemurafenib 960mg orally twice daily.

Repeat cycle every 4 weeks.

▶Adult Intracranial and Spinal Ependymoma (Excluding Subependymoma)1

Recurrence Therapy

Other Recommended Regimens (No Preferred Regimens)

Bevacizumab62-68,j,k

Day 1: Bevacizumab 10mg/kg IV.

Repeat cycle every 2 weeks.

OR

Day 1: Bevacizumab 5-15mg/kg IV.

Repeat cycle every 3 weeks.

Carboplatin

(if failure or intolerance to the preferred or other recommended regimens)44-46

Day 1: Carboplatin AUC 4-6 IV over 30 minutes.

Repeat cycle every 4 weeks.

OR

Day 1: Carboplatin 560mg/m2 IV over 1 hour.

Repeat cycle every 4 weeks.

Carboplatin/Etoposide

(if failure or intolerance to the preferred or other recommended regimens)44,48,49,88,210

Days 1-3: Carboplatin 100mg/m2 IV over 30 minutes daily

Days 1-3: Etoposide 120mg/m2 over 1 hour daily.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

OR

Day 1: Carboplatin AUC 4-6 IV

Days 1-3: Etoposide 100-120mg/m2 over 1 hour daily.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

Carmustine15-18,b

Days 1-3: Carmustine 80mg/m2 IV over 2 hours daily.

Repeat cycle every 8 weeks or until reaching a lifetime cumulative Carmustine dose for a maximum of 6 cycles.

OR

Day 1: Carmustine 150-200mg/m2 IV over 2 hours daily.

Repeat cycle every 8 weeks or until reaching a lifetime cumulative Carmustine dose.

Cisplatin

(if failure or intolerance to the preferred or other recommended regimens) (Category 3)47,73,74,210,211,f

Day 1: Cisplatin 60mg/m2 IV over 1 hour daily.

Repeat cycle every 3 or 4 weeks.

Cisplatin/Etoposide

(if failure or intolerance to the preferred or other recommended regimens) (Category 3)47-49,f

Days 1-3: Cisplatin 25mg/m2 IV over 1 hour daily

Days 1-3: Etoposide 100mg/m2 IV over 1 hour daily.

Repeat cycle every 4 weeks for a maximum of 10 cycles.

Etoposide

(if failure or intolerance to the preferred or other recommended regimens)49,75-79

Days 1-21: Etoposide 50mg/m2 orally daily.

Repeat cycle every 4-5 weeks

Lapatinib + TMZ

(Category 2B)33,83,84,a

Days 1-28: Lapatinib 1,250mg orally once daily

Days 1-7,15-21: Temozolomide 125-150mg/m2 orally once daily.

Administer for one 4-week cycle for a maximum of 24 cycles.

Lomustine19-21,b

Day 1: Lomustine 100-130mg/m2 orally once daily.

Repeat cycle every 6 weeks or until reaching a lifetime cumulative lomustine dose.

TMZ33,49-53,a

Days 1-5: Temozolomide 150-200mg/m2 orally once daily.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

Regimens Following Weekly Vincristine During Craniospinal RTa,o

Preferred Regimens

Cisplatin, Cyclophosphamide, and Vincristine23,47,85,86,f,o,p

Day 1: Vincristine 1.5mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle weekly for 8 weeks with concurrent craniospinal RT, followed by:

Day 1: Cisplatin 75mg/m2 IV over 2 hours

Days 2,8,15: Vincristine 1.5mg/m2 (maximum 2mg) IV over 5-10 minutes (maximum 8 doses)

Days 22-23: Cyclophosphamide 1,000mg/m2 IV over 30 minutes.

Repeat cycle every 6 weeks for 8 cycles beginning 6 weeks after craniospinal RT.

Cisplatin, Lomustine, and Vincristine19,23,47,86,b,f,o

Day 1: Vincristine 1.5mg/m2 (maximum 2mg) IV over 5-10 minutes.

Repeat cycle weekly for 8 weeks with concurrent craniospinal RT, followed by:

Day 1: Lomustine 75mg/m2 orally once daily

Day 2: Cisplatin 75mg/m2 IV over 2 hours

Days 2,8,15: Vincristine 1.5mg/m2 (maximum 2mg) IV over 5-10 minutes (maximum 8 doses).

Repeat cycle every 6 weeks for 8 cycles beginning 6 weeks after craniospinal RT.

Recurrence Therapy

Other Recommended Regimens (No Preferred Regimens)

Carboplatin/Etoposide/

Cyclophosphamide (no prior systemic chemotherapy)44,45,85,87,88,p

Days 1-3: Carboplatin 100mg/m2 IV over 30 minutes

Days 1-4: Etoposide 40mg/m2 IV over 1 hour

Day 4: Cyclophosphamide 1,000mg/m2 IV over 30 minutes.

Repeat cycle every 4 weeks.

Cisplatin/Etoposide/

Cyclophosphamide

(no prior systemic chemotherapy)47,49,85,87,f,p

Days 1-4: Cisplatin 25mg/m2 IV over 1 hour

Days 1-4: Etoposide 40mg/m2 IV over 1 hour

Day 4: Cyclophosphamide 1,000mg/m2 IV over 30 minutes.

Repeat cycle every 4 weeks.

High-dose Cyclophosphamide

(no prior systemic chemotherapy)1,p

See NCCN Central Nervous System Guidelines.1

High-dose Cyclophosphamide + Etoposide

(no prior systemic chemotherapy)1,p

See NCCN Central Nervous System Guidelines.1

High-dose Cyclophosphamide
(prior systemic chemotherapy)1,p

See NCCN Central Nervous System Guidelines.1

High-dose Cyclophosphamide + Etoposide

(prior systemic chemotherapy)1,p

See NCCN Central Nervous System Guidelines.1

Oral Etoposide

(prior systemic chemotherapy)49,75-79

Days 1-21: Etoposide 50mg/m2 orally once daily. Repeat cycle every 4 or 5 weeks.

TMZ

(prior systemic chemotherapy)33,38-42,a

Days 1-5: Temozolomide 150-200mg/m2 orally once daily.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

Useful in Certain Circumstances

Vismodegib

(for mutations in sonic hedgehog pathway and if prior systemic chemotherapy)89,90

Days 1-28: Vismodegib 150 mg orally once daily.

Repeat cycle every 4 weeks.

Consider high-dose chemotherapy with autologous stem cell reinfusion in patients who achieve a CR with conventional doses of chemotherapy or have no residual disease after re-resection.a

▶Primary CNS Lymphoma1

Induction Therapy

Preferred Regimens

High-dose Methotrexate/Procarbazine/Vincristine + Rituximab (R-MPV) and consider WBRT22,23,91-96,a,q-v

Rituximab requires premedication.

Day 1: Rituximab 500mg/m2 IV

Day 2: Methotrexate 3,500 mg/m2 IV over 2 hours

Day 2: Leucovorin 25 mg IV over 15 minutes or orally starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until Methotrexate serum concentration is <0.05micromol/L)u

Day 2: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes

Days 2-8: Procarbazine 100mg/m2 orally once daily of Cycles 1, 3, 5, and 7

Days 5-12: Methotrexate (if CSF cytology positive) 12mg intrathecal OR intraventricular once.

Repeat cycle every 2 weeks for 5-7 cycles, conditionally followed by:

Day 1: Rituximab 500mg/m2 IV

Day 2: Methotrexate 3,500 mg/m2 IV over 2 hours

Day 2: Leucovorin 25mg IV over 15 minutes OR orally starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until Methotrexate serum concentration is <0.05micromol/L)u

Day 2: Vincristine 1.4mg/m2 IV over 5-10 minutes

Days 2-8: Procarbazine 100mg/m2 orally once daily of odd cycles.

Repeat cycle for 4 weeks for a maximum of 1 year.

High-dose Methotrexate + Rituximab 91-93,97-99,q-u

Rituximab requires premedication.

Day 1: Methotrexate 8,000mg/m2 IV over 4 hours (if CrCl >60mL/min) OR Methotrexate 4,000mg/m2 IV over 4 hours (if CrCl <60mL/min), followed by

Day 2: Leucovorin 25 mg IV over 15 minutes OR orally starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until Methotrexate serum concentration is <0.05micromol/L)u

Day 3 or 8: Rituximab 375mg/m2 IV once daily.

Repeat cycle for 2 weeks for 4-6 cycles (induction), followed by:

Day 1: Methotrexate 8,000mg/m2 IV over 4 hours (if CrCl >60mL/min) OR Methotrexate 4,000mg/m2 IV over 4 hours (if CrCl <60mL/min), followed by

Day 2: Leucovorin 25mg IV over 15 minutes OR orally starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until Methotrexate serum concentration is <0.05micromol/L).u

Repeat cycle every 4 weeks for a maximum of 1 year.

High-Dose Methotrexate/

TMZ + Rituximab33,91-93,100,a,q-u

Rituximab requires premedication.

Day 1: Methotrexate 8,000mg/m2 IV over 4 hours

Day 2: Leucovorin 100mg IV over 15 minutes OR orally starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until Methotrexate serum concentration is <0.05micromol/L)u

Day 3 (Cycles 1-6): Rituximab 375mg/m2 IV of

Days 7-11 (Cycles 1, 3, 5, and 7): Temozolomide 150mg/m2 orally once daily of.

Repeat every 2 weeks for 8-11 cycles, conditionally followed by consolidation therapy with:

Day 1: Methotrexate 8,000mg/m2 IV over 4 hours

Day 2: Leucovorin 100mg IV over 15 minutes starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until Methotrexate serum concentration is <0.05micromol/L)u

Days 7-11 (Odd Cycles)Temozolomide 150mg/m2 orally once daily.

Repeat cycle every 4 weeks for a maximum of 1 year.

High-Dose Methotrexate/

TMZ + Rituximab followed by Postirradiation TMZ and consider WBRT33,91,92,101,a,q-v

Rituximab requires premedication.

Day 1: Rituximab 375mg/m2 IV

Day 4: Methotrexate 3,500mg/m2 IV over 4 hours

Day 5: Leucovorin 25mg IV over 15 minutes or orally starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until Methotrexate serum concentration is <0.05micromol/L).u

Administer for one 2-week cycle, followed by:

Day 1: Methotrexate 3,500 mg/m2 IV over 4 hours

Day 2: Leucovorin 25mg IV over 15 minutes or orally starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until Methotrexate serum concentration is <0.05micromol/L)u

Days 8-12: Temozolomide 100mg/m2 orally once daily.

