CHEMOTHERAPY DRUGS

-- A -- B -- C -- D -- E -- F -- G -- H
-- I -- J -- K -- L -- M -- N -- O -- P
-- Q -- R – S -- T – U – V – W – X – Y
-- Z

Complications (Abnormal Clotting, Emesis, Extravasation, Taxol Neuropathy, Radiation Esophagitis, Toxicity by Organ System)

 

A: Abraxane, Actinomycin-D, Adriamycin, Anagrelide, amifostine, aminoglutethimide, Arimidex, anastrozole, Ara-C, azacytadine, asparaginase, alemtuzumab, Alimta, Alkeran, ATRA, Antibodies, Aranesp

 

AGRYLIN (anagrelide)

For treatment of ET. Selectively lowers platelet counts.

Inhibits platelet aggregation, but at doses > than those required to platelet count. Mechanism not known.

DOSE: 0.5mg QID x 1wk, then adjust to maintain platelet count <600 and ideally 150-400. Do not increase dose by more than 0.5 mg/d in any one wk. Dose should not exceed 10 mg/d or 2.5 mg/single dose. Platelet counts should be checked q 2d during first week, then weekly thereafter until maintenance dose reached. Typically platelet counts begin to respond in 7-14d. Usually dose 1.5-3.0 mg/day. Can be taken with food.

Suppl: 0.5 and 1 mg caps in bottles of 100.

CR=73%, PR=9% RR=82%
Time to CR=3weeks
Time to PR=2wks

Adverse effects:

Headache ___45 (relieved by Tylenol)
Palpitations__ 25 (due to increased inotropy & vasodilation. Use with caution in pts with known or suspected ht disease)
Diarrhea_____25
Asthenia_____22 (relieved by lactase supplement)
Edema_______20
Abd pain_____17
Nausea_______15
Dizziness_____14
Dyspnea______10
Flatulence____10

 

AMIFOSTINE (Ethyol)

MDS: 200-400 mg/m2 IV/3-5min TIW

Neurotox: 200-340 mg/m2 IV/3-5min TIW

Prior to chemo: 740 mg/m2 IV/5-10min. Premed & hydrate.

Prior to RT: 200-340 mg/m2 QD prior to RT

 

AMINOGLUTETHIMIDE (Cytadren, AG)

Aromatase inhibitor, blocking conversion of androgens to estrogens and the biosynthesis of all steroid hormones. In effect, a medical adrenalectomy.

Usual dose: 250 mg QID

Must give HCT to prevent adrenal insufficiency:

50mg BID x 2 wks, then 20mg BID

Toxicity: Reversible leukopenia & thrombocytopenia (rare). N&V - rare and mild. Rash - morbilliform. Usually during first wk. Disappears within first wk. Neuro - lethargy common. Usually mild and transient. Uncommon to see ataxia, nystagmus, or vertigo.

 

ANASTROZOLE (ARIMIDEX)

Selective oral aromatase inhibitor.

Dose:       1mg po QD

 

 

AZACYTIDINE (5-AZA)

Pyrimidine analogue

Used in AML

Usual dose: 100 mg/m2 IV q8h x 5 days OR 150-200 mg/m2 CIV x 5 days

Unstable. Must give as soon as prepared with Ringers. Change q 8h.

Toxicity: Severe myelosuppression, Nausea/vomiting, Diarrhea

 

B: BCNU, bicalutamide, bleomycin, Busulfan,

 

BCNU (CARMUSTINE)

Alkylation and carbamoylaton by carmustine metabolites interfere with synthesis and function of DNA, RNA, and proteins. Carmustine is lipid soluble and enters brain easily.

Uses: Lymphoma, brain, myeloma, melanoma

Usual dose: 200-240 mg/m2 IV/30-45 min q 6 wks. Often divided and given over 2-3 days.

Some recommend limiting cumulative dose to 1000 mg/m2 to limit pulmonary and renal toxicity.

Precautions: Because of delayed myelosuppression, do not give more often than q6 wks. Await return of normal platelet and wbcs before repeating therapy.

Toxicity: Counts. Delayed and often biphasic. Nadir 3-6 wks. With successive doses, may be cumulative -> recovery that takes several months. N/V common. Usually starts 2 hrs p therapy and lasts 4-6 hrs. Alcohol used to reconstitute the drug can --> facial flushing and pain at injection site, especially if given rapidly.

Hyperpigmentation of skin following accidental contact.

Liver toxicity rare, but can be severe.

Pulmonary fibrosis at doses >1000 mg.

Renal toxicity uncommon at doses <1000 mg.

 

BICALUTAMIDE (CASODEX)

Like flutamide.

Dose: 50mg po qD

Suppl: 50mg tabs

May have more cardiac effects, and less proven than flutamide.

 

BLEOMYCIN (Blenoxane)

Binds to DNA, causing single- and double-strand breaks. Inhibits DNA and protein synthesis.

Uses: Testis, H&N, cervix, penis, vulva, anus, skin, lung, lymphomas

Usual dose: 10-20 u/m2 IV or IM 1-2 x/wk OR

- 30 u IV weekly for 9-12 wks in comb with other drugs

- 60 u in 50cc NS instilled intrapleurally

Test Dose: Bec of risk of anaphylactoid rx, give 2u in 50cc D5W or NS IV/15min. Observe 1-2 hrs. Some recommend observing 24h since rx may occur late, especially in pts with lymphoma (1-8% incidence in lymphoma)

Precautions:

1. In pts with lymphoma, risk of anaphylactic, acute pulmonary, or hyperpyretic reactions. Give test dose of 1-2 units IM prior to first dose. If no rx in 4 hrs, may begin.

2. Adjust for renal failure:

__Serum Creat ___% of full dose

____2.5-4.0_________25

____4.0-6.0_________20

______> 6.0________10

3. Cumulative lifetime dose should not exceed 400 units due to pulmonary toxicity. In older pts may want to give even less. Same for pts with lung disease.

4. Glass containers recommended for continuous infusion to maintain stability.

Toxicity: Counts UNcommon, so can use in full dose with other drugs. Mucocutaneous-Alopecia, stomatitis, erythema, edema, thickening of nail bed, hyperpigmentation, and desquamation - all common.

Pulmonary - Acute anyphylactoid or pulmonary-edema-like rxs

Dose-related pneumonitis with cough, dyspnea, rales, infiltrates

Fever common. Occasionally severe. Antipyretics help control.

IM or SQ injections - pain at injection site

Can cause Raynaud's in 5-10% pts who receive it as bolus. Risk reduced if given as infusion.

 

BUSULFAN (Myleran)

Alkylator. May act on cellular thiol groups more than nucleic acids.

Use: CML

Usual dose: 3-4 gm/m2 po QD in adults until WBC is 50% of              original level, then 1-2 gm/m2 QD. May be given con-tinuously or intermittently.

For CML (MKSAP): 2-8mg QD x 5-10d or until WBC 20.

Busulfan affects an earlier stem cell and provides longer periods of disease control than Hydrea, but is assoc with unpredictable prolonged myelo-suppression in 10% and occasionally with organ fibrosis (lungs, heart, marrow) and Addison's disease. Often used in older pts who are not candidates for BMT.

Obtain CBC weekly while pt on therapy. If WBC falls rapidly to <15, d/c until nadir is reached and rising counts indicate need for further treatment.

Toxicity: Counts. May not see fall for 2 wks. Recovery 3-6 wks.

Occasional hyperpigmentation, especially in skin creases.

Rare interstitial pulm fibrosis (d/c drug). Treatment: steroids.

May suppress adrenals and ovaries (--> amenorrhea)

 

C: 2cda, Campath, Camptosar, capcitabine, carboplatin, CCNU, chlorambucil, cisplatin, cladribine, CPT-11, cyclophosphamide, Cytoxan, cytarabine, cetuximab,

 

2-CDA (cladribine, Leustatin)

Purine analog with high cellular specificity for B cells. Resistant to effect of adenosine deaminase. Probably --> NAD depletion --> cell death. Effect is independent of cell division.

Use: Hairy cell leuk, CLL, other B cell neoplasms

Dose: 0.05-0.2 mg/kg (2-8 mg/m2) CIV x 7 days

For HCL: 0.1 mg/kg OR 4 mg/m2 QD CIV x 7d OR 3.4 mg/m2/d SQ x7d

Precaution: Pretreat with allopurinol

Toxicity: Moderate granulocyte suppression, N/V not a problem. Fever, possible due to release of endogenous pyrogens.

