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Benefits

Risks

 systemic therapy
Palliative therapy - macrometastasis (stage IV) - longer survival, QOL, PFS Adjuvant therapy - micrometastasis (stage I,II,III) - curable, DFS or OS Neoadjuvant therapy - convert inoperable to (stage II,III) operable - reduce local recurrence - save more breast

Palliative therapy

Adjuvant therapy

EBCTCG OVERVIEW

Adjuvant Therapy Help Reduce Breast Cancer Deaths

Breast cancer mortality decreased by 21.3% from 1975-2000 in USA 7 independent meta-analysis showed median decline in mortality of 30% (range: 25%-38%) Due to screening: 15% (range: 7%-23%) Due to adjuvant therapy: 19% (range: 12%- 21%)
Berry DA et al. NEJM 2005

Neoadjuvant therapy

A case from NACT

After 4 cycles of NACT

TNM Staging System for Breast Carcinoma

Stage Grouping: Stage 0 Stage I Stage IIA Tis T1 T0 T1 T2 N0 N0 N1 N1a N0 M0 M0 M0 M0 M0 5-year survival rate 100 100 92

Stage IIB
Stage IIIA Stage IIIB Stage IIIC Stage IV

T2 T3
T0 T2 T3 T4 Any T Any T

N1 N0
N2 N1-2 N1,2 N3 Any N

M0 M0
M0 M0 M0 M0 M1

81
67 54 20

Earlier stage - better survival

Gene Expression Patterns Predict Survival

Adapted from Sorlie et al. PNAS, 2001

Systemic therapy

Hormonal therapy

Chemotherapy

Targeted therapy

Breast Cancer Guidelines

NCCN guidelines NIH guidelines ESMO minimal clinical recommendations St. Gallen recommendations/guidelines www.adjuvantonline.com Oncotype Dx Nottingham prognostic index

Factors that considering in systemic treatment

Staging TNM Hormonal receptor ER, PgR Her-2/Neu receptor Lymphovascular invasion Age and life expectancy Underlying disease or Co-morbidity Histology type and grade

Disadvantages
Side effect : short term and long term Time consuming Cost

Short-term
Nausea, vomiting, stomatitis (mucositis), and bone marrow suppression are acute and reversible side effects of systemic chemotherapy. Alopecia is nearly universal with regimens containing an anthracycline or a taxane, while the extent of alopecia varies with the dose and schedule of CMF. Taxanes (paclitaxel, docetaxel) are associated with both a motor and sensory neuropathy that is dose and schedule-dependent, and cumulative. Doserelated myalgias and arthralgias may develop within 72 hours of paclitaxel and are much less common with weekly compared to every three weekly schedule. Moderate to severe fatigue is a common complaint during adjuvant chemotherapy; contributory factors include anemia, vasomotor symptoms, and depression. Vasomotor symptoms may develop because of premature cessation of ovarian function caused by the administration of adjuvant chemotherapy or the use of adjuvant hormone therapy

Long-term
The incidence, persistence, and mechanisms of cognitive dysfunction during and after adjuvant chemotherapy are uncertain. Chemotherapy-induced amenorrhea (CIA) is a well-recognized side effect of cytotoxic chemotherapy. The frequency and duration varies according to age, the specific chemotherapy regimen, and use of endocrine therapy. Several studies report better relapse-free and overall survival in women who become amenorrheic compared to those whose menses persist following adjuvant chemotherapy. The consequences of premature ovarian failure include menopausal symptoms and bone loss. Anthracyclines directly damage the myocardium in a dose-dependent fashion and cause cardiomyopathy. Delayed cardiac events have not been reported in women receiving adjuvant chemotherapy in whom the cumulative dose of doxorubicin was <300 mg/m2. However, in trials of patients treated with trastuzumab plus an anthracycline-based adjuvant chemotherapy regimen, 5 percent had objective evidence of cardiac dysfunction, 2 percent developed symptomatic congestive heart failure, and 1 percent developed severe heart failure. There is an increased risk for second cancers associated with breast cancer treatment, whether breast-irradiation, chemotherapy, or tamoxifen.

