1. Xeloda X-panding options in the adjuvant treatment of breast cancer
Christopher J Poole
Macmillan Senior Lecturer Medical Oncology University Hospital Birmingham, UK

2. Evaluation of Xeloda in adjuvant chemotherapy for women with early BC (n>20 000)
Building on its high activity in MBC, Xeloda is currently being evaluated in a comprehensive, worldwide adjuvant and neoadjuvant trial program.
These studies, which together will include more than 20,000 patients with early breast cancer, are aiming to more fully elucidate the clinical utility of Xeloda-based therapy in the adjuvant setting.
Patient numbers for the trials are shown below:
US Oncology – completed January 2006 (2610 patients)
TACT2 - ongoing (4400 patients)
CALGB - ongoing (600 patients)
GEICAM - ongoing (1302 patients)
GEICAM-CIBOMA - planned (3538 patients)
GAIN - ongoing (3130 patients)
FinXX - ongoing (1500 patients)
ICE - ongoing (1394 patients)
MINDACT - planned (5000 patients)
MDACC - ongoing (930 patients).
Patients with HER2 positive tumors will receive Herceptin for 52 weeks

4. Registration trial of Xeloda/Taxotere in sequential adjuvant treatment
R A N D O M I Z
A T I O N
AC x4
T100 x4
US Oncology
n=2 610
N+ N0, tumor >2cm N0, ER-/PR–
The US Oncology registration study is a large, phase III trial evaluating XT as adjuvant therapy.
The trial, which has completed recruitment of 2610 patients with high-risk, early-stage, primary operable breast cancer, compared postoperative treatment with four cycles of doxorubicin/cyclophosphamide (AC) followed by four cycles of either Taxotere monotherapy (100mg/m2 every 21 days) or XT (Xeloda 825mg/m2 twice daily, days 1–14 plus Taxotere 75mg/m2 on day 1, every 21 days).
Patients with ER+ and/or PR+ tumors will receive tamoxifen or anastrozole for 5 years.
Patients with human epidermal growth factor receptor 2 (HER2) positive tumors will receive Herceptin for 52 weeks.
Primary endpoint: disease-free survival (DFS) at 5 years.
Recruitment completed in January 2006.
Study contact: Joyce O’Shaughnessy (USA).
AC x4
X825 T75 x4
Primary endpoint: disease-free survival at 5 years
Status: recruitment completed January 2006

5. UK adjuvant study of sequential Xeloda monotherapy (TACT2)
R A N D O M I Z
A T I O N
n=4 400
Medium-risk breast cancer with definite indication for adjuvant chemotherapy
Epirubicin x4
CMF x4
2x2 bifactorial design:
3-weeky vs 2-weekly epirubicin/Neulasta
The UK TACT2 adjuvant trial is evaluating sequential treatment with epirubicin followed by randomization to four cycles of Xeloda or CMF. This trial follows on from the NEAT study.
The National Epirubicin Adjuvant Trial (NEAT) compared epirubicin (100mg/m2 for four cycles) followed by classical cyclophosphamide/methotrexate/5-FU (CMF; four cycles) with classical CMF (six cycles) in women with early stage breast cancer [1].
After a median follow-up of 32 months there was a highly significant benefit in favor of ECMF for both relapse-free (hazard ratio [HR] 0.70, 95% confidence interval [CI]: ; p=0.0003) and overall survival (HR 0.64, 95% CI: ; p=0.0001), which hold when adjusting for trial and prognostic factors. The ECMF advantage is irrespective of lymph node status, age and ER status (Poole CJ et al, 2003).
TACT2 aims to recruit 4400 patients with medium-risk breast cancer (T0–3, N0–2, M0), which represents a definite indication for adjuvant chemotherapy
patients will be randomized to four cycles of accelerated epirubicin followed by either classical CMF (four cycles) or Xeloda
in a 2 x 2 factorial design, the effect of granulocyte-colony stimulating factor (G-CSF) support during epirubicin therapy will also be evaluated
patients with HER2-positive tumors should also receive Herceptin according to local guidelines.
Principal investigator: David Cameron (UK).
1. Poole CJ et al. Proc Am Soc Clin Oncol 2003;22:4 (Abstract 13).
Epirubicin x4
Xeloda x4
Primary endpoint: disease-free survival at 5 years
Xeloda vs CMF comparison powered as non-inferiority study
Status: first patient recruited December 2005

