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ONCOLOGY

Epidemiology
Male cancer statistics
Estimated incidence Estimated deaths
Melanoma of skin 4% 3% Esophagus

Oral cavity & pharynx 3% 31% Lung & bronchus

Lung & bronchus 14% 5% Pancreas

Pancreas 2% 3% Liver & intrahepatic bile duct

Kidney & renal pelvis 3% 3% Stomach

Colon & rectum 10% 10% Colon & rectum

Prostate 29% 11% Prostate

Urinary bladder 6% 3% Urinary bladder

Leukemia 3% 4% Leukemia

Non-Hodgkin’s lymphoma 5% 5% Non-Hodgkin’s lymphoma

All others 19% 22% All others

Adapted from Greenlee RT, et al. CA Cancer J Clin. 2000;50:16.


ONCOLOGY
Epidemiology
Female cancer statistics
Estimated incidence Estimated deaths
Melanoma of skin 3% 2% Brain & other nervous system
Thyroid 2% 15% Breast
Breast 30% 25% Lung & bronchus
Lung & bronchus 12% 5% Pancreas
Pancreas 2% 2% Stomach
Colon & rectum 11% 11% Colon & rectum
Ovary 4% 5% Ovary
Uterine corpus 6% 2% Uterine corpus
Urinary bladder 2% 5% Non-Hodgkin’s lymphoma
Non-Hodgkin’s lymphoma 4% 4% Leukemia
All others 22% 2% Multiple myeloma
21% All others

Adapted from Greenlee RT, et al. CA Cancer J Clin. 2000;50:16.


American Joint Committee
Estadificación de Cáncer de Colon
TNM Duke’s SV 5 años %

Etapa I T1, N0, M0 A 85–95


T2, N0, M0 B1
B2
Etapa II T3, N0, M0 60–80
T4, N0, M0

Etapa III T, N1–3, M0 C 30–60

Etapa IV T, any N, M1 D <5


Macdonald JS. CA Cancer J Clin 1999; 49:202-219
Etapa Inicial al Diagnóstico
Cáncer de Colon

Etapa IV: 20–25% Etapa I: 15%

Etapa III: 30–40% Etapa II: 20–30%

Hamilton and Grem. Current Cancer Therapeutics (3rd ed.) 1998


Factores pronosticos?
Invasión
CEA Habilidad Quirúrgica
Distal intramural
Estatus
Conteo de
Socioeconómico
Cel. Dendriticas
Perforación
Alelos: • Multifactorial Obstrucción
CCND1 870A • Role de marcadores
BRCA1 LOH No. de ganglios
no definido? examinados
Invasion:
Linfática Invasión
Venosa Mutaciónes: Peri tumoral
Perineural p53
K-ras DNA ploidia
Serosa Diferenciación Mad2
Watanabe T et al. NEJM 2001; 344: 1196-206
Prognosis factors
for patients with complete resection
Proven prognostic factors Probable prognostic factors
pT&N , stage group Anatomical site of primary (lower
Histological grade rectum)
Venous invasion Tumor perforation/obstruction
Lymphatic invasion
Histological pattern of tumor margins
(infiltrative) Perineural invasion
Peritumoral lymphoid invasion

Microsatellite instability

From DeVita 6th Ed, Lipincott; H Bleiberg colorectal cancer guide, 2002, M Dunitz, and C Ribic, NEJM 2003,
Prognostic factors for colon cancer:
Stage II/III
Disease-free survival Hazard ratio p-value
Positive nodes
1–4 2.1 <0.0001
≥5 4.2 <0.0001
Tumour depth
T3 1.2 0.2545
T4 1.8 0.0033
High grade 1.3 0.0017
Age ≥ 60 yrs 1.0 0.6447
Female 0.94 0.4130
Right colon 0.92 0.2537
Overall survival Hazard ratio p-value
+Age ≥ 60 yrs 1.20 Significant

7 studies; n=3341 Gill S et al. J Clin Oncol 2004; 22:1797-1806


Main advances in the adjuvant treatment
of colon cancer - overview
1990 - 1994 Treatment (5-FU + LV or levamisole)
better than no treatment1
1998 5-FU/LV better than 5-FU/levamisole2
1998 6 months = 12 months of 5-FU/LV3
1998 Levamisole unnecessary with LV4
1998 High-dose LV = low-dose LV5
1998 Weekly = monthly schedules6
2001 Elderly = “young”7
2002 Infusional safer than bolus8