Repeat cycle every 2 weeks for 4 cycles, followed by post-irradiation:

Days 1-5: Temozolomide 150-200mg/m2 orally once daily.

Repeat cycle for 4 weeks for a maximum of 10 cycles.

Other Recommended Regimens

High-dose Methotrexate/Cytarabine/ Thiotepa/Rituximab (MATRix)91-93,102-104,q-u,w-y

Rituximab requires premedication.

Days -5,0 of Cycles 1-4: Rituximab 375mg/m2 IV.

Day 1: Methotrexate 500mg/m2 IV over 15 minutes, followed by:

Methotrexate 3,000mg/m2 IV over 3 hours

Leucovorin 15mg/m2 IV over 15 minutes or orally every 6 hours for 12 doses (beginning 24 hours after the start of Methotrexate)u

Days 2-3: Cytarabine 2,000mg/m2 IV over 1 hour every 12 hours

Day 4: Thiotepa 30mg/m2 IV over 30 minutes.

Repeat cycle every 3 weeks for 4 cycles.

Useful in Certain Circumstances

Cytarabine

(intra-CSF therapy if CSF positive or spinal MRI positive)103-105,a

Days 1,4: Cytarabine 50mg intrathecal or intraventricular.

Repeat cycle weekly for 4 cycles (induction), followed by:

Day 1: Cytarabine 50mg intrathecal or intraventricular.

Repeat cycle weekly for 8 cycles if CSF cytology negative (consolidation), followed by:

Day 1: Cytarabine 50mg intrathecal or intraventricular.

Repeat cycle every 2 weeks for 2 cycles (consolidation), followed by:

Day 1: Cytarabine 50mg intrathecal or intraventricular.

Repeat cycle every 4 weeks for 4 cycles (maintenance).

Methotrexate

(intra-CSF therapy if CSF positive or spinal MRI positive)92,105,106,a

Days 1,4: Methotrexate 10-15mg intrathecal or intraventricular.

Repeat cycle weekly for 4 cycles (induction), followed by:

Day 1: Methotrexate 10-15mg intrathecal or intraventricular.

Repeat cycle weekly for 4 cycles if CSF cytology negative (consolidation), followed by:

Day 1: Methotrexate 10-15mg intrathecal or intraventricular.

Repeat cycle every 2 weeks for 4 cycles (consolidation), followed by:

Day 1: Methotrexate 10-15mg intrathecal or intraventricular.

Repeat cycle every 4 weeks (maintenance).

Rituximab

(intra-CSF therapy if CSF positive or spinal MRI positive)91,107,108,a,r,s

Rituximab requires premedication.

Days 1,4: Rituximab 25mg intrathecal or intraventricular

Repeat cycle weekly for 4 cycles (induction), followed by:

Days 1,4: Rituximab 25mg intrathecal or intraventricular

Repeat cycle every 4 weeks if CSF cytology negative (maintenance).

If patient is unsuitable for or intolerant to high-dose Methotrexate, see “Other Recommended Regimens” for Relapsed or Refractory Disease.

Consolidation Therapy

Preferred Regimens

High-dose Cytarabine103,109,110

Days 1-2: Cytarabine 3,000mg/m2 IV over 3 hours.

Repeat cycle every 4 weeks for 2 cycles (this course is preceded by 5-7 cycles of High-dose Methotrexate/
Vincristine/Procarbazine + Rituximab and then whole brain RT).

Cytarabine + Thiotepa followed by Carmustine + Thiotepa

(for high-dose chemotherapy stem cell rescue)1,a-c

See NCCN Central Nervous System Guidelines1

High-dose Cytarabine + Etoposide (EA)49,100,103

Days 1-4: Etoposide 10mg/kg IV continuous infusion over 24 hours daily

Days 1-4: Cytarabine 2,000mg/m2 IV over 2 hours every 12 hours.

Administer for one 4-week cycle (this course is preceded by 8-11 cycles of High-dose Methotrexate/Temozolomide + Rituximab course).

Thiotepa, Busulfan, and Cyclophosphamide (TBC)

(for high-dose chemotherapy stem cell rescue)85,102,111,112,p

Days 1-3: Thiotepa 250mg/m2 IV over 3 hours

Days 4-6: Busulfan 0.67-0.8mg/kg IV over 2 hours every 3 hours

Days 7-8: Cyclophosphamide 60mg/kg IV over 30 minutes. Mesna 12mg/kg IV over 15 minutes three times daily (one dose before Cyclophosphamide, then at 4 and 8 hours from the start of each Cyclophosphamide dose).

Administer for one cycle prior to HSCT.

Relapsed or Refractory Disease

Other Recommended Regimens (No Preferred Regimens)

High-dose Cytarabine103,109,110

Days 1-2: Cytarabine 3,000mg/m2 IV over 3 hours.

Repeat cycle every 3 weeks.

Ibrutinib113,114,z

Days 1-28: Ibrutinib 560mg orally once daily.

Repeat cycle every 4 weeks.

OR

Days 1-28: Ibrutinib 840mg orally once daily.

Repeat cycle every 4 weeks.

Lenalidomide115,116

Days 1-21: Lenalidomide 15mg orally once daily

Repeat cycle every 4 weeks.

Lenalidomide + Rituximab91,108,115,116,r,s

Rituximab requires premedication.

Days 1-21: Lenalidomide 15mg orally once daily

Days 1,8,15,22: Rituximab 375mg/m2 IV,followed by:

Days 1,8,15,22: Rituximab 25mg intrathecal or intraventricular administered 1 hour after initiation of rituximab.

Administer for one 4-week cycle, followed by

Days 1-21: Lenalidomide 15mg orally once daily

Days 1,15: Rituximab 25mg intrathecal or intraventricular.

Repeat cycle every 4 weeks.

Pemetrexed117,118,aa

Pemetrexed requires premedication.

Day 1: Pemetrexed 900mg/m2 IV over 10 minutes.

Repeat cycle every 3 weeks.

Pomalidomide119,120

Days 1-21: Pomalidomide 5mg orally once daily

Days 1,8,15,22: Dexamethasone 40mg orally once daily.

Repeat cycle every 4 weeks for 2 cycles, followed by

Days 1-21: Pomalidomide 5 mg orally once daily.

Repeat cycle every 4 weeks.

Retreat with High-dose Methotrexate92,93,121-123,q,t,u

Day 1: Methotrexate 3,500-8,000mg/m2 IV over 4 hours

Day 2: Leucovorin 25mg IV over 15 minutes or orally once starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until methotrexate serum concentration is <0.05micromol/L).u

Repeat cycle every 2 weeks for a maximum of 8 cycles, followed by:

Day 1: Methotrexate 3,500-8,000mg/m2 IV over 4 hours

Day 2: Leucovorin 25mg IV over 15 minutes or orally once starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until methotrexate serum concentration is <0.05micromol/L).u

Repeat cycle every 2 weeks for 2 cycles, followed by:

Day 1: Methotrexate 3,500-8,000mg/m2 IV over 4 hours

Day 2: Leucovorin 25mg IV over 15 minutes or orally once starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until Methotrexate serum concentration is <0.05micromol/L).u

Repeat cycle every 4 weeks.

Retreat with High-dose Methotrexate with Rituximab91-93,97-99,q-u

Rituximab requires premedication.

Day 1: Methotrexate 8,000mg/m2 IV over 4 hours (if CrCl >60mL/min) OR Methotrexate 4,000mg/m2 IV over 4 hours (if CrCl <60mL/min), followed by

Day 2: Leucovorin 25 mg IV over 15 minutes OR orally starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until Methotrexate serum concentration is <0.05micromol/L)u

Day 3 or 8: Rituximab 375mg/m2 IV once.

Repeat cycle for 2 weeks for 4-6 cycles (induction), followed by:

Day 1: Methotrexate 8,000mg/m2 IV over 4 hours (if CrCl >60mL/min) OR Methotrexate 4,000mg/m2 IV over 4 hours (if CrCl <60mL/min), followed by:

Day 2: Leucovorin 25 mg IV over 15 minutes OR orally starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until Methotrexate serum concentration is <0.05micromol/L).u

Repeat cycle every 4 weeks.

Retreat with High-dose Methotrexate with Rituximab and Ibrutinib91-93,113,124,q-u,z

Rituximab requires premedication.

Days 1,15,29 of Cycle 1: Rituximab 500mg/m2 IV, followed by:

Days 15,29 of Cycle 2-3: Rituximab 500mg/m2 IV, followed by:

Days 15 of Cycle 4: Rituximab 500mg/m2 IV

Days 2,16: Methotrexate 3,500mg/m2 IV over 4 hours every 2 weeks

Days 3,17: Leucovorin 25mg IV over 15 minutes or orally once daily starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until Methotrexate serum concentration is <0.05micromol/L)u

Days 6-15,20-29: Ibrutinib 560mg orally once daily (dependent on Methotrexate clearance) OR Ibrutinib 840mg orally once daily (dependent on Methotrexate clearance).

Repeat cycle every 29 days for 4 cycles, followed by maintenance therapy with:

Days 1-28: Ibrutinib 560mg orally once daily OR Ibrutinib 840mg orally once daily.

Repeat cycle every 4 weeks.

Rituximab91,125,r,s

Rituximab requires premedication.

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle weekly for 8 cycles.

Rituximab + TMZ33,91,126,127,a,r,s

Rituximab requires premedication.

Day 1,8,15,22: Rituximab 750mg/m2.

Day 1-7,15-21: Temozolomide 100-200mg/m2 orally once daily.

Repeat cycle every 4 weeks for 1-2 cycles (induction), followed by:

Day 1-5: Temozolomide 150-200mg/m2 orally once daily.

Repeat cycle every 4 weeks for 6 cycles or until disease progression or unacceptable toxicity (consolidation), followed by:

Day 1: Methylprednisolone 1,000mg IV over 90 minutes.

Repeat every 4 weeks (optional maintenance).