 

CAPECITABINE (Xeloda)

For refractory breast ca, colon cancer. Xeloda activated to 5FU in cancer cells by thymidine phosphorylase. This enzyme can be up-regulated by most chemo agents, also by RT.

PDR Dose: 2500 mg/m2/d divided BID with food. Give 14 on/7 off. Take only with water.

See for use in Breast Cancer:

See for use in Colon Adjuvant

For use with RT: 825 mg/m2 BID 14 days on/7 days off during RT, M-F during RT, or straight through RT.

Caution in pts with renal impairment:

ClCr > 50 --> 100%
If 30-50 --> 25% reduction
If < 30 --> contraindicated

Supplied: 500 mg

 

CARBOPLATIN (CBDCA, Paraplatin)

Alkylator

Usual dose: 300-400 mg/m2 IV/15-60min q 4 wks OR dose by AUC=5-7 (JCO 11/1989)

AUC Dosing: Dose (mg)=target AUC x (GFR+25) [Calvert form]

Target AUC:

5 - untreated pts when given in combination

5 - in previously treated pts

7 - single agent, untreated pts

Precautions:

Much less nephrotoxicity than CDDP, so no need to hydrate.

If dose by BSA, adjust for GFR:

41-59      -->          250 mg/m2

16-40 -->               200 mg/m2

Toxicity: Counts. May need RBC transfusions also.

Thrombocytopenia may be delayed (18-28 days)

Emesis not quite as severe as CDDP.

Occasional rise in creat. Still see electrolyte abnormalities.

Abnl LFTs common

Occasional abd pain

Peripheral neuropathy Uncommon

 

CCNU (LOMUSTINE)

Alkylation & carbamoylation by lomustine metabolites interfere with synthesis and function of DNA,RNA, and proteins. Lipid soluble so readily enters the brain.

Use: lung, kidney, lymphoma, brain

Dose: 100-130 mg/m2 once every 6-8 wks ( if poor marrow)

Some recommend limiting cum dose to 1000 mg/m2 to limit pulmonary and renal toxicity.

Precautions: Do NOT treat more often than q 6wks due to delayed myelosuppression (3-6 wks). Wait for normal WBC/platelet counts before repeating treatment.

Toxicity: Counts - universal

Nausea - begins 3-6h later; lasts 24h

Rare CNS effects

Pulm fibrosis at doses > 1000 mg/m2.

Renal toxicity at doses > 1000 mg/m2.

 

CHEMOTHERAPY DRUG CLASSES

Alkylators

               Cyclophosphamide
               Chlorambucil
               Busulfan
               Melphalan
               Thiotepa
               Ifosfamide
               Nitrogen mustard

Antimetabolites

               Methotrexate
               5FU
               Cytosine arabinoside

               Purine analogues: 6-MP and 6-TG interfere with guanine incorporation into DNA

                               Fludarabine

                               Deoxycoformycin

               Trimetrexate (folate analog)

Antibiotics

               DOX
               DNR
               Dactinomycin
               Bleomycin
               Mitomycin C
               Plicamycin (mithramycin)
               Idarubicin
               Mitoxantrone

Vincas

               VCR
               VBL
               VDS

Epipodophyllotoxins

               Etoposide
               Teniposide

Nitrosoureas

               BCNU (carmustine)
               CCNU (lomustine)
               methyl-CCNU (semustine)

Enzymes & Random Synthetics

               L-asparaginase
               Dacarbazine (DTIC)
               Hexamethylmelamine
               Hydroxyurea
               Mitotane
               Procarbazine
               CDDP
               Carboplatin

 

CHLORAMBUCIL (Leukeran)
Alkylator.

Use: CLL, NHL

Dose: 3-4 mg/m2 QD until response or cytopenia, then 1-2 mg/m2 po QD maintenance.

OR

30 mg/m2 po once every 2 wks (usually with prednisone 80 mg/m2 on days 1-5)

 Precaution: Increased toxicity with prior barbituate dose.

Toxicity:

Counts

N/V uncommon except at higher doses.

Amenorrhea and azoospermia common.

 

CISPLATIN (CDDP, Platinol)

Alkylator, especially with DNA strand cross-linking.

Use: Testis, ovary, endometrial, cervical, bladder, H&N, GI, and lung.

Dose: 40-120 mg/m2 IV on day 1 as infusion q 3 wks.

OR

15-20 mg/m2 IV days 1-5 as infusion q 3-4 wks.

Precautions:

DO NOT GIVE IF CREAT > 1.5.

- If giving doses > 40mg/m2, can -> irreversible renal tubular damage, especially if receiving other nephrotoxic drugs. Must use mannitol and hydration.

My hydration:

1L NS + 20meq KCl + 8meq MgSO4 IV/90min

Give before and after CDDP

CDDP: mix in 1L NS + 12.5 gm Mannitol IV/60min

If use amifostine, dose: ___ mg/m2 IV/5-15min

Hydration (for pts with good heart and doses up to 80 mg/m2):

* 2L NS + 20 meq KCl/L + 1 gm MgSO4/L IV/2 hrs

* As soon as infusion started, give Lasix 40 mg IV

* If pt has voided at least 250cc after 30 min, then give mannitol 12.5 gm IVP. (If pt unable to void, do NOT give cisplatin.)

* Following mannitol, give CDDP IV/30 min.

* Give additional mannitol or lasix, if necessary, to maintain urine flow > 500cc/hr for first 2 hrs or if pt shows any evidence of CHF.

* At end of 2 L infusion, decrease IV rate to 150 cc/hr or d/c.

For doses > 80 mg/m2:

*Have pt void, then start 2L D5 1/2NS + KCl 20 meq/L + MgSO4 1 gm/L IV/2 hrs.

*As soon as infusion started, give Lasix 40 mg IV

*At 2 hrs, if pt has voided at least 1000cc, give mannitol 12.5 gm IVP. (If hasn't voided, hold cisplat)

*Following, mannitol and additional lasix, give cisplat IV/30 min.

*After cisplat infusion, restart D5 1/2 NS with KCl at 500 cc/hr for another 4 hrs. Give at least 4L fluid over next 24 hrs.

For pts with known or suspected cardiac impairment (EF <45):

Use less vigorous hydration or consider carboplatin.

Toxicity:

Counts - anemia bigger problem than WBCs.

N/V - severe

Renal tubular damage

Ototoxic - high freq loss. Tinnitus UNcommon.

Lytes: Na, Mg, Ca, K for several days after treatment.

Anaphylaxis: may occur p several doses

Peripheral neuropathy - usually at cum dos > 300mg/m2

Autonomic dysfunction with hypotension

 

COMMON SIDE EFFECTS

VESICANTS AND ANTIDOTES

DNR                      Topical DMSO

DOX                      " "

Chlormethine Na thiosulfate

Vincas     Hyaluronidase

Dacarbazine            None

Mitomycin               None

Amsacrine               None

ALOPECIA

DOX                      5FU

CTX                       DNR

AraC                      Mechlorethamine

MUCOSITIS

Very common: MTX, 5FU infusion, Bleo infusion

Common : DOX, DNR, 5FU bolus, AraC, Bleo

Occasional : vincas, hydrea

CARDIOTOXIC

DOX above 450-550 mg/m2

Acute: SVT, heart block, CHF

Chronic: cardiomyopathy

CTX: hemorrhagic myopericarditis

5FU: ischemia, MI

HEPATOTOXIC

MTX                      Mithramycin (plica-mycin)

6MP                       L-Asp

AraC

NEPHROTOXIC

CDDP                    Mithramycin

MTX                      Nitrosoureas

CTX

NEUROTOXIC

L-Asparaginase - somnolence, lethargy

VCR - peripheral neuropathy, autonomic (constipation)

5FU - cerebellar toxicity

AraC- " "

CDDP- ototox, peripheral neuropathy

HEMATOLOGIC

Most drugs nadir at 2 wks

Nitrosoureas (x streptozocin) nadir at 4 wks

CTX and Adria spare platelets

Rapid recovery: CTX, DOX, 5FU, AraC, VP16, MTX

Slow (6-8 wk) recovery:

Busulfan                  Mustard

Melphalan                              Mitomycin

Melamine                Procarbazine

Nitrosoureas

 

CYCLOPHOSPHAMIDE (Cytoxan, CTX)

Metabolized by hepatic enzymes -> active alkylating metabolites

Dose:

1000-1500 mg/m2 IV q 3-4 wks OR

400 mg/m2 po days 1-5 q 3-4 wks OR

60-120 mg/m2 po QD

Consider Mesna for doses > 1000mg/m2. Calc Mesna dose same as Ifos (ie, 20% at 0,4 & 8 hrs).

