Transcript PowerPoint Presentation - Colorectal Cancer: New
Colorectal Cancer: New Approaches
Daniel G. Haller, MD Professor of Medicine Abramson Cancer Center at the University of Pennsylvania Philadelphia, PA USA St. Louis, MO 10/1/04
Incidence of colorectal cancer in the U.S. and Western Europe 2003 (n~300,000) Stage I 24% Stage IV 22% Stage II Stage III 29% 26% Initially eligible for systemic therapy n~60,000 Eligible for adjuvant chemotherapy n~160,000 (55%)
Environmental Associates for Colorectal Cancer
Dietary Factors: Dietary Fiber Dietary Fat Red Meat Alcohol Folate Methionine Calcium and vitamin D Non-Dietary Factors: Body Mass Index Physical Activity Smoking Aspirin Endoscopy Use
Old Paradigm for Colorectal Cancer Patients
Preclinical stage Localized disease Advanced disease Early diagnosis S Adjuvant Rx CT 1 st -line Cure CT 2 nd -line S = Surgery CT = Chemotherapy
Key Therapeutic Agents in CRC: Historical Perspective
~ 1960: 5-FU is the cornerstone of first-line therapy in MCRC ~ 1985: Addition of LV (biochemical modulator) to 5-FU bolus regimens 1998: Irinotecan as single agent approved as second-line in CRC 2000: Irinotecan approved as first-line in CRC in bolus regimen (IFL) 2001: Capecitabine approved as first-line in CRC 2002: Oxaliplatin approved as second-line agent 2004: Oxaliplatin approved as first-line agent 2004: Introduction of biologics
– –
bevacizumab cetuximab
5-FU = 5-fluorouracil; MCRC = metastatic CRC; LV = leucovorin; IFL = irinotecan/5-FU/LV;
5-Fluorouracil; 5-FU
Irinotecan (CPT-11, Camptosar ®) C H 3 C H 2 N N O C O N Irinotecan hydrochloride N O H O O O C H 2 C H 3
•Topoisomerase I inhibitor
Phase III Trial of First-Line Irinotecan + 5-
M I Z E R A N D O
n=231
FU/LV
IFL
n=226 n=226
5-FU/LV Irinotecan monotherapy
End points: PFS OS PFS = progression-free survival; OS = overall survival.
Saltz et al.
N Engl J Med
. 2000;343:905.
Phase III Trial of First-Line Irinotecan + 5-FU/LV: Efficacy
PFS (mo)
5-FU/LV
4.3
IFL
7.0
P Value*
.004
Irinotecan
4.2
ORR (%) OS (mo) 21 12.6
39 14.8
<.001
.04
18 12.0
*
P
values comparing IFL with 5-FU/LV.
ORR = objective response rate.
Saltz et al.
N Engl J Med
. 2000;343:905.
Chemical Structure of Platinum Analogues
NH 3 Cl Diaminocyclohexane (DACH) carrier ligand NH 2 NH 2 Pt O O C C OXALATE hydrolysable ligand NH 3 O Pt NH 3 CISPLATIN Cl O O C O C NH 3 trans-l-diaminocyclohexane oxalatoplatinum OXALIPLATIN, Eloxatin ® Pt O CARBOPLATIN
Preclinical Synergy of Oxaliplatin and 5-FU
300 250 200 HT-29 colon tumor xenograft 150 D13 - Treatment 100 Control 5-FU 50 mg/kg Oxali 10 mg/kg Oxali 10 mg/kg + 5-FU 50 mg/kg 50 0 10 13 16 20 24 27 33 Days post tumor graft 35 40 45 Raymond et al. Anti Cancer Drugs. 1997.
