(neo)adjuvant
chemotherapy-antimetabolite

• Methotrexate (Antimetabolite)
• Fluorouracil (aka 5-FU) (Antimetabolite)

(neo)adjuvant
chemotherapy (anti-HER2 antibody)

• Trastuzumab

what are the contraindications for ACs?

-Lifetime cumulative dose met
-Severe hepatic impairment
-Recent MI
-Severe arrythmias
-Severe cardiac disease

AC Adverse rxns.

-Nausea/vomiting
-Cardiotoxicity
-Neutropenia
-Thrombocytopenia
-Alopecia
-Extravasation risk
-Fatigue
-Mucositis
-Diarrhea

ACS interactions

-CYP3A4 (doxorubicin)
-CYP2D6 (doxorubicin)
-CCBs may increase cardiotoxicity
-Trastuzumab associated with increased risk of cardiotoxicity

alkylating agent contraindications

May cross react with other
alkylating agents

alkylating agents side effects

Myelosuppression
Cardiac dysfunction at high doses
Nausea/vomiting
Hemorrhagic cystitis
Nasal stuffiness

akylating agents interactions

Grapefruit juice

taxanes contraindications

Caution in pre-existing liver
impairment

taxanes adverse effects

Anemia
Neutropenia
Thrombocytopenia
Intestinal obstruction
Nausea/vomiting
Hypersensitivity reactions
Arthralgias/myalgias
Peripheral neuropathy
Alopecia
Extravasation risk

taxane interactions

Metronidazole
CYP3A4
CYP2C8 (paclitaxel)
p-gp (docetaxel)

methotrexate contraindication

Caution in pleural effusions (negatively affects PK, as the drug
will accumulate there and take longer to clear causing more
toxicity)

methotrexate adverse effects

Neutropenia
Thrombocytopenia
Stomatitis
Nausea/vomiting
Hepatotoxicity
Pulmonary toxicity
Renal dysfunction
Tumour lysis

methotrexate interactions

Alcohol enhances hepatotoxicity
NSAIDs delay clearance and increase toxicity
PPIs “”
Penicillin competes for renal tubular secretion, impairing
clearance and increasing toxicity.

5FU contraindications

Complete or near absence of DPD activity Hypersensitivity to capecitabine

5FU adverse effects

Myelosuppression
Cardiotoxicity
Chest pain
PPE
Diarrhea
Stomatitis

5FU interactions

Thiazide-like diuretics may prolong 5-FU neutropenia

Trastuzumab antiHER2 contraindications

Hx of hypersensitivity to Chinese hamster ovary cell proteins
Caution in existing cardiac dysfunction

Trastuzumab antiHER2 adverse effects

CHF
Reduced EF
Infusion-related reactions

Trastuzumab antiHER2

Anthracyclines- Increased risk of
cardiac toxicity

define carcinogenesis?

A multistage and multistep process involving modification and mutation to genes that regulate normal cellular function including cell growth control processes.

what are the stages of carcinogenesis?

initiation - exposes normal cells to carcinogens

promotion- carcinogens altar environment to favor mutated cell growth

malignant conversion- overtime mutated cells become cancerous

progression- further growth/genetic changes increases cellular proliferation-causes tumor invasion into local tissue and envetually develop into metastases.

initiation -

exposes normal cells to carcinogens

promotion-

carcinogens altar environment to favor mutated cell growth

malignant conversion-

overtime mutated cells become cancerous

progression-

further growth/genetic changes increases cellular proliferation-causes tumor invasion into local tissue and envetually develop into metastases.

what are the 6 acquired cancer characteristics?

immortality-Infinite” number of cell
divisions

produce go signal-mutated proto-oncogenes cause stimulatory proteins to be overactive.

override stop signals-cancer cells remove brakes on proliferation capacity

resist cell death-

angiogenesis

metastasis

immortality- what is a potential drug target for cancer's cells ability to activate telomerase

telomerase inhibitors

Azacitadine

what drug targets cancer cells ability to produce go signals (oncogenes)

imatinib- (PDGF-receptor inhibitor)-Extracellular.

cetuximab- (anti-epidermal growth factor)-Transcellular

trastuzumab- (anti-HER2) [breast cancer] growth factor receptor 2 (HER2)

what drug targets cancer cells ability to remove brakes off normal proliferation (loss of function mutation)?

Olaparib-PARP inhibitors – in BRCA1/2 mutated ovarian cancer and
prostate cancer
Palbociclib- CDK4/6 inhibitors–in hormone receptor positive/HER2
negative breast cancer

how do cancer cells resist cell death?

they bypass apoptosis

-mutations of the p53 tumor suppressor gene results in loss of proapoptotic regulators.

-p53 activates DNA repair pathways or apoptosis in response to DNA damage.

tumor cells can turn on angiogenesis which turns a small cluster into a large malignant growth able to spread to other sites, which drugs target angiogenesis?

-axitinib

-bevacizumab

MEtastAsiS

damaged cells passing thru the circulatory system are recognized by immune system as non self and killed-cancer cells can pass thru the system to colonize distant sites; how they do this?

