What do we use for (neo)adjuvant
chemotherapy?
• Doxorubicin (Anthracycline)
• Epirubicin
(Anthracycline)
• Paclitaxel (Taxane)
• Docetaxel
(Taxane)
• Cyclophosphamide (Alkylating agent)
•
Methotrexate (Antimetabolite)
• Fluorouracil (aka 5-FU)
(Antimetabolite)
• Trastuzumab (anti-HER2 antibody)
(neo)adjuvant
chemotherapy- anthracyclines
doxorubicin
epirubicin
(neo)adjuvant
chemotherapy -taxane
• Paclitaxel (Taxane)
• Docetaxel (Taxane)
(neo)adjuvant
chemotherapy-(Alkylating agent)
Cyclophosphamide
(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