Current firstline treatment options: reassessing the evidence

1
Current first-line treatment options
reassessing the evidence

• Martin Stockler
• Sydney Cancer CentreNHMRC Clinical Trials
  Centre, University of SydneyAustralia New
  Zealand Breast Cancer Trials Group

2
Options for first-line chemotherapy in
HER2-negative metastatic breast cancer (MBC)
Anthracyclines
Taxanes
Xeloda / Taxotere (XT)
Xeloda
CMF
Other
3
Limited evidence to support anthracycline re-use
in metastatic setting

• Anthracycline-based therapy for MBCafter
  adjuvant anthracyclines versus no adjuvant
  anthracyclines
• lower response rates
• shorter time to treatment failure

4
Unpredictable safety of anthracyclines

• Cumulative toxicity, particularly after use in
  adjuvant setting
• Cardiovascular complications are unpredictable
  and potentially fatal (3)1
• symptomatic CHF in 218 at doses below typical
  maximum cumulative dose14
• doxorubicin 550mg/m2, epirubicin 900mg/m2
• significant LVEF impairment can occur early and
  variably3,4
• High incidence of febrile neutropenia (16)1
• Complete alopecia in majority (gt90)1

1Chan S et al. J Clin Oncol 199917234154 2Frenc
h Epirubicin Study Group. J Clin Oncol
1988667988 3Jain KK et al. J Clin Oncol
1985381826 4Brambilla C et al. Cancer Treat
Rep 1986702616
5
The changing treatment landscape

• Most patients with metastatic disease are now
  anthracycline pretreated
• Options for anthracycline-pretreated patients
• docetaxel or paclitaxel
• XT
• gemcitabine / paclitaxel
• Xeloda monotherapy
• CMF
• other
• What is the evidence for these options?

6
Docetaxel is more effective than paclitaxel . . .
ORR overall response rate CR complete
response PR partial response TTP time to
disease progression OS overall survival
Jones S et al. Breast Cancer Res Treat
200382(Suppl. 1)S910
7
. . . but is significantly more toxic
Jones S et al. Breast Cancer Res Treat
200382(Suppl. 1)S910
plt0.05
8
XT extending survival in MBC

• Only cytotoxic combination to improve survival
  over Taxotere monotherapy in patients with
  pretreated MBC
• Phase III trial comparing 3-weekly cycles of XT
  versus Taxotere
• XT (X 1 250mg/m2 twice daily, days 114 plus T
  75mg/m2, day 1) (n255)
• Taxotere (100mg/m2, day 1) (n256)
• One-third of patients were treated in first line

OShaughnessy J et al. J Clin Oncol
200220281223
9
XT superior response rate and TTP
Estimated probability
1.0 0.8 0.6 0.4 0.2 0.0
ORR
XT (n255) 42 Taxotere (n256) 30
p0.006
Log-rank p0.0001
4.2
6.1
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Months
OShaughnessy J et al. J Clin Oncol
200220281223
10
Addition of Xeloda to Taxotere extends survival
Estimated probability
1.0 0.8 0.6 0.4 0.2 0.0
XT (n255) Taxotere (n256)
Hazard ratio 0.77
Log-rankp0.013
11.5
14.5
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Months
OShaughnessy J et al. J Clin Oncol
200220281223
11
Similar overall survival in patients relapsing
2 years after adjuvant anthracyclines
Estimated probability
1.0 0.8 0.6 0.4 0.2 0.0
XT Taxotere
Overall population1
Relapse 2 years2
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Months
1OShaughnessy J et al. J Clin Oncol
200220281223
2F. Hoffmann-La Roche, data on file
12
XT potential for overlapping toxicity
1OShaughnessy J et al. J Clin Oncol
200220281223 2Nabholtz JM et al. J Clin Oncol
199917141324 3Blum JL et al. J Clin Oncol
19991748593
13
XT a manageable safety profile
Patients ()
50 40 30 20 10 0
Grade 3 Grade 4 Grade 3 Grade 4
XT (n251)
Taxotere (n255)
Hand-foot syndrome
Fatigue/ asthenia
Diarrhoea
Stomatitis
Nausea
Neutropenic fever
OShaughnessy J et al. J Clin Oncol
200220281223
14
Dose reductions for side-effect management

• Dose reductions required by 65 in XT arm and 36
  in Taxotere arm1
• With XT, 78 of dose reductions were of both
  drugs2
• Taxotere to approximately 60mg/m2
• Xeloda to approximately 1 000mg/m2 twice daily
• Nausea, vomiting, diarrhoea and stomatitis are
  overlapping toxicities with Xeloda and Taxotere
• Neutropenia driven by Taxotere alone rare with
  Xeloda3,4