Precautions: Give in the morning, maintain adequate fluid intake, and have pt empty bladder several times/day to avoid cystitis.

Toxicity:

- Counts (spares platelets). Nadir p IV dose is 10-14 days.

- Large IV doses -> N/V, usually a few hrs after dose. Better next day.

- Reversible alopecia common, usually starting p 2-3 wks.

- Darkening of skin & nails.

- Mucositis UNcommon.

- Hemorrhagic or nonhemorrhagic cystitis may occur in 5-10%. It is usually reversible on d/c of drug, but may persist and lead to fibrosis or death.

- Immunosuppression common.

- Amenorrhea/azoospermia-common

- SIADH - only of significance with large doses

 

CYTARABINE (Ara-C, Cytosar)

Pyrimidine analogue that is triphosphorylated to arabino-syl-

cytosinetriphosphate (ara-CTP), a competitive inhibitor of DNA polymerase.

Dose: 100-200 mg/m2 CIV x 5-7 days (in comb with other drugs)

Intrathecal: 40-50 mg/m2 q4d in preservative-free isotonic diluent

High dose: 3 gm/m2 IV/1hr q 12h x 6-12 doses

Precaution: With high dose, longer infusion --> greater toxicity

Toxicity (standard dose):

- Counts (nadir 7-10 days)

- N/V common, especially if given as a push or rapid infusion

- Occasional stomatitis

- Occasional flu-like syndrome with fever, arthralgia, & occasional rash

- Occasional mild hepatic dysfunction

Toxicity (high dose):

- Counts

- N/V

- Occasional-common mucositis

- Cerebellar toxicity, especially elderly, but usually mild and reversible. Pyridoxine 150 po/iv BID probably does NOT prevent or ameliorate symptoms.

- Conjunctivitis: Hydrocortisone 2 drops OU QID x 10 days or Prednisolone acetate 1% eye drops OU QID x 10 days

- Hepatic toxicity with cholestatic jaundice

- Diarrhea

- Pulmonary toxicity - dose-related- CHF like picture

 

D: dacarbazine, darbepoetin, DTIC, Dactinomycin, daunorubicin, Daunoxome (liposomal), docetaxel, Doxil (liposomal), doxorubicin, droloxifene, dexrazoxane

 

DACARBAZINE (DTIC)

Probably interacts with preformed macromolecules by alkylation

Pharm: 40% renal tubular excretion (not filtration)

Hepatotoxic: hepatic v thrombosis & liver necrosis reported (0.01%).

Use: melanoma, soft-tissue sarcomas, HD

Dose:       150-250 mg/m2 IVP days 1-5 q3-4 wks OR

400-500 mg/m2 IVP days 1-2 q3-4 wks OR

200 mg/m2 CIV x 96 hrs

Precautions:

Vesicant

Venous pain along injection site may be reduced by diluting in 100-200 cc D5W and infusing over 30 min rather than rapidly. Ice application may also help.

Toxicity:

Counts - mild-moderate

N/V - common and severe, but s with each subsequent dose. Onset within 1-3 hrs, lasting up to 12 hrs.

Alopecia UNcommon

Flu-like syndrome UNcommon.

 

DACTINOMYCIN (Actinomycin, Act-D, Cosmegen)

Binds to DNa and inhibits DNA-dependent RNA synthesis. Inhibits Topo II.

Use: Gestational trophoblasic neoplasms, Wilm's, rhabdomyosarcoma, and Ewing's

Dose:

Children- 0.4-0.45 mg/m2 (up to max 0.5mg) mg IV d1-5 q3-5 wks

Adults-    0.4-0.45 mg/m2 IV d1-5 every 2-3 wks

                               0.5 mg IV QD d1-5 q 3-5 wks

Precautions:

Vesicant

Avoid giving if recent herpes or varicella zoster infection bec can become generalized causing death

Toxicity:

Counts - nadir may not occur until 3 wks

N/V - severe in first few hrs, lasts 24 hrs

Erythema, hyperpigmentation, and desquamation of the skin in previous or concurrent RT sites

Oral mucositis with RT

Alopecia common

Rare mental depression

 

DAUNORUBICIN (Daunomycin, DNR, cerubidine)

Anthrcycline effects on Topo II

Dose:

60 mg/m2 IVP days 1-3
45 mg/m2 IVP days 1-2

Precautions:

Vesicant

Avoid if EF <45% or other heart problems

Do not exceed cumulative dose of 400-550 mg/m2

Reduce dose if pt has impaired renal or liver function:

Bilirubin Creatinine %Full Dose

1.2-3.0   --          75

> 3.0       > 3.0     50

 

Toxicity:

 

Counts

N/V - occurs on day of administration in 50%

Alopecia common

Heart failure. Discontinue if EF falls to:

< 45%

< 50% if total is > 10% (eg, 59%->49%)

If repeat EF shows return of function, drug may be cautiously restarted, but EF should be measured before each dose.

Transient EKG changes are not usually serious.

Red urine

Phlebitis

 

DAUNOXOME (liposomal Daunorubicin)

For advanced AIDS-associated Kaposi's

Dose: 40 mg/m2 IV/1hr q 2 wks

Hold: If ANC < 750. Treat until max response or progression.

Mix: 1mg/cc D5W

Reduce: Bili 1.2-3, reduce to 75%. If bili or creat >3 50%

Adverse:

Nausea                 50%

Fatigue                 45

Fever                   42

Diarrhea               34

Cough                  26

Dyspnea               23

HA                       22

Allergic                 21

Anorexia              21

Abd pain              20

Vomiting               20

Rigors                  19

Back pain             16

Increased sweating 12

Neuropathy          12

Rhinitis                 12

Chest pain            9

Edema                  9

Alopecia               6

Back pain + flushing + chest tightness (triad) 14%

 

DOCETAXEL (Taxotere)

Made from needles of yew plant. Inhibits microtubule disassembly and promotes assembly, thereby inhibiting mitosis.

Indicated in breast ca that has progressed on anthracyclines.

DOSE: 60-100 mg/m2 IV/1hr q 3wks

Premed: Decadron 8mg BID x 5d starting 1 day prior to reduce fluid retention & hypersens rxs.

Adjust 100 -> 75 mg/m2 if experience febrile neutropenia or ANC <500 that lasts >7 days, severe cutaneous rx, or severe peripheral neuropathy.

Adjust to 55 mg/m2 or d/c if above persist.

Adjust 60 ->100 if none of the above experienced (ie, intensify dose if possible)

WEEKLY:

35 mg/m2 IV/1hr weekly x 6 (8 wk cycle). Premed: Dex 4 mg IV 30 min prior.

Adverse:

Counts (spares platelets somewhat)

Hypersens 15%

Fluid ret 48

Neurosens 54

Nausea 40

Diarrhea 40

Alopecia 80

Asthenia 62

Stomatit 40

Myalgia 19

CAUTIONS:

Avoid using if:

- Bili > ULN (upper limit normal)

- AST and/or ALT > 1.5 x ULN concomitant with AlkP > 2.5X ULN

Mixing: 20 & 80mg vials. Mix in 250cc D5 or NS.

If skin contact, wash with water.

 

DOXIL (liposomal DOX)

Indicated for pts who cannot tolerate or who have failed combination chemo for AIDS-RELATED KAPOSI'S.

Dose: 20 mg/m2 q 3wk

1/2 life ~55 hrs

Think STEALTH liposomes allow higher penetration into the altered and compromised vasculature of tumors better than normal tissue.

Side effects same as DOX, but degree of cardiotox not known. Major effect is myelosuppression.

IS a vesicant.

 

DOXORUBICIN (DOX, Adriamycin)

Causes DNA strand breaks by effects on Topo II.

Pharm: Liver excretion

Dose:

60-75 mg/m2 IV q 3wks

30 mg/m2 IV d1,8 q 4wks (in comb with other drugs)

15-20 mg/m2 IV weekly

50-60 mg into bladder weekly x 4, then q 4wks x 6 cycles

Precautions:

- Vessicant

- Avoid if cardiac EF < 45%, arrhythmias, angina, recent MI.

- After 350-450 mg/m2, check EF and stop if EF has decreased by > 10% or if decrease drops it below 45%.

