Introduction
Selection of studies for review
Publication | n | Trial design | Trial duration | Patient population | Dose titration | GH and IGF-1 entry criteria | Target threshold values for GH and IGF-1 | Biochemical control rates | |||
---|---|---|---|---|---|---|---|---|---|---|---|
Previous treatment | Prior response to SSA | GH n (%) | IGF-1 n (%) | GH + IGF-1 n (%) | |||||||
Lancranjan et al. [8] | 101 | OL, P | 30 mo | TSS + oct sc (n = 101) | 83 pts were considered good responders to oct sc | Dose-ranging study: suppression of GH and IGF-1 assessed Biochemical control not defined | 55 (55)a
| 66 (65)b
| – | ||
Davies et al. [7] | 13 | OL, P | 1–3 yr | TSS (n = 2); RT (n = 1); TSS + RT (n = 4); Y implant (n = 1); de novo (n = 5) | Pts not selected for prior response | Dose-ranging study: suppression of GH and IGF-1 assessed Biochemical control not defined | 6 (46)c
| 7 (54)d
| – | ||
Lancranjan et al. [9] | 151 | OL, P | 12 mo | Oct sc (n = 49); TSS + oct sc (n = 56); RT + oct sc (n = 8); TSS + RT + oct sc (n = 38) | Only pts with GH < 10 µg/L during ≥4 wk treatment with oct sc were selected | Individualized according to the mean GH after the second dose | GH > 2 µg/L after OGTT and elevated IGF-1 | GH ≤ 2.5 µg/L IGF-1 normal | 104 (69) | 98 (65) | – |
Colao et al. [5] | 36 | OL, P | 24 mo | TSS (n = 5); TSS + oct sc (n = 5); TSS + oct LAR (n = 3); TSS + lan SR (n = 8); de novo (n = 15) | 16/21 pts with previous surgery received oct sc | Uptitrated in 15 pts with GH > 5 µg/L | GH > 2 µg/L after OGTT and elevated IGF-1 for age | GH ≤ 2.5 µg/L IGF-1 normal | 20 (56) | 19 (53) | – |
Cozzi et al. [6] | 110 | OL, Ret | 18–54 mo | TSS + oct LAR (n = 29); RT + oct LAR (n = 7); TSS + RT + oct LAR (n = 23); oct sc (n = 39); de novo (n = 12) | Pts had to have a GH and/or IGF-1 decrease of at least 20 % after a 6-month trial with oct LAR | Individualized to achieve normal age-adjusted IGF-1 levels and GH <2.5 µg/L | GH > 1 µg/L after OGTT and elevated IGF-1 for age | GH < 2.5 µg/L IGF-1 normal | 79 (72)e
| 83 (75)e
| – |
Ayuk et al. [24] | 91f
| OL, Ret | 48 wk | Oct sc (n = 34); TSS + oct sc (n = 29); RT + oct sc (n = 5); TSS + RT + oct sc (n = 23) | Only patients who completed 48 wk treatment were considered | Individualized according to the mean GH after the second dose | GH > 2 µg/L after OGTT and elevated IGF-1 | GH < 2.0 µg/L | 61 (67) | 48 (72) | – |
Jallad et al. [25] | 80 | OL, P | 12 mo | TSS + oct LAR (n = 24); TSS + RT + oct LAR (n = 28); lan (n = 14); DA (n = 1); de novo (n = 13) | Pts not selected for prior response | Individualized to achieve normal age-adjusted IGF-1 levels | GH > 1 µg/L after OGTT and elevated IGF-1 for age and sex | GH < 2.5 µg/L IGF-1 normal | 34 (43) | 20 (25) | – |
Cozzi et al. [12] | 67 | OL, P | 6–108 mo | De novo (n = 67) | Pts not selected for prior response | Individualized at 3- to 6-mo intervals if GH or IGF-1 levels remained elevated | GH > 1 µg/L after OGTT and elevated IGF-1 for age | GH < 2.5 µg/L IGF-1 normal | 46 (69)e
| 47 (70)e
| 38 (57)e
|
Colao et al. [11] | 56 | OL, Ret | 24 mo | De novo (n = 56) | 16 pts were excluded from the efficacy analysis because of lack of response before 24 mo | Uptitration in pts with IGF-1 levels above the normal range and/or GH > 2.5 mg/L | GH > 1 µg/L after OGTT and elevated IGF-1 for age | GH ≤ 2.5 µg/L IGF-1 normal | 48 (86) | 47 (84) | 45 (80) |
Mercado et al. [18] | 98 | OL, P | 48 wk | De novo (n = 98) | Pts not selected for prior response | Uptitration in pts with GH > 2.5 μg/L or IGF-1 above the adjusted normal range at 4 and 6 mo | GH > 1 µg/L after OGTT and IGF-1 > 97th percentile of the normal range for age and sex | GH ≤ 2.5 µg/L IGF-1 normal | 30 (31) | 23 (23) | 17 (17) |