Infusional 5-FU/LV Regimens
Oxaliplatin Irinotecan 400 400 FOLFOX4 85 FOLFOX6 100 mFOLFOX6 85 x 400 600 LV5FU2 q2w 600 x 2400 sLV5FU2 q2w 400 x 2400 sLV5FU2 q2w “Douillard” 180 FOLFIRI 180 m FOLFOX7 130 (85) x 2400 vsLV5FU2 q2w
IFL Failures
Oxaliplatin Second-Line Registrational Trial
n=272
R A N D O M I Z E
n=270 n=274 Infusional LV5FU2 FOLFOX4 Oxaliplatin
Primary end point: OS Secondary end points: TTP, ORR, safety
Rothenberg et al.
JCO 6/03
.
Oxaliplatin Second-Line Registrational Trial: Efficacy
TTP (mo)
5-FU/LV
2.6
FOLFOX4
5.6
P Value*
<.0001
Oxaliplatin
1.9
OS (mo) ORR (%) 8.7
0.7
9.8
9.6
.07
<.0001
8.1
1.1
% Relief from tumor related symptoms *
P
values for FOLFOX4 vs 5-FU/LV.
Rothenberg et al.
JCO 6/03
15 28 <.002
10
N9741 Phase III Trial of
First-line IFL vs FOLFOX4 vs IROX
Schema
R A N D O M I Z A T I O N N=245 N=246 N=250 Bolus IFL (5-FU/LV + Irinotecan) FOLFOX4 (5-FU/LV + Oxaliplatin) IROX (Irinotecan/Oxaliplatin)
Goldberg RN et al.
JCO
1/1/04 .
N9741: Safety Profile
Grade 3/4 Adverse Events* 50 45 40 35 30 25 20 15 10 5 0 14 4 11 Febrile neutropenia 29 12 25 Diarrhea 15 6 19 Nausea
P
.002 for all comparisons of IFL and IROX vs FOLFOX.
*Observed in >10% of patients in any treatment arm.
Goldberg et al.
J Clin Oncol
. 2004;22:23.
13 4 23 Vomiting 22 8 8 IFL FOLFOX4 IROX 2 19 7 Infections Overall neuropathies
N9741 Phase III Trial of First-line IFL vs FOLFOX
Results
RR
IFL
31%
FOLFOX
45%
p value
0.002
Median Time to Progression (mo) Overall Survival (mo) 6.9
14.8
8.7
19.5
0.0014
0.0001
FOLFOX: Second-line approval in US 8/02; First line approval 2/04
Goldberg RN et al.
JCO
1/1/04 .
XELOX international phase II trial: first-line metastatic colorectal cancer
• Regimen recommended from phase I trial 1 • Male/female 64%/36%; median age 64 years 2 • n=96 • Overall response rate: 55%
Oxaliplatin 130mg/m 2 d1 Day 1 8 15 21 Capecitabine 1,000mg/m 2 twice daily Day 1 (pm) –15 (am) Rest Repeat cycle at day 22 1 D íaz-Rubio E, et al. Ann Oncol 2002;13:558–65 2 Van Cutsem E, et al. Proc Am Soc Clin Oncol 2003;22:255 (abst 1023)
Is There an Optimal Sequence in Therapy of Metastatic CRC?
• 5-FU, oxaliplatin, and irinotecan all have activity in first- and second-line settings • No compelling data exist to choose one sequence unless there is comorbid illness
The Evolution of Chemotherapy for CRC
50 45 40 35 30 25 20 15 10 5 0 BSC 5FU FU/LV Cape CIFU IFL FOLFIRI FOLFOX FOLFOX RR % median survival:mos
Pericyte PDGFr Imatinib VEGFr-1 PTK Endothelial Cell VEGFr-2 PTK VEGFr-3 PTK EGFr Gefitinib/Erlotinib COX-2 Cetuximab Trastuzumab Gefitinib/Erlotinib EGFr HER-2 Tumor Cell Imatinib PDGFr
Bevacizumab (Avastin ™) • A recombinant humanized anti-VEGF MAb – human IgG1 framework with antigen-binding regions from a murine MAb • Binds all forms of VEGF and prevents receptor binding • Effectively depletes circulating VEGF • Targets angiogenic components of tumor, stroma, and endothelial cells – Effect on drug delivery • Terminal half-life, 17-21 days
Phase III Study in Metastatic CRC: 5-FU/LV/CPT-11 +/- bevacizumab
• Previously untreated metastatic colorectal cancer • n=900
Previously untreated metastatic CRC 5-FU/LV/CPT-11 (Saltz regimen) 5-FU/LV/CPT-11/ bevacizumab Primary endpoint: survival Randomization 5-FU/LV/ bevacizumab
Bevacizumab (anti-VEGF) in First-line Therapy
• Phase III trial of irinotecan/5-FU/LV in 815 CRC patients bevacizumab (BV)
IFL/Placebo IFL/BV
N ORR 412 35% Median Survival 15.6 mo PFS 6.3 mo 403 45% ( p=0.0029) 20.3 mo ( p=0.00003) 10.6 mo ( p=<0.00001) Hurwitz H et al.