6. GEICAM: ET X vs EC T in adjuvant BC
R A N D O M I Z
A T I O N
E90C600 x4
Taxotere100 x4
n=1 302 N+
ER/PR +/-
This phase III study is comparing the effectiveness of adjuvant chemotherapy comprising epirubicin (90mg/m2 plus cyclophosphamide 600 mg/m2 followed by Taxotere 100mg/m2 versus epirubicin 90mg/m2 plus Taxotere 75mg/m2 followed by Xeloda 1250mg/m2 twice daily.
The primary endpoint of the trial is superiority in relapse-free survival 72 vs 79% at 5 years.
Secondary endpoints include overall survival, toxicity, QoL, biomarkers and MTHFR.
Patients are stratified by pre- vs post-menopausal, number of positive lymph nodes 1–3 vs 4–9 vs >9, hormone-receptor-positive versus negative.
Can choose Tamoxifen or anastrozole for 5 years in hormone-receptor-positive patients after completing chemotherapy.
Radiation therapy according to each center’s local practice.
Herceptin in HER2-positive patients.
Primary investigator: Miguel Martin.
Started 2003, completes January 2007.
E90T75 x4
Xeloda1250 bid x4
Primary endpoint: relapse-free survival at 5 years
Status: 900 patients recruited

7. GEICAM-CIBOMA trial: maintenance Xeloda after adjuvant anthracyclines
R A N D O M I Z A T I O N
n=3 538
Operable N+
ER/PR–
Six prior cycles anthracycline-based adjuvant chemotherapy
Xeloda 8 cycles
Patients with operable node-positive breast cancer are eligible for this adjuvant study. The recruitment aim is approximately 3500 patients.
Patients are randomized to eight cycles of Xeloda (1000mg/m2 twice daily, days 1–14) or observation after completing six cycles of anthracycline-based adjuvant therapy.
The primary endpoint is 5-year DFS and the study has been powered to detect an approximate 5% absolute increase or 14.18% relative increase (59.77–64.30%; HR ).
This study will be carried out in centers in Spain and Latin America.
Study coordinators: Drs Barrios (Brazil), Torrecillas (Mexico), Lluch (Spain).
Observation
Primary endpoint: 14% increase in 5-year disease-free survival (HR 0.86)
Status: recruitment begins next month

8. AGO GAIN: phase III study of adjuvant E P C versus EC XP
R A N D O M I Z A T I O N
E P C
n=3 130
Primary BC N+
2x2 ± Bondronat (daily for 2 years)
2x2 ± darbepoietin (during EPC and EC)
This phase III study is comparing the effectiveness of adjuvant chemotherapy comprising epirubicin→paclitaxel →cyclophosphamide (E→P→C) versus epirubicin/cyclophosphamide (EC) followed by Xeloda/paclitaxel (XP) in patients with primary node-positive breast cancer.
Primary endpoints
disease-free survival after adjuvant chemotherapy with E→P→C versus EC→XP
disease-free survival with or without Bondronat treatment for 2 years.
Secondary endpoints: overall survival; compliance; safety; response to erythropoesis stimulating factors; event-free survival in subgroups of hormone-sensitive and insensitive disease and in groups with 1–3, 4–9 or 10+ involved nodes.
Patients are randomized to receive:
three 2-weekly cycles of epirubicin 150mg/m2 on day 1 followed by three 2-weekly cycles of paclitaxel 225mg/m2 on day 1 followed by three 2-weekly cycles of cyclophosphamide 225mg/m2 on day 1
four 2-weekly cycles of epirubicin 112.5mg/m2 plus cyclophosphamide 600mg/m2 followed by four 3-weekly cycles of Xeloda 1000mg/m2 twice daily plus ten weekly doses of paclitaxel 67.5mg/m2.
As part of the 2 x 2 factorial design, the effect of Bondronat 50mg orally administered daily for two years will also be examined.
During treatment with EC or EPC, patients will receive prophylaxis with pegfilgrastim (G-CSF) and darbepoetin.
After chemotherapy, anastrozole 1mg will be administered to patients with ER- or PR-positive tumors for 5 years.
Expected total enrolment: 3000
Study start: July 2004; expected recruitment completion: end 2007.
Primary investigator: V Moebus, Frankfurt, Germany.
EC XP
Primary endpoints
disease-free survival E P C versus EC XP
disease-free survival with or without Bondronat
Status: 700 patients recruited

