Where , When and How to give

chemotherapy in Early Breast Cancer.

Dr Deepika Malik

JR II, Department of Radiotherapy

Breast cancer –

second most common cancer in the world ,

most frequent cancer among women with an estimated

1.67 million new cancer cases diagnosed in 2012 (25%

of all cancers).

It is the most common cancer in women both in more

and less developed regions with slightly more cases in

less developed (883,000 cases) than in more developed

(794,000) regions

Early stage breast cancer

Introduction

Breast cancer is most often curable when

detected in early stages

Micrometastases exist at the time of

diagnosis in most of the patients, leading

to spread of disease , locoregionally and

distant.

Adjuvant systemic therapy has been found

to prolong both overall and disease-free

survival in breast cancer patients

History

Henri Francois Le Dran (1685-

1770), a French surgeon

proposed that breast cancer was

a localized disease that spread to

regional lymph nodes (RLNs) and

that the only hope for cure was

early surgery

Le Dran’s proposal was further taken to its logical conclusion by Halstead.

The Halstedian theory was based upon:

Local and regional nodes were the first level of metastatic spread

They were effective barriers against further spread

This concept , that breast cancer was a

localized disease that spread in an orderly

manner dominated cancer theory for the

next 200 years.

The concept was challenged by the Fisher brothers (Edward and Bernard), who showed in a series of trials conducted by the NSABP that:

Lymph nodes were not effective as barriers against systemic spread

Hematogenous dissemination was as important as lymphatic dissemination

Systemic therapy is therefore effective in

Breast cancer.

Timeline!!!!

THE PAST

2 Because adjuvant polychemotherapy improves survival, it should be recommended to the majority of women with localized breast cancer regardless of lymph node, menopausal, or hormone receptor status.

The inclusion of anthracyclines in adjuvant chemotherapy regimens produces a small but statistically significant improvement in survival over non-anthracycline-containing regimens. 00 (2000 NCI Consensus Development Conference on Adjuvant Breast Cancer 0 NCI Consensus

National Institutes of Health Consensus Development Conference Statement: Adjuvant Therapy for Breast Cancer, November 1–3, 2000

Adjuvant Breast Cancer)

THE PRESENT AND FUTURE

We are moving towards a more indivisualistic approach in giving chemotherapy to early stage breast cancer patients!!!!!!!!!

What does NCCN panel

say?

NCCN Version 3.2015

After surgical treatment , adjuvant systemic therapy should be considered.

The decision to use systemic adjuvant chemotherapy requires considering and balancing risk for

-disease recurrence alone

-magnitude of benefit from applying

adjuvant therapy

-toxicity of therapy

-comorbidity.

Adjuvant!Online

Validated computer based model

Algorithm which estimates rates of

recurrence

estimates 10 year DFS and OS

Making use of all prognostic factors for

breast cancer ( except HER2 tumor status) ie

patient age, comorbidity , tumor size, tumor

grade, number of LN’s involved, LVE, PNI.

Adjuvant online contd..

Aids clinician in objectively estimating

- outcome with local treatment only

- absolute benefits expected from

systemic adjuvant therapy

These estimates are utilised by clinician for

patient to decide regarding toxicities and

benefits of systemic therapy.

HER2 Status

HER2 tumor status provides predictive information

in selecting optimal adjuvant therapy and in the

selection of therapy for recurrent or metastatic

disease

For example, retrospective analyses have

demonstrated that

-anthracycline-based adjuvant therapy

is superior to non-anthracycline

based adjuvant chemotherapy in

patients with HER2-positive disease

Five major subtypes of breast cancer have

been identified

DNA microarray assays

Characterize breast cancer

Allow for classification of breast cancer

by gene expression profile.

In retrospective analyses, these gene

expression subtypes are associated with

differing relapse-free survival and OS.

Oncotype DX

The 21-gene assay using reverse transcription polymerase chain reaction (RT-PCR) on RNA isolated from paraffin-embedded breast cancer tissue (OncotypeDX)

among the best-validated prognostic assays

And can predict who is most likely to respond to systemic chemotherapy.

Patients with a high score benefited from chemotherapy

patients with a low score did not appear to benefit from the addition of chemotherapy regardless of the number of positive lymph nodes.

