Alkylating agents (chlorambucil, cyclophosphamide, busulfan, ifosfamide, meclorethamine, melphalan, thiotepa)

Antracycline Antibiotics (doxorubicin [Adriamycin], daunorubicin, idarubicin)

Other Antibiotics (dactinomycin, mitomycin, mitoxantrone)

Nitrosureas (carmustine, lomustine, streptozocin)

Miscellaneous Alkylator-like agents (altretamine, carboplatin, cisplatin, dacarbazine, procarbazine)

Antimetabolites (methotrexate, 5-FU, floxuridine, thioguanine, 6-MP, cytarabine, fludarabine, cladribine, pentostatin, gemcitabmine)  - S phase

Bleomycin, Etoposide, Teniposide - G2 phase

steroids, asparaginase - G1 phase

hematopoeitic toxicity

GI tox

Gonadal tox

Carcinogenesis

dacarbazine

procarbazine

temozolomide

Pyrimidine antimetabolites end in what suffix?

Purine antimetabolites end in what suffix?

What phase of the cell cycle do antimetabolites work in?

pyrimidines end in "-abine"

(ex: cytarabine [Ara-C], capecitabine [Xeloda], gemcitabine [Gemzar], fludarabine [Fludara], and 5-FU is the exception)

purines end in "-purine"

(ex: 6-mercaptopurine, 6-thioguanine is an exception)

Antimetabolites work in the S phase of the cell cycle

Cisplatin - Nephrotoxicity, neurotoxicity, ototoxicity, N/V

Carboplatin - Myelosuppression, N/V

Oxaliplatin - Neurotoxicity, N/V

The formation of platinum agent crosslinks are normally on the same strand. Is this usually...

A. G-G

B. G-C

C. A-T

D. A-A

For the microtubule targeting drugs match the drugs to the correct mechanism of action:

A. Vinca Alkaloids stabilize the microtubule structure by inhibiting depolymerization

B. Taxanes trigger depolymerization which disables the microtubules

C. Vinca Alkaloids trigger depolymerization which disables the microtubules

D. Taxanes stabilize the the microtubule structure by inhibiting depolymerization

E. Both A and B are correct

F. Both C and D are correct

Yes.

Give dexamethasone 20mg PO 12 and 6 hrs prior, benadryl and antiemetic with paclitaxel (Taxol)

Give dexamethasone 8mg PO BID 1 day before and 4 days after a dose of docetaxel (Taxotere)

Breast cancer

Colorectal cancer

Prostate cancer

Lung cancer

Renal cancer

Lymphomas

Acute Myeloid Leukemia

Chronic Leukemia

Multiple Myeloma

What agents are topoisomerase II inhibitors?

(Hint: there are only 2)

Etoposide (VePesid)

Teniposide (Vumon)

Camptothecin

Topotecan

Irinotecan (Camptosar)

What agent can be used to prevent cardiac toxicity or treat extravasation with the Anthracyclines?

(ie with doxorubicin [Adriamycin], daunorubicin, etc) 

Leucovorin!!!

MTX followed by leucovorin preferentially kills the cancer cell. It allows dose of MTX 10-100x that of the conventional dose

p53 (Guardian of the genome baby)

 Rb

BRCA-1 and BRCA-2

Ras (signal transducer, part of MAP-k pathway)

C-myc (transcription factor)

BCR- ABL (enhances tyrosine kinase activity)

advantages- Specificity for cells in single phase of cell cycle; complete inhibition of enzymes at subclinical/clinical doses; plateau in cell survival with increasing drug dose; minimal risk of leukomogenesis or carcinogenesis

disadvantages - fewer target sites; little or no effect on slow growing/stem cells

They all have a Z in the name:

dacarbaZine, procarbaZine, temoZolomide

Where do postmenopausal women get most of their estrogen from?

What impact does this have on therapy?

most comes from the adrenal gland (androstenedione is converted by aromatase to estrone --> estradiol)

We can use aromatase inhibitors for them

(Anastrozole [Arimidex], Letrozole [Femara], Exemestane [Aromasin])

Use these drugs after progression following Tamoxifen therapy

This is a SERM (pure antiestrogen)

It is used in POST menopausal women with disease progression following antiestrogen therapy

Where does most of the estrogen come from in PRE-menopausal women?

