Improving chemoradiotherapy regimens in rectal cancer

1
Improving chemoradiotherapy regimens in rectal
cancer
2
Rationale for the development of Xeloda

• To generate 5-FU at the tumour site to maximise
  antitumour activity and/or improve tolerability
• Oral administration
• mimics continuous infusion 5-FU
• lacks complications associated with i.v.
  administration
• provides convenient therapy

3
Tumour-activated Xeloda
Intestine
Liver
Tumour gtgt healthy tissue
Xeloda
Xeloda
CE
5'-DFCR
5'-DFCR
CyD
CyD
5'-DFUR
5'-DFUR
Thymidine phosphorylase (TP)
5-FU
5'-DFCR 5'-deoxy-5-fluorocytidine 5'-DFUR
5'-deoxy-5-fluorouridine CyD cytidine
deaminase CE carboxylesterase
4
No tumour selectivity with 5-FU
x 1
x 1
Normal tissue
Normal tissue
Plasma
Plasma


Tumour tissue
Ratio of median values
Kovach JS, Beart RW Jr. Invest New Drugs
198971325
5
More 5-FU in the tumour with TP-activated Xeloda
x 3.2
x 21.4
Normal tissue
Plasma
Normal tissue
Plasma
Tumour tissue
Tumour tissue
Ratio of median values
Ratio of median values
Schüller J et al. Cancer Chemother Pharmacol
2000452917
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Irradiation further upregulatesTP in WiDr colon
cancer xenografts
TP (units/mg protein)
5Gy 2.5Gy Control
25 20 15 10 5 0









0 3 6 9 12 15 18 21
Days after X-ray irradiation
plt0.05
Sawada N et al. Clin Cancer Res 19995294853
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Preclinical WiDr xenograft activityXeloda gt5-FU
in chemoradiation
Tumour inhibition ()
120 100 80 60 40 20 0

5Gy
5-FU
Xeloda
5-FU 5Gy
Xeloda 5Gy
Sawada N et al. Clin Cancer Res 19995294853
plt0.05
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Xeloda plus radiotherapy a powerful combination

• Potential for enhanced therapeutic ratio1
• Oral Xeloda simplifies chemoradiation and is
  highly appealing to patients

1Sawada N et al. Clin Cancer Res 19995294853
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Xeloda chemoradiation in rectal cancer German
phase II study (n68)
Day 1 8 15 22 29 35
Radiotherapy 1.8Gy/day pluspresacral boost (3 x
1.8Gy)
Oral Xeloda 825mg/m2 twice daily
Continuous (days 137)

• Male/female () 63/37 median age 65
  yearsECOG 0/1 54/41
• T3 48, T4 52 N0 35, N13 57

Dunst J et al. Proc Am Soc Clin Oncol 200322277
(Abst 1113)
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Xeloda chemoradiation is well tolerated
Patients ()

• No grade 4 adverse events

80 60 40 20 0
Diarrhoea Local Neurological Hand-foot Nausea
erythema pain syndrome
Dunst J et al. Proc Am Soc Clin Oncol 200322277
(Abst 1113)
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Xeloda chemoradiation highly active

• Seven studies have published similar results

1Dunst J et al. ECCO 12 2003 (Abst 282) 2Lin E et
al. Proc Am Soc Clin Oncol 200322287 (Abst 1152)
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NSABP R-04 neoadjuvant rectal cancer trial to
open in 2003

• Objectives
• pCR
• recurrence rate
• DFS

Xeloda continuously throughout radiotherapy
(45Gy)
S U R G E R Y
Resectable rectal cancer, stage IIIII n1,600
5-FU continuous infusion throughout radiotherapy
(45Gy)
Plus 5.4Gy boost for non-fixed tumours, 10.8Gy
for fixed tumours
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Xeloda combinations with radiotherapy potential
to further enhance efficacy
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SOCRATES Xeloda plus oxaliplatin and
radiotherapy

• DLTs (2 patients) grade 3 diarrhoea,
  desquamation/rectal pain
• Study ongoing in phase II (n80 total)

25 fractions
Glynne-Jones R et al. Proc Am Soc Clin Oncol
200322292 (Abst 1174)
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Xeloda/oxaliplatin chemoradiation enhances
surgical resection
1Glynne-Jones R et al. Proc Am Soc Clin Oncol
200322292 (Abst 1174)2Rödel C et al. J Clin
Oncol 2003213098104
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Belgian phase II study in locally advanced rectal
cancer (n20)
1 8 15 22 29
Day
Radiotherapy 45Gy/25 fractions/33 days
Oral Xeloda825mg/m2 twice daily Monday to Friday
Oxaliplatin50mg/m2weekly

• Male/female () 60/40 median age 59 years
  (3377) ECOG 0/1 85/15
• T2N 5 T3N0 50 T3N 45

Duck L et al. ECCO 12 2003 (Abst 260)
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Early safety results of XELOX-RT

• Relative dose intensity
• Xeloda 93 and oxaliplatin 95
• radiotherapy 100
• Myelosuppression was rare (4 patients, no grade
  3/4)
• Principal toxicity diarrhoea
• grade 3 in 3 patients
• grade 4 in 1 patient
• led to chemotherapy dose reduction or
  interruption in 5 patients

Duck L et al. ECCO 12 2003 (Abst 260)
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CORE European phase II study in locally
advanced/inoperable rectal cancer
Day
1 8 15 22 29
Radiotherapy 45Gy/25 fractions/33 days
Oral Xeloda 825mg/m2 twice daily Monday to Friday
Oxaliplatin50mg/m2weekly
Capecitabine, Oxaliplatin, Radiotherapy and
Excision
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UK OxaliCap-RT project first phase chemotherapy
escalation completed

• ³80 receiving gt80 of planned dose PC/CR 50
• Level 3 recommended no grade 4 low grade 3
• 12-week duration

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The next phase radiotherapy escalation ongoing
(first cohort complete)
OxaliCap for 12 weeks
RT for 25 fractions, Monday to Friday

• Six patients per cohort, 5 cohorts
• Escalation from 1.22.0Gy/fraction
• 0.2Gy increments
• total 3050Gy
• Preliminary assessment of efficacy in each cohort
• Pathological sub-study

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Planned CHRONICLE trial in locally advanced
rectal cancer
XELOX 6 cycles

• 1º objective
• DFS
• 2º endpoints
• overall survival
• tolerability

n800 Rectal cancer post-operative
post-5-FU-based chemoradiation
Observation
XELOX Xeloda plus oxaliplatin
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Xeloda chemoradiation a one-stop shop for
rectal cancer patients

• Oral Xeloda is replacing 5-FU as the standard
  combination partner for radiotherapy
• Xeloda is highly effective and well tolerated in
  combination with radiotherapy
• Xeloda simplifies chemoradiation and is highly
  appealing to patients and clinicians alike
• New combinations show potential to further
  improve efficacy