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2013 ASCO CRC Poster Discussion
(Old Dog, New Tricks)
Weijing Sun, MD, FACP
University of Pittsburgh
• Bevacizumab in CRC Therapy: Doses, efficacy,
maintenance, and impact of ages
- 3515, 3516, 3517, 3521
• S-1 in CRC: the un-replaceable role of fluoropyrimidines
in CRC therapy, and equivalence of different analogs :
-3518, 3519
• Early response is critical and an indicator for the overall
outcome: 3520
• What can we learn from these studies?
• What is the potential impact of these studies
on clinic practice?
3516: FOLFIRI plus bevacizumab as second-line therapy in
patients with metastatic colorectal cancer who have failed firstline bevacizumab plus oxaliplatin-based therapy: the randomized
phase III EAGLE study
Hiroshi Tamagawa, et al
Evaluated the optimal dose of Bevacizumab (2nd-line):
A long-time question since the first day of bevacizumab in
clinical practice: 5mg/kg vs. 10 mg/kg vs. 7.5 mg/kg
(commonly used in q3wks regimen with XELOX)
Oxaliplatin based CTx
+ bevacizumab 5mg/kg
Arm A: FOLFIRI
+ bevacizumab 5mg/kg
R
N=367
Primary End Point: PFS
Secondary end points: Toxicity, RR, TTF, OS,
OS from the first-line, duration from the start
of the first-line
Arm B: FOLFIRI
+ bevacizumab 10mg/kg
PFS
100
PFS Probability (%)
80
60
A
B
Hazard ratio: 0.95 (95% CI: 0.75-1.21)
p= 0.676 (log-rank test)
Median PFS:
A = 6.1 month (95% CI: 5.3-7.0);
B = 6.4 month (95% CI: 5.6-7.4)
40
20
0
6
12
18
Months
24
30
36
Subgroup Analysis of PFS
Hazard Ratio (95% CI)
LY metastasis
no
0.99(0.75-1.29)
yes
1.08(0.71-1.66)
Peritoneal metastasis no
0.93(0.72-1.20)
yes
1.31(0.78-2.20)
<65 years
1.02(0.73-1.41)
≥65 years
1.00 (0.73-1.38)
<180 days
0.75(0.46-1.24)
≥180 days
1.14(0.88-1.48)
<20 ng/mL
1.25(0.88-1.77)
≥20 ng/mL
0.82(0.60-1.13)
<35 ng/mL
1.09(0.77-1.55)
≥35 ng/mL
0.96(0.70-1.33)
Sum of
<50 mm
1.22(0.87-1.71)
target lesions
≥50 mm
0.81(0.59-1.12)
Age
Pretreatment
CEA
CA 19-9
Arm B better
Arm A better
Arm A
(n=180)
Arm B
(n=187)
PR, No. (%)
20 (11.1)
20 (10.7)
SD, No. (%)
127 (70.6)
132 (70.6)
PD, No. (%)
25 (13.9)
22 (11.8)
NE, No. (%)
8 ( 4.4)
13 ( 7.0)
p=1.00
No differences:
- dose intense of chemotherapy
- subgroup analysis: sex, age, PS, primary site (rectal vs. colon)
metastatic characteristics (location, numbers, peritoneal
mets), CEA, CA19-9…
The Potential Impact of Bevacizumab Dose on the
CRC Chemotherapy Efficacy
Initial Phase II: Kabbinavar
PFS
RR
5FU/LV
5.2 months
17 %
5-FU/LV + Bev. 5mg /Kg
9.0 months
40 %
5-FU/LV + Bev 10 mg /Kg
7.2 months
24 %
First line: AVF 2107g
PFS
RR
IFL + Placebo
6.2 months
35 %
IFL + Bev. 5 mg/kg
10.6 months
45%
Second line: E3200
PFS
RR
FOLFOX
4.8 months
9.2%
FOLFOX + Bev. 10 mg/kg
7.2 months
21.8%
(Bev. 10 mg/kg)
(2.8 months)
(3.0%)
Conclusion
• No significant difference was found in PFS between Arm A and
Arm B.
• No Surprise - dose of Bevacizumab was based on neither the
Tumor mass (size or numbers) nor the biologics (VEGF, or
VEGFR levels) of Cancer.