TMZ33,38-42,a

Days 1-5: Temozolomide 150-200mg/m2 orally once daily.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

Useful in Certain Circumstances

Consider high-dose chemotherapy with autologous stem cell reinfusion with eligible patients

High-dose Cytarabine/Etoposide followed by Thiotepa/Bisulfan/
Cyclophosphamide49,102,103,111,11,p

Days 1-4: Etoposide 10mg/kg IV continuous infusion over 24 hours daily

Days 1-4: Cytarabine 2,000mg/m2 IV over 2 hours every 12 hours

Administer for one 4-week cycle, followed by:

Days 1-3: Thiotepa 250mg/m2 IV over 3 hours

Days 4-6: Bisulfan 0.67-0.8mg/kg IV over 2 hours every 6 hours

Days 7-8: Cyclophosphamide 60mg/kg IV over 30 minutes

Mesna 12mg/kg IV over 15 minutes three times daily (one dose before Cyclophosphamide, then at 4 and 8 hours from the start of each Cyclophosphamide dose)

Administer for one cycle prior to HSCT.

High-dose Cytarabine + Rituximab + Thiotepa followed by Rituximab + Carmustine15,91,102,103,212,b,r,s

See NCCN Central Nervous System Guidelines1

High-dose Methotrexate followed by Cytarabine + Thiotepa followed by Carmustine + Thiotepa15,92,102,103,112,b,t

See NCCN Central Nervous System Guidelines1

For intra-CSF therapy, see induction therapy above.a

▶Meningiomas1

Recurrent or Progressive

(No Preferred Regimens)

Other Recommended Regimens

Bevacizumab62-68,j,k

Day 1: Bevacizumab 10mg/kg IV.

Repeat cycle every 2 weeks.

OR

Day 1: Bevacizumab 5-15mg/kg IV.

Repeat cycle every 3 weeks.

Bevacizumab + Everolimus (Category 2B)6,62,128,j,k

Days 1,15: Bevacizumab 10mg/kg IV

Days 1-28: Everolimus 10mg orally once daily.

Repeat cycle every 4 weeks.

Sunitinib (Category 2B)129,130

Days 1-28: Sunitinib 50mg orally once daily.

Repeat cycle every 6 weeks.

Useful in Certain Circumstances

Octreotide Acetate LAR

(Category 2B)131-133

Day 1 of Cycles 1-2: Octreotide Acetate (LAR) 30mg IM.

Repeat cycle every 4 weeks for 2 cycles, followed by:

Day 1 (Beginning with Cycle 3): Octreotide Acetate (LAR) 40mg IM.

Repeat cycle every 4 weeks.

Octreotide Acetate

(short-acting) (Category 2B)134,135

Day 1: Octreotide acetate 150mcg subcutaneous twice daily, followed by:

Day 2: Octreotide acetate 250mcg subcutaneous twice daily, followed by:

Day 3-28: Octreotide acetate 500mcg subcutaneous three times daily.

Administer for one 4-week cycle, followed by:

Day 1-28: Octreotide acetate 500mcg subcutaneous three times daily.

Repeat cycle every 4 weeks (for at least 6 months if stable disease).

▶Miscellaneous CNS Tumors1

Useful in Certain Circumstances (No Preferred or Other Recommended Regimens)

Belzutifan

(VHL-associated CNS

hemagioblastoma not requiring immediate surgery)136,137

Days 1-28: Belzutifan 120mg orally once daily.

Repeat cycle every 4 weeks.

▶Brain Metastases1

Tumor Agnostic (See appropriate NCCN treatment guidelines for systemic therapy recommendations for newly diagnosed brain metastases for any cancers not listed here)1

Preferred Regimens

Entrectinib

(if NTRK gene fusion positive)50-52

Days 1-28: Entrectinib 600mg orally once daily.

Repeat cycle every 4 weeks.

Larotrectinib

(for NTRK gene fusion tumors)53-56

Days 1-28: Larotrectinib 100mg orally twice daily.

Repeat cycle every 4 weeks.

TMZ 5/28 Schedule33-36,a

Days 1-5: Temozolomide 150-200mg/m2 orally once daily.

Repeat cycle every 4 weeks for a maximum of 12 cycles.

Breast Cancer (Use active agents against primary tumor)

HER2 Positive Regimensa

Ado-Trastuzumab Emtansine

(T-DM1)138,139

Day 1 (Cycle 1): Ado-trastuzumab emtansine 3.6mg/kg IV over 90 minutes, followed by:

Day 1 (Beginning with Cycle 2): Ado-trastuzumab emtansine 3.6mg/kg IV over 30 minutes.

Repeat cycle every 3 weeks.

Capecitabine + Lapatinib140-143

Days 1-14: Capecitabine 1,000mg/m2 orally twice daily

Days 1-21: Lapatinib 1,250mg orally once daily.

Repeat cycle every 3 weeks.

Capecitabine + Neratinib140,144,145,cc

Days 1-14: Capecitabine 750mg/m2 orally twice daily

Days 1-21: Neratinib 240mg orally once daily.

Repeat cycle every 3 weeks.

Fam-Trastuzumab Deruxtecan-nxki146-148

Day 1: Fam-Trastuzumab 5.4 mg/kg IV.

Repeat cycle every 3 weeks.

Paclitaxel + Neratinib

(Category 2B)144,149,150,cc,dd

Paclitaxel requires premedication.

Days 1-21: Neratinib 240mg orally once daily

Days 1,8,15: Paclitaxel 80mg/m2 IV over 1 hour.

Repeat cycle every 4 weeks.

Pertuzumab + High-dose Trastuzumab151-153,bb

Day 1 (Cycle 1): Pertuzumab 840mg IV followed by:

Day 1 (Beginning with Cycle 2): Pertuzumab 420mg IV

Repeat cycle every 3 weeks, with:

Day 1: Trastuzumab 6mg/kg IV.

Repeat cycle weekly.

Tucatinib + Trastuzumab + Capecitabine (Category 1)

(if previously treated with 1 or more anti-HER2-based regimens)140,151,154,155,a,bb

Days 1-14: Capecitabine 1,000mg/m2 orally twice daily

Days 1-21: Tucatinib 300mg orally once twice daily

Day 1 (Cycle 1): Trastuzumab 8mg/kg IV over 90 minutes, followed by:

Day 2 (Beginning with Cycle 2): Trastuzumab 6mg/kg IV over 30 minutes.

Repeat cycle every 3 weeks.

HER2 Non-Specific Regimensa

Capecitabine140,156,157

Days 1-14: Capecitabine 1,000mg/m2 orally twice daily

Repeat cycle every 3 weeks.

Cisplatin (Category 2B)47,73,74,210,211

Day 1: Cisplatin 100mg/m2 IV over 2 hours.

Repeat cycle every 3 weeks.

Cisplatin + Etoposide

(Category 2B)47,49,158,211,f

Day 1: Cisplatin 100mg/m2 IV over 2 hours

Days 1,3,5: Etoposide 100mg/m2 IV over 1 hour daily.

Repeat cycle every 3 weeks.

OR

Day 1-3: Cisplatin 40mg/m2 IV over 1 hours

Days 1-3: Etoposide 150mg/m2 IV over 1 hour daily.

Repeat cycle every 3 weeks.

Etoposide (Category 2B)49,159,211

Days 1,3,5: Etoposide 100mg/m2 IV over 1 hour daily.

Repeat cycle every 3 weeks.

High-dose Methotrexate
(Category 2B)92,93,121-123,q,t,u

Day 1: Methotrexate 3,500mg/m2 IV over 4 hours

Leucovorin 25mg IV over 15 minutes or orally once starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until Methotrexate serum concentration is <0.05micromol/L).u

Repeat cycle every 2 weeks.

Melanoma

BRAF V600E Positive Regimens

Dabrafenib/Trametinib if BRAF V600E mutation positive 2-5

Days 1-28: Dabrafenib 150mg orally twice daily.

Days 1-28: Trametinib 2mg orally once daily.

Repeat cycle every 4 weeks.

Vemurafenib/Cobimetinib if BRAF V600E mutation positive
(Category 2B)10-14

Days 1-21: Cobimetinib 60mg orally once daily

Days 1-28: Vemurafenib 960mg orally twice daily.

Repeat cycle every 4 weeks.

BRAF Non-Specific Regimens

Ipilimumab 160,161,ee

Day 1: Ipilimumab 10mg/kg IV over 90 minutes.

Repeat cycle every 3 weeks for 4 cycles, conditionally followed by:

Day 1 (Beginning with Week 24): Ipilimumab 10mg/kg IV over 90 minutes.

Repeat cycle every 12 weeks beginning week 24.

Ipilimumab + Nivolumab (preferred)160,162-164,ee

Day 1: Nivolumab 1mg/kg IV over 30 minutes, followed by:

Day 1: Ipilimumab 3mg/kg IV over 90 minutes.

Repeat cycle every 3 weeks for 4 cycles, followed by:

Day 1: Nivolumab 240mg IV over 30 minutes.

Repeat cycle every 2 weeks.

OR

Day 1: Nivolumab 1mg/kg IV over 30 minutes, followed by:

Day 1: Ipilimumab 3mg/kg IV over 90 minutes.

Repeat cycle every 3 weeks for 4 cycles, followed by:

Day 1: Nivolumab 480mg IV over 30 minutes.

Repeat cycle every 4 weeks.

Nivolumab162,163,164,166,ee

Day 1: Nivolumab 240mg IV over 30 minutes.

Repeat cycle every 2 weeks.

OR

Day 1: Nivolumab 480mg IV over 30 minutes.

Repeat cycle every 4 weeks.

Pembrolizumab167-169,ee

Day 1: Pembrolizumab 10mg/kg IV over 30 minutes.

Repeat cycle every 2 weeks.

OR

Day 1: Pembrolizumab 200mg IV over 30 minutes.

Repeat cycle every 2 weeks.

Non-Small Cell Lung Cancer (Use active agents against primary tumor)

EGFR-Sensitizing Mutation Positive Regimensa

Afatinib (Category 2B)170-172

Days 1-28: Afatinib 40mg orally once daily.

Repeat cycle every 4 weeks.

Gefitnib (Category 2B)173-175

Days 1-28: Gefitnib 250mg orally once daily.

Repeat cycle every 4 weeks.

Osimertinib176-179

Days 1-28: Osimertinib 80mg orally once daily.

Repeat cycle every 4 weeks.

Pulsatile Erlotinib180-183

Days 1,8,15,22: Erlotinib 1,500mg orally once daily.

Repeat cycle every 4 weeks.

OR

Days 1-28: Erlotinib 150mg orally once daily.

Repeat cycle every 4 weeks.