Proc ASCO
. 2003;23 (abstr 3646).
Bevacizumab
• Approved by FDA 2.26.04
• 1 st line therapy with any IV 5-FU-based chemotherapy • 5 mg/kg Q2W dose • Safety – Hypertension – Perforation – Cardiovascular events
Cetuximab (C225, Erbitux ™)
• Chimeric monoclonal antibody to EGFR – ABX-EGF: fully humanized • Inhibits EGFR function and downstream signal transduction pathways, promoting apoptosis • Synergistic with chemotherapy and radiation O‘Dwyer PJ, Benson AB III.
Semin Oncol
. 2002;29(suppl 14):10.
“BOND” Trial
• Randomized Phase II trial in CPT 11-refractory CRC • Cetuximab+CPT-11 versus Cetuximab alone • 2:1 randomization, 300 pts • 1 o endpoint: response rate
Cetuximab in Irinotecan Refractory EGFR
+
Patients
Cetuximab Cetuximab + (n=111) Irinotecan (n=218)
11% 23% PR TTP 1.5 mo Overall Survival 6.9 mo 4.1 mo 8.6 mo Cunningham D et al.
NEJM 7/04
Van Laethem JL et al.
Proc ASCO
. 2003;23 (abstr 1058).
Cetuximab Approval
• 2/04 • For CPT-11 failures, in combination with CPT-11 • Monotherapy, for CPT-11 “intolerant” patients • EGFR status known ???
• Role in 1 st line therapy?
Phase III Trials
First-line Metastatic Disease
“Dealer’s choice” Chemotherapy
mFOLFOX6 FOLFIRI XELOX XELIRI ? US TRIAL 2004 A T I O N R A N D O M I Z Cetuximab Bevacizumab Bevacizumab + Cetuximab
The future of treatment of colon cancer
• Cost: Shrag, NEJM, 7/2004 – Average patient with 1 st line FOLFOX+ bevacizumab (8 months) followed by CPT 11 + cetuximab (4 months)= $161,000 USD
Adjuvant Therapy of Colon Cancer 1990 5-FU/lev better than surgery alone 1994 5-FU/LV better than surgery alone 1998 5-FU/LV better than 5-FU/lev 1998 6 months = 12 months 1998 Levamisole unnecessary 1998 HDLV = LDLV 1998 Weekly = monthly 2002 LV5FU2 = monthly bolus
Adjuvant Therapy of Colon Cancer 1990 5-FU/lev better than surgery alone 1994 5-FU/LV better than surgery alone 1998 5-FU/LV better than 5-FU/lev 1998 6 months = 12 months 1998 Levamisole unnecessary 1998 HDLV = LDLV 1998 Weekly = monthly 2002 LV5FU2 = monthly bolus
CRC: AJCC 6 th Edition Staging Guidelines
• The AJCC 6 th edition staging manual refined stages II and III of the TNM system: – Smooth nodules in fat are considered LNs – Stage II divided into IIA (T 3 ) and IIB (T 4 ) – Stage III divided into • IIIA (T 1-2 N 1 M 0 ) • IIIB (T 3-4 N 1 M 0 ) • IIIC (T Any N 2 M 0 ) – N 2 denotes metastases to 4 or more regional lymph nodes American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 6th Edition (2002).
