1. Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing (MRC FOCUS)
- a 2135-patient randomised trial in advanced colorectal cancer
Matt Seymour, on behalf of the UK NCRI Colorectal Clinical Studies Group and FOCUS Trial Investigators
(Enquiries:

2. Background and rationale for study
Both oxaliplatin and irinotecan are well-established active agents in metastatic colorectal cancer. Each can be used in combination with fluoropyrimidines in 1st-line therapy or as 2nd-line therapy. Irinotecan may also be used as single-agent 2nd-line therapy.
Phase III trials reported in gave proof of improved RR and PFS, but also some additional toxicity, with 1st-line combination therapy. OS advantage was seen in irinotecan but not oxaliplatin trials, a difference which was thought to have arisen from differing usage of effective 2nd-line/cross-over therapy.
From 2002, UK Health Service guidance recommended 1st-line FU alone followed by 2nd-line single-agent irinotecan for most patients (but 1st-line FU/Ox combination for patients where a response may potentially allow liver resection).
QUESTION: does 1st-line combination therapy improve overall survival and/or quality of life compared with 1st-line FU plus a consistent policy of 2nd-line combination therapy or 2nd-line irinotecan?

3. Aims
To determine if there is an advantage to the use of combination chemotherapy for colorectal cancer compared with the UK standard approach of sequential FU then Ir (“staged single agents”)
To determine if combination therapy is best used 1st-line, or reserved for 2nd-line after single-agent FU (“staged combination”).
To compare the efficacy and toxicity of an irinotecan-containing combination vs the equivalent oxaliplatin-containing combination

4. to find predictive variables
Design
A:(700 pts) FU until it fails, then change to Ir
B(ir): (350) FU until it fails, then add Ir
B(ox): (350) FU until it fails, then add Ox
C(ir): (350) FU+Ir from the start until it fails
C(ox): (350) FU+Ox from the start until it fails
Ox+fluoropyrimidine Ox+fluoropyrimidine
Ir +fluoropyrimidine
Ox +fluoropyrimidine
2100
patients
3rd drug salvage
introduced Feb 03; prior to that “no crossover” salvage with Mitomycin/FU
time to failure
of first 2 drugs.
molecular pathology
to find predictive variables
(Adlard et al ASCO‘04 #9506)
Power: 80% (α = 0.01) to detect a difference of 22.5% vs 15% in 2-year overall survival of each plan against Plan A.

5. Endpoints Primary - Overall survival
Secondary - PFS, RECIST response, Time to failure of first two drugs
Other – Quality of Life & Economic evaluation

6. Drug Regimens FU “MdG” Ir + FU “IrMdG” Ox + FU “OxMdG” Ir
dexamethasone 8 mg iv
l-LV 175 mg 2hr ivi
5FU 400 mg iv bolus
5FU 2800 mg 46-hr ivi
oral dexamethasone d2-4
cycle repeat 14 days
Ref: Cheeseman et al,
Br J Cancer 87:393-9, 2002
Ir + FU
“IrMdG”
dexamethasone 8 mg iv
irinotecan 180mg/m2 30 mins ivi, then
l-LV 175 mg, 2hr ivi
FU 400 mg/m2 iv bolus
FU 2400 mg/m2 46hr ivi
oral dexamethasone d2-4
cycle repeat 14 days
Ref: Leonard et al,
Br J Cancer 87: , 2002
Ox + FU
“OxMdG”
dexamethasone 8 mg iv
oxaliplatin 85mg/m2 plus l-LV 175 mg, 2hr ivi (concurrent), then
FU 400 mg/m2 iv bolus
FU 2400 mg/m2 46hr ivi
oral dexamethasone d2-4
cycle repeat 14 days
Ref: Cheeseman et al,
Br J Cancer 87:393-9, ‘02 Ir
single-agent Ir
dexamethasone 8 mg iv
irinotecan 350 mg/m2, 90 mins ivi (300 mg/m2 if PS2 or age >70)
oral dex d2-4
cycle repeat 21 days
Reference: SPC

7. Eligibility Criteria
Histologically confirmed adenocarcinoma of the colon or rectum
Inoperable metastatic of locoregional disease
No previous chemotherapy for established metastatic disease
WHO performance status 0, 1 or 2
BUT:
Patients with with metastases which may potentially become operable after a chemotherapy response were not entered (eligible for 1st-line Ox+FU combination under national guidance)

8. Results A n=701 B(ir) n=356 B(ox) n=356 C(ir) n=356 C(ox) n=357
2135 patients were entered between May 2000 and December 2003
at 61 participating oncology centres in the UK and Cyprus
Pre-treatment characteristics
Plan
A n=701
B(ir) n=356
B(ox) n=356
C(ir) n=356
C(ox) n=357
male female
70% 30%
69% 31%
66% 34%
67% 33%
Age: median (interquartiles)
63 (56-69)
64 (57-70)
64 (56-69)
64 (57-69)
PS = 0 PS = 1 PS = 2
41% 50% 9%
41% 51% 8%
41% 50% 8%

9. Chemotherapy delivery
Plan A
B(ir)
B(ox)
C(ir)
C(ox)
first two drugs on FOCUS plan
1st line regimen (mean cycles)
MdG 10
MdG 9.7
IrMdG 10.5
OxMdG 10.6
2nd line regimen (mean cycles
Ir 4.9
IrMdG 7.7
OxMdG 7.7 -
salvage: third and further drugs
received any salvage chemo
24%
27%
25%
46%
41%
received cross-over drug (Ox/Ir)
13% (Ox)
12% (Ox)
17% (Ir)
27% (Ox)
26% (Ir)