(clinical practice)

Mamma print Assay

uses microarray technology

to analyze a 70-gene expression profile from breast tumor

to help identify patients with early-stage breast cancer likely to develop distant metastases.

approved by the FDA and assigns women of all ages with ER-positive or ER-negative breast cancer as having high versus low risk for recurrence.

but it does not predict benefit from adjuvant systemic therapy.

the prospective RASTER study reported

that breast cancer patients classified by

MammaPrint as low risk (of whom 85% did

not receive adjuvant chemotherapy) had

an overall 97% distant recurrence-free

interval at five years.

PAM 50

The Prediction Analysis of Microarray 50

(PAM50)

50-gene test

identifies intrinsic breast cancer subtypes

(luminal A, luminal B, HER2 enriched and

basal-like) in addition to generating a risk

of recurrence (ROR) score that can be

used to predict prognosis among

postmenopausal women with hormone-

positive breast cancer

The NCCN Panel members acknowledge

that many assays, including PAM50 and

MammaPrint, have been clinically

validated for prediction of prognosis.

However, based on the currently available

data, the panel believes that the 21-

gene assay has been best-validated for its

use as a prognostic test as well as in

predicting who is most likely to respond

to systemic chemotherapy

Chemotherapy regimens

Cyclophosphamide+methotrexate+5-

fluorouracil (CMF) – the first effective

chemotherapy regimen for breast cancer

(Bonadonna et al, 1976).

2 weeks of oral cyclophosphamide for

each cycle, and produced significant and

long-lasting nausea

the first anthracycline-containing regimen to

become a ‘gold standard' was

doxorubicin+cyclophosphamide (AC), investigated

initially by the NSABP in the 1990s (Fisher et al,

1990)

The rationale for including anthracycline was to

reduce the duration of treatment, the number of

hospital visits and the need for antiemetic.

Over the ensuing 30 years, CMF and AC became

references for the development of newer, more

effective chemotherapy regimens.

Owing to potential cardiotoxicity of

doxorubicin, epirubicin was introduced .

(French Adjuvant Study Group, 2001)

In the 1970s, the development of the taxanes,

the first new cytotoxic drugs after several

decades with activity in metastatic breast cancer

(Wani et al, 1971)

inclusion of paclitaxel or docetaxel in various

adjuvant chemotherapy trial regimens

(Henderson et al, 2003; Mamounas et al,

2005; Martin et al, 2005; Bear et al, 2006).

AC followed by paclitaxel was shown to be

more effective than AC alone (Henderson et al,

2003).

subsequently ‘accelerated' – given every 2

weeks rather than every 3 weeks (an

adaptation made possible through the use of

granulocyte colony-stimulating factor),

Chemotherapy regimens

NCCN Version 3.2015

HER 2 negative disease

Preferred regimens:

• Dose-dense AC (doxorubicin/cyclophosphamide)

followed by paclitaxel every 2 weeks

• Dose-dense AC (doxorubicin/cyclophosphamide)

followed by weekly paclitaxel

• TC (docetaxel and cyclophosphamide)

Dose-dense AC followed by paclitaxel chemotherapy

• Doxorubicin 60 mg/m2 IV day 1

• Cyclophosphamide 600 mg/m2 IV day 1

Cycled every 14 days for 4 cycles.

(All cycles are with myeloid growth factor support)

Followed by:

• Paclitaxel 175 mg/m2 by 3 h IV infusion day 1 Cycled every

14 days for 4 cycles.

Dose-dense AC followed by weekly paclitaxel

chemotherapy1

• Doxorubicin 60 mg/m2 IV day 1

• Cyclophosphamide 600 mg/m2 IV day 1

Cycled every 14 days for 4 cycles.

(All cycles are with myeloid growth factor support)

Followed by:

• Paclitaxel 80 mg/m2 by 1 h IV infusion weekly

for 12 wks.

TC chemotherapy

• Docetaxel 75 mg/m2 IV day 1

• Cyclophosphamide 600 mg/m2 IV day 1

Cycled every 21 days for 4 cycles.