Revised, node-positive TNM classification for Stage III CRC (n=50,042) IIIA: T1/2, N1 Observed 5-year survival (%) 70 59.8% 60 50 40 30 20 10 0 IIIA IIIB: T3/4, N1 p<0.0001
42.0% IIIB Node-positive subgroups IIIC: Any T, N2 27.3% IIIC Greene et al (2002)
Model-Derived Estimates of 5 year DFS (%) with Surgery plus Adjuvant Therapy T stage Low Grade High Grade Nodal Status 0 nodes 1-4 nodes > 5 nodes T4 T1-T2 T3 T4 T1-T2 T3 T4 S 63 71 53 37 51 27 13 +AT 82 74 81 66 53 64 44 27 S 57 67 46 30 44 21 9 +AT 79 70 77 61 46 59 37 21
Adjuvant Therapy for Stage II Colon Cancer
?
CPT-11 , Oxalii FU/LV Surgery
Adjuvant Therapy for Stage II Colon Cancer: Cancer Care Ontario Metaanalysis
• Data: 62 randomized trials; 11 metaanalysis – Primary analysis based on subset of 3586 pts in whom deaths in pts with stage II disease were provided – OR: 0.82 (95% CI 0.67-1.01; p=0.07) • ASCO Guidelines : 8/15/04
JCO
Adjuvant Therapy for Stage III Colon Cancer
?
?
?
CPT-11 OXALI FU/LV Surgery
Extending Benefit in
over
Stage II/III colon cancer
• Do combination therapies offer advantages 5-FU alone?
– oxaliplatin-based regimens: MOSAIC, NSABP C0-7 – irinotecan-based regimens: CALGB, PETACC-3/V-307, FFCD/FNCLCC • Can convenience of administration be improved?
– replace 5-FU with capecitabine • Can we further improve results? The role of biologics: – anti-EGFR (cetuximab) – anti-VEGF (bevacizumab)
R
MOSAIC: Treatment arms
FOLFOX4 : LV5FU2 + Oxaliplatin 85mg/m² LV5FU2 Endpoints
Primary:
–
3-yr Disease Free Survival (DFS) Secondary:
– –
Safety (including long-term) Overall Survival (OS)
Probability 1
DFS by treatment arm (ITT)
3-year FOLFOX4 (n=1123) 77.8% LV5FU2 (n=1123) 72.9% 0,9 0,8 0,7 0,6 Hazard ratio: 0.77 [0.65 – 0.92] p < 0.01
0,5 0 10 20 30 DFS (months) 40 50 23% risk reduction in the FOLFOX4 arm
Probability 1 0,9
Disease-Free Survival Stage III patients
3-year FOLFOX4 (n=672) 71.8% LV5FU2 (n=675) 65.5% 0,8 0,7 0,6 Hazard ratio: 0.76 [0.62-0.92] 0,5 0 10 20 DFS (months) 30 40 24% risk reduction for stage III patients in the FOLFOX4 arm 50
0.8
0.75
0.7
0.65
0.6
0.55
0.5
0.5
3 Year DFS vs 5 Year OS: Approved by ODAC
r
=0.90
0.55
5 yr OS= 0.0002+0.998*3 yr DFS 0.6
0.65
0.7
Disease Free Survival 0.75
0.8
Adjuvant therapy for colon
NO16968 (complete 10/04)
cancer
XELOX vs. FU/LV INT NO147 (open 2/04; 151/4800 pts) mFOLFOX6 vs. FOLFIRI vs. mFOLFOX6/FOLFIRI ± cetuximab NSABP C-07 (completed) 5-FU/LV (Roswell Park) ± oxaliplatin (FLOX) X-ACT Trial/C-06(ASCO 2004) Capecitabine vs FU/LV (Mayo) UFT/LV vs RPMI NSABP C-08 mFOLFOX6 ± bevacizumab (12 mo?) MOSAIC (completed) LV5FU2 vs. FOLFOX4
AVANT
FOLFOX4 ± bevacizumab vs. XELOX + bevacizumab
Surveillance
