Chemo basic

Question 0

Gompertzian tumor growth

Answer 0

pattern of exponential growth with exponential growth retardation.

Question 1

What are the 3 cell growth types?

Answer 1

1) Static – neurons, striated muscle, oocytes
2) Expanding (normally quiescent except under stress/injury a proliferative burst is followed by return to quiescence)- hepatocytes, bile duct epithelium, vascular endothelium
3) Renewing (continuous proliferation) – bone marrow, epithelium, GI epithelium, sperm

Question 2

Tumor doubling curve

Answer 2

-As tumor mass increases the time to double the tumor volume decreases.
-At later stages of tumor growth a small # of doublings produce a marked change in tumor size w/ increased potential for adverse clinical consequences.
-In general metastases have faster doubling times than their corresponding primary lesions.
Average doubling time for human cancers is 50 days.

Question 3

1 cm mass ~ X number of doubling

Answer 3

30

Question 4

Growth Fraction

Answer 4

The proportion of tumor cells that are actively cycling.
Usually those cells near small blood vessels.
Variable by tumor type – 25-95%
Cell loss in tumors is high…70-95%

Question 5

First order Cell Kill Kinetics

Answer 5

A constant fraction of exposed cells are killed, rather than a constant number.
For curative chemotherapy, log cell kill (% of cells killed each cycle) must be very large (>99%) and repetitive.

Question 6

Cure or prolonged survival achieved when…

Answer 6

cell pop reduced to 10 ^1 and 10^ 4 (not clinically detectable.

Question 7

Hepatic metabolism (ICE VAT)

If you don’t take the liver into account, you’ll need an ice vat

Answer 7

• Vinca alkaloids (vincristine, vinblastine, vinorelbine)
• Ifos, Cytoxan, etoposide (hepatically metabolized, renally cleared)
• Taxanes (Taxol, Taxotere)
• Anthracycylines (doxil, doxorubicin)
• VEGF inhibitors (cleared)
• dose reduce MTX bc can cause hepatic fibrosis (Renault cleared)
• 5 FU

Question 8

Renal clearance (Top BMI Promotes Cancer)

Answer 8

Platinums
Bleomycin
MTX
Topotecan
Ifos
Cytoxan

Question 9

Alkylating agents (contain + charged alkyl groups that bind neg charged DNA)

Answer 9

• Direct DNA damage (X-link, free radical, strand breakage) G1, S, G2 arrest
• RT, platinum
• Nitrogen mustards(cytoxan, ifos, melphalan)
• Temodar
• Bleomycin (not exactly alkylating agent, produces ROS-> DNA breaks)

Question 10

Antimetabolites

Answer 10

• Inhibition of nucleotide synthesis. G1, S arrest

- Antifolates(MTX, pemextred), nucleoside analogs (5FU, gemzar), hydroxyurea

Question 11

Microtubule

Answer 11

M arrest
Taxanes (taxol, doxetaxol) promote tubulin polymerization
Vinka alkaloid inhibit polymerization

Question 12

Topoisomerases

Answer 12

• Topo II inhibitors :anthracyclines (doxorubicin, doxil),etoposide, actinomysin D
• Topo I inhibitors: Topotecan
• S phase

Question 13

Signal transduction

Answer 13

• Growth factor blockade: Trastuzumab, cetuximab, bevicizumab, pertuzumab
• Inhibition of Tyr kinase signal transduction: erlotinib, gefitinib, imitanib, sorafenib, sunitinib, lopatinib
• Hormonal inhibition

Question 14

RECIST = Response Evaluation Criteria in Solid Tumors

Answer 14

At least one 2cm (one dimension) target lesion
Other non target lesions
CR – disappearance of all target & nontarget
PR – disappearance of all target, without progression of nontarget & no new, at least 30% decrease in sum LD
PD – 20 % increase sum LD of targets
SD – BTWN PR and PD
CR: complete response, PR: partial response, LD: longest diameter, PD: progressive disease, SD: stable disease

Question 15

Bone Marrow Toxicity

Answer 15

• Neutropenia #1 manifesting 7-14 days from tx, lasting 3-10 days
• RT, alkylating agents,DNA damaging agents (nitrosoureas, mitomycin C) can have cumulative effects

Question 16

Emetogenicity

Answer 16

High: Cisplatin, carboplatin, Cytoxan, dactinomycin
Low: Bleomycin, taxanes, vinca alkaloids, 5FU, MTX, doxil, gemzar, topotecan

Question 17

Which chemotherapies cause Alopecia?