• However, patients with first-line treatment <180 days, CEA ≥20
ng/mL, sum of target lesions ≥50 mm seem to benefit from bev
10 mg/kg.
• May make sense as larger tumor burden may be benefit with
more Bev.
• The results from study suggest that the optimal dose of
continuous bev as second-line treatment is 5 mg/kg.
• With the efficacy from this and other studies and cost-effective
ration—Agree!
No need to have any further debate regarding the appropriate
dose of Bevacizumab in CRC therapy (in the 2nd line setting)
3517: Effectiveness of bevacizumab added to gold
standard chemotherapy in metastatic colorectal
cancer (mCRC): Final results from the ITACa
Alessandro Passardi et al
randomized clinical trial
Alessandro Passardi, et al
Baseline Characteristics
Patient Characteristics
Age: median years (range)
Male %
Performance Status (ECOG) %
0
1-2
Tumor localization %
rectum
colon
Stage at diagnosis %
I-III
IV
CT regimen %
folfox
folfiri
KRAS %
wild type
mutant
Prior cancer therapy %
surgery
radiotherapy
Adjuvant chemotherapy
CT+bevacizumab N=176
CT N=194
66 (34-83)
61
66 (33-82)
59
82
18
79
21
23
77
26
74
17
83
17
83
59
41
61
39
59
41
55
45
76
10
19
75
10
13
1.00
Treatment cycles (N)
Treatment cycles per patient
median (range)
Cycles with reduction of CT:
N (%)
CT Cumulative dose: median
(range)
0.80
PFS
PFS
0.60
0.40
0.20
0.00
0
6
12
18
months
24
30
Events / n (%)
Median PFS
(95% CI)
-------- CT + B
159 / 176 (90.3)
9.6 (8.2-10.3)
-------- CT
178 / 194 (91.8)
8.4 (7.2-9.0)
= 1.2 months
HR = 0.87, 95% CI (0.70-1.08), p = 0.212
OS: 20.6 months in both arms [p=0.278,
HR 1.18 (0.88-1.58)]
RR: 48.9 (CT +B) vs. 47.9 % (p=0.371)
36
CT + B
CT
2083
8 (1-43)
1945
6 (1-28)
291
(14.0)
90 (44100)
404
(20.8)
87 (48100)
- A relative small study with
diverse CT regimens (60%
FOLFOX)
- Appeared as ‘NO16966’
Data
- No data in 2nd and 3rd line
therapy
- Will not change current
practice
3515: Maintenance therapy with bevacizumab with or without
erlotinib in metastatic CRC according to KRAS: Results of the GERCOR
DREAM phase III trial.
C. Tournigand, et al
INDUCTION, N=700
R
E
G
I
S
T
R
A
T
I
O
N
mFOLFOX7
bevacizumab
XELOX2
bevacizumab
FOLFIRI
bevacizumab
No
Prog
MAINTENANCE, N=446
R
A
N
D
O
M
I
Z
A
T
I
O
N
Bevacizumab
(7.5 mg/kg q3w)
+ erlotinib
(150 mg/d)
until PD
N=222
Bevacizumab
(7.5 mg/kg q3w)
until PD
N=224
Primary end point:
PFS on maintenance therapy
Secondary endpoints :
OS, OS from maintenance, Duration without
chemotherapy, RR, Survival according to KRAS mutational status
Clinic Chemptherapy Goal: Increasing the efficacy, minimize/delay
the toxicity
- Optimox 1: maintain the efficacy and decreasing the toxicity with ‘stop
and go’ strategy
- Biological agents benefit in combination with chemotherapy
- VEGF inhibitors vs. EGFR inhibitor(s) and combination? Maintenance?
The impacts of Kras status?
