SIOG Guidelines Update 2014:

Use of Taxanes in Older Breast

Cancer Patients

Laura Biganzoli

Medical Oncology Dept

New Hospital of Prato

Istituto Toscano Tumori

Italy

Fundamental steps

• Task Force (TF) on Use of Taxanes in Older Breast

Cancer Patients

• First meeting: 26th October in Copenhagen, during the

SIOG 2013 Annual Conference

• Several drafts…..(thanks to Rob Stepney, medical writer)

• Last draft circulated to all the members of the TF on

September 2014… document still to be finalized

Writing Committee

Matti Aapro - Clinique de Genolier, Genolier, Switzerland

Laura Biganzoli - New Hospital of Prato, Istituto Toscano Tumori, Prato, Italy

Tadeusz Pienkowski - Maria Sklodowska-Curie Memorial Cancer Center and Institute of

Oncology,Warsaw Poland

Sibylle Loibl - German Breast Group, Neu-Isenburg; and Sana-Klinikum Offenbach, Germany

Hans Wildiers - CSIR, KU Leuven, Belgium

Rationale & aims

• Taxanes are key agents in the treatment of breast

cancer both in the neo/adjuvant and metastatic setting

• Review available data on the use of docetaxel, paclitaxel

and nab-paclitaxel in elderly breast cancer patients

• Expert recommendations (position paper)

� There is no significant data to support dose modification of docetaxel and paclitaxel based on age alone

Taxanes in early breast cancer

• In sequence with anthracyclines in the

neo/adjuvant setting ie. (F)AC->T

• In anthracycline-free regimens in low-risk

patients ie. TC

F, 5-fluorouracil; A, anthracycline; T, taxane; TC, docetaxel plus cyclophosphamyde

N =4 adjuvant/neoadjuvant German studies antracycline/taxane based

Age groups (< 60, 60 to 64, 64+)

• Higher rates of dose delays and reductions, hospitalization,

therapy discontinuation, hematological toxicity, and some non-

hematological toxicities (ie, loss of appetite, severe fatigue,

and mucositis)

• The incidence of treatment-related deaths increased

linearly with advancing patient age (P.0022)

CALGB 8541: three different dose schedule of CAF; CALGB 9344: AC +/-

paclitaxel; CALGB 9741: AC� paclitaxel q 3 vs 2 wks

Age in Years at Enrollment: <50, 51-64, 65+

Muss et al. J Clin Oncol 2007

26

Loibl et al. Brest Cancer Res 2008

Older women experienced more febrile neutropenia (8% vs 4%)Primary prophylaxis with G-CSF not allowed

25

TC was superior in older patients as well as in younger women

Romond et al. JCO 2012; Perez et al. JCO 2008; Sutter et al. St Gallen 2007; Russel et al. JCO 2010

Potential risk factors for CHF/cardiac events in adjuvant Trastuzumab trials

NSABP B31* NCTG N9831 HERA ACREC

Age 50+ Hypertension medic. Baseline LVEF (<55%) Post-AC LVEF

Age 60+ Hypertension medic. Baseline LVEF (<55%)

Baseline LVEF (<65%) High BMI (>25)

Age >50 Post-AC LVEF

Adapted from Biganzoli et al. Crit Rev Oncol Hematol 2009

1

Focusing on elderly patients…

Adapted from Biganzoli et al. Crit Rev Oncol Hematol 2009

Weekly docetaxel and paclitaxel in elderly patients: safety data

• Efficay was age indepedent

• Grade ≥3 leucopenia,granulocytopenia, anorexia, bilirubin elevation and

neurotoxicity increased linearly with age

• Patients over 65 years receiving second-line therapy had the shortest time to

neurotoxicity (35% at 6 cycles)Ann Oncol 2011

1 Hainsworth et al. Cancer 2000; 2 Perez et al. Breast Cancer Res Treat 2002, 3 ten Tije et al. Eur J Cancer 2004; 4 Del Mastro et al: Ann Oncol 2005

2

1

3

4

Nab-paclitaxel

• Solvent-free paclitaxel; no need for premedication; at

least as effective as standard taxanes

The Breast 2011

The Breast 2011

till disease progression or toxicity

nab-paclitaxel 125 mg/m2

day 1, 8, 15 q 28

nab-paclitaxel 100mg/m2

day 1, 8, 15 q 28

R

Stratification factors:age 65-74 vs ≥ 75 yrs; diabetes yes, no G3-4 CIRS yes, no IADL deficient yes, no

• Age ≥ 65;

• Advanced HER2-neg breast cancer*

• No prior CT for advanced breast cancer*HER2- positive but considered not eligible for anti-HER2 therapy

Primary endpoint: Event-free survival

(event= progressive disease or death without progression or decrease in function

defined as loss of >= 1 ADL or IADL from baseline considered by the investigator

to be treatment related and confirmed at the subsequent cycle)

Nab-paclitaxel 100 mg/m2

days 1, 8, 15 q 28 x4Epirubicin 30 mg/m2

days 1, 8, 15 q 28 x 4

R

• In the adjuvant setting taxanes are associated with

increased toxicity compared with younger women, but

can be added to anthracyclines in high-risk healthy

elderly patients, or replace anthracyclines to reduce the

cardiac risk (SIOG and Eusoma Recommendations1)

• In HER-2 positive patients, the combination of docetaxel

plus cyclophosphamide offers an alternative to

anthracycline-taxane based chemotherapy and reduces

the risk of trastuzumab-related cardiac toxicity

Conclusions

1Biganzoli et al. Lancet Oncol 2012

• Weekly taxanes are a reasonable option for the treatment of older patients with advanced breast cancer

• Close monitoring of side effects is recommended since fatigue (docetaxel) and neurotoxicity (paclitaxel) might have a negative impact on function

• Nab-paclitaxel represents a potential alternative to standard taxanes due to a favorable safety profile (when

the 100-125 mg/m2 weekly dose-schedule is used) and shorter time to resolution of sensory neuropathy to a lesser grade without the the need for steroid premedication

• Studies are ongoing to define the role of nab paclitaxel in older patients

Conclusions (I)

Back up

Nab-paclitaxel

plus

capecitabine x 6

Adjuvant setting

• Interim safety analysis after 207 patients completed treatment

• Treatment A better tolerated than nab-paclitaxel plus capecitabine

(treatment discontinuation for AEs 6.6 vs 34.7%).

• More G 3-4 non-hematological AEs in arm B (59% vs 19%)

• At 48 months, rates of invasive disease-free survival equivalent between the

treatments(hazard ratio [HR] 0.98, [P = .9597])

Age ≥ 65 yearsStage pT3/4 or pN2/3 or stage pT1/2 and pN0/1 (0-3 involved lymph nodes) with an increased risk according to the clinico-pathological or uPA/PAI-1 criteria

nab-Paclitaxel 100 mg/m2 on days 1, 8, 15 q22 with a week of rest every 6 weeks in combination with

capecitabine 2000 mg/m2, days 1 - 14 orally, divided into 2 daily doses every 3 weeks for 6 cycles

AC x 4

or

CMF x 6R

N=100 N=107

A B