TEA CUP

Answer 17

Worst: Taxanes, doxorubicin/doxil, IV etoposide
Possible: platinums, Cytoxan, 5FU

Question 18

Which chemotherapies cause Neurotoxicity?

Answer 18

Cisplatin*, taxanes, hexalen,

-cisplatin sx’s come on later and continue after stopping tx

Question 19

What dugs cause PPE?

Answer 19

Oral etoposide, 5 FU, Doxil, bleomycin, docetaxel, MTX

FU Doxil Making Beautiful Toes Erythematous

Question 20

Which chemotherapies are vesicants (can cause extravasion necrosis)?

Answer 20

Doxorubicin, dactinomycin, Taxotere, vincristine, mitomycin C

Question 21

Genitourinary complication of chemotherapy

Answer 21

• Cisplatin: AKI if UOP not maintained. Mg and K loss known

- Hemorrhagic cystitis: Ifos-use mesna to bind acrolein. Can also happen with cytoxan

Question 22

What EXACTLY is cremephor??

Answer 22

• Carrier of paclitaxel

- Mixture of polyoxyethylated castor oil and dehydrated alcohol (leads to mast cell degranulation and clinical HSR)

Question 23

Timing of hypersensitivity reactions

Answer 23

• Platinum: second cycle of second course (~eighth)

- Taxol: 1st or 2nd cycle

Question 24

Treatment of hypersensitivity reactions

Answer 24

- Platinum - **** - Taxol

Question 25

What are the 3 phases of clinical trials?

Answer 25

- Phase 1: determine max tolerated dose & dose limiting toxicity - Phase 2: determine efficacy (e.g. RR) and toxicity. Done for a specific dx - Phase 3: RCT comparing new agent to standard therapy

Question 26

How is body weight used in chemo?

Answer 26

- Actual: measured body weight - Adjusted (ABW) = ideal body weight (IBW) + 0.4(ABW - IBW). Used for obese patients (e.g BMI >25) - ASCO recommends using ACTUAL - GOG calculator uses adjusted

Question 27

Infertility

Answer 27

- High risk: cytoxan, ifos, melphalan - Medium risk: cisplatin, doxorubicin - Low risk: MTX, 5FU, bleomycin, vincristine, dactinomycin - taxane risk unclear due to limited studies - should wait 6months after chemo to try to get preg - ovarian suppression effectiveness controversial Whole abdominal or pelvic radiation doses > 6 Gy in adult > 15 Gy in pre-pubertal girls > 10 Gy in post -pubertal girls Ref: American Cancer Society and Breast Cancer.org

Question 28

What is an AUC?

Answer 28

- AUC: the area under the curve is a plot of concentration of drug in plasma against time. (correlates with anti-tumor activity) - The amount eliminated by the body = clearance (volume/time) * AUC (mass*time/volume). - Calvert Formula: Carboplatin dose (mg) = (Target AUC) x (GFR + 25) -GFR about equivalent to the estimated creatinine clearance (Ccr). Calculated with Cockcroft-Gault: Ccr (ml/min) = ([140 - Age(years)] x Weight (kg) x 0.85) /72 x Serum Creatinine (mg/dl)

Question 29

platinum drugs

Answer 29

Gain access to intracellular compartment by passive diffusion and carrier mediated uptake; resistance MOA include increased efflux, reduced influx, intracellular detoxification by glutathione and metallothionenines, changes in DNA repair, defective apoptosis

Question 30

Goldie Coldman hypothesis

Answer 30

treatment should begin as soon as possible to treat the smallers amt of bulk; multiple non cross resistant agents should be used to avoid selection of resistant clones; use drugs often and at highest possible doses

Question 31

mechanisms of chemotherapy resistance

Answer 31

alteration of drug movement across cell membrane; increased DNA repair, defective apoptosis ; alterations of drug targets

Question 32

Prodrugs

Answer 32

``` o Hexamethylamine (liver demethylation) o Cyclophosphamide (liver P450) o Xeloda(capecitabine) gets transformed to 5-FU (cells via dihydropyrimidine reductase) o Gemzar (cells via deoxycitidine kinase) o Ifos (liver microsomal enzymes) o Irinotecan (liver to active SN-38) o Mitoycin (reduction to alkylating agent) ```

Question 33

Chemo dosing adjustments

Answer 33

- Cr capped w/ carbo for < 0.7?