What does this mean for treatment?

Most comes from the ovaries.

Can do an ovariectomy + SERM (tamoxifen and toremifene)

Could also use LHRH agonists:

(Leuprolide [Lupron], Goserlin [Zoladex], Triptorelin [Trelstar])

Name the 3 small molecule inhibitors

that target BCR-ABL

Imatinib (Gleevec)

Dasatinib

Nilotinib

Name the 3 small molecule inhibitors

that target EGFR and HER2

Erlotinib

Lapatinib

Gefitinib

Sorafenib

Sunitinib

It is a 1st generation BCR-ABL inhibitor

It is a 3A4 inducer

Indications: CML and GIST (the Kit+ kind)

Adverse effects: fluid retention and edema

Interacts with anything 3A4

It is a 2nd generation BCR-ABL inhibitor

Adverse effects: QT prolongation and sudden death

It is a HER-1 (EGFR) inhibitor

Only used in 2 cancers: NSCLC and metastatic pancreatic cancer

(Treat pancreatic cancer 1st with Gemcitabine, but if that does not work, then try Erlotinib)

Adverse effects : GI bleeding or perforations

This targets HER-2

It is used in combo with capecitabine for breast cancer

Adverse effects: Cardiac tox (QT prolongation)

It is used for hepatocellular carcinoma and advanced renal cell carcinoma

Adverse effects: bleeding!!

It is a direct inhibitor of cancer cell proliferation

It enhances the cytotoxicity of T cell activity against cancer cells

It causes tumor cell cytostasis and apoptosis by interfering with the cell cycle regulation

Indications: AIDS related Kaposi sarcoma, Malignant melonoma

May potentiate risk of renal failure

in combo with IL-2

Adverse effects: DEPRESSION

Do not use INF-alpha when someone has AUTOIMMUNE hepatitis

It is metabolized by the kidneys

Indications: METASTATIC renal cell carcinoma, and metastatic melonoma

Glucocorticoids reduce antitumor effectiveness of IL-2

Adverse effects: HYPOTENSION, Capillary Leak Syndrome

Match these drugs the their targets:

Alemtuzumab              EGFR

Gemtuzumab              CD20

Trastuzumab               HER-2

Cetuximab                  CD52

Bevacizumab              VEGF

Rituximab                  CD33 and calicheamicin

Alemtuzumab - CD52

Gemtuzumab - CD33 and calicheamicin

Trastuzumab - HER-2

Cetuximab - EGFR (EGF receptor)

Bevacizumab - VEGF

Rituximab - CD20

those ending in:

"-Momab" are Murine

"-iximab" are chimeric

"-Zumab" are humaniZed

It is a humaniZed monoclonal antibody (ends in "-Zumab")

It is specific for HER-2

Indication: adjuvant breast cancer and metastatic breast cancer (with paclitaxel)

MOA: uses ADCC (antibody dependent cell-mediated cytotoxicity)

Adverse reactions: cardiomyopathy, infusion reactions

It is a chimeric monoclonal antibody (ends in "-ximab"

It is specific for EGFR (HER-1)

Indication: Head and neck cancer; colorectal cancer w/o kRAS mutation (combined with Irinotecan)

MOA- direct induction of cell apoptosis

Adverse reactions: Cardiopulmonary Arrest and Sudden DEATH

It is a FULLY HUMAN monoclonal antibody

It is specific for EGFR (HER-1)

It is specific for VEGF (not the receptor!!!!)

