Identification of potential surrogate end points in randomized clinical trials of aggressive and indolent non-Hodgkin's lymphoma: correlation of complete response, time-to-event and overall survival end points.
BACKGROUND
The correlation between efficacy end points in randomized controlled trials (RCTs) of systemic therapy for non-Hodgkin's lymphoma (NHL) was investigated to identify an appropriate surrogate end point for overall survival (OS).


METHODS
RCTs of previously untreated NHL published from 1990 to 2009 were identified. Associations between absolute differences in efficacy end points were determined using nonparametric Spearman's rank correlation coefficients (r(s)).


RESULTS
Thirty-eight RCTs representing 85 treatment arms for aggressive NHL and 20 RCTs representing 42 arms for indolent NHL were included. For aggressive NHL, differences in 3-year progression-free survival (PFS)/event-free survival (EFS) were high correlated with differences in 5-year OS {r(s) of 0.90 [95% confidence interval (CI) 0.73-0.96]} and linear regression determined that a 10% improvement in 3-year EFS or PFS would predict for a 7% ± 1% improvement in 5-year OS. For indolent histology disease, differences in complete response were strongly correlated with differences in 3-year EFS [r(s) 0.86 (95% CI 0.35-0.97)], but there was no correlation between 3-year time-to-event end points and 5-year OS.