1OShaughnessy J et al. J Clin Oncol
200220281223 2F. Hoffmann-La Roche, data on
file 3Nabholtz JM et al. J Clin Oncol
199917141324 4Blum JL et al. J Clin Oncol
19991748593
15
Fewer grade 3 / 4 adverse events afterTaxotere
and Xeloda doses are reduced
Cycles ()
20 16 12 8 4 0
Both full doses (670 cycles)
Both reduced (405 cycles)
Diarrhoea Stomatitis Hand-foot Neutropenic syn
drome fever
F. Hoffmann-La Roche, data on file
16
XT dose reduction does not compromise efficacy
overall survival
Estimated probability
1.0 0.8 0.6 0.4 0.2 0.0
Cycle 2 dose Both full Both reduced
15.0
14.6
0 5 10 15 20 25 30 35 40 45 50
Months
F. Hoffmann-La Roche, data on file
17
XT the first-line standard for fitter patients
with fast-progressing disease

• Xeloda extends survival beyond Taxotere and is
  the standard of care for fitter patients with
  fast-progressing disease
• Dosing flexibility allows management of XT side
  effects recommended starting doses
• Xeloda 1 000mg/m2 twice daily, days 114, every 3
  weeks
• Taxotere 60mg/m2, day 1

18
Goals of treatment and research in advanced
breast cancer

• The goals of treatment in advanced breast cancer
  are to improve length and quality of life
• Recent clinical research has focused attention on
  whether more intensive therapy can improve
  outcomes for women fit enough to receive it

19
Practical questions in advanced breast cancer

• However, many women with advanced breast cancer
  are unsuited to intensive therapy
• those with co-existing medical problems
• those with extensive metastatic disease
• the elderly
• those who prefer less intensive chemotherapy
• What is the best approach for these women?

20
Basis for chemotherapy regimens

• Intensive treatment
• eradication of clone
• high growth fraction
• fast doubling time
• low treatment to overall survival time
• intermittent bolus regimens
• i.v. combinations
• younger and fitter patients

• Palliative treatment
• control of clone
• low growth fraction
• slow doubling time
• high treatment to overall survival time
• continuous chronic therapy
• oral antimetabolites
• frail patients with comorbidities

21
Single-agent Xeloda a highly active and
well-tolerated first-line option
22
Efficacy of Xeloda compares favourably with
paclitaxel
Talbot D et al. Br J Cancer 200286136772
23
Efficacy of Xeloda compares favourably with CMF
Upper limit not reached
OShaughnessy J et al. Ann Oncol 200112124754
24
Randomised phase III trialoral vs i.v. CMF in
advanced breast cancer
Engelsman E et al. Eur J Cancer 19912796670
25
Ongoing comparison Xeloda versus CMF in
first-line MBC
R A N D O M I S A T I O N
n245 / 465
Xeloda 1 000mg/m2 b.i.d. days 114, every 21 days
Classical Bonadonna CMF every 28 days
Continuous Xeloda 666mg/m2 b.i.d.
QoL-adjusted progression-free survival Progression
-free survival QoL and treatment
acceptability Overall survival Tumour response
rate Toxicity Cost effectiveness
ANZ Breast Cancer Trials Group
26
What troubles women starting chemotherapy for
advanced breast cancer in a randomized trial?

• Baseline data on quality of life in
  ANZ0001Abstract 8144ASCO 2004
• Anna Nowak, Karen Byth, Val Gebski, Akiko Fong,
  Alan Coates, Vernon Harvey, Martin Stockler on
  behalf of the ANZ Breast Cancer Trials Group

27
What troubled women before chemotherapy?

• Aspects that troubled women most
• uncertainty about the future
• the thought of chemotherapy
• anxiety, depression, tiredness
• problems doing vigorous activities
• problems doing what they wanted
• Aspects that troubled women least
• loneliness loss of self-confidence
• difficulties with self-care
• inconvenience problems coping with
  treatmentproblems with tablets needles and
  injections

28
Xeloda monotherapy in the elderlyeffective and
well tolerated in first-line MBC

• Median age 73 years (6589)
• No grade 3 / 4 myelosuppression
• Only one patient on 1 000mg/m2 required dose
  reduction

Procopio G et al. Eur J Cancer 20031(Suppl.
5)S138 (Abst 451)
29
Xeloda monotherapy in MBC low incidence of
grade 3 / 4 events (n728)
Patients ()
40 30 20 10 0

• Minimal alopecia
• No treatment-related deaths

Hand-foot Diarrhoea Neutropenia Fatigue Stomatit
is Nausea Dehydration syndrome
n498
Blum JL et al. J Clin Oncol 19991748593 Blum
JL et al. Cancer 200192175968 Reichardt P et
al. Ann Oncol 200314122733 Fumoleau P et al.
Eur J Cancer 20044053642 Maung K. Clin Breast
Cancer 200333757
30
Options for first-line chemotherapy in
HER2-negative metastatic breast cancer (MBC)
Anthracyclines
Integrate evidence withpreferences
Taxanes
Xeloda / Taxotere (XT)
Xeloda
CMF
Other
31
Xeloda first in MBC treatment

• First-line Xeloda monotherapy
• less fit patients with slow progressing disease
• recommended starting dose
• Xeloda 1 000mg/m2 twice daily, days 114, every
  3 weeks
• First-line XT is standard of care
• fitter patients with fast progressing disease
• recommended starting dose
• Xeloda 1 000mg/m2 twice daily, days 114
  Taxotere 60mg/m2, day 1, every 3 weeks