Andries et al. [28] | 12 | OL, R, P, CO | 12 mo | TSS alone (n = 4); TSS + radiotherapy (n = 3); oct LAR (n = 11) | 4 pts had control of both GH and IGF-1 at study entry | – | – | GH < 0.38 µg/L IGF-1 normal | 5 (42) | 5 (42) | 4 (33) |
Colao et al. [16] | 48 | OL, R, P | 48 wk | De novo (n = 48) | Pts not selected for prior response | Uptitration in pts with mean GH >2.5 μg/L and/or elevated IGF-1 at 3 and 6 mo | GH > 1 μg/L after OGTT and IGF-1 > 97th percentile for age and sex | GH ≤ 2.5 µg/L IGF-1 normal | – | – | 13 (27) |
Ghigo et al. [26] | 56 | OL, R, P | 12 mo | All pts naïve to medical therapy and RT; TSS in an unreported number of pts | Pts not selected for prior response | Uptitration in pts with IGF-1 within 20 % below ULN or > ULN every 16 wk | GH > 1 μg/L after OGTT and IGF-1 ≥ 1.3xULN | IGF-1 normal | – | 19 (34) | – |
Oki et al. [27] | 30 | OL, Ret | 24 mo | TSS alone (n = 12); TSS + DA (n = 11); TSS + radiotherapy (n = 1); TSS + radiotherapy + DA (n = 5); de novo (n = 1) | Pts not selected for prior response | Uptitration in pts with mean GH >2.5 μg/L and/or elevated IGF-1 every 3 mo | – | GH ≤ 2.5 µg/L IGF-1 normal | 17 (57) | 16 (53) | 11 (37) |
Karaca et al. [17] | 11 | R, P | 12 mo | De novo (n = 11) | Pts not selected for prior response | Dose titration according to biochemical response at 3, 6 and 12 mo | – | GH ≤ 2.5 µg/L IGF-1 normal | 9 (82) | 3 (27) | 3 (27) |
Carlsen et al. [15] | 32 | R, P | 24 wk | De novo (n = 11) | Pts not selected for prior response | Fixed dose | GH > 5 mIU/L after OGTT | GH ≤ 2 mIU/L during OGTT IGF-1 ≤ ULN | 11 (34) | 10 (31) | 7 (22) |
Tutuncu et al. [14] | 36 | OL, Ret | 18 mo | TSS (n = 36) | Pts not selected for prior response | Dose titration according to biochemical response at 6 mo | GH > 1 μg/L after OGTT or mean GH > 5 µg/L and IGF-1 > ULN for age and sex | GH ≤ 2.5 µg/L IGF-1 normal | 24 (67) | 24 (67) | 23 (64) |
Colao et al. [19] | 182 | R, P, DB | 12 mo | TSS (n = 80); RT (n = 1); de novo (n = 101) | Pts not selected for prior response | Optional uptitration in pts with mean GH ≥2.5 μg/L and/or IGF-1 > ULN at 3 and 7 mo | GH > 1 μg/L after OGTT or mean GH > 5 µg/L and IGF-1 > ULN for age and sex | GH < 2.5 µg/L IGF-1 normal | 94 (52) | 43 (24) | 35 (19) |
Publication | n | Trial design | Trial duration | Patient population | Dose titration | GH and IGF-1 entry criteria | Target threshold values for GH and IGF-1 | Biochemical control rates | |||
---|---|---|---|---|---|---|---|---|---|---|---|
Previous treatment | Prior response to SSA | GH n (%) | IGF-1 n (%) | GH + IGF-1 n (%) | |||||||
Caron et al. [29] | 130 | OL, P | 12 mo | TSS (n = 99); RT (n = 57); lan SR (n = 130); lan ATG (n = 130) | All pts had completed a 3-month study of lan ATG in which pts were selected based on response to lan SR | Dose titration according to biochemical response at study entry, 4 and 8 mo | – | GH < 2.5 µg/L IGF-1 normal | 83 (64) | 62 (48) | 52 (40) |
Alexopoulou et al. [30] | 25 | OL, P | 24 wk | TSS (n = 13); RT (n = 5); oct LAR (n = 25) | All pts had been treated with oct LAR at a fixed dose for ≥6 mo | Dose titration according to biochemical response at 8 wk | – | GH < 2.5 µg/L IGF-1 normal | 12 (48) | 13 (52) | – |
Lucas et al. [36] | 98 | OL, P | 12–30 wk | TSS (n = 76); radiotherapy (n = 53); lan SR (n = 98) | All pts had been treated with lan SR for ≥ 2 mo immediately prior to study entry | Fixed dose | GH > 2 µg/L after OGTT and IGF-1 > ULN for age and sex | GH < 2.5 µg/L IGF-1 normal | 53 (54) | 55 (56) | 39 (40) |