- No > 550 mg/m2 lifetime dose (or 450 mg/m2 if previous RT or concomitant CTX)

- Reduce for impaired liver function:

             Bili 1.2-3.0 --> reduce by 50%

             Bili > 3.0 --> reduce by 75%

             Bili > 5.0 --> omit

Toxicity:

- Counts (WBC and platelets)

- Emesis

- Stomatitis with high dose

- Alopecia (begins 2-5 wks after start)

- RT recall

- Vessicant

- Hyperpigmentation over veins

- Cardiac:

             Transient EKG changes (usually no problem)

             CHF: Discontinue if EF falls to < 45% or if EF falls to < 50% if total decrease is >= 10% (eg, from 59% to 49%). If repeat EF improves, may restart cautiously, but chk EF before each new dose.

Red urine

 

DROLOXIFENE

Antiestrogen like TAM.
Potential advantages over TAM:

10-60 fold higher binding affinity to ER receptor
Less estrogenic effect
Greater antiestrogenic effect
Less carcinogenic in animals
More effectively arrests cell growth in cell lines

Side effects:

Hot flushes
Malaise
Nausea

Dose:    40mg po QD

 

E: Epo, estramustine, Emcyt, etoposide, Eulexin, Elspar

 

ERYTHROPOIETIN (Procrit, Epogen, Aranesp)

Guidelines for Pts receiving chemotx:

Candidate: Anemic pt (Hb < 10) with non-myeloid malignancy. Obtain baseline Hb and Epo levels. If baseline Hb < 10 and Epo level <200, then:

Start: Procrit 150 u/kg = ~10,000u SQ TIW.

Chk Hb in 4 wks:

If Hb rise <1 g/dl, then make sure patient is not iron deficient. Increase to 300u/kg = ~20,000u TIW. If still no response after another 4 wks, stop Procrit.

If Hb rise 1.0-1.3, continue. Monitor iron level.

If Hb rise > 1.3 in two week period, reduce dose.

If Hb > 12g/dl, Stop Procrit. Resume at 75% when Hb <= 11g/dl.

End: Stop at completion of chemo and resolution of anemia.

Supplied: 2,000 / 4,000 / 10,000 unit 1cc vials in boxes of 10.

 

ESTRAMUSTINE (Emcyt)

Combination of mechlorethamine and estradiol PO4. Originally thought to selectively enter cells with estrogen receptors then act as alkylator. Now thought to act as spindle inhibitor (or is it topo II?).

Use: Prostate

Dose: 600 mg/m2 po QD divided TID [Suppl: 140mg tabs]

Number pills/day = 4.3*BSA

Toxicity: Counts, Nausea (usually gets better with time), CHF - may occur in pts with pre-existing disease, Gynecomastia – occasional

 

ETOPOSIDE (VP-16, VePesid, epipodophyllotoxin)

Interacts with Topo II producing single-strand breaks in DNA. Arrests cells in late S phase or G2.

Use: SCLC, NSCLC, germ cell, refractory lymphomas

Dose:       50-100 mg/m2 IV days 1-5 q 2-5 wks
               125-140 mg/m2 IV days 1,3,5 q3-5 wks
                50 mg/m2 PO QD x 21d. Repeat after 1-2 wk rest.

Precautions:

1.            Give over 30-60 min to avoid severe hypotension.
2.            Avoid extravasation
3.            Ideal dilution: 0.4 mg/cc (The more concentrated it is, the more likely it is to precipitate and the shorter the shelf life after mixing.)

Toxicity:

Counts
Nausea - mild.
Anorexia is common.
Alopecia – common
Rare
: liver, diarrhea, peripheral neuro, allergic rx

 

F: Floxuridine (FUDR), 5FU, fludarabine, flutamide,

 

FLOXURIDINE (FUDR)

Pyrimidine antimetabolite that is converted to active nucleotide that inhibits thymidylate synthetase.

Use: liver mets

Contraindications  :

TB > 2
KPS < 60%
SGOT > 2x normal
Symptoms of ulcer or gastritis

Monitor:

CBC monthly
LFTs q 2 wks

New dose schedule (Cancer 73:1134, 2/94)

               FUDR 0.3 mg/KG/d \ cont infusion 2 wks on, 2 wks off

               LV 15 mg/M2/d

               Add to mixture: Decadron 20mg and Heparin 10,000u

               Prior to FUDR, flush cath with 20cc NS, then 5cc heparin

Make dose reductions as follows:

SGOT > 2x baseline --> reduce FUDR to 80%

SGOT 3x baseline OR TB 1.5x baseline OR ALP 2.5x baseline --> reduce FUDR to 50%

SGOT 4x baseline OR TB 2x baseline OR ALP 3x baseline --> HOLD FUDR

No adjustments are made to LV dose.

With this regimen, RR=~70% with median duration 11mon

Precautions:

1.            Catheter must be placed by surgeon familiar with procedure.

2.            Pt should have prophylactic cholecystectomy, and ligate arteries that would result in chemo infusion to stomach or duodenum.

3.            Reduce dose if compromised liver function.

4.            Ulcer-like pain or gastic symptoms are indications to STOP therapy as hemorrhage or perforation may occur.

Toxicty:

Nausea UNCOMMON unless catheter has become dislodged.

Stomatitis, esophagitis, proctitis, diarrhea

Occasional hyperpigmentation over vein used for infusion (if vein)

Sun exposure increases skin rxs.

Rare CNS neurotoxicity

Occasional increased lacrimation

Abdominal cramps if catheter dislodged and stomach/duodenum being infused.

Liver function/jaundice - common when given by artery. Reduce dose next cycle.

Sclerosing cholangitis can happen when given by artery.

(Stop FUDR and infuse HCT or prednisolone).

 

FLUDARABINE (9-B-D arabinofuranosyl 2-fluoroadenine monophosphate)
Purine analogue.

Dephosphorylated in plasma, then enters cell by carrier-mediated transport. Phosphorylated to F-ara-ATP by deoxycytidine kinase. Accumulation inhibits DNA synthesis by interfering with ribonucleotide reductase & DNA polymerase-a.

Use: CLL, low-grade lymphomas, macroglobulinemia CR=38% PR=19% in previously txd pts. Addition of prednisone did not help, but increases risk for opportunistic infxs.

Dose: 25-30 mg/m2 IV/15-30 min QD x 5d. Repeat q 4wks

Precautions:

- Watch and prep for tumor lysis
- Consider alternative if renal insufficiency.

Toxicity:

               Rarely develop ITP and/or AIHA
               Counts, but suppression becomes less common in people who are responding.
               Infection common early on, but less common after 6th course.
               Nausea unusual.
               Occasional mucositis.
               NO alopecia
               Neurotoxicity UNcommon at usual dose. May see somnolence, fatigue, paresthesias, and twitching of extremities. Visual disturbances & other severe symptoms noted at higher-than-recommended doses.

 

FLUOROURACIL (5FU)

Pyrimidine antimetabolite that inhibits thymidylate synthetase.

Ways of giving 5FU:

Lokich - 5FU infusion
Roswell Park - 5FU/LV
Mayo

 

Dose:

Systemic

               500 mg/m2 IV d1-5 q 4wks OR
               450-600 mg/m2 IV weekly
               200-400 mg/m2/d CIV

Intracavitary

               500-1000 mg for pericardial effusion; 2000-3000mg for pleural or peritoneal effusion

Intraarterial (liver):

               800-1200mg/m2 CIV on d1-4, then 600mg/m2 CIV on d5-21

 

Precautions:

               Reduce dose in liver disease
               For intraarterial infusion, add 5000u heparin.
               Same precautions as FUDR.

 

Toxicity:

Counts
Nausea – rare
Stomatitis - early sign of severe toxicity.
Can progress to frank mucositis or hemorrhagic diarrhea.
Hyperpigmentation over vein
Maculopapular rash - UN-common
Sun exposure increases rxs
"Hand-foot" syndrome with painful, red desquamation and fissures of palms and soles--common with cont infusion
Rare CNS toxicity
Occasional increased lacrimation
Cardiac - angina and arrhythmias, especially with infusion

 

FLUTAMIDE (Eulexin)

Antiandrogen that inhibits androgen uptake by tissue and/or by inhibiting nuclear binding of androgen in target tissue, or both.

Contraindicated in pts with known hypersens.

Dose: Two 125mg caps (ie, 250mg) TID

Toxicity:

Hot flashes (60%)
Decreased libido     36
Diarrhea                  12
N/V                        11
Gynecomastia         9
Drowsinwss,confusion 1

 

G: gefitinib, gemcitabine, goserelin, glutamine, Gleevec

 

GEMCITABINE (Gemzar (R))

Nucleoside (deoxycytidine) analogue that targets cells in S phase. Metabolized intracellularly by nucleoside kinases to active di- and triphosphates. Inhibits ribonucleoside reductase; competes with dCTP (deoxycytidine triphosphate) for incorp into DNA. Ie, protects against excision by DNA repair mechanisms. 1/2 life is influenced by infusion.