References in comments
Why examine the benefits of oxaliplatin
in stage II/III?: evidence from MCRC
de Gramont, 20001 Goldberg, 20042
FOLFOX LV5-FU2 FOLFOX IFL
RR
(%) 50.7* 22.3 45 †
31
PFS
(months) 8.2* 6.0 8.7 †
6.9
OS
(months) 16.2 14.7 19.5* 15.0

Highly efficacious first-line treatment should improve the


outcome of patients with earlier stage disease

*p<0.001; †p<0.01 de Gramont A, et al. J Clin Oncol 2000;18:2938–47


1

2
Goldberg RM, et al. J Clin Oncol 2004;22:23–30
Do
Do the
the benefits of oxaliplatin
oxaliplatin in
in advanced
advanced
colon
colon cancer
cancer translate
translate to
to earlier
earlier disease?
disease?

Highly efficacious first-line treatment should


improve outcome of patients with earlier stage
disease

MOSAIC trial
LV5FU2 in adjuvant colon cancer

Mayo Bolus 5FU

R
LV5FU2
905 patients
Median follow up 41 months
DFS similar in both arms (127 vs 124 events, p= 0.74)
(73% patients disease free at 3 y)
Deaths : 73 in LV5FU2 vs 59 in Mayo, p= 0.18
Toxicities significantly lower in the LV5FU2 (p<0.001)
André T et al. J Clin Oncol, 2003, 21, 2896 - 2903
M O S A I C

MOSAIC
Multicenter International Study of
Oxaliplatin/5FU-LV in the Adjuvant treatment of
Colon Cancer
MOSAIC: Design

FOLFOX4 - LV5FU2 + Oxaliplatin 85mg/m²

R
LV5FU2

Endpoints ■ Primary:
– Disease Free Survival (DFS)
■ Secondary:
– Safety (including long-term)

– Overall Survival (OS)


MOSAIC: treatment arms

FOLFOX4: LV5FU2 + oxaliplatin 85mg/m²


D1 5-FU bolus D2 5-FU
5-FU bolus
bolus

LV LV
LV
5-FU infusion* 5-FU infusion*
Oxali

R
D1 5-FU bolus D2 5-FU
5-FU bolus
bolus

LV 5-FU infusion* LV 5-FU infusion*


LV5FU2

Every 2 weeks, 12 cycles of treatment

*Baxter LV5 infusors


André T et al. N Engl J Med 2004; 350:2343-51
MOSAIC: main inclusion criteria

Stage II (Dukes B2: T3, T4, N0, M0) or


Stage III (Dukes C: any T; N1, N2, M0)
Complete resection of the primary tumor
Treatment within 7 weeks following surgery
No prior chemo-, immuno-, or radiotherapy
Age 18–75 years old
ECOG PS ≤2

André T et al. N Engl J Med 2004; 350:2343-51


MOSAIC: statistical hypotheses

Stage II / III ratio = 40 / 60%


2.5 year-inclusions
Expected 3-year DFS: 79% for test arm and 73% in control
arm or 25% decrease in risk of recurrence
Probability of disease recurrence is very low after 3 years

N = 2200 for a statistical power of 90% (α =0.05)

André T et al. N Engl J Med 2004; 350:2343-51


MOSAIC: randomization

Stratification for:

Center
Extent of invasion of the primary tumor (T2, T3, or T4)
Number of involved lymph nodes (N0, N1, N2)
Bowel obstruction or tumor perforation

André T et al. N Engl J Med 2004; 350:2343-51


MOSAIC: Follow-up and recurrence

Every 6 months:
Clinical examination, imaging, CEA

Diagnosis of recurrence:
- radiological recurrence on imaging
- and/or positive cytology or biopsy

An elevated CEA, as a solitary finding, was not


considered as acceptable evidence of recurrence.