Ronchi et al. [31] | 23 | OL, P | 34–42 wk | TSS (n = 16); oct LAR (n = 23) | Only pts with GH reduction of >50 % during 6–18 mo treatment with oct LAR were selected | Dose titration according to biochemical response at 18 wk | GH reduction of >50 % during 6–18 mo treatment with oct LAR | GH < 2.5 µg/L IGF-1 normal | 13 (57) | 9 (39) | 7 (30) |
Chanson et al. [13] | 63 | OL, P | 48 wk | TSS (n = 37); RT (n = 12); prior medical therapy (n = 49) | Pts not selected for prior response | Dose titration according to biochemical response at 16 and 32 wk | IGF-1 ≥ 1.3xULN | GH < 2.5 µg/L IGF-1 normal | 53 (84)a
| 27 (43)a
| 24 (38) |
Attanasio et al. [32] | 27 | OL, P | 12 mo | TSS (n = 8); de novo (n = 19) | Pts not selected for prior response | Individualized every mo according to biochemical response | GH > 1 μg/L after OGTT and IGF-1 > ULN for age and sex | GH < 2.5 µg/L IGF-1 normal | 11 (41) | 14 (52) | 10 (37) |
Andries et al. [28] | 12 | OL, R, P, CO | 12 mo | TSS alone (n = 4); TSS + radiotherapy (n = 3); oct LAR (n = 11) | 4 pts had control of both GH and IGF-1 at study entry | – | – | GH < 0.38 µg/L IGF-1 normal | 5 (42) | 6 (50) | 5 (42) |
Colao et al. [33] | 26 | OL, P | 12 mo | De novo (n = 26) | Pts not selected for prior response | Dose titration according to biochemical response at 12 wk | GH > 1 μg/L after OGTT or mean GH > 2.5 µg/L and IGF-1 > ULN for age and sex | GH ≤ 5 mU/L IGF-1 normal | 15 (58) | 15 (58) | 14 (54) |
Lombardi et al. [34] | 63 | OL, P | 48–52 wk | TSS (n = 12); de novo (n = 39)b
| Pts not selected for prior response | Dose titration according to biochemical response at 24 wk | GH > 1 μg/L after OGTT or mean GH > 5 µg/L and IGF-1 > ULN for age and sex | GH < 2.5 µg/L IGF-1 normal | 32 (51) | 19 (30) | 18 (29) |
Melmed et al. [20] | 107 | OL, R, P | 52 wk | TSS (n = 59); RT (n = 12); lan SR (n = 21); oct LAR (n = 27); oct sc (n = 4); DA (n = 4); de novo (n = 15) | Pts not selected for prior response | Dose titration according to biochemical response at 16 and 32 wk | GH > 3–5 µg/L | GH ≤ 2.5 µg/L IGF-1 normal | 55 (51) | 62 (58)c
| 44 (41)c
|
Salvatori et al. [21] | 26 | OL, P | 6 mo | TSS (n = 22); oct LAR (n = 4); oct sc (n = 1); DA (n = 6); no prior medical therapy (n = 15) | Pts not selected for prior response | Dose titration according to biochemical response at 16 wk | – | GH < 1.0 µg/L post-OGTT IGF-1 normal | 9 (35) | 10 (38)d
| 7 (27)d
|
Schopohl et al. [35] | 37 | OL, P | 24–48 wk | Oct LAR (n = 37); TSS in an unreported number of pts | Pts were adequately treated with oct LAR for ≥6 mo (IGF-1 ≤ 1.3xULN) | Dose titration after 3 injections to lan ATG every 28, 42 or 56 days | IGF-1 ≤ 1.3xULN while on oct LAR | GH < 2.0 µg/L IGF-1 normal | 25 (68)e
| 22 (59) | – |
Tutuncu et al. [14] | 32 | OL, Ret | 18 mo | TSS (n = 32) | Pts not selected for prior response | Dose titration according to biochemical response at 6 mo | GH > 1 μg/L after OGTT or mean GH > 5 µg/L and IGF-1 > ULN for age and sex | GH < 2.5 µg/L or < 1 µg/L post-OGTT IGF-1 normal | 25 (78) | 25 (78) | 25 (78) |
Annamalai et al. [22] | 30 | OL, P | 24 wk | De novo (n = 30) | Pts not selected for prior response | Uptitration in pts with mean GH ≥ 2.5 μg/L and/or IGF-1 > ULN at 3 mo | GH > 0.4 μg/L after OGTT and IGF-1 > ULN for age and sex | GH < 1.0 µg/L IGF-1 ≤ 1.1xULN | 12 (40) | 12 (40) | 10 (33) |
Shimatsu et al. [23] | 32 | OL, R, P | 24 wk | TSS (n = 26), RT (n = 4), medical therapy (n = 13) | Pts not selected for prior response | Fixed dose | GH > 1.7–2.8 µg/L | GH < 2.5 µg/L IGF-1 normal | 17 (53) | 14 (44) | 13 (41) |
Shimatsu et al. [23] | 32 | OL, P | 12 mo | TSS (n = 27), RT (n = 6), medical therapy (n = 20) | 8 patients had completed a previous study of lan ATG | Uptitration in pts with mean GH ≥1.0 μg/L and/or IGF-1 > ULN at 4 and 8 mo | GH > 2.5 µg/L | GH < 2.5 µg/L IGF-1 normal | 15 (47) | 17 (53) | 13 (41) |