Warnings: Infusions >1hr or dosing more than weekly increases toxicity.
               Renal or liver disease: Not studied. Use with caution.
               No drug interactions.
               NOT a vessicant.

Dose: 1000 mg/m2 IV/30min weekly x 7, then rest 1 wk, then weekly x 3 every 4 weeks.

Adjustments:

ANC:

500-999 or Platelet 50-99 --> 75%
<500 or Platelet <50 --> Hold

Pts who tolerate 7 or 3 wk cycles with nadirs >1500 / 100 may have dose escalated to 1250 mg/m2, then up to 1500 mg/m2.

Toxicity:

               Hematologic dose-limiting (grans, platelets)
               N/V common          69
               Inc AST                  66
               Fever                      41%
               Edema                    34
               Flu symptoms                         19
               Diarrhea                  19
               Alopecia                 15

Mix: Use as reconstituted (200cc). May dilute in NS.

 

H: Herceptin, hexamethlymelamine, Hydrea, Hycamtin

 

HERCEPTIN (trastuzumab)

Indicated for 2nd line treatment in HER2+ patients.

Dose: 4 mg/kg IV/90 min (loading dose) then 2 mg/kg IV/30 min weekly.

Do NOT mix or administer with dextrose.

May be given with weekly Taxol 80 mg/m2 or Taxotere 35 mg/m2 (6 wks out of 8)

 

HEXAMETHYMELAMINE (Hexalen, HXM, Altretamine)

Unknown mechanism of action. Resembles the alkylator tri-ethylenemelamine, but has some antimetabolite properties.

Use: Ovary

Dose:

200-320 mg/m2 PO QD divided tid-QID x 14-21d q 4wks (when used as single agent)
150-200 mg/m2 po QD divided tid-QID for 2 out of 3-4 wks when used in combination

Toxicity:

Anemia common. Other counts uncommon.
Nausea usually dose-limiting.
Peripheral sensory neuropathies - respond to pyridoxine
CNS (agitation, confusion, hallucinations, depression, Parkinson's-like effects) more common with continuous rather than intermittent administration.
Occasional renal function

 

HYDROXYUREA (Hydrea)

Dose:

800-2000 mg/m2 po QD OR 3200 mg/m2 PO every third day (not for leukemias)

For CML: 40 mg/kg/d until WBC <50K, then reduce by 50%, then adjust to keep WBC between 2-8K.

Precaution: Daily dose must be adjusted for blood counts

Toxicity:

Counts - occurs at doses > 1600 mg/m2/d by day 10. (Prompt recovery.)
Causes hypersegmentation of PMNs.
Nausea common at high doses
May see maculopapular rash
RT-induced Mucositis may be exaggerated

 

I: idarubicin, ifosfamide, IFNa, imatinib, Interleukin2, Iressa, irinotecan

 

IDARUBICIN (IDA)

DNA strand breakage mediated by anthracycline effects on Topo II or free radicals.

Use:

AML
Blast crisis of CML
ALL

Dose:       12-13 mg/m2 IV x 3 d (usually in combo with Ara-C) during induction. 10-12 mg/m2 IV QD for consolidation.

Toxicity:

Counts
Nausea
Alopecia
Liver dysfunction common, but usually not severe and not clearly due to Ida
Common renal effect, but not significant
Vessicant
Occasional neuro effects

 

IFOSFAMIDE (Ifex)

Activated by liver microsomal enzymes --> active intermediates that attack nucleophilic sites, especially on DNA.

Use: germ cell, lung, sarcomas

Precautions: Must be used with Mesna. Mesna dose is at least 20% of the ifos dose (on a weight basis) given at 0,4,8 hours after the ifos. If give ifos as an infusion, then mix the mesna in the same bag with dose same as ifos mg for mg. Higher doses of ifos may require higher doses and longer durations of mesna.

Neither mesna nor its only metabolite, mesna disulfide, affect ifos or its antineoplastic mteabolites. Mesna is reduced in the kidney to a free thiol compound which then reacts chemically with urotoxic metabs resulting in their detoxification.

Vigourous hydration is also required with a minimum of 2L of hydration daily. Administer as a slow IV infusion over at least 30 min.

Dose:

1.2 gm/m2 IV/30 min QD x 5d q 3-4 wks. Mesna given as 120 mg/m2 just before ifos, then 1200 mg/m2/d CIV until 16 hrs after Ifos.

3.6 gm/m2 IV/4hrs QD x 2 days. Mesna given as 750 mg/m2 IV at 0,4,8 hrs after start of Ifos.

Higher doses up to 14 gm/m2 have been used experimentally

Toxicity:

Counts
Nausea
Alopecia
Hemorrhagic cystitis.
With mesna, incidence is 5-10%.
Occasional CNS toxicity (somnolence, confusion, psychotic, seizures)
Infertility
Occasional renal impairment

 

INTERFERON-ALPHA (Roferon-IFNa2a, Intron A-IFNa2b)

Directly inhibits tumor cell growth and modulates host immune response, including activation of NK cells, Ab production, and induction of major histocompatibility genes.

Use: hairy cell, CML, AIDS-related Kaposis, melanoma, renal cell, colon. NOT good for myeloma anymore.

Dose: 3-10mu IM/SQ in various schedules.

Toxicity:

Counts-mild to mod, usually transient
Anorexia 50%
Nausea 33%
Vomiting 10%
Occasional stomatitis. May reactivate oral herpes simplex.
Alopecia-mild
Flu-like symptoms.
Usually controlled with Tylenol
Neuro: occasional paresthesias, ability to concentrate, confusion, rare seizures
Increased LFTs, mild proteinuria common, occasional hypercalcemia

 

INTERLEUKIN-2 (IL-2, Proleukin)

Enhances mitogenesis of T cells, NK cells, and LAK-cells. Augments cytotoxicity of NK and LAK cells; induces IFN-g

Use: renal cell, melanoma

Dose: (1mg = 3million CETUS units)

1.            0.33 mg/m2 SQ 5d/wk x 12 wks

2.            Induce: 2 mg/m2 IVB (over 3-5 min) TIW x 4 wks. Rest 2 wks.

               Maintenance: 1 mg/m2 IVB TIW x 2 wks q4wks (ie, 2 on/2 off)

3. 1 mg/m2 IVB QD x 5 for 2wks

4. 3 mg/m2 CIV over 24h weekly x 6 wks (should do as in-pt)

Premed::

- Tylenol 650-1000mg po 1h prior to treatment and q3h x 2 doses
- Indocin 25-50mg prior
- Demerol 25-50mg IV when chills start after first dose. For subsequent doses, Demerol 150mg po 1.5h before chills are predicted to start (based on first treatment)
- Benadryl 50 mg po q3h x 3 doses may be substituted for demerol

Precautions: With higher doses, capillary leak --> hypotension, pulm edema, MI, arrhythmia, azotemia, and altered mental status may occur. May require ICU/intubation.

Toxicity:

Anemia occasional.
Nausea common
Pruritic rash common
CV: arrhythmia-common, dose-related
Hypotension:dose-related usually
MI at higher dose
Cap leak
Wt gain from edema
GI: Anorexia common, Occasional diarrhea, Common but transient LFTs/ albumin, Rare colonic perf
CNS:Common mental status change
Common dizziness
Occasional visual disturb
Uncommon seizures
Renal imapirment-common but reversible
Fever: with/without chills-universal
Occasional bact infection due to induced chemotactic defect in PMNs
Myalgias/arthralgias
Malaise/fatigue-common

 

IRINOTECAN (CPT-11, Camptosar)

Inhibits Topoisomerase I supercoiling & breakage of DNA. Metabolized to 7-ehtyl-10-hydroxycamptothecin (SN-38) which is 40-200 x as potent as CPT-11. Has triphasic elimination pattern with an elimination half-life of 16-18h. SN-38 has elimination half-life of 7-14h.