André T et al. N Engl J Med 2004; 350:2343-51


MOSAIC: enrolment per country

F 477 patients Hn 103 patients At 27 patients


UK PL
364 patients NL 69 patients 26 patients
Sp IL
294 patients 58 patients Dk 22 patients
It 51 patients 21 patients
249 patients No

B D 37 patients Cy 17 patients
135 patients
Au
133 patients S
36 patients Sg 17 patients

Gr 3 patients
107 patients Ch

2246 patients
(Oct 98-Jan 01)
André T et al. N Engl J Med 2004; 350:2343-51
MOSAIC: Patients characteristics

FOLFOX4 LV5FU2
(n=1123) (n=1123)

Median age, years 61 60


Male / Female % 56 / 44 52 / 48
KPS 80-100% 86.2 87.6
Stage II / III % 40 / 60 40 / 60

Bowel obstruction % 18 19
Perforation % 7 7

André T et al. N Engl J Med 2004; 350:2343-51


Disease-free survival: all patients
Median follow-up 44.2 months
Probability 3-year DFS
1.0 FOLFOX4 (n=1123) 78.7%
LV5FU2 (n=1123) 73.3%
0.9

0.8

0.7

HR (95% CI): 0.76 (0.64─0.89); p=0.0008


0.6
24% risk reduction in the FOLFOX4 arm

0.0
0 6 12 18 24 30 36 42 48 54 60 66
DFS (months) de Gramont A et al. ESMO 2004 accepted abstract
Disease-free survival: stage III patients
Median follow-up 44.2 months
Probability
3-year DFS
1.0 FOLFOX4 (n=672) 72.8%
LV5FU2 (n=675) 65.8%
0.9
HR (95% CI): 0.75 (0.62─0.90); p=0.002
25% risk reduction in the FOLFOX4 arm
0.8

0.7

0.6

0.0
0 6 12 18 24 30 36 42 48 54 60 66
DFS (months) de Gramont A et al. ESMO 2004 accepted abstract
Disease-free survival: stage II patients
Median follow-up 44.2 months
Probability
3-year DFS
1.0 FOLFOX4 (n=451) 87.4%
LV5FU2 (n=448) 84.3%
0.9

0.8

0.7

HR (95% CI): 0.79 (0.57─1.09); p=0.151


0.6
21% risk reduction in the FOLFOX4 arm

0.0
0 6 12 18 24 30 36 42 48 54 60 66
DFS (months) de Gramont A et al. ESMO 2004 accepted abstract
Analysis of DFS according to disease stage

FOLFOX better LV5FU2 better

T4
T1, T2, T3
N2
N0, N1
Stage III
Stage II
0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6
Hazard ratio and 95% CI

André T et al. N Engl J Med 2004; 350:2343-51


Safety results
Grade 3-4 Toxicities (per patient)
NCI ≥ Gr 3 % FOLFOX4 LV5FU2
(n=1108) (n=1111)
Thrombocytopenia 1.7 0.4
Neutropenia 41.1 (Gr 4: 12.2) 4.7

Febrile neutropenia 0.7 0.1


Neutropenic sepsis 1.1 0.1
Diarrhoea 10.8 6.7
Stomatitis 2.7 2.2
Vomiting 5.9 1.4
Allergy 3.0 0.2
Alopecia (Gr 2) 5.0 5.0
André T et al. N Engl J Med 2004; 350:2343-51
Grading of Neurotoxicity
--------------------------------- Grade --------------------------------
0 1 2 3
NCI Common Toxicity Scale version 1 (Severity)
None or Mild paresthesia, loss Mild or moderate Severe objective
no change of deep tendon objective sensory loss; sensory loss
reflexes moderate paresthesia or paresthesia that
interfere with function
Oxaliplatin Specific Scale for Paresthesias (Duration)
Absent Short lasting Paresthesia Persisting with
paresthesia with persisting between functional impairment
complete regression cycles without functional
prior to next cycle impairment

Pharyngo-laryngeal paresthesias
None Mild Moderate Severe
Gamelin E et al. Semin Oncol 2002, 29 (suppl 15):21-33
Eloxatin dose modifications for
neurotoxicity (add mg/m²/cycle into table)
Duration < 7 days > 7 days, Persistent
Type of toxicity < 14 days between courses
Cold related None None None
dysesthesia
Paresthesia None None STOP until recovery,
without pain then restart at 75
Paresthesia with None Reduction: 75 STOP
pain
Paresthesia with None Reduction: 75 STOP
functional
impairment