It is indication for metastatic colorectal cancer, non-squamous NSCLC, metastatic breast cancer, glioglastoma, and metastatic renal cell carcinoma

Adverse reactions: GI perforation; wound healing complications; hemorrhage

** Do not administer as IV push or bolus bc it would cause infusion reactions

It is specific for CD20 (on B cells)

It is chimeric (ends in "-ximab")

Indicated for Non-Hodgkin's lymphoma

needs premedication prior to dose

Adverse reactions: Tumor Lysis Syndrome, Infusion reactions

MOA- complement dependent cytotoxicity

It is specific for CD52

Indicated for B cell chronic lymphocytic leukemia (B-CLL)

Adverse reactions: infusion reactions

It is specific for CD33 (conjugated with cytotoxic chemo agent class Calicheamicins, found in WACO, TEXAS)

Indicated for Acute Myeloid Leukemia (AML) when first relapse >60 yrs old

Adverse reactions: Myelosupression (>99%), thrombocytopenia (>90%)

Premedicate with acetaminophen and diphenhydramine

Associated with Multiple Myeloma (MM)

C - hyperCalcemia

R - Renal failure

A - Anemia

B - Bone metastasis

MP - melphalan/prednisone

VAD - vincristine/Adriamycin (doxorubicin)/ dexa.

TD - thalidomide / dexamethasone

DVD - lipo dexa/ vincristine / dexameth

D - high dose dexamethasone

VTD - bortezomib[Velcade]/ thalidomide/ dexa

VD - bortezomib[Velcade]/ dexa

LD - lenalidomide/ dexa

MPT - melphalan/ pred/ thalidomide

MPV - melphalan/ pred/ bortezomib[Velcade]

VTD - newer regimen consisting of bortezomib[Velcade]/ thalidomide/ dexa

Give Q21 days for 3 cycles

VD - newer regimen with bortezomib[Velcade]/ dexa

Give Q21 days for 4 cycles

or can use TD or DVD (older regimens) or low dose dexa

Give in 6 week cycles (instead of every 3 weeks)

Choice is Mephalan based

can use MPV - newer regimen with melphalan/pred/bortezomib[Velcade]

(**Note: adverse cytogenetics like 13q deletion, advanced age, and renal fxn had no effect on efficacy of V

May also use MPT, or MP (not as good as MPT)

It is a proteasome inhibitor with chymotrypsin like activity; it arrests the cell cycle and induces apoptosis

Use in multiple myeloma after two treatment failures. It is not first line therapy.

Do not give a new dose within 72 hrs of the last dose. 

DO NOT GIVE IF ALLERGIC TO BORON OR MANNITOL!!!

Adverse effects: mainly neuropathy (serious)

How do you treat a multiple myeloma patient who has had a relapse >6 months later

vs.

a patient who had a relapse within 6 months (ie refractory multiple myeloma)?

For a patient relapsing >6months later, repeat the primary chemo regimen

For a patient with refractory, use:

bortezomib +/- Doxil (a pegylated form of doxorubicin)

or lenalidomide + dexa

other options for refractory: (thalidomide +/- dexa; dexa pulse or high dose; Arsenic trioxide + Vit C)

Bone Disease: Use pamidronate (Aredia) or Zoledronic acid (Zometa, Reclast etc)

Anemia: Use Epoetin (40,000 units SC weekly), darbepoetin (200 mcg SC Q 2 weeks) and/or iron supplementation

Infection: give pneumococcal vaccine and Hib vaccine

Vinca alkaloids

(vincristine, vinblastine etc)

AML-M2:  t(8;21)  (seen in 40% of cases)

AML-M3:  t(15;17)  (seen in 98% of cases)

AML-M4:  inv(16)  (seen in 40% of cases)

Leukocytosis

High LDH

anemia

ANC >1500

Plt >100,000

BM >20% cellularity with <5% blasts and no Auer rods

1) Age (>60 yrs old have much worse outcomes)

2) cytogenetics (good cytogenetics include [t15;17], [t8;21], [inv16/t16;16], and t11;variable.)

3) peformance status (a good performance status is <3; after that mortality increases significantly)

4) comorbidities (diabetes, CHF, hyperlipidemia- these may affect performance status and how closely we monitor the patient)

Goal for induction therapy in AML is to eradicate malignant clone and restore normal hematopoiesis

Use the 7+3 regimen

(consists of 7 days of Cytarabine and 3 days of either idarubicin, daunorubicin, mitoxantrone)

First look at age!!!!

