adjuvant and neoadjuvant

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Systemic
chemotherapy
of
breast cancer
:

adjuvant and neoadjuvant

Alexandru Eniu, MD, PhD

Medical Oncologist

Department of Breast Tumors

Cancer Institute Ion Chiricu
ţă

Cluj
-
Napoca, Romania


Cancer treatment

Localised disease


CURAB
LE

Metastatic disease


INCURAB
LE

Therapy


Surgery


Radiation therapy


Systemic therapy


Endocrine therapy


Chemotherapy


Biologic therapy

Natural history

Bernard Fisher
-

surgeon


“Breast cancer is a
systemic

disease
involving a complex
spectrum of host
-
tumor interactions […]
variations in
effective

locoregional

treatment
are unlikely to affect
survival substantially.”

First studies of adjuvant
chemotherapy


First trial(1958) initiated by the NSABP with
thiotepa
-

positive results (1968)


1973: Bonadonna study using CMF

Evolution of Systemic Adjuvant
Chemotherapy for Early
-
Stage

Breast Cancer

Mastectomy alone

Adjuvant CMF

Adjuvant CAF, CEF

Adjuvant AC, EC, FEC

Adjuvant AC +T

Dose
-
dense AC + T

Addition of
tamoxifen,
aromatase
inhibitors

Progressive
improvement

in disease
-
free and
overall
survival

TAC

Bonadonna G et al.
N Engl J Med.

1995;332:901
-
906; Citron ML et al.
J Clin Oncol
. 2003;21:

1431
-
1439; Early Breast Cancer Trialists' Collaborative Group.
Lancet.

1998;351:1451
-
1467;

Early Breast Cancer Trialists' Collaborative Group.
Lancet.

1998;352:930
-
942; Henderson IC et
al.

J Clin Oncol.
2003;6:976
-
983;
Nabholtz JM et al. ASCO 2002; Orlando, Fla. Presentation.


Effect of chemotherapy:

average 15 years results ( n=14 250)

EBCTCG overview, Lancet 2005 May;365(9472):1687
-
717

Chemotherapy

Basic Principles


Greatest efficacy against cycling cells




growth fraction =


chemosensitivity


neoplastic cells


gastrointestinal mucosa


bone marrow




growth fraction =


chemosensitivity


plateau phase of growth


cells in G
0


Chemotherapy

Basic Principles


Pharmacologic principles


therapeutic index


ratio of toxic dose to
effective antitumor dose


optimal dose balances tumor
vs. host toxicity


body surface area vs. body
weight dosing

Chemotherapy Safety

Drug Reconstitution

ACUTE TOXICITY

CONSILIERE

BONE
MARROW

ALOPECIA

ORAL MUCOSA

DIGESTIVE TUBE

TOXICITY


ACUTE ( common for most drugs)


Hematologic (except: Bleomicin, Vincristin)


Digestive


Nausea/Vomiting (CTX, ADR, DDP…)


Diarheea (5
-
FU, irinotecan…)


Alopecia


Chronic
-

drug related


Cardiac ( anthracyclines > Total dose, 5
-
FU)


Renal (CDDP, HD MTX)


Pulmonary (Bleo)


Long term:


sterility, second cancer, cognitive function

Common Toxicity Criteria

CTCAE v3.0 2006


standardised classification of side effects
used in assessing drugs for cancer therapy


range of grades from 0
-
5


general guideline is:


1
-

Mild,


2
-

Moderate


3


Severe


4
-

Life threatening


5
-

Death

When to use chemotherapy?


Adjuvant chemotherapy:


after complete removal of all tumor


for patients at risk for distant metastases


goal: eradication of micrometastases


Neoadjuvant chemotherapy:


before local treatment, to facilitate surgery


goal: treatment of primary tu and micromets


excellent research opportunities
-

in vivo test


Palliative chemotherapy:


for metastatic or inoperable tumors


goal: palliate, improve QoL, prolong survival

Contraindications of chemotherapy




1. Previous extensive squelletal radiotherapy


2. Unrecovered myelosupression (N< 1500/mm3)


3. Diffuse bone & liver metastases


4. Renal failure


5. Anemia <8g%, hypoproteinemia , Plt <100000/mm3


6. Vomiting, uncontrolled diarrhea, HE & AB

imbalance


7. Cachexia


8. Depression or patient’s refusal



9. Performance status 3
-
4

EVALUATION CRITERIA OF PERFORMANCE INDEX

PI

Disease signs

Decreased effort capacity

Weight
loss

Fatigue

Walking

Personal
hygiene

Work

0

1

2

3

4


< 5%

5


10%

> 10%


low

medium

severe


low

medium

severe



low

medium

severe


low

medium

severe

0 =
Able to carry on normal activities as before , no restrictions

1 = Restriction in difficult activities, but ambulatory and capable to
carry on daily activities (e.g. office work, housekeeping)

2 = Ambulatory and capable of self care, but incapable to work . He
spends less than 50% of day time in bed or armchair

3 = Capable of limited self care. The patient spends more than 50% day
time in bed or armchair

4 = Bedridden, the patient can not take care of personal hygiene.