FOLFOX4
(n=312)
OPTIMOX 1
R
6 cycles
12 cycles
6 cycles
FOLFOX7
(n=313)
LV5FU2
FOLFOX7
PACCE: PFS and OS
Ox-CT + BEV
(n=410)
Ox-CT + BEV + Pmab
(n=413)
HR
(95% CI)
PFS (mos)
11.1 months
9.6 months
1.27 (1.05-1.53)
OS ( mos)
>24 months
19.4 months
1.43 (1.11-1.83)
46%
45%
Iri-CT + BEV
(n=115)
Iri-CT + BEV + Pmab
(n=115)
HR
(95% CI)
PFS (mos)
11.7
10.1
1.21 (0.80-1.82)
OS (mos)
20.5
20.7
NR
ORR
39%
43%
1.15 (OR)
ORR
CAIRO2
CAPOX/ Bev CAPOX/BEV/Cet p value
Median PFS (months)
(HR; 95% CI)
Median OS (months)
(HR; 95% CI)
n = 368
n = 368
10.7
9.6
0.018
(9.7-12.5)
(8.5-10.7)
(1.21;1.03-1.45)
20.4
20.3
0.21
(18.1-26.1)
(17.9-21.6)
(1.15;0.93-1.43)
44%
44%
0.88
83%
81%
0.39
Response rate
(CR + PR)
Disease control rate
(CR + PR + SD)
Survivals
Bev alone
(N=228)
Bev + erlotinib
(N=224)
HR
[95% CI]
P value
Maintenance PFS
(from randomization)
4.6
[4.1-5.7]
5.9
[4.5-6.4]
HR 0.76
[0.61-0.94]
0.0096
PFS
(from registration)
9.3
[8.7-10.1]
10.2
[9.5-11.5]
HR 0.75
[0.61-0.93]
0.0088
OS
(from registration)
27.9
[24.1-31.1]
28.4
[25.1-33.9]
HR 0.89
[0.70-1.12]
0.8857
Grade 3/4 Toxicity (%)
Bevacizumab
N=228
Bevacizumab + Erlotinib
N=224
Diarrhea
2 (1)
20 (9)
Skin toxicity
0 (0)
46 (20)
Maintenance PFS
(randomized population, from randomization)
B
B+E
No. of patients
228
224
Events
183
159
Censored
45
65
Median maint.
PFS
4.6
5.9
HR [95% CI]
P value
0.76 [0.61-0.94]
0.0096
CAIRO2: KRAS genotyping (n=501)
Kras WT
(n=305) 61%
Kras Mutated
(N=196) 39%
p
CAPOX +B
CAPOX +B+C
10.7
10.5
12.5
8.6
0.92
0.47
p
OS (months)
CAPOX +B
0.10
0.043
23.0
24.9
0.90
CAPOX +B +C
p
22.2
0.49
19.1
0.35
0.52
PFS (months)
Survivals
m PFS
(from randomization)
PFS
(from registration)
OS
(from registration)
Maintenance PFS
(from randomization)
PFS
(from registration)
OS
(from registration)
Bev alone
(N=111)
5.9
[4.0-6.5]
9.7
[8.7-11.0]
31.5
[27.5-38.1]
Bev + erlotinib
(N=129)
6.0
[4.5-7.8]
10.9
[9.7-12.6]
31.8
[26.6-37.9]
HR
[95% CI]
HR 0.86
[0.64-1.15]
HR 0.82
[0.61-1.11]
HR 0.92
[0.66-1.30]
Bev alone
(N=89)
4.4
[3.8-5.3]
9.9
[8.6-10.8]
26.9
[22.4-33.2]
Bev + erlotinib
(N=91)
4.7
[3.6-7.1]
9.8
[8.4-12.2]
26.3
[21.0-34.4]
HR
[95% CI]
HR 0.77
[0.54-1.08]
HR 0.80
[0.57-1.13]
HR 1.06
[0.72-1.55]
P value
0.3153
0.1974
0.6443
P value
0.124
0.212
0.767
Maintenance PFS
Conclusions
- The addition of erlotinib to bevacizumab following induction
therapy with bevacizumab-based chemotherapy significantly
increases the maintenance PFS.
- In contrast to anti-EGFR Mabs, KRAS tumor status does not
select patients with mCRC benefiting from erlotinib
However: Will the results change the practice?
• Bevacizumab alone is not standard, and without clear benefit
(SAKK 41/06, abs 3503); and after OPTIMOX 1, 5-FU (or
Capecitabine)+ bevacizumab is already the maintenance
therapy in many practices (which is supported by CAIRO3, abs
3502).