OR

Days 1-2,8-9,15-16: Erlotinib 1,200mg orally once daily, followed by:

Days 3-7,10-14,17-21: Erlotinib 50mg orally once daily.

Repeat cycle every 3 weeks.

MET Exon 14 Skipping Mutated Regimensa

Capmatinib184,185

Days 1-28: Capmatinib 400mg orally twice daily.

Repeat cycle every 4 weeks.

RET Fusion-Positive Regimens

Selpercatinib186,187

Days 1-28: Selpercatinib 120mg orally twice daily (<50mg); 160mg orally twice daily (≥50kg).

Repeat cycle every 4 weeks.

ALK Rearrangement Positive Regimensa

Alectinib188-190

Days 1-28: Alectinib 600mg orally twice daily.

Repeat cycle every 4 weeks.

Brigatinib191-193

Days 1-7: Brigatinib 90mg orally once daily, followed by:

Days 8-28: Brigatinib 180mg orally once daily.

Administer for one 4-week cycle, followed by:

Days 1-28: Brigatinib 180mg orally once daily.

Repeat cycle every 4 weeks.

Ceritinib194-196

Days 1-28: Ceritinib 450mg orally once daily.

Repeat cycle every 4 weeks.

Lorlatinib197,198

Days 1-28: Lorlatinib 100mg orally once daily.

Repeat cycle every 4 weeks.

ALK Rearrangement Positive or ROS1 Rearrangement Positive Regimensa

Crizotinib (Category 2B)199,200

Days 1-28: Crizotinib 250mg orally twice daily.

Repeat cycle every 4 weeks.

PD-L1 Positive Regimensa

Nivolumab162,163,165,166,ee

Day 1: Nivolumab 240mg IV over 30 minutes.

Repeat cycle every 2 weeks.

OR

Day 1: Nivolumab 480mg IV over 30 minutes.

Repeat cycle every 4 weeks.

Pembrolizumab167-169,ee

Day 1: Pembrolizumab 10mg/kg IV over 30 minutes.

Repeat cycle every 2 weeks.

OR

Day 1: Pembrolizumab 200mg IV over 30 minutes.

Repeat cycle every 2 weeks.

Small Cell Lung Cancer (Use active agents against primary tumor)

Preferred Regimen

Topotecan (Category 2B)201,202

Days 1-5: Topotecan 1.5mg/m2 IV over 30 minutes.

Repeat cycle every 3 weeks.

Lymphoma (Use active agents against primary tumor)

Preferred Regimen

High-dose Methotrexate
(Category 2B)92,93,121-123,t,u

Day 1: Methotrexate 3,500mg/m2 IV over 4 hours

Day 2: Leucovorin 25mg IV over 15 minutes or orally once starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until Methotrexate serum concentration is <0.05micromol/L).u

Repeat cycle every week for a maximum of 12 cycles.

▶Leptomeningeal and Spine Metastases1

Non-Small Cell Lung Cancer (Use active agents against primary tumor)

Systemic therapy specific to primary cancer type; emphasizing drugs with good CNS penetration.

Intra-CSF Systemic Chemotherapy

Cytarabine103,203

Days 1,4: Cytarabine 50mg intrathecal or intraventricular.

Repeat cycle weekly for 4 cycles (induction), followed by:

Day 1: Cytarabine 50mg intrathecal or intraventricular.

Repeat cycle for weekly for 8 cycles if CSF cytology negative (consolidation), followed by:

Day 1: Cytarabine 50mg intrathecal or intraventricular.

Repeat cycle every 2 weeks for 2 cycles (consolidation), followed by:

Day 1: Cytarabine 50mg intrathecal or intraventricular.

Repeat cycle every 4 weeks for 4 cycles (maintenance).

Etoposide49,204

Days 1-5: Etoposide 0.5mg intrathecal or intraventricular.

Repeat cycle for 2 weeks for 4 cycles, followed by:

Days 1-5: Etoposide 0.5mg intrathecal or intraventricular.

Repeat cycle every 4 weeks (maintenance if CSF cytology negative).

Methotrexate92,111,203

Days 1,4: Methotrexate 10-15mg intrathecal or intraventricular.

Repeat cycle for 1 week for 4 cycles (induction), followed by:

Day 1: Methotrexate 10-15mg intrathecal or intraventricular.

Repeat cycle for 1 week for 4 cycles if CSF cytology negative (consolidation), followed by:

Day 1: Methotrexate 10-15mg intrathecal or intraventricular.

Repeat cycle every 2 weeks for 4 cycles (consolidation), followed by:

Day 1: Methotrexate 10-15mg intrathecal or intraventricular.

Repeat cycle every 4 weeks (maintenance).

Thiotepa102,205,206

Day 1,4: Thiotepa 10mg intrathecal or intraventricular.

Repeat cycle weekly for 8 cycles (induction), followed by:

Day 1: Thiotepa 10mg intrathecal or intraventricular.

Repeat cycle weekly for 4 cycles if CSF cytology negative (consolidation), followed by:

Day 1: Thiotepa 10mg intrathecal or intraventricular.

Repeat cycle every 4 weeks for 4 cycles (maintenance).

Topotecan201,207

Day 1,4,8,11: Topotecan 0.4mg intrathecal or intraventricular.

Repeat cycle every 2 weeks for 3 cycles (induction), followed by:

Day 1,8: Topotecan 0.4mg intrathecal or intraventricular.

Repeat cycle every 2 weeks for 3 cycles (consolidation), followed by:

Day 1: Topotecan 0.4mg intrathecal or intraventricular.

Repeat cycle every 2 weeks for 8 cycles (maintenance 1), followed by:

Day 1: Topotecan 0.4mg intrathecal or intraventricular.

Repeat cycle every 4 weeks (maintenance 2).

Lymphoma

High-dose Methotrexate92,93,121-123,q,t,u

Day 1: Methotrexate 3,500mg/m2 IV over 4 hours

Day 2: Leucovorin 25mg IV over 15 minutes or orally once starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until Methotrexate serum concentration is <0.05micromol/L).u

Repeat cycle weekly for a maximum of 12 cycles.

Rituximab
(Intra-CSF systemic chemotherapy)91,107,108,a,r

Rituximab requires premedication.

Days 1,4: Rituximab 25mg intrathecal or intraventricular

Repeat cycle for weekly for 4 cycles (induction), followed by:

Days 1,4: Rituximab 25mg intrathecal or intraventricular

Repeat cycle every 4 weeks if CSF cytology negative (maintenance).

Breast Cancer

High-dose Methotrexate92,93,121-123,q,t,u

Day 1: Methotrexate 3,500mg/m2 IV over 4 hours

Day 2: Leucovorin 25mg IV over 15 minutes or orally once starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until Methotrexate serum concentration is <0.05micromol/L).u

Repeat cycle every 2 weeks.

Methotrexate

(Intra-CSF systemic chemotherapy)92,111,204,a

Days 1,4: Methotrexate 10-15mg intrathecal or intraventricular.

Repeat cycle weekly for 4 cycles (induction), followed by:

Day 1: Methotrexate 10-15mg intrathecal or intraventricular.

Repeat cycle weekly for 4 cycles if CSF cytology negative (consolidation), followed by:

Day 1: Methotrexate 10-15mg intrathecal or intraventricular.

Repeat cycle every 2 weeks for 4 cycles (consolidation), followed by:

Day 1: Methotrexate 10-15mg intrathecal or intraventricular.

Repeat cycle every 4 weeks (maintenance).

Trastuzumab (HER2 positive)
(Intra-CSF systemic chemotherapy)152,208,209,a,bb

Days 1: Trastuzumab 25-150mg intrathecal or intraventricular.

Repeat cycle for 1-3 weeks.

Non-Small Cell Lung Cancer

Weekly Pulse Erlotinib

(for EGFR exon 19 deletion or exon 21 L858R mutation) (Category 2B)180-183,a

Days 1,8,15,22: Erlotinib 1,500mg orally once daily.

Repeat cycle every 4 weeks.

OR

Days 1-28: Erlotinib 150mg orally once daily.

Repeat cycle every 4 weeks.

OR

Days 1-2,8-9,15-16: Erlotinib 1,200mg orally once daily, followed by:

Days 3-7,10-14,17-21: Erlotinib 50mg orally once daily.

Repeat cycle every 3 weeks.

Osimertinib

(for EGFR mutation positive)176-179

Days 1-28: Osimertinib 80mg orally once daily.

Repeat cycle every 4 weeks.

Metastatic Spine Tumors

Use regimen for disease-specific site.

  a ALK = anaplastic lymphoma kinase; CR = complete response; CrCl = creatinine clearance; CSF = cerebral spinal fluid or colony-stimulating factor; EGFR = epidermal growth factor receptor; HER2 = human epidermal growth factor receptor 2; HSCT = hematopoietic stem cell transplantation; KPS = Karnovsky performance scale; transition; RT = radiation therapy; PA = pilocytic astrocytoma; PCV = Procarbazine/Lomustine/Vincristine; PD-L1 = programmed death-ligand 1; PXA = pleomorphic xanthoastrocytoma; RT = radiotherapy; SEGA = subependymal giant cell astrocytoma; TMZ = temozolomide; TTF = tumor treating fields; WBRT = whole brain radiotherapy

  b Cumulative Lomustine and Carmustine dosages should be monitored.

  c When PCV is recommended, Carmustine may be substituted for Lomustine.

  d There are multiple reasonable options, but there is no uniform standard of care at this time for recurrent disease.

  e For patients not previously treated.

  f Hydration is required with supplemental electrolytes pre- and post-administration of cisplatin.

  g The NCCN panel recommends that PCV be administered right after RT (as per EORTC 26951) since the intensive PCV regimen given prior to RT (RTOG 9402) was not tolerated as well.

  h Consider TMZ if tumor is MGMT promoter methylated.

  i Strongly suggest consideration of clinical trials prior to treating recurrent disease with standard chemotherapy, as additional therapies may eliminate the majority of clinical trial options.

  j Patients who have evidence of radiographic progression may benefit from continuation of Bevacizumab to prevent rapid neurologic deterioration.

  k An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

  l Bevacizumab + chemotherapy can be considered if Bevacizumab monotherapy fails and it is desirable to continue the steroid-sparing effects of bevacizumab.

  m Moderate to significant myelosuppression was observed, but the toxicity profile for this regimen is not fully defined.