Nausea and Vomiting

Certain classes of drugs are worse than others --Cis-Platinum --Doxorubicin (Adriamycin) Which anti-emetic agents should be used is determined by the emetic potential of the drug

Neurotransmitter Sites For Nausea

Muscarinic Dopaminergic Histamine Serotonin (5HT-3) Neurokinin 1 (NK 1)

Serotonin Receptor Inhibitors

Granisetron (Kytril) Ondansetron (Zofran) Palonosetron (Aloxi) : Benefit of longer duration of action Best used as a cocktail with steroid (dexamethasone) and lorazepam

Serotonin Receptor Inhibitors: Common Side Effects

Headache Constipation
Prevent with use of laxatives and stool softeners

NK 1 Receptor Inhibitor
Aprepitant (Emend) Used for acute and delayed nausea in combination with a serotonin receptor-blocking drug

Dopamine Antagonists
Phenothiazines Chlorpromazine (Largactil) Metoclopramide (Plasil) Domperidone (Motilium) Limited role except for mildly emetogenic drugs and may be helpful in delayed nausea

Delayed Nausea
Dexamethasone Lorazepam (Ativan) Dopamine antagonists
Prochlorperazine (Compazine) Trimethobenzamide (Tigan)

Mucositis (Mouth Sores)

More common with certain drugs:
5-fluorouracil (5-FU) Methotrexate Doxorubicin (Adriamycin) Cyclophosphamide (Endoxan)

Mucositis (Mouth Sores)

Prevention Icing of the mouth during treatment Treatment Options Gel Clear Magic Mouthwash Viscous lidocaine

Diarrhea
Major toxicity of several drugs used to treat gastrointestinal cancers, for example, 5-FU and irinotecan (Camptosar) Acute diarrheal reaction to irinotecan
Atropine at time of treatment

Delayed Diarrhea: Treatment

Anti-Motility Drugs Loperamide (Imodium) Diphenoxylate (Lomotil)

Octreotide (Sandostatin) Somatostatin analogue Works to prolong GI transit time Subcutaneous administration

Diarrhea: Changes in Diet

Increased fluid intake Increased starch content

Hand-Foot Syndrome
Pain, redness, swelling, and peeling of the skin of the palms and soles Associated with certain agents
Capecitabine (Xeloda) Liposomal doxorubicin (Doxil) Infusional 5-FU Weekly taxane therapy

Hand-Foot Syndrome: Treatment Options

Dose reduction Avoid tight-fitting shoes; repetitive rubbing or prolonged heat to hands and feet Emollients
Eucerin Bag Balm Can be used effectively with cotton socks and/or gloves at bedtime

Fatigue: Multifactorial
Anemia
Erythropoietin (Eprex, Recormon)/darbepoetin (Aranesp)

Depression
Selective serotonin reuptake inhibitor (SSRI)

Sleep Disturbance
-- Sleep aid: benzodiazepine

Psychostimulants
-- Methylphenidate (Ritalin)

Neuropathy
Painful burning sensation Progressive numbness Motor weakness

Neuropathy
Acute, cold induced Oxaliplatin (Eloxatin) Chronic, dose related Oxaliplatin Taxanes

Neuropathy: Prevention
Avoidance of cold exposure for 48-72 hours after oxaliplatin therapy Amino acid therapy (glutamine) Vitamin B6 (pyridoxine)

Neuropathy: Treatment Options

Dose reduction Gabapentin (Neurontin) Amitriptyline

Report Your Side Effects Early

It is important to report any side effects to your oncologist Side effects can be minimized effectively with early intervention

Conclusion
Balance risks and benefits of the treatment Educated the patients Closely monitor side effects Put the right treatment on the right patients