André T et al. N Engl J Med 2004; 350:2343-51


MOSAIC: peripheral sensory neuropathy
No of patients
Total Gr 0 (%) Gr 1 (%) Gr 2 (%) Gr 3 (%)
During 1106 87 (7.9) 533 (48.2) 349 (31.5) 137 (12.4)
treatment
1-month 1092 424 (38.8) 439 (40.2) 174 (15.9) 55 (5.0)
follow-up
6-month 1058 624 (59.0) 338 (31.9) 82 (7.7) 14 (1.3)
follow-up
12-month 1018 718 (70.5) 240 (23.6) 49 (4.8) 11 (1.1)
follow-up
18-month 967 738 (76.3) 191 (19.8) 33 (3.4) 5 (0.5)
follow-up

André T et al. N Engl J Med 2004; 350:2343-51


MOSAIC: peripheral sensory neuropathy

100 Grade 0 – no change or


 symptoms
90
80 Grade 1 – mild
 paresthesia, loss of deep
70 tendon reflexes
Patients (%)

60 Grade 2 – mild or
 moderate objective
50 sensory loss, moderate
paresthesia
40
30  Grade 3 – severe
objective sensory loss
20 or paresthesia that
interfere with function
10
0
During 1 month 6 months 12 months 18 months
treatment
Follow-up

André T et al. N Engl J Med 2004; 350:2343-51


Advances in the adjuvant treatment
of colon cancer
1990 - 1994 Treatment (5-FU + LV or levamisole) better
than no treatment
1998 5-FU/LV better than 5-FU/levamisole
1998 6 months = 12 months of 5-FU/LV
1998 Levamisole unnecessary with LV
1998 High-dose LV = low-dose LV
1998 Weekly = monthly schedules
2001 Elderly = “young”
2002 Infusional safer than bolus
2003 FOLFOX better than 5-FU/LV*

*
André T et al. N Engl J Med 2004; 350:2343-51
Disease-free survival
versus overall survival

Rate of relapse = chance of cure

Prolong life without disease = QoL


Pooled analysis
Methods
Data from large randomized trials
Individual patient data from all trials
Compare DFS, OS for each arm
Landmarks: 3 years for DFS, 5 years for OS

Based on individual patient data, replicate analysis that


would have been completed at 3, 5 year time points

Pooled analysis: 39 treatment arms; 17367 patients

Primary comparison: Hazard ratios


Sargent D et al, 2004 ASCO Annual Meeting (abstr 3502)
Sargent D et al, 2004 ASCO Annual Meeting (abstr 3502)
Sargent D et al, 2004 ASCO Annual Meeting (abstr 3502)
3-year DFS vs 5-year OS
Conclusions

On a patient by patient basis, 3 years seems reasonable


Rate of recurrence
Survival following recurrence: Median 1.1 years

On an arm-by-arm basis:
3-year DFS is an excellent predictor of 5-year OS

Based on these data, DFS is an appropriate endpoint for adjuvant


colon trials

Adoption of DFS endpoint allows more rapid availability of


promising therapies to patients

Sargent D et al, 2004 ASCO Annual Meeting (abstr 3502)


3-year DFS of stage III patients in major
studies
Study Treatment 3-year DFS
Moertel Observation 52%
IMPACT Observation 44%
IMPACT 5FU/LV 62%
Punt 5FU/LV 65%
Fields 5FU/LV 67%
André 5FU/LV 61%
MOSAIC 5FU/LV 65%
MOSAIC FOLFOX4 72%
X-ACT Capecitabine 64.2%
3rd International Conference:
perspectives in CRC

Stage II: high risk population


T4
Perineural invasion
Venous invasion 5-year OS
30–40%
Lymphatic vessel invasion
Poor tumour differentiation
Colonic obstruction

Van Cutsem E et al. Eur J Cancer 2002 Jul; 38(11): 1429-36


Model-derived estimates of 5-year DFS (%)
with surgery plus adjuvant therapy

Nodal+AT
status Gill S et al. J Clin Oncol, 2004, 22:1797-1806
From trials to clinical practice…
Based on the Gill et al data and taking into account clinical trials data, the Mayo Clinic has developed a model to estimate the 5 year relapse-free survival and overall survival for a given patient profile with:
- no treatment
- LV/5FU adjuvant treatment
- FOLFOX adjuvant treatment

www.mayoclinic.com/calcs/

Gill S et al. J Clin Oncol, 2004, 22:1797-1806