(All cycles are with myeloid growth factor

support)

HER2 negative disease

Other regimens

• Dose-dense AC

(doxorubicin/cyclophosphamide)(60,600), every

14 days , 4 cycles

• AC (doxorubicin/cyclophosphamide)

(60,600)every 3 weeks ,4 cycles

•FAC(fluorouracil/doxorubicin/cyclophosphamide

) 500 mg/m2i/v day 1 and day 8 or day 1 nd day

4; 50mg/m2; 500 mg/m2) every 3 weeks, 6

cycles

• FEC

(cyclophosphamide/epirubicin/fluorouracil)

(75 mg/m2 p/o d1-d14; 60 mg/m2 i/v

d1,d8;500mg/m2 i/v d1,d8) every 28 days,

6cycles

• CMF

(cyclophosphamide/methotrexate/fluorouracil) (

100 mg/m2 p/o d1-14; 40 mg/m2 d1,d8; 600

mg/m2 d1,d8) every 28 days, 6 cycles

• AC followed by docetaxel every 3 weeks

• AC followed by weekly paclitaxel

• EC (epirubicin/cyclophosphamide)

• FEC/CEF followed by T (fluorouracil/epirubicin/cyclophosphamide followed by docetaxel) or (fluorouracil/epirubicin/cyclophosphamide followed by weekly paclitaxel)

• FAC followed by T

(fluorouracil/doxorubicin/cyclophosphamide followed by weekly paclitaxel)

• TAC (docetaxel/doxorubicin/cyclophosphamide)

HER 2 positive disease

Preferred regimens

AC followed by T + trastuzumab ± pertuzumab

Doxorubicin 60 mg/m2 IV day 1

Cyclophosphamide 600 mg/m2 IV day 1

Cycled every 21 days for 4 cycles.

Followed by:

Paclitaxel 80 mg/m2 by 1 h IV weekly for 12 wks

With:

• Trastuzumab 4 mg/kg IV with first dose of paclitaxel

Followed by:

• Trastuzumab 2 mg/kg IV weekly to complete 1 y of treatment.

As an alternative, trastuzumab 6 mg/kg IV every 21 days may be used following the completion of paclitaxel, and given to complete 1 y of trastuzumab treatment.

Cardiac monitoring at baseline, 3, 6, and 9 mo.

TCH

Docetaxel 75 mg/m2 IV day 1

Carboplatin AUC 6 IV day 1

Cycled every 21 days for 6 cycles

With:

• Trastuzumab 4 mg/kg IV wk 1

Followed by:

• Trastuzumab 2 mg/kg IV for 17 wks

Followed by:

• Trastuzumab 6 mg/kg IV every 21 days to complete 1 year of trastuzumab therapy

Cardiac monitoring at baseline, 3, 6, and 9 months.

Her 2 positive disease

Other regimens

• AC followed by docetaxel + trastuzumab ± pertuzumab

• Docetaxel + cyclophosphamide + trastuzumab

• FEC followed by docetaxel + trastuzumab + pertuzumab9

• FEC followed by paclitaxel + trastuzumab + pertuzumab

• Paclitaxel + trastuzumab

• Pertuzumab + trastuzumab + docetaxel followed by FEC

• Pertuzumab + trastuzumab + paclitaxel followed by FEC9

The biggest concern- toxicities!!!

Chemotherapy toxicities!!!!

Specific drug considerations

Anthracyclines

Very strong vesicants!!!!

- dilute with NS to yield a final

concentration of 2mg/ml

- reconstituted solution stable for 7 days at

room temperature;15 days under refrigeration

Anthracyclines..

• administered slowly with a

rapidly flowing IV

• if extravasation suspected ,

immediately stop infusion,

withdraw fluid, elevate

extremity , apply ice to involved

site.

• if severe, may consult a plastic

surgeon

5- fluoro uracil.

“Hand –foot syndrome”

(palmar- plantar erythrodysestheia)--- tingling

numbness,pain, erythema, dryness, rash, pruritis

and/or desquamation of hands and feet

Paclitaxel

Administration

-dilute in 5%D or NS to a final

concentration of 0.3-1.2 mg/ml

-administer in either glass or polyolefin

containers using 0.22 micrometer filter

and polyethylene lined i/v sets

- do not use PVC i/v sets since

cremaphor EL causes leaching into

infusion fluid.

Toxicities- severe myelosuppression, hypersensitivity

reactions, neurotoxicity.

Chemotherapy is an integral part of mutidisciplinary

management of early breast cancer

From giving chemotherapy to all Breast cancer patients

after surgery , we are now moving towards a more

indivisualistic approach

TAKE HOME

Her 2 neg disease

• AC ( 4)followed by paclitaxel(4).. every 2

weeks , 4 cycles

• AC( 4) every 2 weeks followed by weekly

paclitaxel (12)

• TC , every 21 days, 4 cycles

HER 2 positive disease

AC followed by T + trastuzumab

TCH

Thank you.

Have a good day