-cell-cell adhesion molecules

-integrins

-matrix metalloproteinases (MMPs)

all HR+ Bcancer PTs shud take......?

Endocrine Therapy

premenopausal pts receiving OFS and postmenopausal pts on aromatase inhibitors (Anastrazole, letrazole, exemestane ) shud get?

adjuvant bisphosphonates

cancer pts HR+/HER2- can recieve?

neoadjuvant therapy

primary surgery +/- radiation therapy or systemic therapy

What do we use for (neo)adjuvant chemotherapy for HER2 negative ?

Dose dense AC

1. Doxorubicin/cyclophosphamide.

-Followed or preceded by paclitaxel Q2 weeks or weekly.

2. TC

-docetaxel and cyclophosphamide

Also :

-CMF(cyclophos/methotre/5FU)

What neoadjuvant chemo is given to HER2-positive?

1. Paclitaxel + Trastuzumab

2. TCH (docetaxel/carboplatin/trastuzumab)

3. TCHP (docetaxel/carboplatin/trastuzumab/pertuzumab)

what shud u give if someone has a contraindication to ancthracyclines ie the elderly with reduced ejection fraction on baseline ECHO?

1.TC

2.CMF (6 cycles of cmf-4 cycles of AC-option for low risk patients)

non pharm antiemetix shud be given in conjunction with pharmacologic choices; but pharmacologic options are the main stay of prevention.

FACTS

what is the PRECHEMO anti emetic therapy for HEC (>90%)(major option)?

dexa 8-12 mg PO

plus NK, 5-HT antagonist (ondansetron 8 mg)

netupitant-palonosetron 300mg -0.5 mg PO

plus/- olanzepine 2.5 to 10mg PO

what is the Post-CHEMO anti emetic therapy for HEC?

-Dexa 4mg evening of chemo then BID 2-4 DAYS.

we dont need netupitant-palonosetron post chemo

what is the PRECHEMO anti emetic therapy for HEC(the other option)?

Aprepitant 125 mg

plus one 5HT antagonist-ondansetron 8mg

plus/- olanzepine 2.5 to 10mg PO

what is the Post-CHEMO anti emetic therapy for HEC (the alternative)?

Aprepitant 80 mg on days 2 and 3

+/- one antiemetic prn if not using olanzapine ; prochlorperazine 10 mg q6h prn 3-10 days.

antiemetics for MEC (moderate emetogenicity= 30-90%) Pre-Chemo.

-dexa 8 to 12mg

-plus one 5-HT antagonist(ondansetron 8mg)

-/+ olanzapine 2.5-10mg po

antiemetics for MEC (moderate emetogenicity) Post-Chemo.

-dexa-4mg evening of chemo then bid 2-3 days

+/- one antiemetic prn if not using olanzapine. (metoclopramide or prochlorperazine 10mg q h prn 3-4 days)

+/-olanzapine 2.5-10mg PO

antiemetics for low emetogenicity Pre-Chemo.

dexamethasone 4-12mg OR

-ondansetron or metoclopromide

-or prochlorperazine 10 mg

antiemetics for low emetogenicity (10-30%)Post-Chemo.

dexa 4mg BID prn for up to 2-3 days OR prochlorperazine or metoclopramide. or no prophylaxis

what do you give post chemo if the emetogenicity is rare or minimal(<10%)?

prochlorperazine or metoclopramide. or no prophylaxis

how would you manage high to moderate nausea with oral agents?

consider prophylaxis daily per pt experience.

5 HT3 receptor antagonist -ondansetron 8 mg BID

Antiemetics: When to seek medical attention.

You are not able to keep any water, food or pills in your stomach
• Severe nausea that lasts for more than 24 hours
• You are weak, dizzy and confused
• If you vomit and notice there is a dark coffee ground substance (old
blood) or bright red blood (new blood).

CMF anti emetic Regimen

Moderately emetogenic
Dexamethasone 8 mg PO and ondansetron 8 mg PO given pre-chemo
Dexamethasone 4 mg PO BID, starting in the evening of day 1,
continuing to day 3 or 4
Metoclopramide 10 mg PO q4-6h PRN
Olanzapine is also an option here

what do we use for ET?

1. SERMs
• Tamoxifen

2. Aromatase inhibitors
• Anastrozole
• Letrozole
• Exemestane

what ET does ASCO and ESMO recommend for premenopausal women?

tamoxifen

-after 4 years if she is pre or peri menopausal consider continuing tamoxifen for another five years
• If postmenopausal, can consider still offering tamoxifen for another five years.

what Endocrine therapy is given to post-menopausal
women?

Aromatase inhibitor for five years
• Tamoxifen and an aromatase inhibitor in either order for a total of five
years
• Tamoxifen for 5 years, then aromatase inhibitor for 5-10 years
• Tamoxifen for 10 years

Who requires that extended interval?

Those with node-positive breast cancer should be offered an
extended interval for up to a total of 10 years (more than 5 years).

What should Sammi receive for ET?
• She is postmenopausal, and had no positive lymph nodes, or high-risk
features

• Aromatase inhibitor for five years
• Tamoxifen for five years
• Tamoxifen for 2-3 years, then an aromatase inhibitor to complete 5 years