Dose: 125 mg/m2 IV/90 min weekly x 4, repeated q 6wks. Other dose schedules include:

100 mg/m2 IV/90min qwk x 3. Repeat q 4wk
125-150 mg/m2/wk x 4 wks. Repeat q 6wk
150 mg/m2 every other week
200-240 mg/m2 q 3-4 wks
40 mg/m2/d x 5d q 4wks
20 mg/m2/dose BID x 7d q 4wks
40 mg/m2/d x 3d weekly
30 mg/m2/d CIV x 5d q 4wk

Admin:    Mix 500cc D5W or NS and infuse over 60-90 min

Toxicity:

N/V

Early-onset Diarrhea (usually within 24hrs). Cholinergic. Treat with 0.25-1mg atropine

Late-onset diarrhea - Usually ~10 days later. At first sign of diarrhea, begin loperamide 4 mg then 2mg q2h until diarrhea free for 12hrs. (This dose exceeds usually recommended doses)

Neutropenia

 

L: L-asparaginase, Lupron (leuprolide), Leucovorin

 

L-ASPARAGINASE (Elspar)

From E. coli. Malignant cells depend upon exogenous asparagine, while normal cells can more rapidly synthesize it when depleted by the enzyme.

Use: ALL

Contra: Hx of pancreatitis (acute hemorrhagic pancreatitis reported in a few cases following administration) or hx of anaphylactic rx to the drug.

Toxicity:

Anaphylaxis
Pancreatitis
Hypofibrinogenemia & DIC
CNS: Somnolence, depression, fatigue, confusion, etc
Azotemia rare
Transient BM depression

Dose: usually 6000u /m2 IV or SQ

Usual mix is 10,000u in 5cc.

If injecting >2cc, may need to use more than 1 site.

Skin test: Do before first dose or if >7d since last administration. To test: dilute to 20u/ml and inject 0.1cc (2u) intradermally. If no reaction within 1hr, OK to proceed. [Neg skin test does not guarantee won't react]

Suppl: 10cc vial of 10,000u.

 

LEUPROLIDE (Lupron) GOSERELIN (Zoladex)

Stimulates release of LH and FSH from ant pit followed by of gonadotropin release due to sensitivity to GnRH. May also have direct effect on cancer cells, at least in breast ca in which GnRH bind-ing sites have been demon-strated.

Dose:

Lupron 1 mg (0.2 ml) SQ QD
Lupron 7.5 mg IM monthly
Lupron ? mg IM q 3 months

Goserelin 3.6 mg SQ monthly

Precaution: can lead to initial flare of symptoms first few wks

Toxicity:

Occasional nausea
Rx at inj site
Occasional CHF, edema
Hot flashes common
Decreased libido common
Gynecomastia uncommon
Impotence uncommon

 

LEUCOVORIN RESCUE
(Following from PDR)

Start LV 15 mg po q6h x 8 doses.
Obtain MTX level at 24 and 48 hrs. and adjust as follows:

NORMAL MTX ELIMINATION:

24 hr level <= 10 micromolar
48 hr level <= 1 micromolar
72 hr level <= 0.2 mM

LV dose: 15 mg po/IM/IV q6h for 60 hours (10 doses starting 24 hr after START of MTX infusion)

DELAYED EARLY MTX ELIMINATION AND/OR ACUTE RENAL INJURY:

24 hr level >= 50 mM
48 hr level >= 5 mM OR

100% or greater increase in serum creatinine level at 24 hrs after MTX given (eg, increase from 0.5 mg/dl to 1 mg/dl or more)

LV Dose: 150 mg IVq 3hrs until MTX level is < 1 mM, then 15 mg IV q 3 hrs until MTX level < 0.05 mM

DELAYED LATE MTX ELIMINATION:

72 hr level > 0.2 mM
96 hr level > 0.05 mM

LV dose: continue 15 mg po/IM/IV until MTX level < 0.05 mM.

 

M: 6-MP (mercaptopurine), mechlorethamine (mustard), melphalan, Mesna, methotrexate, mitomycin, mitotane, mitoxantrone

 

6-MP (MERCAPTOPURINE )

Purine metabolite that, when converted to nucleotide, inhibits the formation of nucleotides necessary for DNA and RNA synthesis.

Use: ALL, juvenile CML

Dose: 100 mg/m2 PO QD if alone.
50-90 mg/m2 po QD if with MTX

Precautions: Reduce by 75% when used concurrently with allopurinol. Increase interval between doses or decrease dose in pts with renal failure

Toxicity: Counts, but mild at recommended doses. Stomatitis, rash uncommon. Intrahepatic cholestasis/mild focal centrilobular necrosis with jaundice -uncommon. Tumor lysis

 

MECHLORETHAMINE (Mustargen, HN2, Nitrogen mustard)

Prototype alkylator. Txfers alkyl group to amino, car-boxyl, hydroxl, imidazole, PO4, and sulfhydryl groups within the cell, altering structure & funct of DNA, RNA, and proteins.

Use: HD, malignant effusions

Dose:

6 mg/m2 d1,8 q 4 wks (in MOPP)
8-16 mg/m2 by intra-cavitary injection

Precautions: Vessicant - wear glasses/gloves to mix/give. If eye contact, flush with NS & get ophthal consult. If skin, flush with tap water at least 15 min, than 2.6% Na thiosulfate solution (1/6 M) Should be used within 30 min of mixing and should not be mixed with anything else.

Toxicity:

Counts
Nausea universal.
Starts 3h, lasts 4-8h
Vessicant-instill Na thiosulfate into area to neutalize drug, and ice packs for 6-12h
Phlebitis / thrombosis
Amenorrhea & azoospermia common
Tumor lysis

 

MELPHALAN (Alkeran, L-PAM, L-sarcolysin, Phenyalanine mustard)

Alkylator

Myeloma, breast, ovary

Dose:

8 mg/m2 PO d1-4 q 4wks OR
10 mg/m2 PO d1-4 q 6 wks OR
3-4 mg/m2 PO QD x 2-3 wks, then 1-2 mg/m2 PO QD maintenance

Precaution: delayed myelosuppression

Toxicity:

Counts: nadir at 14-21d
Rare pulm fibrosis

Supplied: 2mg tabs

 

MESNA

Dose same for Ifos or CTX: 20% of chemo dose at 0,4,8 hrs.

First dose should be given IV. 2nd and 3rd doses may be given orally, but double dose due to poor absorption. For IV, mix 1:1. For oral, mix 1:10 concentration. May give with carbonated beverage, juice, or milk to disguise sulphur odor.

If pt vomits within 1 hr, repeat dose IV.

 

METHOTREXATE (MTX, Mexate, Amethopterin)

Inhibits dihydrofolate reductase --> FH2 to FH4 --> formation of thymidylate and purines --> DNA production

Use: breast, H/N, GI, lung, gestational trophoblastic ca, osteosarcoma, ALL, meningeal carcinomatosis

Methotrexate Levels should be:

< 5 uMOL/L at 24 hrs
< 0.5 uMOL/L at 48 hrs
< 0.05 uMOL/L at 72 hours

Give Leucovorin 100 mg IV/po q6h until methotrexate level is < 0.05 uMOL/L.

Dose:

1. Gestational trophoblastic ca 15-30 mg PO/IM on d1-5 q 2weeks
2. Other Ca 40-80 mg/m2 IV/PO 2-4 x per mon with 7-14d interval between doses
3. ALL 15-20 mg/m2 PO/IV weekly (with 6-MP)
4. Osteogenic sarcoma up to 10 gm/m2 with leucovorin rescue
5. Intrathecal 12 mg/m2 (up to 20 mg) BIW (See Neoplastic Meningitis)

Precautions:

1. Doses > 80 mg/m2 are experimental-do only where MTX levels can be measured.
2. Avoid aspirin, sulfonamides, TCN, phenytoin, and other protein-bound drugs that may displace MTX -> increased free drug.
3. MTX can potentiate coumadin.
4. Reduce dose or d/c if renal failure.

Toxicity:

Counts
Occasional nausea
Stomatitis - sign that max tolerated dose reached
Alopecia mild
Acute liver damage uncommon at standard dose
Rare liver fibrosis, pneumonitis, polyserositis, ATN
Rare seizures and Guillan-Barre-like syndrome after IT treatment.

 

MITOMYCIN
Alkylator

Use: Bladder (intravesical), GI

Dose:

20 mg/m2 IV d1 q4-6 wks
2 mg/m2 IV d1-5 & d8-12 q4-6 wks
10 mg/m2 IV d1 q 8wks in comb with 5FU and DOX
30-40 mg into bladder weekly x 4-8 wks, then monthly x 6

Precautions: Give slow IV or rapid infusion thru running IV

Toxicity:

Delayed myelosuppression. Nadir at 4 wks, but may be later. Recovery is prolonged over wks, and occasional may not occur.

Nausea at higher doses
Stomatitis in 4%
Alopecia
Cellulitis at injection site if extravasates
Renal - UNcommon (2%)
Pulmonary - uncommon, but may be severe. Causes xray changes and can ARDS type picture.