• Erlotinib is not indicated in CRC
May help future investigation of anti-VEGF mAb + Anti-EGFR TKI
in mCRC
3521: Results according to age in AVEX, a randomized
phase 3 trial of bevacizumab with capecitabine for
elderly patients with mCRC
Mark P. Saunders, et al
Previously untreated
mCRC, age 70 years
N=280
Randomize
1:1
Stratification factors:
• ECOG PS (0–1 vs 2)
• Geographic region
Bevacizumab 7.5 mg/kg
day 1, q21d
+
Capecitabine 1000 mg/m2 b.i.d.
days 1–14, q21d
Capecitabine 1000 mg/m2 b.i.d.
days 1–14, q21d
Are elderly patients at increased risk for toxicity
secondary to Bevacizumab, and how old is old?
Progression-free and overall survival*
A. Progression-free survival
B. Overall survival
Capecitabine (n=140)
1.0
1.0
0.8
HR=0.53 (95% CI: 0.41–0.69)
0.8
P<0.001
0.6
0.6
OS estimate
PFS estimate
Bevacizumab + Capecitabine (n=140)
0.4
HR=0.79 (95% CI: 0.57–
1.09), P=0.182
0.4
9.1 mo
0.2
0.2
5.1 mo
20.7 mo
16.8 mo
0.0
0.0
0
4
8
12
16
20
24
28
32
36
40
0
4
8
12
16
Time (months)
20
24
28
32
36
40
44
Time (months)
Number at risk
140
BEV + cape
99
68
41
23
13
8
2
2
1
0
Number at risk
BEV + cape
140
120
95
81
60
44
34
16
12
8
5
2
140
82
38
13
6
4
1
1
1
1
0
Cape
108
85
62
49
33
19
11
9
6
5
1
Cape
140
*Overall population. 113 PFS events in the BEV + cape arm; 127 PFS events in the cape arm; 75 OS events in each treatment arm.
BEV = bevacizumab; cape = capecitabine; CI = confidence interval; OS = overall survival; PFS = progression-free survival
Progression-free and overall survival
70 – 74 years
75 – 79 years
≥80 years
Outcome
Bev + Cape
n=55
Cape
n=46
Bev + cape
n=57
Cape
n=66
Bev + cape
n=28
Cape
n=28
Median PFS, mos
(95% CI)
7.6
(6.0–11.8)
5.0
(4.0–6.5)
9.8
(7.1–11.4)
5.1
(4.1–7.4)
10.5
(5.0–14.5)
5.1
(2.2–7.1)
Hazard ratio (95% CI)
Log-rank P
Median OS, months
(95% CI)
Hazard ratio (95% CI)
Log-rank P
0.52 (0.32–0.83)
<.001
20.7
(13.7–26.1)
0.60 (0.40–0.89)
.016
22.2
19.8
17.4
(9.7–42.7) (13.8–27.3) (11.9–23.0)
0.91 (0.50–1.66)
.55
0.79 (0.48–1.30)
.37
0.36 (0.19–0.71)
.003
19.7
(7.5–26.9)
12.6
(6.6–17.0)
0.62 (0.31–1.24)
.24
70 – 74 years
75 – 79 years
≥80 years
Bev + Cape
n=54
Cape
n=46
Bev + cape
n=53
Cape
n=64
Bev + cape
n=27
Cape
n=26
Any AE
96
94
96
95
93
100
Grade ≥3 AE
63
41
55
41
59
58
SAE
35
28
26
30
30
46
Grade 5 AE*
7
11
8
9
11
19
AE leading to dose
interruption/modification
61
33
70 – 74 years
AE, %
Any AE leading to
discontinuation
AE, %
4975 – 79 years
47
52 ≥80 years 54
Bev 22
+ Cape
n=54
Cape
7
n=46
Bev30+ cape
n=53
Cape
17
n=64
Bev 22
+ cape
n=27
Cape
19
n=26
Bleeding/hemorrhage
20
11
30
6
26
–
Hypertension
15
2
26
6
15
8
VTE
11
7
13
6
11
–
Proteinuria
13
–
4
2
4
–
ATE
4
–
2
2
11
12
No major difference of AEs comparing with other Bevacizumab
studies
Conclusions
• A statistically significant improvement in PFS with the addition of
bevacizumab to capecitabine (HR, 0.53; P<.001)
– Patients grouped according to age (70–74 years, 75–79 years,
≥80 years) had a similar PFS benefit
• The safety profile was consistent with previously reported data
and consistent across age subgroups
• Suggests that the combination of bevacizumab and capecitabine is
an effective and well-tolerated regimen for elderly with good PS
- Age is ‘relative’, even with anti-angiogenic agent,
(however, data here is only for Bev… ).
