Transcript Normal cell growth

Systemic chemotherapy of
breast cancer:
adjuvant and neoadjuvant
Alexandru Eniu, MD, PhD
Medical Oncologist
Department of Breast Tumors
Cancer Institute Ion Chiricuţă
Cluj-Napoca, Romania
Cancer treatment
Natural history
Therapy
•Surgery
•Radiation therapy
•Systemic therapy
•Endocrine therapy
Localised disease
•Chemotherapy
CURABLE
•Biologic therapy
Metastatic disease
INCURABLE
Bernard Fisher- surgeon
 “Breast cancer is a
systemic disease
involving a complex
spectrum of hosttumor 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
Addition of
tamoxifen,
aromatase
inhibitors
Adjuvant CAF, CEF
Adjuvant AC, EC, FEC
Adjuvant AC +T
Dose-dense AC + T
Progressive
improvement
in diseasefree 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 G0
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
ALOPECIA
BONE
MARROW
ORAL MUCOSA
DIGESTIVE TUBE
CONSILIERE
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
0
1
2
3
4
Disease signs
Decreased effort capacity
Weight
loss
Fatigue
Walking
< 5%
5 – 10%
> 10%
low
medium
severe
low
medium
severe
Personal
hygiene
low
medium
severe
Work
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
• Established • Costly in many
role in the
instances
treatment
• Absolute benefits
of women
decrease with
with
increasing age
invasive
• Requires a
breast
chemotherapycancer
experienced health
care team
Anderson, BO et al, Cancer 113:S8, 2221-2243, 2008
Required Resources
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
Therapy checklist: chemotherapy
Regimen
Strengths
Weaknesses
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)
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
 CMF
Chemotherapy regimens
– Cyclophosphamide 100 mg po d1-14
– Methotrexate 40 mg/mp iv d 1+8
q28z
– 5-Fluorouracil 600/mp iv d 1+8
 EC
– Farmorubicin 100mg/mp iv d 1 q21z
– Cyclophosphamide 600 mg/mp iv d 1
 AC
– Doxorubicin 60 mg/mp iv d 1
q21z
– Cyclophosphamide 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
100
100
80
80
Probability of
Overall Survival (%)
Probability of
Relapse-Free Survival (%)
20-year follow-up (N = 386)
60
40
20
0
0
5
10
15
20
Optimal Dose (%)
85 (n = 42)
65-84 (n = 94)
65 (n = 71)
Control (n = 179)
60
40
20
0
0
5
Years After Mastectomy
Adapted from: Bonadonna G et al. N Engl J Med. 1995;332:901-906.
10
15
20
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
36%
13%
B-27 60%
26%
B-18
4 x AC
n=1506
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
Kuerer
4 x FAC
n=372
12%
Predictive
ER-, G3
Green (n=258)
4x q3wP
+
4 x FAC
15,7%
12 x wP
+
4 x FAC
28,2%
ER-, PR-
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 ?
Would more chemotherapy
be better?
 Many (all?) patients had anthra+alkylator
and taxanes
Yes, tumor is really sensitive to chemo
 No data to suggest further
chemo
No, benefit
prognosisfrom
is already
very good
 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, 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
RECIST
 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
Response evaluation
Patient A
Baseline
Week 12
Quality of Life
Physical Well Being and
Symptoms
Psychological Well Being
Functional Activities
Anxiety
Strength/Fatigue
Depression
Sleep and Rest
Enjoyment/Leisure
Overall Physical Health
Fear of Recurrence
Control
Cognition/Attention
Fertility
Pain
Social Well Being
QoL
Distress of Diagnosis and Control
of Treatment
Spiritual Well Being
Family Distress
Meaning of Illness
Roles and Relationships
Religiosity
Affection/Sexual Function
Transcendence
Appearance
Hope
Enjoyment
Uncertainty
Isolation
Inner Strength
Finances
Work
Ferrell, BR and Grant, M. City of Hope
Beckman Research Institute(2004)
Major Therapeutic Approaches in
Hormone-Dependent Breast Cancer
E
production Reduce Estrogen
- Ovarian Function
Suppression (Pre)
- Aromatase Inhibitors
(Post)
ER
E
Block Estrogen
-TAMOXIFEN (Pre or Post)
- SERMs
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
Therapy checklist: endocrine therapy
Strengths
•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
Weaknesses
•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
Anderson, BO et al, Cancer 113:S8, 2221-2243, 2008
Required Resources
•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
Therapy checklist: ovarian ablation
Regimen
Ovarian
ablation
(medical,
surgical,
radiother
apy)
Strengths
•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
Anderson, BO et al, Cancer 113:S8, 2221-2243, 2008
Weaknesses
•Long-term adverse
effects of estrogen
deprivation in
young women
•High cost of LHRH agonists
Therapy checklist: tamoxifen and AI
Regimen
Strengths
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
Weaknesses
•Toxicity
•Hot flashes
•Thromboembolic disease
•Endometrial carcinoma
•Rare ocular toxicities
Aromatase •In postmenopausal women with ER+ and/or
inhibitors PR+ or -unknown resected breast cancer:
(AIs)
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 diseasefree survival is small
•No clear impact on
survival
•Substantially higher cost
compared with tamoxifen
•Toxicity: increased risk of
bone fracture, arthralgias
Anderson, BO et al, Cancer 113:S8, 2221-2243, 2008
Factors driving treatment
decisions
TUMOR
BIOLOGY
Fear of
symptoms
Chance of response
to therapy
Personal issues
Patients
preference
Risk of death
Risk of progressive
disease
Toxicity data
Impact on QoL
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