CONCLUSIONS
Improvements in 3-year EFS/PFS are highly correlated with improvements in 5-year OS in aggressive NHL and should be explored as a candidate surrogate end point. Definition of these relationships may inform future clinical trial design and interpretation of interim trial data.
Division of Medical Oncology and Hematology.
L
L
Lee
Department of Biostatistics, Princess Margaret Hospital, Toronto, Canada.
L
L
Wang
Division of Medical Oncology and Hematology. Electronic address: michael.crump@uhn.on.ca.
M
M
Crump
D014408:Biomarkers, Tumor / Q000032:analysis*; D018572:Disease-Free Survival; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000737:chemistry / Q000401:mortality* / Q000628:therapy*; D016032:Randomized Controlled Trials as Topic; D012074:Remission Induction; D012107:Research Design; D016896:Treatment Outcome
D014408:Biomarkers, Tumor
Ann Oncol. 1998 Jun;9(6):633-8
9681077
N Engl J Med. 1993 Dec 9;329(24):1770-6
7694148
Leuk Lymphoma. 1995 Feb;16(5-6):457-63
7540460
Ann Oncol. 2000;11 Suppl 1:87-90
10707786
Blood. 2002 Dec 15;100(13):4351-7
12393618
Ann Oncol. 1999 Sep;10(9):1079-86
10572606
J Clin Oncol. 1998 Oct;16(10):3264-9
9779700
Leuk Lymphoma. 2007 Feb;48(2):367-73
17325898
Ann Intern Med. 1996 Oct 1;125(7):605-13
8815760
Blood. 2005 Dec 1;106(12):3725-32
16123223
J Clin Oncol. 1997 Mar;15(3):1110-7
9060552
Int J Hematol. 2004 Nov;80(4):341-50
15615259
Leuk Lymphoma. 2006 Nov;47(11):2321-30
17107904
J Clin Oncol. 1998 Apr;16(4):1538-46
9580385
Cancer. 1990 Nov 1;66(9):1888-96
1699653
Ann Oncol. 2008 Mar;19(3):545-52
18065407
J Natl Cancer Inst. 2007 Mar 21;99(6):428-32
17374832
Stat Med. 1989 Apr;8(4):431-40
2727467
J Natl Cancer Inst. 2009 Dec 2;101(23):1642-9
19903805
Leuk Lymphoma. 2000 Dec;40(1-2):95-103
11426633
Blood. 2004 Aug 1;104(3):626-33
14982884
Ann Oncol. 2010 Mar;21(3):518-524
19759186
Blood. 2003 Dec 15;102(13):4284-9
12920037
J Clin Oncol. 1999 Apr;17(4):1244
10561185
Blood. 2004 Aug 1;104(3):634-41
15016643
Ann Oncol. 2005 Mar;16(3):466-72
15695500
Int J Hematol. 2005 Apr;81(3):246-54
15814336
J Clin Oncol. 2006 Apr 1;24(10):1590-6
16575010
Haematologica. 1998 Sep;83(9):800-11
9825577
Br J Cancer. 2006 Mar 27;94(6):806-13
16508640
Ann Oncol. 1999 Oct;10(10):1191-7
10586336
J Clin Oncol. 2006 Jul 1;24(19):3121-7
16754935
J Clin Oncol. 2007 Nov 20;25(33):5218-24
18024867
N Engl J Med. 1992 Nov 5;327(19):1342-9
1383819
Blood. 2008 Dec 15;112(13):4824-31
18799723
Ann Oncol. 1994;5 Suppl 2:85-9
7515651
Cancer J. 2007 Sep-Oct;13(5):327-34
17921732
Leukemia. 2001 Jul;15(7):1118-22
11455982
N Engl J Med. 1993 Nov 25;329(22):1608-14
8232429
Ann Oncol. 2010 Jan;21(1):7-12
19901012
N Engl J Med. 2002 Jan 24;346(4):235-42
11807147
J Clin Oncol. 2003 Jan 1;21(1):5-15
12506163
Cancer. 1998 Jun 1;82(11):2282-8
9610711
J Clin Oncol. 2007 Feb 10;25(5):579-86
17242396
J Clin Oncol. 2008 Oct 1;26(28):4579-86
18662969
Blood. 2007 Apr 1;109(7):2759-66
17132720
Blood. 2001 May 15;97(10):2991-7
11342422
J Cancer Res Clin Oncol. 2006 Feb;132(2):105-12
16088404
Br J Haematol. 2005 Aug;130(4):536-41
16098067
J Thorac Oncol. 2009 Mar;4(3):311-7
19190515
Cancer Biother Radiopharm. 2007 Apr;22(2):194-9
17600466
Lancet Oncol. 2006 May;7(5):379-91
16648042
Leukemia. 1996 May;10(5):836-43
8656680
J Clin Oncol. 1994 Jul;12(7):1366-74
7517442
Blood. 2003 May 15;101(10):3840-8
12531794
Ann Oncol. 2008 Mar;19(3):481-6
18029973
Eur J Haematol. 2006 Mar;76(3):217-29
16451396
Cancer. 2008 Jul 15;113(2):367-75
18470902
J Clin Oncol. 2007 Oct 10;25(29):4562-8
17876010
J Clin Oncol. 2007 May 20;25(15):1986-92
17420513
N Engl J Med. 1993 Apr 8;328(14):1002-6
7680764
Eur J Cancer. 1997 Jul;33(8):1195-201
9301442
Ann Oncol. 1997;8 Suppl 1:71-5
9187435
Leuk Lymphoma. 1995 Apr;17(3-4):313-20
8580801
Ann Oncol. 1994;5 Suppl 2:67-71
7515649
J Clin Oncol. 2008 Aug 1;26(22):3721-6
18669458
Blood. 2007 Mar 1;109(5):1810-6
17095617
Eur J Haematol. 2002 Mar;68(3):135-43
12068793
J Clin Oncol. 2010 Apr 20;28(12):2094-100
20308668
J Clin Oncol. 2008 Apr 20;26(12):1987-92
18421050
Oncologist. 2006 Jun;11(6):624-9
16794241
Biostatistics. 2000 Mar;1(1):49-67
12933525
Lancet. 2008 Aug 9;372(9637):427-9
18653227
J Clin Oncol. 2005 Dec 1;23(34):8664-70
16260700
J Clin Oncol. 2010 Jun 10;28(17):2853-8
20439641
J Clin Oncol. 2009 Jan 1;27(1):114-9
19047289
Cancer. 2006 Sep 1;107(5):1014-22
16878325