Therapy checklist: chemotherapy

Strengths

Weaknesses

Required Resources


Established
role in the
treatment
of women
with
invasive
breast
cancer


Costly in many
instances


Absolute benefits
decrease with
increasing age


Requires a
chemotherapy
-
experienced health
care team

Laboratory facilities


Monitor CBC and chemistry


Blood bank

Pharmacy services


Compound the drugs


Antiemetics


Prophylactic and side effect
management drugs

Physical facilities
to administer
intravenous chemotherapeutic drugs

Medical services to monitor and manage
the toxicities of treatment


Microbiology and general laboratory
facilities


Hydration facilities


Transfusion services for RBC, platelets


Broad
-
spectrum antibiotics


Growth factors


Pulmonary and cardiac monitoring

Anderson, BO et al,
Cancer

113:S8, 2221
-
2243, 2008

Classical
(oral) CMF


Equivalent to regimens of
anthracycline
-
based chemotherapy
in certain situations


An effective and less expensive
adjuvant chemotherapy regimen


6 month treatment duration


Multiple infusions


Variable patient compliance

Anthracycline
-
based
chemotherapy
(e.g., AC, EC,
or FAC)


Superior overall to CMF
chemotherapy in unselected
patients


Generally a short course of
therapy


Doxorubicin generally less
expensive than epirubicin


Potential cardiac toxicity


Costly


4
-
6 months treatment duration

Taxanes


Taxane chemotherapy may add
benefit to anthracycline
-
based
chemotherapy in some patients


Expensive


Additional toxicity
(neurologic, bone marrow)

Regimen

Strengths

Weaknesses

Therapy checklist: chemotherapy

Anderson, BO et al,
Cancer

113:S8, 2221
-
2243, 2008

Treatment resource allocation

Stage II breast cancer

Anderson, BO et al,
Cancer

113:S8, 2221
-
2243, 2008

Chemotherapy regimens


CMF


C
y
clo
ph
os
ph
amid
e
100

mg po d1
-
14


Met
h
otrexat
e
40

mg/mp iv d 1+8 q28z


5
-
Fluorouracil

600
/mp
iv

d
1+8


EC


Farmorubicin 100mg/mp iv d 1 q21z


C
y
clo
ph
os
ph
amid
e 600 mg/mp iv d 1


AC


Doxorubicin 60 mg/mp iv d 1 q21z


C
y
clo
ph
os
ph
amid
e 600 mg/mp d 1


Docetaxel

100mg/mp iv z1 q 21 z


Paclitaxel
80mg/mp qw for 12 w

Dose is Important for Adjuvant
Chemotherapy for Early
-
Stage Breast
Cancer

The Milan Study: Relapse
-
Free and Overall Survival With CMF

20
-
year follow
-
up (N = 386)

Adapted from: Bonadonna G et al.
N Engl J Med
. 1995;332:901
-
906.

Probability of

Relapse
-
Free Survival (%)

5

10

15

20

0

20

40





60

80

100

Probability of

Overall Survival (%)

5

10

15

20

0

20

40

60

80

100

Years After Mastectomy

0

0




85 (n = 42)



65
-
84 (n = 94)



65 (n = 71)



Control (n = 179)


Optimal Dose (%)

Primary chemotherapy for LABC

What we know?


Initially used to shrink inoperable cancers


Not formally compared to local therapy alone…


Improvements in survival with combined
modality established it as STANDARD OF
CARE


Few studies conducted specifically in LABC



Heterogeneity (definition, regimens,
endpoints)


Standard regimens are Anthracycline
-
based


Taxanes were evaluated in newer studies

The NSABP data

OPERABLE breast cancer


cCR

pCR

B
-
18

36%

13%

4 x AC

n=1506


B
-
27

60%

26%

4 x AC


+

4x Docetaxel

n=2411

Wolmark
, J Nat Cancer Inst Monogr. 2001, 30:96;
Bear
, J Clin Oncol 2006,24:2019

The MD Anderson experience
-

LABC



pCR Predictive


Kuerer
12% ER
-
, G3

4 x FAC

n=372


Green (n=258)

4x q3wP


+


15,7% ER
-
, PR
-

4 x FAC


12 x wP


+
28,2%

4 x FAC

Kuerer
, J Clin Oncol,1999;
Green
, J Clin Oncol 2005;
Hennessy
, J Clin Oncol 2005

Treatment resource allocation

Locally advanced breast cancer

Anderson, BO et al,
Cancer

113:S8, 2221
-
2243, 2008

Evaluation prior to primary systemic
therapy for LABC


Clinical examination (schematic represent):


Clinical size of tumor ( measure it!)


