definition of oxaliplatin sensitivity in pts with advanced colorectal cancer previously treated with...

Definition of oxaliplatin sensitivity in pts with advanced

colorectal cancer previously treated with oxaliplatin-based

therapy

A. de Gramont, B. Chibaudel, O. Bourges, N. Perez-Staub, C. Tournigand, F. Maindrault-Goebel, T. André, A. K. Larsen, P. Afchain, C. Louvet;

Hôpital Saint Antoine, Paris VI, France; GERCOR, Paris, France; Hôpital La Pitié Salpétrière, Paris, France; INSERM UMRS938, Paris, France

Abstract:

Background: Oxaliplatin combined with fluoropyrimidines is standard adjuvant therapy in stage III colon cancer and first-line therapy in stage IV colorectal cancer. Oxaliplatin can be reintroduced either at relapse, or after maintenance or after chemotherapy holidays. In this study we defined the sensitivity to oxaliplatin reintroduction based on the oxaliplatin-free interval.Methods: Stage IV pts entered in the OPTIMOX1 and 2 studies (FOLFOX4, FOLFOX7 followed by maintenance without oxaliplatin or chemotherapy holidays) and pts having relapsed after metastases surgery and neoadjuvant or adjuvant FOLFOX for resectable stage IV were eligible if they were rechallenged with FOLFOX. Endpoints were: survival from reintroduction according to interval between the last cycle of oxaliplatin first-line and reintroduction, survival and response at reintroduction according to first FOLFOX response and PFS.Results: 330 pts were included: male 60%, colon/rectum/both 62%/35%/2%, resectable/unresectable: 14%/86%, PS 0-1 / >1: 90%/10%, sites 1/>1: 57%/43%. 23 pts had adjuvant and 22 pts had neoadjuvant chemotherapy. 58 pts (18%) had FOLFOX reintroduction before progression. PFS/OS from reintroduction according to induction FOLFOX response were 8.7/19.5 mths if CR, 4.6/15.2 mths if PR, and 3.2/9.7 mths if SD (P=.0019/.01). PFS/OS from reintroduction according to induction FOLFOX PFS were 2.9/9.3 mths if PFS<6 mths, 4.6/14.7 mths if PFS 6-12 mths and 8.5/23.7 if PFS=12 mths. There was no difference between 0-3 and 3-6 mths or 6-9 and 9-12 mths intervals.Conclusion: A prolonged interval between two FOLFOX therapies or a prolonged PFS at first-line FOLFOX predict the efficacy of oxaliplatin reintroduction. The interval between two FOLFOX therapies does not identify a completely refractory population. Resistance (PD rate) is divided by two at each 6 month intervals.

Introduction• Oxaliplatin combined with fluoropyrimidines is a standard first-

line treatment for patients with metastatic coloretal cancer. Despite a high response rate in first-line, the majority of patients will ultimately experience disease progression. In ovarian cancer, it is well known that patients who responded to an initial chemotherapy with a platinum compound may respond again to the same or another platinum derivative when they relapse (Markman 91-97).

• In metastatic colorectal cancer, we previously reported that reintroduction of oxaliplatin in patients pre-treated with oxaliplatin and who later had a progressive disease, 73% had a disease control with a median progression-free survival of 18 weeks (Maindrault, Ann Oncol, Tournigand JCO).

• In an effort to better define the oxaliplatin sensitivity in patients with metastatic colorectal cancer who previously received oxaliplatin, we performed an analysis of clinical characteristics and survival outcomes of patients included in two prospective studies allowing reintroduction of oxaliplatin (OPTIMOX1, OPTIMOX2) and in patients having adjuvant or neoadjuvant oxaliplatin and surgery of metastases.

Eligible patients entered in two randomized studies including a stop and go strategy

Patients who relapsed after surgery of metastases and adjuvant/neoadjuvant therapy were also included

Patients and Methods

R

FOLFOX7–LV5FU2–FOLFOX7

FOLFOX4

FOLFOX7–LV5FU2–FOLFOX7

FOLFOX7–STOP–FOLFOX7

R

OPTIMOX 1 N=165/620 OPTIMOX 2 N=120/202

FOLFOX7–Surgery–FOLFOX

Surgery–FOLFOX7N=45

Specific problems

Parameters which could influence oxaliplatin sensitivity at reintroduction are:

• R0-R1 surgery of metastases before chemo, or after chemo, or no surgery

• Chemotherapy-free interval (CFI) after induction or maintenance or no CFI

• Bevacizumab with reintroduction or no Bev: N=19

• No proof of progression before reintroduction: N=58

N=330

Surgery first Neoadj FOLFOX orFOLFOX+/-sLV5FU

FOLFOX+/-sLV5FU

FOLFOXReintroduction

Surgery after chemo

Unresectable M+

FOLFOX+/-sLV5FU

PFS: 14.5 mOS: >92 m

PFS: 14.7 mOS: 39.3 m

PFS: 9.0 mOS: 22.5 m



PFS: 6.9 mOS*: 43 mRR: 11SD: 5PD: 3NE: 3

* from reintroduction

PFS: 6.7 mOS*: 18.6 mRR: 18SD: 20PD: 5NE: 12


N=22 N=55 N=253

P= 0.46P= 0.14

Regrouping of these patients

Surgery

N=330

R0-R1 M+ Surgery

FOLFOX+/-sLV5FU


Unresectable M+

FOLFOX+/-sLV5FU


* from reintroduction


N=77 N=253

P= 0.13P= 0.10

No separation of these patients

Break in ChemotherapyN=79

No Break in ChemotherapyN=174



Chemotherapy duration

Statistical Analyzes• Patients having R0-R1

resection of metastases• Patients having no surgery• Patients having no surgery,

proof of progressive disease before oxaliplatin reintroduction and not received bevacizumab

• All patients

• Cut-off determination

PFS and Survival from reintroduction3 classes according to interval between last cycle of induction FOLFOX and first cycle of FOLFOX reintroduction: <6 months, 6-<12 months, >12 months

Overall Survival according to time from end of oxaliplatin to first progression

0 26 52 78 104 130 156 182 208 234 260 286 312 338 364 3900

10

20

30

40

50

60

70

80

90

100

<3 months: n=44 ; 14.9 months

3-<6 months: n=75 ; 17.2 months



>=12 months: n=29 ; 43.7 months

Weeks

Pe

rce

nt

surv

iva

l

Response Rate

• PFS/OS from reintroduction according to induction FOLFOX response were 8.7/19.5 months if CR, 4.6/15.2 months if PR, and 3.2/9.7 months if SD (P=.0019/.01).

• PFS/OS from reintroduction according to induction

FOLFOX PFS/OS were 2.9/9.3 mths if PFS<6 months, 4.6/14.7 months if PFS 6-12 months and 8.5/23.7 if PFS>12 months.

FOLFOX ReintroductionResponse Rate (%)

Interval N CR+PR SD PD NE

<6 months 116 15 30 52 3

6-12 months 148 24 39 24 13

>12 months 66 35 36 11 18

PFS

0 13 26 39 52 65 78 91 1040.0

0.2

0.4

0.6

0.8

1.0

<6 months, N=116, median 3.0 m

6-12 months, N=148, median 5.0 m

>12 months, N=66, median 7.1 m

P<0.0001

Weeks

Pro

bab

ility

Progression-free Survival from Reintroduction

SURVIVAL

0 13 26 39 52 65 78 91 104 117 130 143 156 169 182 195 2080.0

0.2

0.4

0.6

0.8

1.0<6 months, N=116, median 8.9 m



P<0.0001

Weeks

Pro

bab

ility

Survival from Reintroduction

SURVIVAL - Surgery

0 13 26 39 52 65 78 91 104 117 130 143 156 169 182 195 2080.0

0.2

0.4

0.6

0.8

1.0<6 months, N=3


>12 months, N=44, median 26.4

P=0.48

Weeks

Pro

bab

ility

SURVIVAL - no surgery - no bev. - progression

0 13 26 39 52 65 78 91 104 117 130 143 156 169 182 195 2080.0

0.2

0.4

0.6

0.8

1.0<6 months, N=101, median 8.4 m



P<0.0001

Weeks

Pro

bab

ility

PFS - surgery

0 13 26 39 52 65 78 91 1040.0

0.2

0.4

0.6

0.8

1.0

<6 months, N=3



P=0.6

Weeks

Pro

bab

ility

PFS - no surgery - no bev. - progression

0 13 26 39 52 65 78 91 1040.0

0.2

0.4

0.6

0.8

1.0

<6 months, N=101, median 2.8 m



P<0.0001

Weeks

Pro

bab

ility

Subsets of Patients

RO-R1 Surgery No Surgery –No bev. – Prog.

Conclusions Oxaliplatin reintroduction efficacy in patients previously responders

or stable with FOLFOX for advanced colorectal cancer depends on RR and PFS of induction FOLFOX and on the oxaliplatin-free interval between the last cycle of induction FOLFOX and the first cycle of FOLFOX reintroduction.

An oxaliplatin-free interval of at least one year define a sensitive population with results of reintroduction in the range of oxaliplatin naive patients, an interval between 6 and 12 months define a partially sensitive patients with results better than most second-line options, an interval of less than 6 months define a partially resistant population with results in the range of second- or third-line therapies

Next steps will be to study:

oxaliplatin combination in first-line therapy in patients who relapsed after adjuvant FOLFOX for stage III colon cancer

oxaliplatin reintroduction after second-line irinotecan-based therapy and the efficacy of oxaliplatin-based chemotherapy with targeted

therapies

definition of oxaliplatin sensitivity in pts with advanced colorectal cancer previously treated with...

Documents