- Key issue is careful patient selection.
3518: Non-inferiority of S-1 to UFT/LV as adjuvant chemotherapy
for stage III colon cancer: A randomized phase III trial (ACTS-CC)
Yoshihiko Nakamoto, et al. ACTS-CC study
group
pStage III
Colon Cancer (C-RS)
・Curatively resected
・Age: 20 - 80 y.o.
・PS: 0-1
R
Stratification factors
・ LN metastasis (N1/N2)
・ Institution
Test arm
S-1
S-1: 80, 100, 120 mg/day according to BSA
in 2 divided doses daily
Day 1-28, q6w x 4 cycles (24w)
Control arm
UFT/ LV
UFT: 300-600 mg/day according to BSA
LV: 75mg/day
in 3 divided doses daily
Day 1-28, q5w x 5 cycles (25w)
Primary End Point: 3-yr DFS, Non inferiority margin of HR in DFS: 1.29
Target sample size： 1,480 pts. with one-sided α=0.05, β=0.20
Biochemical action of S-1 and UFT/LV
Effector
S-1
UFT/LV
tegafur
Prodrug of 5-FU
DPD： Dihydropyrimidine dehydro- genase
Modulator ①
Modulator ②
CDHP
oteracil
DPD inhibition
（strong）
Decreasing
GI toxicity
uracil
LV
DPD inhibition
（moderate）
Potentiation of
TS inhibition
CDHP： 5-chloro-2,4-dihydroxypyridine
- Potent DPD inhibitory activity
- Easy administration (Twice-daily p.o.)
- Low price (1/2 of UFT/LV, 1/3 of mFOLFOX6 in Japan)
TS： thymidylate synthetase
DFS and OS
EAS：n=1,518
Median follow-up: 41.3 months (1.8-52.2)
98.8%
96.8%
93.6%
88.2%
80.1%
98.9%
75.5%
71.8%
86.5%
77.6%
72.5%
66.1%
0y
1y
2y
3y
4y
S-1
758
658
594
533
167
UFT/LV
760
649
573
476
77
92.7%
86.1%
S-1
UFT
S-1
UFT/LV
HR 0.86 [95%CI: 0.621.19]
P=0.3600
HR 0.85 [95%CI: 0.70-1.03],
p=0.1003
One-sided p<0.0001 (noninferiority)
No. at
risk
96.6%
88.3%
5y
No. at
risk
0y
1y
2y
3y
4y
S-1
758
743
723
666
144
UFT/L
V
760
741
713
658
147
5y
Conclusions
-
S-1 for stage III CRC is non-inferior in DFS to that of UFT/LV.
- AEs were acceptable, and the completion rate of the protocol
Tx. was high.
- Adjuvant chemotherapy using S-1 will be a
treatment option for stage III colon cancer in Japan
- Might fit in US pts, based on NSABP C-06 data, however, not
available in USA
NSABP C-06
3 yr. DFS
5 yr DFS
5 yr. OS
5-FU/LV
UFT
74.5 %
74.5 %
68.2 %
67.2 %
78.7 %
78.5 %
3519: A randomized phase III trial of S-1/oxaliplatin (SOX) plus
bevacizumab versus 5-FU/l-LV/oxaliplatin (mFOLFOX6) plus
bevacizmab in patients with metastatic colorectal cancer: the SOFT
D. Takahari, et al SOFT Study Group
study.