Age <60 will use 7+3 regimen (HiDAC). A major side effect is cerebellar toxicity (difficulty speaking);

May also use Stem Cell Transplantation [allogenic- HLA matched; autologous- does not have HLA match)

Age >60 will use 5+2 (aka reduced dose cytarabine)

If elderly person goes into relapse, use Gemtuzumab (works on CD33 and uses other chemo drug calicheamicin)

Tumor Lysis Syndrome

Transfusion dependent thrombocytopenia, anemia

GI toxicity

Febrile neutropenia

DIC (disseminated intravascular coagulopathy)

When is prophylaxis necessary for AML?

What are the options for prophylaxis?

It is necessary for AML patients that have ANC <500, especially if elderly (age >60)

Use G-CSF (Filtrastim) or GM-CSF (Sargramostim)

If long duration of neutropenia, may use antibiotics, antifungals or antivirals (inconclusive evidence)

This is called APL (acute promyelocytic leukemia)

It presents in YOUNGER patients, DIC is common, and there are lower WBCs and platelet counts

A patient with WBC >10,000

[Note: Low risk is WBC <10,000 and Plt >40,000, while intermediate risk is WBC <10,0000 and Plt <40,000)

Use ATRA + idarubicin

[Note: ATRA stands for all-trans retinoic acid]

If WBC remains >10,000, begin prophylactic dexamethasone 10 mg BID to prevent retinoic acid syndrome

When ATRA is used, 90-95% of patients achieve a favorable response

When is consolidation used for AML-M3 (APL) patients?

What is used in each cycle?

Consolidation is used 1-2 weeks after recovery

Cycle 1: Idarubicin + ATRA

Cycle 2: mitoxantrone + ATRA

Cycle 3: Idarubicin

What is the maintenance therapy for AML-M3 (APL patients that are at low risk?

(low risk = WBC <10,000 and Plt >40,000)

Maintenance can be started when WBC are <3,000 and Plt >75,000

Treat with ATRA x 15 days Q 3 months or

6-MP daily [**drug interaction w/ allopurinol] or

MTX weekly

all of that for 2 years!!!!

RAS is Retinoic Acid Syndrome

Sxs include edema and weight gain, fever, pleural and pericaridal effusions, hypotension and renal failure

If RAS develops, d/c ATRA and give dexamethasone 10 mg IV Q12 H x 3 or more days

Cancer of the YOUNG!!! Leading cause of cancer death in patients <35

Median age of diagnosis is 10 years old

More common in males and twice as common in Caucasians

ALL- L1 is the Childhood type (and the most common)

(ALL-2 is adult, ALL-3 is Burkitt-like)

L2, L3 (adult and Burkitt type)

BCR-ABL (philadelphia) chromosome

abnormal cytogenetics

WBC >50,000

Male

African American

CNS leukemia

absence of mediastinal mass

Age <1 yr or >10 yrs

14 days to remission, hepatosplenomegaly, lymphadenopathy

Combination chemo is the mainstay!!!

1) Remission induction

2) Consolidation/intensification

3) Maintenance

4) CNS prophylaxis

The standard 4 drug regimen is: prednisone, vincristine, L-asparaginase, +/- daunorubicin

Intrathecal chemo provides the BEST protection with the least morbidity

Give this during induction, consolidation and maintenance

Adults should receive IT methotrexate

******Make sure that this is not mistaken with vincristine. If that is given IT the patient will DIE ***

Doxorubucin [Adriamycin] and the other anthracyclins

Vincristine and the other Vinca alkaloids

Dactinomycin (antibiotic)

Mitomycin (antibiotic/alkylating agent)

Mechlorethamine (alkylating agent)

What is the treatment for etravasation of anthracyclines?

(doxorubicin [Adriamycin], daunorubicin etc)

DMSO (dimethyl sulfoxide)

allow to air dry with no occlusive dressings

cold compress

Dexrazoxane is being studied right now.

Do not administer dexrazoxane to a patient currently receiving DMSO

Antidote is Sodium Thiosulfate

Use a cold compress

Use DMSO

Use cold compress

Antidote is hyaluronidase

Use a HOT compress

Name the most important things about Hypercalcemia and cancer

What cancers most commonly cause hypercalcemia?