10. CALGB: phase III adjuvant CMF or AC versus Xeloda in elderly patients
R A N D O M I Z
A T I O N
CMF or AC
n=600
Stage I–IIIC disease
³65 years
Tumor ³3cm, N0, M0 or
T1–3, N1–3, M0
This CALGB/SWOG phase III study is comparing the effectiveness of adjuvant chemotherapy comprising standard CMF or AC versus Xeloda in elderly women with operable breast cancer.
The primary endpoint of the trial is 5-year DFS. Secondary objectives include overall survival, quality of life (QoL), tumor markers and physical functioning, toxicity and evaluating the adherence of older patients to an oral chemotherapy regimen.
A total of 600–1800 patients (300–900 per treatment arm) will be accrued for this study within 2–6 years. Patients will be stratified according to age (65–69 vs 70–80 vs >80) and performance status (0–1 vs 2).
Patients are randomized to one of two treatment arms:
arm I: patients with insufficient left ventricular ejection fraction (LVEF) are assigned to group A. Patients with normal LVEF are assigned to group A or B based on physician/patient choice
group A (CMF): patients receive oral cyclophosphamide daily, days 1–14 and i.v. methotrexate and 5-FU on days 1 and 8, every 4 weeks for six courses in the absence of disease progression or unacceptable toxicity
group B (AC): patients receive i.v. doxorubicin and cyclophosphamide on day 1, every 3 weeks for four courses in the absence of disease progression or unacceptable toxicity
arm II: patients receive oral Xeloda twice daily, days 1–14, every 3 weeks for six courses in the absence of disease progression or unacceptable toxicity.
Beginning within 12 weeks after treatment in arm I or II, patients with ER- or PR-positive disease receive oral tamoxifen or an aromatase inhibitor daily for 5 years. Beginning 4–6 weeks after treatment in arm I or II, eligible patients who previously underwent breast-conservation surgery undergo radiotherapy. HER2-positive patients will receive Herceptin.
Primary investigators: Richard Schilsky, Hy Muss, Julie Gralow.
Recruitment completes 2006.
Xeloda
Primary endpoint: disease-free survival at 5 years
Status: 500 patients recruited

11. BIG: Bondronat ± Xeloda in elderly patients with early BC (ICE)
R A N D O M I Z
A T I O N
n=1 394
Stage II/III, high risk
N+/–
³65 years
Charlson Scale £2 score points
ECOG PS £2
Bondronat
oral or i.v.
This study is investigating the effect of Bondronat, with and without Xeloda, on breast cancer in older patients. Bisphosphonates are established as a treatment for osteoporosis and adjuvant treatment with a bisphosphonate can reduce the risk of breast cancer recurrence and the formation of metastases. Since many older female patients with breast cancer are at risk of both breast cancer recurrence and osteoporosis, it is meaningful to offer a treatment regimen that could address both conditions.
The primary study endpoint is 5-year DFS. Secondary endpoints include overall survival, compliance, side effect profile, number of osteoporosis-conditioned events between patients with hormone-receptor-positive and -negative tumors, preference for oral or intravenous administration and evaluation of QoL.
This is a prospective, multicenter, double-blind, randomized phase III trial. Patients will receive:
oral Bondronat 50mg daily over 2 years or
i.v. Bondronat 6mg every 4 weeks over 2 years
plus
no chemotherapy or six cycles of oral Xeloda 1000mg/m2 twice daily, days 1–14, every 21 days.
Hormone receptor-positive patients will also receive oral anastrozole 1mg daily over 5 years. Supportive therapy with anti-emetics can be given with Xeloda.
Three interim safety analyses planned; the final analysis will be in January 2010.
Primary investigators: G von Minckwitz, Frankfurt; U Nitz, Duesseldorf.
Bondronat + Xeloda
Primary endpoint: increase in 5-year event-free survival from 61.0 to 71.5%
Status: >400 patients recruited

13. Phase III adjuvant study (FinXX) of sequential Xeloda-based combinations
R A N D O M I Z A T I O N
T80 x3
FE75C x3
Risk of BC recurrence >25% in first 5 years or >35% in 10 years
In Finland, there is an ongoing, randomized phase III study comparing single-agent Taxotere followed by 5-FU, epirubicin and cyclophosphamide (FEC) to Taxotere plus Xeloda (XT) followed by cyclophosphamide, epirubicin and Xeloda (CEX) as adjuvant treatment for early breast cancer [1].
Patients receive:
three cycles of Taxotere 80mg/m2 on day 1 of a 3-week cycle
followed by
three cycles of cyclophosphamide 600mg/m2 on day 1, epirubicin 75mg/m2 on day 1 and 5-FU 600mg/m2 on day 1 of a 3-week cycle OR
three cycles of Taxotere 60mg/m2 on day 1 plus Xeloda 900mg/m2 twice daily on days 1–14 of a 3-week cycle
three cycles of cyclophosphamide 600mg/m2 on day 1, epirubicin 75mg/m2 on day 1 and Xeloda 900mg/m2 twice daily on days 1–14 of a 3-week cycle.
Patients in this study receive locoregional radiation per local protocol and pre- and post-menopausal patients with estrogen (ER)/progesterone (PR)-positive disease receive anastrozole or tamoxifen, respectively, for 5 years.
Primary endpoint: relapse-free survival (RFS) at 5 years.
Secondary endpoints: safety and overall survival.
Recruitment started in January 2004 and it is anticipated that recruitment will be complete by the end of 2006.
The study protocol requires that patients have pN+ breast cancer or pN0 breast cancer with tumour size >2cm and PR-negative disease, indicating a risk of breast cancer recurrence of >25% in the first 5 years or >35% in 10 years.
1. Joensuu H et al. J Clin Oncol 2005;23:57s (Abstract 719).
X900 T60 x3
CE75X900 x3
Primary endpoint relapse-free survival
Recruitment complete end of 2006