*Hemolytic uremic syndrome (TTP)
CHF in pts previously txd with DOX.

If have to lower dose, do not repeat until WBC >4 and platelet >100. If cancer progresses after 2 courses, stop because not likely to respond.

 

MITOTANE (Lysodren)

Suppresses adrenal steroid production, modifies peripheral steroid metabolism, and is cytotoxic to adrenal cortical cells.

Use: Adrenal cortical ca

Dose: Begin with 2-6 gm PO daily divided TID-QID. Build to max tolerated daily dose that is usually 8-10 gm, but may range from 2-16 gm.

Precautions: Must replace glucocorticoids and mineralocorticoids during therapy. (HCT acetate 25/12.5 and fludrocortisone acetate 0.1 mg po QD). Pts who experience trauma, shock, infection, should be covered with supplemental steroids. Because of effect on peripheral steroid metabolism, may require higher doses than usually.

Toxicity:

NO myelosuppression
Nausea common - may limit dose
Occasional skin rash
CNS (up to 40%): lethargy, sedation, vertigo, dizziness
Uncommon miscellaneous: Albuminuria, hemorrhagic cystitis, HBP, orthostatic hypotension, visual disturb

 

MITOXANTRONE (Novantrone®, DHAD, dihydroxyanthracenedione)

Mechanism: Causes DNA breaks through effects on Topo II

Dose:

12-14 mg/m2 IV/5-30 min q 3wks for solid tumors

12 mg/m2 IV/5-30 min QD x 3 for AML

For Multiple Sclerosis: 12 mg/m2 q 3 months for up to 2 years (Lancet 12/21/02 p. 1825)

Precaution: Can be a vesicant. Probably less cardiotoxic than DOX, but prior anthracycline therapy, chest RT, or underlying cardiac disease may increase risk.

Toxicity:

Counts

Nausea less than doxorubicin

Alopecia

Cardiac - risk increased at cum doses >125 mg/m2

Blue coloring of skin if extravasates. Rarely --> skin damage

Green/blue urine

 

MONOCLONAL ANTIBODIES

RITUXAN (rituximab) -- targets CD20

BEXXAR (tositumomab) -- Iodine131. 30% incidence of HAMA, however.

LYMPHOCIDE (epituzimab) -- targets CD22. Activity similar to rituximab.

 

N: Novantrone, navelbine, Neumega

 

NAVELBINE (vinorelbine tartrate)

Use In Non-Small Cell Lung ca

Dose:
30 mg/m2 weekly

When used with CDDP, use same dose for NVB.

Toxicity:

Neutropenia : dose limiting: not cumulative: nadir 7-10 days..recovery 7-14 days
Anemia: gr 3/4 < 10%
Thrombocytopenia: < 1%
Neurologic: mod peripheral neuropathy: constipation
Alopecia 10%
GI: mild to mod n/v ~ 40% : routine use of antiemetics not necessary: stomatitis ~ < 20%

Administration:

Moderate Vesicant
Give if granulocyte > 1500/MM3
Dilute In At Least 100ml Nss Or D5w Infuse Over 10 Min And Flush With Additional 100 Ml

Suppl: 10 & 50mg vials

              

NEUMEGA (Oprelvekin)

IL-11: directly stimulates stem cells & mega pro-genitors increased platelet production.

Comes in single-use 5mg vials.

Dose: 50 mcg/kg QD. Continue until post-nadir platelet count >=50,000. Stop at least 2 days prior to next chemo cycle.

Adverse: Edema, tachycardia, palpitations, thrush, dyspnea, pleural effusions, conjunctival injection.

 

O: Octreotide, oxalaplatin

 

OCTREOTIDE (Sandostatin)
NEJM 334:246, 1/96

An analogue of somatostatin. Inhibits the release of growth hormone, insulin, and glucagon. 1/2 life after SQ administration is 2hrs.

Uses: acromegaly, pituitary adenomas, pancreatic islet-cell tumors, carcinoid, AIDS-related diarrhea, pancreatic fistulas.

GI actions:

liver blood flow
inhibits GB contractility and blood flow
inhibits GI and pancreatic peptide hormone secretion
decreases gastric acid & pepsin secretion
decreases pancreatic exocrine secretion
decreases GI transit time
decreases absorption of glucose & amino acids
stimulates H2O and electrolyte absorption in small bowel
inhibits tissue growth and proliferation in rectum
Glucose can either go up or down as drug alters balance between glucagon & insulin

Dose: 100-450mcg SQ QD, divided BID-TID. For severe symptoms, start high and titrate down. Typical: 150 mcg SQ TID. Can start 50-100 mcg BID and work up. t1/2 ~ 2hrs

Supplied: 50mcg/ml, 100,       500

90% RR in pts with carcinoid syndrome. May be life saving in carcinoid crisis by reversing hypotension.

Adverse:

Common (usually subside within 2 wks): Nausea, GI cramps, Diarrhea, Fat malabsorption, Flatulence. Inhibition of insulin secretion might --> glc tolerance can --> high glucose, but also delays absorption of CHOs and inhibits secretion of GH and glucagon, so its a wash.

Tx > 1 month --> Incr chol gallstones.

 

OXALAPLATIN (Eloxatin®, L-OHP, Diaminocyclohexane Oxalatoplatinum)

PHARMACOLOGIC CATEGORY Antineoplastic Agent, Alkylating Agent

USE — Treatment of metastatic colon or rectal carcinoma, in combination with fluorouracil (5-FU) and leucovorin, in patients whose disease has recurred or progressed during or within 6 months of completing therapy with 5-FU/leucovorin and irinotecan

CONTRAINDICATIONS — Hypersensitivity to oxaliplatin, other platinum-containing compounds, or any component of the formulation; pregnancy

WARNINGS / PRECAUTIONS — The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. Anaphylactic-like reaction may occur within minutes of oxaliplatin administration. Two different types of neuropathy may occur: 1) Acute (within first 2 days), reversible (resolves within 14 days), primarily peripheral symptoms that are often exacerbated by cold; and 2) a more persistent (>14 days) presentation that often interferes with daily activities (eg, writing, buttoning, swallowing), these symptoms may improve upon discontinuing treatment. May cause pulmonary fibrosis. Caution in renal dysfunction. Safety and efficacy in pediatric patients have not been established.

ADVERSE REACTIONS — Based on clinical trial data using oxaliplatin alone. Some adverse effects may be increased when therapy is combined with 5-FU/leucovorin.

>10%: Central nervous system: Fatigue (61%), fever (25%), pain (14%), headache (13%), insomnia (11%) Gastrointestinal: Nausea (64%), diarrhea (46%), vomiting (37%), abdominal pain (31%), constipation (31%), anorexia (20%), stomatitis (14%) Hematologic: Anemia (64%), thrombocytopenia (30%), leukopenia (13%) Hepatic: SGOT increased (54%), SGPT increased (36%); total bilirubin increased (13%) Neuromuscular & skeletal: Neuropathy, peripheral (acute 65%, persistent 43%), back pain (11%) Respiratory: Dyspnea (13%), coughing (11%)

1% to 10%: Cardiovascular: Edema (10%), chest pain (5%), flushing (3%), thromboembolism (2%) Central nervous system: Rigors (9%), dizziness (7%), hand-foot syndrome (1%) Dermatologic: Rash (5%), alopecia (3%) Endocrine & metabolic: Dehydration (5%), hypokalemia (3%) Gastrointestinal: Dyspepsia (7%), taste perversion (5%), flatulence (3%), mucositis (2%), gastroesophageal reflux (1%) Genitourinary: Dysuria (1%) Hematologic: Neutropenia (7%) Local: Injection site reaction (9%) Neuromuscular & skeletal: Arthralgia (7%) Ocular: Abnormal lacrimation (1%) Renal: Serum creatinine increased (10%) Respiratory: URI (7%), rhinitis (6%), epistaxis (2%), pharyngitis (2%) Miscellaneous: Allergic reactions (3%), hiccup (2%)

Postmarketing and/or case reports: Anaphylactic shock, angioedema, cranial nerve palsies, deep tendon reflex loss, deafness, decreased visual acuity, dysarthria, fasciculations, hemolytic uremia syndrome, ileus, immuno-allergic thrombocytopenia, interstitial lung diseases, intestinal obstruction, Lhermittes' sign, metabolic acidosis, optic neuritis, pancreatitis, pulmonary fibrosis, visual field disturbance

OVERDOSAGE / TOXICOLOGY — Overdose symptoms are extensions of known side effects (eg, thrombocytopenia, myelosuppression, nausea, vomiting, neurotoxicity, respiratory symptoms). Treatment should be supportive.