How do you calculate corrected calcium?

What are the 4 primary sxs of hypercalcemia?

What are the main treatment option?

Most common cancers causing hypercalcemia: Breast cancer, Multiple Myeloma, Lung cancer

Corrected Ca = measured Ca + 0.8 (4 - albumin)

Use this only when albumin is <3.5

Symptoms:

GI (Nausea); Renal (Polyuria); Neurologic (Fatigue, muscle weakness); Cardiac (Shortened QT interval)

Treatment options:

oral fluids

hydration (NS) +/- furosemide

Bisphosphonates  (inhibit osteoclast activity)

Calcitonin (for Ca>16 or life-threatening)

What cancers have the highest risk of Tumor Lysis Syndrome (TLS)?

[It is an oncologic emergency!!]

Burkitt's lymphoma

lymphoblastic lymphoma

T cell ALL

Acute Myeloid Leukemia (AML)

hyperuricemia

hyperkalemia

hyperphophatemia

HYPOcalcemia (opposite of phosphate)

uremia

What are the prevention strategies

vs

treatment strategies for tumor lysis syndrome?

Prevention: hydration, alkalinize urine (pH>6.5-7), use Rasburicase or allopurinol; monitor closely

Treatment: Rasburicase only (cannot use allopurinol in this case because the uric acid is already formed)

lung cancer (75-80%)

SCLC

Lymphoma (10-15%)

Head and Neck cancer

Radiation is first line bc it will shrink the tumor quickly

Chemo is good but takes longer to work

[Note: supportive measures include bed rest, oxygen, corticosteroid, diuretics, low salt diet]

dexamethasone (to reduce edema and delay onset of paraplegia); helps within hours

Radiation is the treatment of choice - shrinks tumor

surgery for severe cases

chemo takes longer to work

People that go to the VA are the least likely to have problems with chemo emesis. That is because they are typically: older and male

risk factors are: younger, women, dose, rate, combo therapy, intrinsic emetogenicity of the drug

Prevention of acute emesis for High Risk (Level 5) chemotherapy:

[ie, Cisplatin regimen, which is >90% incidence]

What about for delayed emesis (still High Risk)?

Acute:

Aprepitant (blocks NK1 receptor)

5-HT3 antagonist (ex: Ondansetron)

dexamethasone

Delayed:

Apreptitant + dexa

of 5-HT3 + dexa

or metoclopramide + dexa

Prochlorperazine (typical antipyschotic)

Promethazine (H1 antagonist)

Metoclopramide (D2 receptor antagonist)

Lorazepam (benzodiazepine)

dexamethasone (glucocorticoid)

ondansetron (5-HT3 receptor antagonist)

haloperidol (typical antipyschotic)

etc

Single temperature >101 F (38.3 C)

temp greater than 100.4 F (38 C) for >1 hour

ANC <500 or

ANC <1000 predicted to go <500

ANC = WBC x (segs% + bands%)

Example:

So typically people will write WBC in the lab as 2.4. You must put this in the equation as 2400.

And also if there are 45% segs and 5% bands you have to put it in the equation as 0.45 + 0.05

ANC = 2400 x (0.45 + 0.05) = 1200

Gram positive pathogens!!!

(mainly coagulase-negative staphylococci, followed by staph aureus, etc)

[Note: gram positive bacteremia actually has a lower mortality rate than gram negative bacteremia, 6% vs 10% respectively]

FEVER!!!!!!!

If the person does not have an immune system they would not be able to mount an inflammatory response like having sputum etc

inpatient at time of fever

significant comorbid conditions/clinically unstable

anticipated severe neutropenia <100 for >7 days

SCr >2, LFTs >3x normal

uncontrolled/progressive cancer

pneumonia or other complex infection upon presentation

MASCC Risk Index Score <21

ovariectomy + tamoxifen leads to complete estrogen blockade

Or even LHRH agonists (Leuprolide, Goserelin, Triptorelin)