14. Adjuvant XT versus T: less life-threatening toxicity with XT
Patients (%) 50 40 30 20 10
Grade 3/4 adverse events T XT
In the planned interim analysis (n=80) [1], the most frequent grade 3/4 toxicities were neutropenic fever and infection, non-neutropenic infection, and diarrhea.
XT was associated with less neutropenic fever, infection and neuropathy than Taxotere, but more hand-foot syndrome and slightly more diarrhea and stomatitis.
Overall, XT was associated with a manageable toxicity profile.
1. Joensuu H et al. J Clin Oncol 2005;23:57s (Abstract 719).
Diarrhea
Stomatitis
Hand-foot syndrome
Neutropenic fever/infection
Neuropathy
Non-neutropenic infection
Joensuu H et al. J Clin Oncol 2005;23:57s (Abst 719)

15. Xeloda-based regimens: less grade 4 neutropenia
Patients (%)
100 80 60 40 20
Overall, XT was associated with a lower incidence of grade 3/4 neutropenia than Taxotere alone and FEC and CEX were associated with similar incidences of grade 3/4 neutropenia [1].
However, both Xeloda-based regimens were associated with lower incidences of grade 4 neutropenia than the comparator regimen
XT versus T, 48 versus 83%
CEX versus FEC, 26 versus 39%.
Consequently, the dose intensity of all agents studied in this trial remained over 80% for the first three cycles [1].
Most dose reductions were made to Xeloda, which may be attributed to the twice-daily oral dosing schedule that allows for dose reductions to be made on a daily basis if necessary.
In contrast, the dose of the i.v. agents can only be reduced at the beginning of each cycle when the infusion is received.
1. Joensuu H et al. J Clin Oncol 2005;23:57s (Abstract 719). T XT
FEC
CEX
Joensuu H et al. J Clin Oncol 2005;23:57s (Abst 719)

16. Adjuvant CEX versus FEC: comparable side effect profiles
Patients (%) 40 30 20 10
Grade 3/4 adverse events
FEC
CEX
In the same planned interim analysis [1], the most frequent grade 3/4 adverse events were neutropenic fever and infection, non-neutropenic infection and neuropathy.
CEX was associated with less neuropathy than FEC, slightly less neutropenic fever but more non-neutropenic infection.
Overall, CEX has a favorable safety profile.
1. Joensuu H et al. J Clin Oncol 2005;23:57s (Abstract 719).
Neutropenic fever/infection
Non-neutropenic infection
Neuropathy
Joensuu H et al. J Clin Oncol 2005;23:57s (Abst 719)

18. EORTC-BIG MINDACT: AC vs XT in adjuvant node-negative BC
R I SK
EVALUAT I ON AC
Both risks high or
either risk high
X1000T75
The prospective randomised clinical trial MINDACT (Microarray In Node-negative Disease may Avoid ChemoTherapy) trial will compare clinical and genomic risk factors for the decision-making process on whether to administer adjuvant therapy.
In this proposed, phase III, randomised study in node-negative patients, risk evaluation will be made on the basis of a 70-gene signature, as well as conventional clinico-pathological staging guidelines. If a high-risk is determined by either of these methods, the patient will be entered into the randomisation for chemotherapy.
Patients will be randomised to treatment with AC or XT (1000/75).
It is anticipated that patients with hormone-receptor-positive tumours will undergo a further randomisation at the end of chemotherapy to tamoxifen for 2 years followed by letrozole for 5 years or letrozole for 7 years.
The primary endpoint is DFS at 5 years (study powered to detect an absolute difference of 4%).
This study, which aims to recruit 5000 patients is due to commence at the end of Patients will be recruited over 3 years. The study coordinators are Drs Piccart & Cardoso (BIG), Rutgers (EORTC).
Hormone therapy alone if required
Both risks low
Double risk evaluation clinical-pathological and 70-gene signature
Primary endpoint: 5-year DFS
Status: launch summer 2006

19. Xeloda – moving forward into early breast cancer
Extensive adjuvant program with > patients
Proven efficacy in metastatic setting
Well tolerated
minimal myelosuppression and alopecia
addition to Taxotere does not increase toxicity
Dosing flexibility key to managing toxicity