Skin changes: erythema, edema, ulceration, and
dimpling


Lymph node status ( measure!)


Photo documentation (inflammatory, T4’s…)


Elicitation of symptoms suggestive for distant
metastasis


Natural history of the disease (rapid growing
versus neglected tumor…)

Evaluation prior to primary systemic
therapy for LABC (2)


Pathology: CORE BIOPSY /FNA


(grade, invasion, RE, RP and Her2 (?))


Adequate breast imaging: extent of disease


Mammography


Ultrasound for T and N


Staging: X
-
ray, blood tests (CBC, liver, AP)


optional: bone scan, abdominal CT

Response assessment


Clinical exam at each cycle (T, N)
-
> to identify progression


Post therapy: 2 weeks after last cycle of chemo


Clinical exam: notoriously inaccurate!


Mammography / ultrasound ( Chagpar, Ann Surg, 2006)





Clinical

utility?

Surgery after primary chemotherapy


Surgery:
3
-
6 w
after
chemo


WBC nadir : 1,5
-
2 weeks


N>1500,
Plt

>50 000


Type of surgery


MRM for all LABC ?!


Criteria for breast conservation

(
Singletary,
Cancer
Treat Res 1997)


Resolution of skin edema


Residual tumor size <5 cm


Absence of extensive breast lymphatic invasion


Absence of extensive suspicious
microcalcifications

-
>MRM


No evidence of
multicentricity
-
> MRM

Systemic treatment after surgery


Hormone receptor positive
-
> hormone therapy


(Her2 positive
-
> adjuvant trastuzumab )


Further chemotherapy ?


Many (all?) patients had anthra+alkylator and taxanes


No data to suggest further benefit from chemo


In the absence of trial data,
further chemotherapy
should not be administered if anthra and taxanes
have been already used


Would more chemotherapy be better?

Yes, tumor is really sensitive to chemo

No, prognosis is already very good

Would more chemotherapy be better?

Yes, high risk imposes further treatment

No, tumor does not respond to chemo

Conclusions
-
Neoadjuvant
chemotherapy


Standard primary chemotherapy for LABC
should include an anthracycline (FEC, AC, EC…)


Optimal duration is unknown

4
-
8 cycles


Dose
-
intense anthracycline regimen does not
improve outcome (metronomic schedule may)


Addition of taxanes improved outcomes but not
DFS or S ( sequential, not concurrent ?)


4 cycles of Anthra plus 4 cycles of docetaxel or
12 w of weekly paclitaxel,
before surgery

Treatment resource allocation

Metastatic breast cancer

Anderson, BO et al,
Cancer

113:S8, 2221
-
2243, 2008

ASSESMENT OF TREATMENT
RESPONSE


WHO
, bidimensional measurements


-
Complete remission

(disappearance of all
symptoms & signs for at least 1 month)



-
Partial remission

(reduction >50%)



-
Stable disease

(reduction <50%, growth <25%)



-
Progressive disease

(growth >25% or new lesions)



RECIST

criteria principles

One
-
dimensional measurements

Measurable, non
-
measurable disease

Target and non
-
target lesions

Time interval 4
-
6 weeks



CR (complete response) = disappearance of
all target lesions


PR (partial response) = 30% decrease in
the sum of the longest diameter of target
lesions


PD (progressive disease) = 20% increase in
the sum of the longest diameter of target
lesions


SD (stable disease) = small changes that
do not meet above criteria

RECIST

Response evaluation

Patient A

Baseline




Week 12

Social Well Being


Family Distress

Roles and Relationships

Affection/Sexual Function

Appearance

Enjoyment

Isolation

Finances

Work

Psychological Well Being

Control

Anxiety

Depression

Enjoyment/Leisure

Fear of Recurrence

Cognition/Attention

Distress of Diagnosis and Control
of Treatment

Physical Well Being and
Symptoms

Functional Activities

Strength/Fatigue

Sleep and Rest

Overall Physical Health

Fertility

Pain

Spiritual Well Being

Meaning of Illness

Religiosity

Transcendence

Hope

Uncertainty

Inner Strength



QoL

Quality of Life

Ferrell, BR and Grant, M. City of Hope
Beckman Research Institute(2004)

