Table II.

Summary results

Trial	Background CNS treatment	Arm 1	Arm 2*	Conclusions
A: TIT versus IT therapy (n=2029)
CCG-195211	DIT × 1 + IT × 1	TIT × 14 (f) or 18 (m)	IT × 14 (f) or 18 (m)	TIT reduced CNS relapse compared with IT but an increase in non-CNS relapse resulted in similar EFS and worse OS (OR=1·50; p=0·01).
Ba: Radiotherapy plus short-term IT therapy versus extra IT therapy (n=2614)
CCG-16112	IT × 6	CRT	IT × 8	Adding CRT to short-term IT reduced CNS relapses (OR=0·68; p=0·01) compared with adding more IT doses, but did not substantially affect EFS (OR=0·92; 95% CI = 0·80 1·05; p=0·2).
CCG-10513	IT × 6	CRT	IT × 8 (f) or 14 (m)
INEN-P83	IT × 5	CRT	IT × 12
CCG-188214	IT × 15 (f) or 19 (m)	CRT	IT × 7
Bb: Radiotherapy plus short-term IT therapy versus DIT or TIT (n=234)
LAL 7/7816		CRT + IT × 6	DIT × 10	Small numbers make results uncertain but OS was worse with CRT (OR=1·63; p=0·02)
INS 8417	TIT × 6	CRT	TIT × 12
INEN-P85		CRT + IT × 5	TIT × 17
Bc: Radiotherapy plus DIT versus extra TIT (n=155)
DFCI ALL 95-00118	IT × 1 + TIT × 2	CRT + DIT × 6	TIT × 12	Insufficient data to draw any conclusions.
Ca: Addition of IV methotrexate to TIT or TIT with IV methotrexate (n=1751)
SJCRH Total XIIIA19	TIT × 13 or 17 + IV × 9 or 10	IV × 1	Control	Adding IV MTX to TIT reduced both CNS (OR=0·48; p=0·0009) and non-CNS relapse (OR=0·65; p=0·002), giving better EFS (OR=0·65; p=0·00005) and OS (OR=0·71; p=0·02)
POG 900520	IV mp × 17–19 + TIT × 16	IV × 12	Control
FRALLE 93 LR21	TIT × 16	IV × 6	Control
FRALLE 93 IR21	TIT × 18	IV × 4	Control
SJCRH Total XIIIB22	IV mp + TIT × 13 or 15 + IV × 10	IV × 1	Control
Cb: Addition of IV methotrexate to long-term IT therapy (n=2014)
CCG-13923	IT × 15 (f) or 20 (m)	IV × 24 (f) or 33 (m)	Control	Adding IV MTX to long-term IT probably reduced CNS relapse (OR=0·78; p=0·06), but did not improve EFS or OS.
DFCI 8700124	IT × 11 (HR: + CRT)	IV × 1	Control
UKALLXI LWCC25	IT × 16	IV × 3	Control
Cc: Addition of IV methotrexate to radiotherapy with TIT or IT therapy (n=375)
DFCI 8100126	CSCRT + IT × 9	IV × 1	Control	Adding IV MTX to CRT with short-term IT or TIT reduced CNS relapses (OR=0·39; p=0·008) and improved EFS (OR=0·64; p=0·03), but small numbers make these results less reliable.
POG 940427	TIT × 11 + CRT	IV × 4	Control
D: IV methotrexate + IT therapy + TIT versus extra TIT (n=1159)
POG8035/803628	TIT × 6	IV × 17 + IT × 4	TIT × 17	IV MTX was less effective than extra TIT in preventing CNS relapse (OR=1·64; p=0·01) but the reduction in non-CNS relapse (OR=0·82; p=0·08) resulted in equivalent EFS and OS.
E: Addition of IT therapy to radiotherapy plus short-term IT therapy (n=1174)
CCG-16230	CRT + IT × 6	IT × 8	Control	Adding extra IT therapy to CRT with short-term IT did not give benefit.