• Chau, et. al. ECCO 2003 • 550 pts with st II and III CRC treated with bolus or PVI; median f/U • CEA each visit, CT C/A/P at 12 and 24 months; non-randomized • 154 pts detected by – Sx (65), CEA (31), CT (49) • OS better in pts who had CT-detected tumor • 33 pts proceeded to potentially curative surgery
Salvage Surgery
Total patients Recurred
INT-0035 (colon)
1247 548 (43%)
INT-0114
1792 715(42%)
(rectal)
Salvage surgery 222 (41%) --- Curative intent surgery/ recurrences 5-yr 109 (20%) DFS: 23% (25 pts) 173 (34%) OS: 27% (46 pts)
· therefore, 71 potential cures in 3039 patients= 2.3%
INT-0035: Goldberg, et al, Ann Intern Med 1998 INT-0114: Tepper, J Clin Oncol 2003
Liver metastases from colorectal cancer
Liver is the most common site of metastases from CRC - 50 to 75% of patients with advanced CRC will develop liver metastases (1) - 15 to 25% of patients have liver metastases at presentation (1, 2) - 20 to 35% of patients will have metastatic disease confined to the liver (3) Improving the outlook of advanced colorectal cancer necessitates better management of liver metastases •
1 - N. Kemeny, F. Fata, J. Hepatobiliary Pancreas Surg., 1999; 6: 39-49 2 - JK. Seifert, J. R. Coll. Surg. Edinb., 1998; 43: 141-54 3 - MM. Borner, Ann. Oncol., 1999; 10, 6: 623-26
Advances in surgery of liver metastases
Scheele, 1995 (1) Period 1960-1979 1980-1992 1989-1992 N. of patients Operative mortality 52 11.5% 382 3.4% 114 1.8% Doci, 1995 (2) Period N. of patients Operative mortality Operative morbidity Transfusions
1 - J. Scheele,
et al.,
2 - R. Doci,
et al.,
World J. Surg., 1995; 19: 59-71 Br. J. Surgery, 1995; 82: 377-81
1980-1986 78 5.1% 53% 450 ml 1987-1992 130 0.8% 24% 150 ml
Results of liver surgery for metastatic CRC (N > 100)
Adson, 1984 (1) Hughes, 1988 (2) Doci, 1991 (3) Scheele, 1991 (4) Rosen, 1992 (5) Nordlinger, 1992 (6) Gayowski, 1994 (7) Rees, 1997 (8) N. of patients Operative mort 5-yr survival 141 859 100 219 280 1818 204 114 2.8% 5% 6% 4% 2.4% 0% 1% 23% 33% 30% 39% 25% 26% 32% 37%
1 - MA. Adson
et al.,
Arch. Surg., 1984; 119: 647-51 2 - KS. Hugues, Surgery, 1988; 103: 278-88 141-59 3 - R. Doci
et al.,
Br. J. Surg., 1991; 78: 797-801 4 - J. Scheele
et al.,
Surgery, 1991; 110: 13-29 5 - CB. Rosen
et al.,
Ann. Surg., 1992; 216: 493-505 6 - B. Nordlinger
et coll.,
Ed. Paris Springer-Verlag, 1992; 7 - TJ. Gayowski
et al.,
8 - M. Rees
et al.,
Surgery, 1994; 116: 703-11 Br. J. Surg., 1997; 84: 1136-40
Ongoing Trials in Patients With Liver Metastases
• • •
EORTC Study 40983
– FOLFOX + surgery vs surgery alone – Primary endpoint: 3-yr RFS; also resectability – 350 patients, completed accrual (started 10/01)
CLOCC Trial
– FOLFOX +/- RFA for unresectable disease
NCCTG/NSABP
– Is HAI necessary with optimal SYS therapy?