  n There are no identified targeted agents with demonstrated efficacy in glioblastoma. However, the panel encourages molecular testing of tumor because if a driver mutation is detected, it may be reasonable to treat with a targeted therapy on a compassionate use basis and/or the patient may have more treatment options in the context of a clinical trial. Molecular testing also has a valuable role in improving diagnostic accuracy and prognostic stratification that may inform treatment selection.

  o Omission of Vincristine during radiotherapy phase of therapy or dose modification may be required for adults because they do not tolerate this regimen as well. Data supporting Vincristine’s use have been found in pediatric trials only. Patients should be monitored closely for neurologic toxicity with periodic exams.

  p Oral hydration is strongly encouraged with Cyclophosphamide; poorly hydrated patients may need supplemental IV hydration (combined oral and IV hydration of 2,000-3,000mL/day on day of chemotherapy).

  q Consider glucarpidase (carboxypeptidase G2) for prolonged Methotrexate clearance due to Methotrexate-induced renal toxicity.

  r An FDA-approved biosimilar agent may be substituted for Rituximab. Premedication for infusion reactions is required. The recommended dosing is diphenhydramine 12.5mg-50mg IV/orally 30-60 minutes pre-Rituximab AND acetaminophen 650 mg orally 30-60 minutes pre-Rituximab.

  s Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy.

  t Alkaline hydration is required pre- and post-administration of high-dose Methotrexate. Preservative-free formulation must be used for high-dose Methotrexate to prevent benzyl alcohol toxicity.

  u Leucovorin dose should be titrated for delayed Methotrexate clearance or increases in serum creatinine (<10-fold decrement in serum Methotrexate levels per day).

  v Other combinations with Methotrexate may be used.

  w There are concerns about WBRT being used in the trials that evaluated these regimens, especially for patients older than 65 years of age.

  x This regimen is associated with significant myeloid toxicity

  y CSF’s may be considered for primary prophylaxis based on the febrile neutropenia risk of the chemotherapy regimen.

  z Ibrutinib is associated with risk of aspergillus infection.

  aa For Pemetrexed: premedication and supplemental medications to reduce the incidence and severity of hematologic, gastrointestinal, and cutaneous toxicities are required. The recommended dosing is: Vitamin 12 1,000mcg intramuscularly during the week preceding the first cycle and every 3 cycles thereafter AND folic acid 100-1,000mcg orally once daily starting 7 days before the first cycle and continuing for 21 days after the last dose of Pemetrexed AND dexamethasone 4 mg orally twice daily starting the day prior to Pemetrexed.

  bb An FDA-approved biosimilar is an appropriate substitute for Trastuzumab.

  cc For Neratinib: initiate antidiarrheal prophylaxis with loperamide with the first dose of Neratinib, and continue during the first 8 weeks of treatment. Additional antidiarrheal agents may be required to manage diarrhea in patients with loperamide-refractory diarrhea.

  dd Premedication for hypersensitivity is required for Paclitaxel: famotidine 20mg IV or orally (or equivalent H2 blocker) 30-60 minutes pre-paclitaxel AND diphenhydramine 12.5-50mg IV or orally 30-60 minutes pre-Paclitaxel AND dexamethasone 10mg IV 30 minutes pre-Paclitaxel. In the absence of infusion reactions for Doses 1-3, may consider dexamethasone 4mg IV 30 minutes pre-Paclitaxel starting with Dose 4.

  ee Early- and late-onset immune-related adverse events affecting multiple organ systems can occur in patients receiving immune checkpoint inhibitors. Patients with neurologic or life-threatening autoimmune disorders as well as those receiving high levels of immunosuppression for their underlying disease should be approached with caution when considering immunotherapy. All patients will require extensive resources including ongoing intensive monitoring and supportive care.

References

1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Central Nervous System Cancers V.2.2022. https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf. Accessed October 1, 2022.

2. Dabrafenib (Tafinlar) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; June 2022. https://www.novartis.com/us-en/sites/novartis_us/files/tafinlar.pdf. Accessed September 18, 2022.

3. Trametinib (Mekinist) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; June 2022. https://www.novartis.com/us-en/sites/novartis_us/files/mekinist.pdf. Accessed September 18, 2022.

4. Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017;18(7):863-873.

5. Brown NF, Carter T, Kitchen N, Mulholland P. Dabrafenib and trametinib in BRAFV600E mutated glioma. CNS Oncol. 2017;6(4):291-296.

6. Everolimus (Afinitor) [package insert]. East Hanover, NJ: Novartis Pharmaceutical Corporation; February 2022. https://www.novartis.com/us-en/sites/novartis_us/files/afinitor.pdf. Accessed August 17, 2022.

7. Franz DN, Belousova E, Sparagana S, et al. Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol. 2014;15(13):1513-1520.

8. Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2013;381(9861):125-132.

9. Franz DN, Belousova E, Sparagana S, et al. Long-term use of everolimus in patients with tuberous sclerosis complex: Final results from the EXIST-1 study. PLoS One. 2016;11(6):e0158476.

10. Vemurafenib (Zelboraf) [package insert]. South San Francisco, CA: Genentech USA Inc; May 2020. https://www.accessdata.fda.gov/drugsatfda_docs/­label/2020/202429s019lbl.pdf. Accessed September 25, 2022. Accessed ­August 17, 2022.

11. Cobimetinib (Cotellic) [package insert]. South San Francisco, CA: Genentech USA, Inc; July 2022. https://www.gene.com/download/pdf/cotellic_prescribing.pdf. Accessed August 17, 2022.

12. McArthur GA, Maio M, Arance A, et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. Ann Oncol. 2017;28(3):634-641.

13. Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248-1260.

14. Dummer R, Goldinger SM, Turtschi CP, et al. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer. 2014;50(3):611-621.

15. Carmustine (BiCNU) [package insert]. Eatontown, NJ: Heritage Pharmaceuticals; November 2017. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=b9b47082-32ee-4abb-a7b2-52292894d3f8&type=display. Accessed September 18,2022.

16. Brandes AA, Tosoni A, Amistà P, et al. How effective is BCNU in recurrent glioblastoma in the modern era? A phase II trial. Neurology. 2004;63(7):1281-1284.

17. Reithmeier T, Graf E, Piroth T, Trippel M, Pinsker MO, Nikkhah G. BCNU for recurrent glioblastoma multiforme: efficacy, toxicity and prognostic factors. BMC Cancer. 2010;10:30.

18. Gornet MK, Buckner JC, Marks RS, Scheithauer BW, Erickson BJ. Chemotherapy for advanced CNS ependymoma. J Neurooncol. 1999;45(1):61-67.

19. Lomustine (Gleostine) [package insert]. Miami, FL: NextSource Biotechnology, LLC; September 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=7f77526b-4c40-409c-82ea-d0f934d89cc2&type=display. Accessed September 18, 2022.

20. Taal W, Oosterkamp HM, Walenkamp AM, et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014;15(9):943-953.

21. Wick W, Puduvalli VK, Chamberlain MC, et al. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010;28(7):1168-1174.

22. Procarbazine (Matulane) [package insert]. Gaithersburg, MD: Leadiant Biosciences, Inc.; August 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1aa75a3a-18c9-49e1-91a6-293d0b7da756&type=display. Accessed September 18, 2022.

23. Vincristine sulfate (Vincasar PFS) [package insert]. Parsippany, NJ: Teva Pharmaceuticals USA, Inc; September 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=01cee93f-3ab9-44fa-8c9a-dd5958fd2db9&type=display. Accessed September 18, 2022.

24. Triebels VH, Taphoorn MJ, Brandes AA, et al. Salvage PCV chemotherapy for temozolomide-resistant oligodendrogliomas. Neurology. 2004;63(5):904-906.

25. Soffietti R, Rudà R, Bradac GB, Schiffer D. PCV chemotherapy for recurrent oligodendrogliomas and oligoastrocytomas. Neurosurgery. 1998;43(5):1066-1073.

26. Cairncross G, Wang M, Shaw E, et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31(3):337-343.

27. van den Bent MJ, Kros JM, Heimans JJ, et al. Response rate and prognostic factors of recurrent oligodendroglioma treated with procarbazine, CCNU, and vincristine chemotherapy. Dutch Neuro-oncology Group. Neurology. 1998;51(4):1140-1145.

28. van den Bent MJ, Brandes AA, Taphoorn MJ, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31(3):344-350.

29. van den Bent MJ, Carpentier AF, Brandes AA, et al. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial.J Clin Oncol. 2006;24(18):2715-2722.

30. Shaw EG, Wang M, Coons SW, et al. Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802. J Clin Oncol. 2012;30(25):3065-3070.

31. Buckner JC, Shaw EG, Pugh SL, et al. Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma. N Engl J Med. 2016;374(14):1344-1355.

32. Levin VA, Hess KR, Choucair A, et al. Phase III randomized study of postradiotherapy chemotherapy with combination alpha-difluoromethylornithine-PCV versus PCV for anaplastic gliomas. Clin Cancer Res. 2003;9(3):981-990.

33. Temozolomide (Temodar) [package insert]. Whitehouse Station, NJ: Merck & Co Inc; November 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=046a9011-3911-4d3f-a15f-fbb56d5aad56&type=display. Accessed September 18, 2022.

34. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996.

35. Panageas KS, Iwamoto FM, Cloughesy TF, et al. Initial treatment patterns over time for anaplastic oligodendroglial tumors. Neuro Oncol. 2012;14(6):761-767.

36. van den Bent MJ, Baumert B, Erridge SC, et al. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study Lancet. 2017;390(10103):1645-1653.

37. Fisher BJ, Hu C, Macdonald DR, et al. Phase 2 study of temozolomide-based chemoradiation therapy for high-risk low-grade gliomas: preliminary results of Radiation Therapy Oncology Group 0424. Int J Radiat Oncol Biol Phys. 2015;91(3):497-504.

38. ung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000;83(5):588-593.

39. Yung WK, Prados MD, Yaya-Tur R, et al. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J Clin Oncol. 1999;17(9):2762-2771.

40. Rudà R, Bosa C, Magistrello M, et al. Temozolomide as salvage treatment for ­recurrent intracranial ependymomas of the adult: a retrospective study. Neuro Oncol. 2016;18(2):261-268.

41. Makino K, Nakamura H, Hide T, Kuratsu J. Salvage treatment with temozolomide in refractory or relapsed primary central nervous system lymphoma and assessment of the MGMT status. J Neurooncol. 2012;106(1):155-160.