UKALLVII31	CRT + IT × 5	IT × 8	Control
F: Radiotherapy versus IV methotrexate: short-term IT, DIT in both arms (IV MTX in one trial) and some additional IT or TIT in the IV MTX arm (n=1635)
CLB 761132	IT × 6	CRT	IV × 3	CRT given with short-term IT, DIT or TIT, reduced CNS relapse (OR=0·43; p<0·00001) compared with giving IV MTX, with or without extra IT, but non-CNS relapses were increased (OR=1·54; p=0·00001), resulting in no difference in EFS or OS.
ALL-BFM-8134	IT × 6	CRT	IV × 4
Jena ALL VII 8135	IT × 8	CRT	IV × 4
JCCLSG L-87436	DIT × 3	CRT	IV × 3 + TIT × 6
JCCLSG I-87436	IV × 21+ DIT × 1	CRT + DIT × 2	IV × 3
GCMTLA37	TIT ×6	CRT	IV × 4 + TIT × 6
UKALLXI HWCC25	IT × 7 or 9	CRT	IV × 3 + IT × 8 or 9
MRC ALL9739	IT × 7 or 9	CRT	IV × 3 + IT × 8 or 9
G: Higher dose of IV methotrexate (n=1071)
POG 940540	TIT × 22	2·5 g/m2 IV × 12	1 g/m2 IV × 12	No benefit from higher dose of IV MTX.
POG 940640	TIT × 18 + 1 g/m2 IV mp × 6	2·5 g/m2 IV × 6	1 g/m2 IV × 6
H: Higher doses of radiotherapy (n=905)
UKALL V41	IT × 5	24 Gy CRT	21 Gy CRT	No benefit from higher doses of CRT.
UKALLVI(i)42	IT × 10 or IT × 8 + IV × 3	24 Gy CRT	21 Gy CRT
UKALLVI(ii)42	IT × 10 or IT × 8 + IV × 3	24 Gy CRT	18 Gy CRT
UKALLVII31	IT × 5	24 Gy CRT	18 Gy CRT
GBTLI-8043	IT × 13	24 Gy CRT	18 Gy CRT
TCCSG L81-1044	DIT × 5	24 Gy CRT	18 Gy CRT
ALL-BFM-8334	IT × 8 + IV × 4	18 Gy CRT	12 Gy CRT
Ia: Addition of radiotherapy to short-term IT therapy (n=475)
CCG-10150	IT × 6	CRT	Control	Adding CRT to 6 or 7 doses of IT reduced CNS relapses (OR=0·28; p <0·00001) and improved EFS (OR=0·68; p=0·003)
CCG-12351	IT × 7	CRT	Control
Ib: Addition of radiotherapy to IV methotrexate plus IT therapy (n=189)
EORTC 5883252	IV × 4 + IT × 7	CRT	Control	Insufficient data to draw any conclusions.
J: Higher dose of IV methotrexate versus more IT or DIT therapy (n=700)
FRALLE 8753	DIT × 5	8 g/m2 IV × 4	3 g/m2 IV × 4 + DIT × 5	There was no evidence of a difference between high dose and a lower dose with extra IT or DIT.
FRALLE 8921	IT × 5	8 g/m2IV × 4	3 g/m2IV × 4 + IT × 5
K: Addition of IV methotrexate plus IT, DIT or TIT therapy to radiotherapy plus IT or TIT therapy and/or IV methotrexate (n=511)
Jena ALLVII 8135	CRT + IT × 8	IV × 4 + IT × 4	Control	There was no evidence of a benefit from adding IV MTX with extra IT, DIT or TIT to a treatment which included CRT.
TCCSG L84-11 SR38	CRT + TIT × 5 + IV × 4 + IT × 4	IV × 3 + DIT × 6	Control
TCCSG L84-11 HR38	CRT + TIT × 5 + IV × 12 + DIT × 12	IV × 3 + TIT × 6	Control

^*Arm 2 = Control indicates that no CNS treatment was given additional to the background.

CRT, cranial irradiation; CSCRT, craniospinal irradiation; DIT, double intrathecal; f, female; IT, intrathecal; IV, intravenous methotrexate; IV mp, intravenous mercaptopurine; m, male; TIT, triple intrathecal.