– Adjuvant XELOX ± HAI FUdR
Portion of Rectum Upper 1/3 Cm. from anal verge
Rectal Cancer
Left upper valve of Houston Right middle valve of Houston 15 Peritoneum Middle 1/3 11 Ampulla of Rectum Left lower valve of Houston Lower 1/3 7 2 Anal verge Cohen AM, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997, p. 1197
Rectal Cancer
• OBJECTIVES OF TREATMENT – Cure – Quality of Life •
sphincter preservation vs colostomy (distal lesions)
•
anorectal function
–
acute and late toxicity of treatment
Management of Early Rectal Cancer
• SURGERY (TME) • RADIATION – reduce locoregional failure – reduce distant failure (± chemotherapy) • CHEMOTHERAPY – reduce distant failure – reduce locoregional failure (± radiation)
Local failure: 1980s –2000s
35 30 Norway Mayo-NCCTG NSABP-R02 Ulsan NSABP-R01 GITSG-2 INT-PVI GITSG-1 INT-0114 Dutch TME 25 20 15 10 5 0 Surgery only Surgery
RT Surgery
CTRT TME + RT/CTRT
Distant metastases: 1980s –2000s
40 35 30 25 20 15 10 5 0 Surgery only NSABP-R02 GITSG-1 INT-PVI Ulsan Surgery
RT INT-0114 NSABP-R01 GITSG-2 Norway Mayo-NCCTG Dutch TME Surgery
CTRT TME +RT/CTRT
Adjuvant Therapy of Rectal Cancer
•
Postoperative
–
pathologic staging
•
EUS, MRI
–
immediate surgery
• • •
patient bias physician bias referral patterns
–
Positive adjuvant trials in US in postoperative setting
•
Preoperative
–
improved resectability
–
sphincter preservation
–
reduced damage to normal tissue
–
Only positive trial from Swedish study (2500 cGy/5 fx)
Pre-operative adjuvant therapy in rectal cancer: recent advances
• Emphasis on curative resection in addition to sphincter preservation – pre-operative staging (CRM unsafe) – pre-operative tumor down-staging – surgical technique (TME) – accurate pathological staging (R0)
CRM = circumferential resection margin; TME = total mesorectal excision
Preoperative vs Postoperative Chemoradiation
• INT-0147 – terminated prematurely secondary to low accrual • NSABP R-03 – terminated prematurely secondary to low accrual • German Trial – completed accrual!
Sphincter Preserving Surgery ITT Analysis Pre randomization: “APR Necessary“ Postoper. RCT n= 394 85 Sphincter preserved 17/85 (20%) Preoper. RCT p = 0.004
n = 405 109 43/109 (39%)
Cumulative Incidence of Local Relapses Intent-to-treat Analysis (Med. Follow-up: 40 mts)
.14
.12
.10
.08
.06
.04
.02
0.00
0
Postop CRT 12% 6%
10
Preop CRT
20 30 40
p = 0.006
50 60 Months
The Univ. Of Pennsylvania Trial in Rectal Cancer XELOX x2 cycles + cetuximab RT RT RT RT RT CAPE CAPE CAPE CAPE CAPE OXA OXA OXA cetuximab OXA OXA 45 Gy 825 x 2/d (Mon –Fri) 50/weekly CORE SURGERY CT
A New Paradigm for Colorectal Cancer Patients
Preclinical stage Localized disease Advanced disease S S Screening S Adjuvant Rx CT 1 st -line
Prevention
S = Surgery CT = Chemotherapy CT 2 nd -line biological agents CT 3 rd -line
CURE
• • • • • • •
The future of treatment of colon cancer
Improve efficacy Improve convenience Reduce duration Reduce toxicity Individualize treatment –Patient selection (anatomic staging, prognostic markers) –Drug selection (proteinomics, pharmacogenomics, SNPs) Cost/benefit Confusion…
Therapy for Colorectal Cancer
“There are only two tragedies in life: one is not getting what one wants, and the other is getting it.”
Oscar Wilde