42. Nicholson HS, Kretschmar CS, Krailo M, et al. Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children’s Oncology Group. Cancer. 2007;110(7):1542-1550.

43. Perry JR, Bélanger K, Mason WP, et al. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol. 2010;28(12):2051-2057.

44. Carboplatin [package insert]. Lake Forest, IL: Hospira, Inc.; March 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=47677091-fd20-49af-933c-c9dd2be21de9&type=display. Accessed September 18, 2022.

45. Soffietti R, Nobile M, Rudà R, et al. Second-line treatment with carboplatin for recurrent or progressive oligodendroglial tumors after PCV (procarbazine, lomustine, and vincristine) chemotherapy: a phase II study. Cancer. 2004;100(4):807-813.

46. Gornet MK, Buckner JC, Marks RS, Scheithauer BW, Erickson BJ. Chemotherapy for advanced CNS ependymoma. J Neurooncol. 1999;45(1):61-67.

47. Cisplatin lyophilized powder [package insert]. Paramus, NJ: WG Critical Care LLC; February 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=508496cb-3441-46b3-a4fe-e0d440e6adc6&type=display. Accessed September 19, 2022.

48. Massimino M, Spreafico F, Riva D, et al. A lower-dose, lower-toxicity cisplatin-etoposide regimen for childhood progressive low-grade glioma. J Neurooncol. 2010;100(1):65-71.

49. Etoposide injection [package insert]. Eatontown, NJ: Hikma Pharmaceuticals USA Inc; August 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=e0cd61b9-2375-4e3d-a610-d87dad962468&type=display. Accessed September 25, 2022.

50. Entrectinib (Rozlytrek) [package insert]. South San Francisco, CA: Genentech USA, Inc; July 2022. https://www.gene.com/download/pdf/rozlytrek_prescribing.pdf. Accessed August 17, 2022.

51. Drilon A, Siena S, Ou SI, et al. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017;7(4):400-409.

52. Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in ­patients with NTRK fusion-positive (NTRK-fp) tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. [abstract]. ESMO Congress. 2018:Abstract 5033.

53. Larotrectinib (Vitrakvi) [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; March 2021. https://labeling.bayerhealthcare.com/html/products/pi/vitrakvi_PI.pdf. ­Accessed August 17, 2022.

54. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of Larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739.

55. rilon A, DuBois, SG, Farago AF, et al. Activity of larotrectinib in TRK fusion cancer patients with brain metastases or primary central nervous system tumors. J Clin Oncol. 2019; 37, no. 15_suppl (May 20, 2019) 2006-2006.

56. Lassen UN, Albert CM, Kummar S, et al. Larotrectinib efficacy and safety in TRK fusion cancer: An expanded clinical dataset showing consistency in an age and tumor agnostic approach [abstract]. Ann of Oncol. 2018:29(suppl-8):Abstract 4090.

57. Selumetinib (Koselugo) [package insert]. Wilmington, DE: AstraZeneca ­Pharmaceuticals LP; December 2021. https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/22c94947-0a99-4b03-9d06-866a301712bc/22c94947-0a99-4b03-9d06-866a301712bc_viewable_rendition__v.pdf. Accessed August 17, 2021.

58. Fangusaro J, Onar-Thomas A, Young Poussaint T, et al. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol. 2019;20(7):1011-1022.

59. Pouratian N, Gasco J, Sherman JH, Shaffrey ME, Schiff D. Toxicity and efficacy of protracted low dose temozolomide for the treatment of low grade gliomas. J Neurooncol. 2007;82(3):281-288.

60. Baumert BG, Hegi ME, van den Bent MJ, et al. Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2016;17(11):1521-1532.

61. Weller M, Tabatabai G, Kästner B, et al. MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial. Clin Cancer Res. 2015;21(9):2057-2064.

62. Bevacizumab (Avastin) [package insert]. South San Francisco, CA: Genentech Inc; January 2021. https://www.gene.com/download/pdf/avastin_prescribing.pdf. Accessed August 17, 2021.

63. Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27(5):740-745.

64. Raizer JJ, Grimm S, Chamberlain MC, et al. A phase 2 trial of single-agent bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas. Cancer. 2010;116(22):5297-5305.

65. Green RM, Cloughesy TF, Stupp R, et al. Bevacizumab for recurrent ependymoma. Neurology. 2009;73(20):1677-1680.

66. Lou E, Sumrall AL, Turner S, et al. Bevacizumab therapy for adults with recurrent/progressive meningioma: a retrospective series. J Neurooncol. 2012;109(1):63-70.

67. Levin VA, Mendelssohn ND, Chan J, et al. Impact of bevacizumab administered dose on overall survival of patients with progressive glioblastoma. J Neurooncol. 2015;122(1):145-150.

68. hamberlain MC, Johnston S. Bevacizumab for recurrent alkylator-refractory ­anaplastic oligodendroglioma. Cancer. 2009;115(8):1734-1743.

69. Rahman R, Hempfling K, Norden AD, et al. Retrospective study of carmustine or lomustine with bevacizumab in recurrent glioblastoma patients who have failed prior bevacizumab. Neuro Oncol. 2014;16(11):1523-1529.

70. Wick W, Gorlia T, Bendszus M, et al. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med. 2017;377(20):1954-1963.

71. Liu Y, Feng F, Ji P, et al. Improvement of health related quality of life in patients with recurrent glioma treated with bevacizumab plus daily temozolomide as the salvage therapy. Clin Neurol Neurosurg. 2018;169:64-70.

72. Desjardins A, Reardon DA, Coan A, et al. Bevacizumab and daily temozolomide for recurrent glioblastoma. Cancer. 2012;118(5):1302-1312.

73. Khan AB, D’Souza BJ, Wharam MD, et al. Cisplatin therapy in recurrent childhood brain tumors. Cancer Treat Rep. 1982;66(12):2013-2020.

74. Sexauer CL, Khan A, Burger PC, et al. Cisplatin in recurrent pediatric brain ­tumors. A POG Phase II study. A Pediatric Oncology Group Study. Cancer. 1985;56(7):1497-1501.

75. Leonard A, Wolff JE. Etoposide improves survival in high-grade glioma: a ­meta-analysis. Anticancer Res. 2013;33(8):3307-3315.

76. Sandri A, Massimino M, Mastrodicasa L, et al. Treatment with oral etoposide for childhood recurrent ependymomas. J Pediatr Hematol Oncol. 2005;27(9):486-490.

77. Ashley DM, Meier L, Kerby T, et al. Response of recurrent medulloblastoma to low-dose oral etoposide. J Clin Oncol. 1996;14(6):1922-1927.

78. Chamberlain MC. Recurrent intracranial ependymoma in children: salvage therapy with oral etoposide. Pediatr Neurol. 2001;24(2):117-121. 

79. Chamberlain MC, Kormanik PA. Chronic oral VP-16 for recurrent medulloblastoma. Pediatr Neurol. 1997;17(3):230-234.

80. Herringer U, Tzaridis T, Mack F, et al. Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019;393(10172):678-688.

81. Regorafenib (Stivarga) [package insert]. Whippany, NJ: Bayer HealthCare ­Pharmaceuticals Inc; December 2020. https://labeling.bayerhealthcare.com/html/products/pi/Stivarga_PI.pdf. Accessed August 17, 2022.

82. Lombardi G, De Salvo GL, Brandes AA, et al. Regorafenib compared with ­lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol. 2019;20(1):110-119.

83. Lapatinib (Tykerb) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; March 2022. https://www.novartis.com/us-en/sites/novartis_us/files/tykerb.pdf. Accessed August 17, 2022.

84. Gilbert MR, Yuan Y, Wu J, et al. A phase II study of dose-dense temozolomide and lapatinib for recurrent low-grade and anaplastic supratentorial, infratentorial, and spinal cord ependymoma. Neuro Oncol. 2021;23(3):468-477.

85. Cyclophosphamide injection [package insert]. Baxter Healthcare Corp.; https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=­cef038cc-efab-46d9-99c2-95bb11d6c9bc&type=display. Accessed September 2022.

86. Packer RJ, Gajjar A, Vezina G, et al. Phase III study of craniospinal radiation ­therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol. 2006;24(25):4202-4208.

87. Brandes AA, Ermani M, Amista P, et al. The treatment of adults with medulloblastoma: a prospective study. Int J Radiat Oncol Biol Phys. 2003;57(3):755-761.

88. Franceschi E, Cavallo G, Scopece L, et al. Phase II trial of carboplatin and etoposide for patients with recurrent high-grade glioma. Br J Cancer. 2004;91(6):1038-1044.

89. Vismodegib (Erivedge) [prescribing information]. South San Francisco, CA: Genentech USA; July 2020. https://www.gene.com/download/pdf/erivedge_prescribing.pdf. Accessed September 18, 2022”

90. Robinson GW, Orr BA, Wu G, et al. Vismodegib exerts targeted efficacy against ­recurrent sonic hedgehog-subgroup medulloblastoma: results from phase II ­pediatric brain tumor consortium studies PBTC-025B and PBTC-032. J Clin Oncol. 2015;33(24):2646-2654.

91. Rituximab (Rituxan) [package insert]. South San Francisco, CA: Genentech, Inc.: December 2021. https://www.gene.com/download/pdf/rituxan_prescribing.pdf. Accessed ­August 17, 2022.

92. Methotrexate [package insert]. Lake Forest, IL: Hospira, Inc.; June 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0e30eaef-5a09-4104-8a11-c32933eadeab&type=display. Accessed September 19, 2022.

93. Leucovorin calcium for injection [package insert]. Lake Zurich, IL: Fresenius Kabi USA LLC; April 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=d5d4f0fd-7520-43a9-9acc-f7e117e1f6ee&type=display. Accessed September 19, 2022.

94. Shah GD, Yahalom J, Correa DD, et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2007;25(30):4730-4735.

95. Morris PG, Correa DD, Yahalom J, et al. Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol. 2013;31(31):3971-3979. 

96. Omuro A, Correa DD, DeAngelis LM, et al. R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed ­primary CNS lymphoma. Blood. 2015;125(9):1403-1410.

97. Chamberlain MC, Johnston SK. High-dose methotrexate and rituximab with ­deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma. Neuro Oncol. 2010;12(7):736-744.

98. Holdhoff M, Ambady P, Abdelaziz A, et al. High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma. Neurology. 2014;83(3):235-239.