Major Therapeutic Approaches in

Hormone
-
Dependent Breast Cancer

E

E
production

ER

Block

Estrogen

-
TAMOXIFEN

(Pre or Post)

-

SERMs

Reduce
Estrogen

-
Ovarian Function
Suppression (Pre)

-
Aromatase Inhibitors
(Post
)

Menopausal status



Women over 60 years of age



Bilateral ooforectomy


Women over 45 years with spontaneous
cessation of menses for more than 12 months


Women over 45 years with cessation of menses
after chemotherapy AND FSH and estradiol
values in the menopausal range


For patient under 45 years of age,
postchemotherapy amenorheea is a
contraindication for AI*
! *


*
Smith
et al.
J Clin Oncol
.
24:2444
-
2447. © 2006

Effect of TAMOXIFEN:

average 15 years results ( n=46975)

EBCTCG overview, Lancet 2005 May;365(9472):1687
-
717

Effect of ovarian ablation:

average 15 years results ( n=8 000)

EBCTCG overview, Lancet 2005 May;365(9472):1687
-
717


Adjuvant endocrine
therapy in women with
ER+ and/or PR+ or
-
unknown receptors
substantially reduces the
risks of disease recurrence
and death


Limited toxicity


Easily administered by
general practitioner or
surgeon


Absolute benefits in
adjuvant setting increase
with increasing risk of
recurrence


Optimally requires
availability of ER and
PR determination


Benefits are limited in
low
-
risk breast cancer


Compliance varies


Need ability to manage
rare but potentially
serious side effects


Pathology*


Tumor steroid hormone
receptor content


Tumor histologic grade


Stage of disease
(biochemistry and
radiological investigation)


Resources for diagnosis and
management of toxicities


Pharmacy/drug distribution

Strengths

Weaknesses

Required Resources

Therapy checklist: endocrine therapy

Anderson, BO et al,
Cancer

113:S8, 2221
-
2243, 2008

Ovarian
ablation
(medical,
surgical,
radiother
apy)


Effective for pre
-
menopausal women with ER+
and/or PR+ or
-
unknown receptors:


Combined medical oophorectomy (LHRH +
tamoxifen) is equivalent to CMF chemotherapy


Oophorectomy (surgery or radiation) plus
tamoxifen may be considered an appropriate
adjuvant endocrine therapy


Surgical and radiation induced ovarian ablation
is likely to be cost
-
effective compared with
chemotherapy alone


Long
-
term adverse
effects of estrogen
deprivation in
young women


High cost of LH
-
RH agonists

Regimen

Strengths

Weaknesses

Therapy checklist: ovarian ablation

Anderson, BO et al,
Cancer

113:S8, 2221
-
2243, 2008

Tamoxifen


Improves disease
-
free and overall survival in all
age groups and nodal subsets and with or
without chemotherapy in ER+ and/or PR+ or

unknown receptors disease


Reduces risk of second,
contralateral

breast ca


Maintains bone mineral density in
postmenopausal women


Inexpensive


Known long
-
term toxicity profile


Toxicity


Hot flashes


Thromboembolic disease


Endometrial carcinoma


Rare ocular toxicities

Aromatase
inhibitors
(AIs)


In postmenopausal women with ER+ and/or
PR+ or
-
unknown resected breast cancer:


Adjuvant AIs are superior to tamoxifen


Sequential AI following 2

3 years of tamoxifen
is superior to tamoxifen alone


Extended AI therapy following 5 years of
tamoxifen is superior to 5 years of tamoxifen


No increase in thromboembolic events or
endometrial cancer


Absolute difference
between AIs and tamoxifen
alone in terms of disease
-
free survival is small


No clear impact on
survival


Substantially higher cost
compared with tamoxifen


Toxicity: increased risk of
bone fracture,
arthralgias

Therapy checklist: tamoxifen and AI

Regimen

Strengths

Weaknesses

Anderson, BO et al,
Cancer

113:S8, 2221
-
2243, 2008

Fear of

symptoms

Toxicity data

Impact on QoL

TUMOR

BIOLOGY

Factors driving treatment
decisions

Risk of death

Risk of progressive


disease

Personal issues

Chance of response


to therapy

Patients

preference

Conclusions


Important advances have been achieved in
the management of breast cancer


Mortality has decreased in developed
countries


Resource constraints impose alterations of
the multidisciplinary pattern of care


Build a strategy for improving care


Incremental, step
-
by
-
step allocation


Optimal care to all is the ultimate goal