10. A,B(ir) & B(ox) C(ir) C(ox)
Tolerability of 1st-line therapy: CTC grade3 toxicity
A,B(ir) & B(ox)
C(ir)
C(ox)
Treatment regimen (n)
MdG (1316)
IrMdG (339)
OxMdG (340)
neutrophils
8.6%
19.5%
27.7%
platelets
0.4%
1.2%
2.4%
vomiting
3.0%
7.7%
diarrhoea
5.5%
12.4%
10.6%
neuropathy
0.7%
2.7%
11.2%
lethargy
13.0%
21.3%
23.8%
alopecia
0.2%

11. A B(ir) B(ox) Tolerability of 2nd-line therapy: CTC grade3 toxicity
Treatment regimen (n)
Ir (337)
IrMdG (175)
OxMdG (200)
neutrophils
13.1%
19.4%
23.9%
vomiting
5.9%
4.6%
5.1%
diarrhoea
15.7%
8.6%
8.0%
neuropathy
0.6%
1.1%
3.0%
lethargy
17.2%
19.9%
19.1%
alopecia
9.5%
2.9%
0.0%

12. Overall survival (1556 events)
Proportion
Months
Overall survival (1556 events)

13. Overall survival (1556 events)
Proportion
Months

14. Plan First 2 drugs schedule Median OS A FU then Ir 13.9 B(ir) B(ox)
FU then FU/Ir
FU then FU/Ox
14.8
15.2
C(ir)
C(ox)
1st-line FU/Ir
1st-line FU/Ox
16.3
Comparison n
Logrank HR (95%ci) p
B vs A
B(ir) vs A
B(ox) vs A
B(ir)+B(ox) vs A
1066
1422
0.92 (0.60 – 1.07)
0.95 (0.82 – 1.10)
0.93 (0.82 – 1.05)
0.275
0.456
0.247
C vs A
C(ir) vs A
C(ox) vs A
C(ir)+C(ox) vs A
1067
1423
0.86 (0.74 – 1.00)
0.96 (0.83 – 1.11)
0.90 (0.80 – 1.02)
0.043
0.563
0.109
C vs B
C(ir) vs B(ir)
C(ox) vs B(ox)
C(ir)+C(ox) vs B(ir)+B(ox)
712
713
1425
0.93 (0.78 – 1.12)
1.03 (0.90 – 1.29)
0.98 (0.88 – 1.14)
0.441
0.712
0.695
IrMdG vs OxMdG
B(ir) vs B(ox)
C(ir) vs C(ox)
B(ir)+C(ir) vs B(ox)+C(ox)
0.97 (0.82 – 1.16)
0.88 (0.74 – 1.05)
0.93 (0.82 – 1.05)
0.771
0.165
0.220

15. Subgroup OS analysis – [C(ir)+C(ox)] versus [B(ir)+B(ox)]
Age

16. Subgroup OS analysis – [C(ir)+C(ox)] versus [B(ir)+B(ox)]
Performance Status

17. Subgroup OS analysis – [C(ir)+C(ox)] versus [B(ir)+B(ox)]
Prior Adjuvant Chemo

18. A,B(ir) & B(ox) C(ir) C(ox)
Response to 1st line chemotherapy (RECIST) criteria
A,B(ir) & B(ox)
C(ir)
C(ox)
Treatment regimen (n)
MdG (1157)
IrMdG (284)
OxMdG (299)
CR+PR
28.5%
51.4%
56.2% SD
47.9%
37.0%
30.1% PD
23.6%
11.6%
13.7%
(Measurable patients with 1 follow-up assessment)

19. PFS, 1st line (1969 events)

20. A B(ir) B(ox) Response to 2nd line chemotherapy Treatment regimen (n)
IrMdG (141)
OxMdG (155)
CR+PR
11%
21%
23% SD
42%
44%
48% PD
47%
35%
28%

21. PFS, 2nd line (659 events)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0 6 12 18
regimen
186
209
163
182
310
355
Events
Total
Plan A Ir
Plan B(ir)
IrMdG
Plan B(ox)
OxMdG

22. Time to failure of the first two drugs (1505 events)
Median FFS HR (95%CI), p-value (versus A) A
B(ir) (0.78, 1.06) p=0.203
B(ox) (0.77, 1.04) p=0.163
C(ir) (1.08, 1.45) p=0.003
C(ox) (1.03, 1.38) p=0.020
Proportion
Months

23. QoL - EORTC QLQ-C30 - mean global QL scores over time

24. Conclusions: Overall survival:
No major differences: no comparisons reached p<0.01 level.
“Staged single agents” (FU then Ir) tends towards inferiority compared to any other plan (reaches p=0.043 against 1st-line FU+Ir).
“Staged combination” (FU then combination) is non-inferior to 1st- line combination chemotherapy (HR 0.98 [ ]).
Trend toward OS benefit for 1st-line combination in PS2 subgroup.
Secondary endpoints:
We confirm higher RR, PFS and toxicity of combination therapy.
1st-line combination “uses up” first 2 drugs earlier.
The higher RR/PFS of 1st-line combinations does not give better QoL.

25. Questions and issues:
Many of the best prognosis patients (“potentially down-stageable” liver metastases) were not included in this trial:
explains why median OS is lower than in some other trials.
conclusions don’t apply to potentially down-stageable patients.
Low rate of “3rd drug salvage” in this trial (non-crossover policy up to Feb 2003).
would more cross-over have affected the result?
The “MdG” FU regimen is highly active (RR 28.5%, PFS >7 months).
success of staged combination may depend on this high efficacy.
Non-inferiority of the staged combination permits consideration of 1st-line “MdG+novel therapy” arms in future trials.