99. Batchelor T, Carson K, O’Neill A, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol. 2003;21(6):1044-1049.

100. Wieduwilt MJ, Valles F, Issa S, et al. Immunochemotherapy with intensive consolidation for primary CNS lymphoma: a pilot study and prognostic assessment by diffusion-weighted MRI. Clin Cancer Res. 2012;18(4):1146-1155.

101. Glass J, Won M, Schultz CJ, et al. Phase I and II Study of Induction Chemotherapy With Methotrexate, Rituximab, and Temozolomide, Followed By Whole-Brain ­Radiotherapy and Postirradiation Temozolomide for Primary CNS Lymphoma: NRG Oncology RTOG 0227. J Clin Oncol. 2016;34(14):1620-1625.

102. Thiotepa [package insert]. Piscataway, NJ: Novadoz Pharmaceuticals; February 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=­b702dcc9-dd0e-4386-b1e2-f20562fd2ad9&type=display. Accessed September 19, 2022.

103. Cytarabine [package insert]. Lake Forest, IL: Hospira, Inc; June 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=277597b0-7d85-40a3-a34a-70c6a883fc6d&type=display. Accessed September 19, 2022.

104. Ferreri AJ, Cwynarski K, Pulczynski E, et al. Chemoimmunotherapy with ­methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol. 2016;3(5):e217-e227.

105. Glantz MJ, LaFollette S, Jaeckle KA, et al. Randomized trial of a slow-release ­versus a standard formulation of cytarabine for the intrathecal treatment of ­lymphomatous meningitis. J Clin Oncol. 1999;17(10):3110-3116.

106. Chamberlain MC. Neoplastic meningitis. Oncologist. 2008;13(9):967-977.

107. Chamberlain MC, Johnston SK, Van Horn A, Glantz MJ. Recurrent lymphomatous meningitis treated with intra-CSF rituximab and liposomal ara-C. J Neurooncol. 2009;91(3):271-277.

108. Schultz H, Pels H, Schmidt-Wolf I, et al. Intraventricular treatment of relapsed central nervous system lymphoma with the anti-CD20 antibody rituximab. Haematologica. 2004;89(6):753-754.

109. DeAngelis LM, Kreis W, Chan K, Dantis E, Akerman S. Pharmacokinetics of ara-C and ara-U in plasma and CSF after high-dose administration of cytosine arabinoside. Cancer Chemother Pharmacol. 1992;29(3):173-177.

110. Calderoni A, Aebi S. Combination chemotherapy with high-dose methotrexate and cytarabine with or without brain irradiation for primary central nervous system lymphomas. J Neurooncol. 2002;59(3):227-230.

111. Busulfan [package insert]. Lake Forest, IL: Hospira, Inc.; August 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=b9c7f0dc-988d-466e-8031-400ec4f60f21&type=display. Accessed September 25, 2022.

112. DeFilipp Z, Li S, El-Jawahri A, et al. High-dose chemotherapy with thiotepa, busulfan, and cyclophosphamide and autologous stem cell transplantation for patients with primary central nervous system lymphoma in first complete remission. ­Cancer. 2017;123(16):3073-3079.

113. Ibrutinib (Imbruvica) [package insert]. Horsham, PA: Janssen Biotech, Inc. August 2022. https://www.imbruvica.com/files/prescribing-information.pdf. Accessed September 18, 2022.

114. Grommes C, Pastore A, Palaskas N, et al. Ibrutinib unmasks critical role of bruton tyrosine kinase in primary CNS lymphoma. Cancer Discov. 2017;7(9):1018-1029.

115. Lenalidomide (Revlimid) [package insert]. Summit, NJ: Celgene Corporation; May 2022. https://packageinserts.bms.com/pi/pi_revlimid.pdf. Accessed August 17, 2022.

116. Rubenstein JL, Geng H, Fraser EJ, et al. Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma. Blood Adv. 2018;2(13):1595-1607.

117. Pemetrexed (Alimta) [package insert]. Indianapolis, IN: Lilly USA, LLC; August 2022. https://pi.lilly.com/us/alimta-pi.pdf. Accessed September 19, 2022.

118. Raizer JJ, Rademaker A, Evens AM, et al. Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma. Cancer. 2012;118(15):3743-3748.

119. Pomalidomide (Pomalyst) [package insert]. Summit, NJ: Celgene Corporation; October 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a1de8bba-3b1d-4c9d-ab8a-32d2c05e67c8&type=display. Accessed August 17, 2022.

120. Tun HW, Johnston PB, DeAngelis LM, et al. Phase 1 study of pomalidomide and dexamethasone for relapsed/refractory primary CNS or vitreoretinal lymphoma. Blood. 2018;132(21):2240-2248. 

121. Bokstein F, Lossos A, Lossos IS, Siegal T. Central nervous system relapse of systemic non-Hodgkin’s lymphoma: results of treatment based on high-dose methotrexate combination chemotherapy. Leuk Lymphoma. 2002;43(3):587-593.

122. Lassman AB, Abrey LE, Shah GD, et al. Systemic high-dose intravenous methotrexate for central nervous system metastases. J Neurooncol. 2006;78(3):255-260.

123. Batchelor TT, Carson K, O’Neill A, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol. 2003;21(6):1044-1049.

124. Grommes C, Tang SS, Wolfe J, et al. Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. Blood. 2019;133(5):436-445.

125. Batchelor TT, Grossman SA, Mikkelsen T, et al. Rituximab monotherapy for patients with recurrent primary CNS lymphoma. Neurology. 2011;76(10):929-930. 

126. Enting RH, Demopoulos A, DeAngelis LM, Abrey LE. Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Neurology. 2004;63(5):901-903.

127. Nayak L, Abrey LE, Drappatz J, et al. Multicenter phase II study of rituximab and temozolomide in recurrent primary central nervous system lymphoma. Leuk Lymphoma. 2013;54(1):58-61.

128. Shih KC, Chowdhary S, Rosenblatt P, et al. A phase II trial of bevacizumab and everolimus as treatment for patients with refractory, progressive intracranial ­meningioma. J Neurooncol. 2016;129(2):281-288.

129. Sunitinib (Sutent) [package insert]. New York, NY: Pfizer Labs; August 2021. https://labeling.pfizer.com/ShowLabeling.aspx?id=607. Accessed August 17, 2022.

130. Kaley TJ, Wen P, Schiff D, et al. Phase II trial of sunitinib for recurrent and progressive atypical and anaplastic meningioma. Neuro Oncol. 2015;17(1):116-121.

131. Octreotide acetate (Sandostatin LAR Depot) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; March 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=d0b7fe9e-7000-4b79-ba3b-291ce92c14f9&type=display. Accessed September 18, 2022.

132. Chamberlain MC, Glantz MJ, Fadul CE. Recurrent meningioma: salvage therapy with long-acting somatostatin analogue. Neurology. 2007;69(10):969-973.

133. Simo M, Argyiou AA, Macia M, et al. Recurrent high-grade meningioma: a phase II trial with somatostatin analogue therapy. Cancer Chemother Pharmacol. 2014;73(5):919-923.

134. Octreotide acetate (Sandostatin) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp,; May 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=4e2c9856-1836-49f0-9472-4dbeeb408f39&type=display. Accessed August 17, 2022.

135. Johnson DR, Kimmel DW, Burch PA, et al. Phase II study of subcutaneous octreotide in adults with recurrent or progressive meningioma and meningeal hemangiopericytoma. Neuro Oncol. 2011;13(5):530-535.

136. Belzutifan (Welireg) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.: May 2022. https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_pi.pdf. Accessed August 2022.

137. Srinivasian R, Donskov F, Iliopoulos O, et al. Phase 2 study of belzulifan (MK-6482), an oral hypoxia-inducible factor 2α inhibitor for von-Hippel-Lindau disease-associated clear cell renal cell carcinoma [abstract]. J Clin Oncol. 2021;39(suppl_15):Abstract 4555.

138. Ado-trastuzumab (Kadcyla) [package insert]. South San Francisco, CA: Genentech Inc; February 2022. https://www.gene.com/download/pdf/kadcyla_prescribing.pdf. ­Accessed August 17, 2022.

139. Montemurro F, Delaloge S, Barrios CH, et al. Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial. Ann Oncol. 2020;31(10):1350-1358.

140. Capecitabine (Xeloda) [package insert]. South San Francisco, CA: Genentech USA Inc; May 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a1de8bba-3b1d-4c9d-ab8a-32d2c05e67c8&type=display. Accessed August 17, 2022.

141. Lapatinib (Tykerb) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; March 2022. https://www.novartis.com/us-en/sites/novartis_us/files/tykerb.pdf. Accessed August 17, 2022.

142. Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013;14(1):64-71.

143. Petrelli F, Ghidini M, Lonati V, et al. The efficacy of lapatinib and capecitabine in HER-2 positive breast cancer with brain metastases: A systematic review and pooled analysis. Eur J Cancer. 2017;84:141-148.

144. Neratinib (Nerlynx) [package insert]. Los Angeles, CA: Puma Biotechnology Inc; March 2022. https://nerlynxhcp.com/pdf/full-prescribing-information.pdf. Accessed August 17, 2022.

145. Freedman RA, Gelman RS, Anders CK, et al. TBCRC 022: A phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-­positive breast cancer and brain metastases. J Clin Oncol. 2019;37(13):1081-1089.

146. Fam-trastuzumab (Enhertu) [package insert]. Baskiing Ridge, NJ: Daiichi-Sankyo, Inc.; August 2022. https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true. Accessed August 17, 2022.

147. Jerusalem G, Park YH, Yamashita T, et al. Trastuzumab deruxtecan (T-DXd) in ­patients with HER2+ metastatic breast cancer: a subgroup analysis of the DESTINY-Breast01 trial J Clin Oncol. 2021;39(15_suppl_5): Abstract 526.

148. Cortes J, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer:. ­Results of the ­r­andomized, phase 3 study DESTINY-Breast03 study. Ann Oncol. 2021;32(suppl_5): S1283-S1346.

149. Paclitaxel [package insert]. North Wales, PA: Teva Pharmaceuticals USA, Inc. July 2025. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=e4be6cbf-72b9-4f7f-9b1b-459b2d35961a&type=display. Accessed September 25, 2022.

150. Awada A, Colomer R, Inoue K, et al. Neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: the NEfERT-T ­randomized clinical trial. JAMA Oncol. 2016;2(12):1557-1564.