mCRC
1st line
Non-inferiority
Age: 20 - 80
PS: 0-1
n=512
R
Stratification factors:
Control arm
•With vs. without adjuvant chemotherapy
•Institutions
mFOLFOX6+Bev (n=256)
L-OHP: 85 mg/m2 d1
Bev: 5 mg/kg d1
l-LV: 200mg/m2 d1
5-FU: 400mg/m2 bolus d1
5-FU: 2,400mg/m2 46 hr civ d1,2
repeated every 2 wks
Test arm
SOX+Bev (n=256)
L-OHP: 130 mg/m2 d1
Bev: 7.5 mg/kg d1
S-1: 80, 100, 120 mg*/body d1-14
repeated every 3 wks
*According to body surface area,
BSA < 1.25 m2, 1.25=<BSA <1.5, BSA >=1.5
PFS and OS
PFS
mFOLFOX6+Bev : 10.2 M (95% CI:9.5-11.3)
SOX+Bev:
10.2 M (95% CI:9.4-11.1)
1
mFOLFOX6+Bev : 30.9 M (95% CI:28.6-33.1)
SOX+Bev :
29.6 M (95% CI:25.8- …)
OS
HR=1.021 (95% CI:0.847-1.232)
0.75
HR=1.052 (95% CI:0.805-1.376
1
mFOLFOX6+Bev
SOX+Bev
0.75
mFOLFOX6+Bev
SOX+Bev
0.5
0.5
Median follow-up duration:
23.4 M (0.3 to 37.8)
0.25
0.25
0
0
6
12
18
24
30
36
42
0
0
6
12
18
24
mFOLFOX6+Bev (n=233)
SOX+Bev (n=234)
No. of pts*
No. of pts*
NE
16
21
RR (%)
DCR (%)
62.7
89.3
61.5
89.3
R0 resection rate
22
24
R0-R (%)
22 (8.6%)
24 (9.4 %)
Best overall response
30
36
p value
0.8026
0.9872
0.7678
42
Subgroup analysis of PFS(FAS)
P value for interaction
No. of pts
Sub-group
Sex
Male
Female
329
182
0.1880
Age
<65
273
0.2592
65≦
Colon
Rectosigmoid
Rectum
238
tub1,2
por1,2
Other
No
Yes
No
Yes
No
Yes
437
44
467
0.8514
Liver metastases
No
197
0.3837
Lung metastases
Yes
No
314
395
0.0419
Yes
116
< 1.25
14
1.25 ≦ < 1.50
175
1.50 ≦
322
Primary lesion
Histology
History of surgery for
colorectal cancer
History of adjuvant
therapy for CRC
Target lesions
2
BSA(m )
0.5409
257
85
166
0.3367
21
53
119
0.3285
392
433
0.9947
78
0.9150
0.25
0.5
SOX+Bev better
1
2
4
mFOLFOX6+Bev better
D.Takahari, et al. ASCO 2013; Abstract #3519
Conclusions
SOX + Bev can replace with mFOLFOX6 + Bev as a
first-line treatment for mCRC in Japan with a more
convenient regimen
D.Takahari, et al. ASCO 2013; Abstract #3519
3520: Prognostic value of early objective tumor response
(EOTR) to 1stline systemic therapy in mCRC: Individual patient
data (IPD) meta-analysis of randomized trials from the ARCAD
(Aide et Recherche en Cancérologie Digestive) database
15 Studies:
N9741, OPTIMOX 1, FOCUS,
AVF2192g, AVF2107g, HORG,
HORIZON H, FOCUS 2, NO16966,
OPTIMOX 2, PACCE, MAX,
Macco, PRIME, HORIZON IH
EOTR6
5 Studies
16 Arms
4,632 Patients
Target
4 Studies
8 Arms
1,833 Patients
Non-Target
5 Studies
8 Arms
2,799 Patients
Available Data
15 Studies
42 Arms
13,949 Patients
Dirkje W Sommeijer, et al, the ARCAD Group
1962 patients missing
status or dates
Response Data
15 Studies
42 Arms
11,987 Patients w/RR
EOTR8
5 Studies
10 Arms
3,037 Patients
Target
3 Studies
6 Arms
1,828 Patients
Non-Target
4 Studies
4 Arms
1,209 Patients
EOTR12
10 Studies
32 Arms
6,688 Patients
Target
5 Studies
14 Arms
2,382 Patients
Non-Target
9 Studies
18 Arms
4,306 Patients
EOTR at 6 weeks
PFS
OS and PFS
EOTR at 8weeks
PFS
EOTR at 12 weeks
PFS
EOTR at 6, 8, 12 weeks, overall response rate and
PFS and OS
(adjusting with age, gender, PS, Mets in liver and lung)
PFS
OS
Discussion
- Clinic investigation: EORT warrants further consideration
as a potential surrogate endpoint to detect early signals
for future trials, particularly randomized studies .
- Clinic Practice: EORT as a ‘clinic surrogate prognostic
factor’ in mCRC treatment
- Questions:
a) Early response vs. Duration of response
b) Tumor biology
c) Early response brings more treatment options
(resection, local-regional therapy, more lines of
therapy), improved quality of life.