151. Trastuzumab (Herceptin) [package insert]. South San Francisco, CA: Genentech Inc.; February 2021. https://www.gene.com/download/pdf/herceptin_prescribing.pdf. Accessed August 17, 2022.

152. Pertuzumab (Perjeta) [package insert]. South San Francisco, CA: Genentech Inc.; February 2021. https://www.gene.com/download/pdf/perjeta_prescribing.pdf. Accessed August 17, 2022.

153. Lin N, Pegram M, Sahebjam S, et al. Pertuzumab plus high-dose trastuzumab in patients with progressive brain metastases and HEWR2-positive metastatic breast cancer: primary analysis of a phase II study [abstract]. J Clin Oncol. 2021;20:39(24):2667-2675.

154. Tucatinib (Tukysa) [package insert]. Bothell, WA: Seattle Genetics Inc; February 2022. https://www.tukysahcp.com/pdf/TUKYSA_Full_Ltr_Master.pdf. Accessed August 17, 2022.

155. Murthy RK, Loi S, Okines A, et al. tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast. N Engl J Med. 2020;382(7):597-609.

156. Fabi A, Vidiri A, Ferretti G, et al. Dramatic regression of multiple brain metastases from breast cancer with capecitabine: another arrow at the bow?. Cancer Invest. 2006;24(4):466-468.

157. Siegelmann-Danieli N, Stein M, Bar-Ziv J. Complete response of brain metastases originating in breast cancer to capecitabine therapy. Isr Med Assoc J. 2003;5(11):833-834.

158. Viñolas N, Graus F, Mellado B, Caralt L, Estapé J. Phase II trial of cisplatinum and etoposide in brain metastases of solid tumors. J Neurooncol. 1997;35(2):145-148.

159. Cocconi G, Lottici R, Bisagni G, et al. Combination therapy with platinum and etoposide of brain metastases from breast carcinoma. Cancer Invest. 1990;8(3-4):327-334.

160. Ipilimumab (Yervoy) [package insert]. Princeton, NJ: Bristol-Myers Squibb; May 2022. https://packageinserts.bms.com/pi/pi_yervoy.pdf. Accessed August 17, 2022.

161. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13(5):459-465.

162. Nivolumab (Opdivo) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; July 2022. https://packageinserts.bms.com/pi/pi_opdivo.pdf. Accessed August 17, 2022.

163. Long GV, Atkinson V, Lo S, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 2018;19(5):672-681.

164. Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med. 2018;379(8):722-730.

165. Gauvain C, Vauléon E, Chouaid C, et al. Intracerebral efficacy and tolerance of nivolumab in non-small-cell lung cancer patients with brain metastases. Lung Cancer. 2018;116:62-66.

166. Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257-265.

167. Pembrolizumab (Keytruda) [package insert]. Whitehouse Station, NJ: Merck & Co Inc; August 2022. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Accessed August 17, 2022.

168. Kluger HM, Chiang V, Mahajan A, et al. Long-term survival of patients with melanoma with active brain metastases treated with pembrolizumab on a phase II trial. J Clin Oncol. 2019;37(1):52-60.

169. Goldberg SB, Gettinger SN, Mahajan A, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016;17(7):976-983.

170. Afatinib (Gilotrif) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; April 2022. https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Gilotrif/Gilotrif.pdf?DMW_FORMAT=pdf. Accessed August 17, 2022.

171. Hoffknecht P, Tufman A, Wehler T, et al. Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol. 2015;10(1):156-163.

172. Schuler M, Wu YL, Hirsh V, et al. First-Line Afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016;11(3):380-390.

173. Gefitinib (Iressa) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; May 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206995s003lbl.pdf. Accessed August 17, 2022.

174. Ceresoli GL, Cappuzzo F, Gregorc V, et al. Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol. 2004;15(7):1042-1047. 

175. Wu C, Li YL, Wang ZM, Li Z, Zhang TX, Wei Z. Gefitinib as palliative therapy for lung adenocarcinoma metastatic to the brain. Lung Cancer. 2007;57(3):359-364.

176. Osimertinib (Tagrisso) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; January 2022. Tagrisso Full Precribing Information (den8dhaj6zs0e.cloudfront.net). Accessed August 17, 2022.

177. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-125.

178. Goss G, Tsai CM, Shepherd FA, et al. CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. Ann Oncol. 2018;29(3):687-693.

179. Yang JC, Ahn MJ, Kim DW, et al. Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA Study Phase II Extension Component. J Clin Oncol. 2017;35(12):1288-1296.

180. Erlotinib (Tarceva) [package insert]. South San Francisco, CA: Genentech USA Inc; October 2016. https://www.gene.com/download/pdf/tarceva_prescribing.pdf. Accessed August 17, 2022.

181. Grommes C, Oxnard GR, Kris MG, et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. 2011;13(12):1364-1369. 

182. Katayama T, Shimizu J, Suda K, et al. Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib. J Thorac Oncol. 2009;4(11):1415-1419.

183. Arbour KC, Kris MG, Riely GJ, et al. Twice weekly pulse and daily continuous-dose erlotinib as initial treatment for patients with epidermal growth factor receptor-mutant lung cancers and brain metastases. Cancer. 2018;124(1):105-109.

184. Capmatinib (Tabrecta) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; January 2022. https://www.novartis.com/us-en/sites/novartis_us/files/tabrecta.pdf. August 2022. Accessed September 25, 2022. Accessed August 17, 2022.

185. Wolf J, Seto T, Han JY, et al. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. N Engl J Med. 2020;383(10):944-957.

186. Selpercatinib (Retevmo) [package insert]. Indianapolis, IN: Lilly USA, LLC; January 2021. https://uspl.lilly.com/retevmo/retevmo.html#pi. Accessed July 20, 2022.

187. Subbiah V, Gainor JF, Oxnard GR, et al. Intracranial efficacy of selpercatinib in RET fusion-positive non-small cell lung cancers of the LIBRETTO-001 trial. Clin Cancer Res. 2021;27:4160-4167.

188. Alectinib (Alecensa) [package insert]. South San Francisco, CA: Genentech USA Inc; September 2021. https://www.gene.com/download/pdf/alecensa_prescribing.pdf. Accessed September 25, 2022.. Accessed August 17, 2022.

189. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377(9):829-838.

190. Gandhi L, Ou SI, Shaw AT, et al. Efficacy of alectinib in central nervous system metastases in crizotinib-resistant ALK-positive non-small-cell lung cancer: Comparison of RECIST 1.1 and RANO-HGG criteria. Eur J Cancer. 2017;82:27-33.

191. Brigatinib (Alunbrig) [package insert]. Lexington, MA: Ariad Pharmaceuticals Inc; February 2022. https://www.alunbrig.com/assets/pi.pdf. Accessed August 17, 2022.

192. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med. 2018;379(21):2027-2039. 

193. Kim DW, Tiseo M, Ahn MJ, et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol. 2017;35(22):2490-2498.

194. Ceritinib (Zykadia) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; October 2021. https://www.novartis.com/us-en/sites/novartis_us/files/zykadia.pdf. Accessed August 17, 2022.

195. Kim DW, Mehra R, Tan DSW, et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol. 2016;17(4):452-463.

196. Cho BC, Kim DW, Bearz A, et al. ASCEND-8: a randomized phase 1 study of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg in fasted state in patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic non-small cell lung cancer (NSCLC). J Thorac Oncol. 2017;12(9):1357-1367.

197. Lorlatinib (Lorbrena) [package insert]. New York, NY: Pfizer Labs; March 2021. https://labeling.pfizer.com/ShowLabeling.aspx?id=11140. Accessed August 17, 2022.

198. Shaw AT, Bauer TM, de Marinis F, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(21):2018-2029.

199. Crizotinib (Xalkori) [package insert]. New York, NY: Pfizer Labs; July 2022. https://labeling.pfizer.com/ShowLabeling.aspx?id=676. Accessed August 17, 2022.

200. Costa DB, Shaw AT, Ou SH, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol. 2015;33(17):1881-1888.

201. Topotecan injection (Hycamtin) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; October 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=eeee060c-a9ec-423e-a374-8484009f8524&type=display. Accessed September 19, 2022.

202. Lorusso V, Galetta D, Giotta F, et al. Topotecan in the treatment of brain metastases. A phase II study of GOIM (Gruppo Oncologico dell’Italia Meridionale). Anticancer Res. 2006;26(3B):2259-2263.

203. Glantz MJ, Jaeckle KA, Chamberlain MC, et al. A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res. 1999;5(11):3394-3402.

204. Chamberlain MC, Tsao-Wei DD, Groshen S. Phase II trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis. Cancer. 2006;106(9):2021-2027.

205. Grossman SA, Finkelstein DM, Ruckdeschel JC, Trump DL, Moynihan T, Ettinger DS. Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. Eastern Cooperative Oncology Group. J Clin Oncol. 1993;11(3):561-569.

206. Gutin PH, Weiss HD, Wiernik PH, Walker MD. Intrathecal N, N’, N”-triethylenethiophosphoramide [thio-TEPA (NSC 6396)] in the treatment of malignant meningeal disease: phase I-II study. Cancer. 1976;38(4):1471-1475. 

207. Groves MD, Glantz MJ, Chamberlain MC, et al. A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies. Neuro Oncol. 2008;10(2):208-215.

208. Zagouri F, Sergentanis TN, Bartsch R, et al. Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: a systematic review and pooled analysis. Breast Cancer Res Treat. 2013;139(1):13-22.

209. Park WY, Kim HJ, Kim K, et al. Intrathecal trastuzumab treatment in patients with breast cancer and leptomeningeal carcinomatosis. Cancer Res Treat. 2016;48(2):843-847.

210. Roci E, Cakani B, Brace G, et al. Platinum-based chemotherapy in recurrent high-grade glioma patients: retrospective study. Med Arch. 2014;68(2):140-143.

211. Franciosi V, Cocconi G, Michiara M, et al. Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Cancer. 1999;85(7):1599-1605.

212. Soussain C, Hoang-Xuan K, Taillandier L, et al. Intensive chemotherapy followed by hematopoietic stem-cell rescue for refractory and recurrent primary and recurrent CNS and intraocular lymphoma: Societe Francaise de Greffe de Moelle Osseuse-Therapie Cellulaire. J Clin Oncol. 2008;26:2512-2518.

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