DRUG INTERACTIONS Docetaxel, paclitaxel (taxane derivatives): When administered as sequential infusions, taxane derivatives should be administered before platinum derivatives to limit myelosuppression and to enhance efficacy.

Nephrotoxic drugs: Aminoglycosides may increase risk of toxicity.

STABILITY — Store lyophilized powder at room temperature of 25ºC (77ºF) and under normal lighting; excursions permitted to 15ºC to 30ºC (59ºF to 86ºF). Reconstituted solution may be stored up to 24 hours under refrigeration at 2ºC to 8ºC (36ºF to 46ºF). Diluted solution is stable up to 6 hours at room temperature of 20ºC to 25ºC (68ºF to 77ºF) or up to 24 hours under refrigeration at 2ºC to 8ºC (36ºF to 46ºF).

Do not reconstitute using a chloride-containing solution (eg, NaCl). Reconstitute with water for injection USP or D5W (10 mL for 50 mg vial, 20 mL for 100 mg vial). Further dilution with D5W (250 or 500 mL) is required prior to administration. Incompatible with alkaline solutions (eg, 5-FU) and chloride-containing solutions. Flush infusion line with D5W prior to, and following, administration of concomitant medications via same I.V. line.

COMPATIBILITY — Incompatible with alkaline solutions (eg, 5-FU) and chloride-containing solutions. Flush infusion line with D5W prior to, and following, administration of concomitant medications via same I.V. line.

MECHANISM OF ACTION — Oxaliplatin is an alkylating agent. Following intracellular hydrolysis of the "leaving group," the platinum compound binds to DNA, RNA, or proteins. Oxaliplatin is thought to be noncross-resistant with cisplatin and carboplatin on the basis of lack of recognition of oxaliplatin/DNA adducts by DNA repair systems.

PHARMACODYNAMICS / KINETICS Distribution: 400 L

Protein binding: >90% primarily albumin and gamma globulin (irreversible binding to platinum)

Metabolism: Nonenzymatic (rapid and extensive), forms active and inactive derivatives

Half-life elimination: 391 hours; Distribution: 0.4-16.8 hours

Excretion: Primarily urine

DOSAGE — I.V.: Dosed in combination with 5-FU/leucovorin on Day 1 of a 2-day treatment protocol that is repeated on a 2-week cycle; premedication with antiemetics is recommended.

Adults: Day 1: 85 mg/m2 oxaliplatin infused over 2 hours (administered simultaneously with leucovorin via a Y-line), followed by a 5-FU bolus and 22-hour infusion of 5-FU Day 2: Leucovorin and 5-FU administered as on Day 1.

Elderly: No dosing adjustment recommended

Dosage adjustment for toxicity: Prolongation of oxaliplatin infusion time from 2 hours to 6 hours may reduce some acute toxicities. Persistent grade 2 neuropathy: Consider reducing dose to 65 mg/m2 Persistent grade 3 neuropathy: Consider discontinuing therapy Patients recovering from grade 3/4 gastrointestinal or hematologic toxicity: Consider reduced dose (65 mg/m2)

Dosage adjustment in renal impairment: Use with caution; specific guidelines not established

ADMINISTRATION — Administer as a diluted solution (in D5W) over 2 hours.

MONITORING PARAMETERS — CBC, serum creatinine, liver function tests; signs of neuropathy, hypersensitivity, and/or respiratory effects

NURSING IMPLICATIONS — Consider premedication with antiemetics. Monitor for signs and symptoms of anaphylaxis.

DOSAGE FORMS — Injection, powder for reconstitution: 50 mg, 100 mg

 

P: paclitaxel, pemetrexed, procarbazine

 

PROCARBAZINE (Matulane)

Appears to affect preformed DNA,RNA, & protein.

Dose: 100 mg/m2 QD x 7-14 d q 4 wks (in combo with other drugs)

Suppl: 50mg caps

Precautions: Many food/drug interactions:

Ethanol --> Disulfiram-like rxs (nausea, visual disturbances, headache)

Sympathomimetcs --> HBP crisis, tremors, excitation, angina,

Tricyclics --> palpitations

Tyramine-rich foods

CNS depressants Additive depression

Toxicity:

Counts
Nausea first few days until tolerance develops
Stomatitis, alopecia, itching – uncommon
CNS: paresthesias, neuropathies, HA, dizziness, anxiety, insomnia, nightmares, hallucinations, ataxia, confusion, seizures, and coma reported with varying frequency.

 

R: Rituxan

 

RITUXIMAB

MoAb to CD20 used in Follic small cleaved NHLs

Dose: 375mg/m2 per week x 4.

Adverse: Fever, chills, flu - usually within minutes of starting.

Admin: Premed with Benadryl+Tylenol

- Start at 50 mg/hr. Increase rate by 50 mg/hr every 30min to max of 400 mg/hr.

- If rx occurs, stop infusion until rx over, then resume at last rate that didnt have problem. Rxs nearly always occur only during first infusion.

- On 2nd and other infusions, start at 50 and increase by 100 mg/hr up to 400 mg/hr.

 

S: Sandostatin, streptozocin, STI-571

 

STREPTOZOCIN (streptozotocin, Zanosar)

Modified nitrosourea

May interfere with pyridine nucleotide syn. Appears to have some specificity for neoplastic pancreatic endocrine cells. Glucose moiety attached to nitrosourea appears to myelotoxicity.

Use: pancreatic islet cell, carcinoid

Dose: 1-1.5 gm/m2 IV weekly x 6, then 4 wks obs

500 mg/m2 IV d1-5 q 6wks

Precaution: Infuse over 30-60 min to pain at IV site

Avoid extravasation
Have D50W on hand

Toxicity:

Nausea - common/severe. May get worse over 5 day course.

Renal - common. Not clearly dose-related, but may limit continued use in certain pts. D/C treatment if develop severe proteinuria, glucosuria, azotemia, hypo-phosphatemia.

Hydration may help ameliorate problem.

Hypoglycemia in pts with insulinoma (due to sudden release of insulin)

Hyperglycemia uncommon in normal pts or diabetics bec normal beta cells are insensitive to drug's effects.

Occasional transient, mild liver toxicity

 

T: thioguanine, traustuzamab, tamoxifen, targretin, Taxol, Taxotere, temozolomide (Temodar), teniposide, Thiotepa, topotecan, tretinoin

 

6-TG (THIOGUANINE)

Purine metabolite that is converted to active nucleotide --> substitutes for guanine in DNA synthesis. Also inhibits purine synthesis and conversion reactions.

Use: AML

Dose:

Induction: 100 mg/m2 PO BID x 8-21d

Maintenance: 40 mg/m2 PO QD d1-4 weekly OR 100 mg/m2 PO BID d 1-4 q 3-4 wks

Precautions: None (NO dose reduction needed if given with allopurinol)

Toxicity: Counts. Occasional nausea. Stomatitis/diarrhea - uncommon. Rare liver toxicity

 

TAMOXIFEN (Nolvadex)

Binds to estrogen receptors. This complex transported to nucleus where it affects nucleic acid function. Also affects cellular growth factors, epidermal GFs, and TGFs (a & B).

Use: breast, endometrial

Dose: 10mg BID

Precaution: can see increased Ca++ during initial treatment (?)

Toxicity:

Nausea in 20% early in treatment. Resolves as treatment continues.
Skin rash
Vulvar itching
Dyspareunia
Hot flashes
Vag bleeding uncommon
Peripheral edema occasional
Occasional flare in bone pain - can signal either good reponse or disease progression
Occasional diarrhea
osteoporosis
chol
Rare thrombosis

 

TARGRETIN (bexarotene)

An oral retinoid that is indicated for Cutaneous T-cell lymphoma (CTCL).

 

TAXOL (paclitaxel)  (see Abraxane)

Enhances formation & stabilization of microtubules--> mitotic arrest

Dose: 135-200 mg/m2 IV/3-96h

Precautions: Anaphylactic rxs with dyspnea, hypotension, bronchospasm, urticaria, and erythematous rashes may occur as result of drug itself or cremophor vehicle required to make drug water soluble. Pre-med with steroids, antihistamines. Must be filtered with 0.2 micron in-line filter.

When given in combination with CDDP, must give Taxol first to reduce toxicity.

Dose adjustment in Hepatic Impairment:

TB <= 1.5 and AST > 2x normal: total dose < 135 mg/m2
TB 1.6-3.0 : Dose <= 75 mg/m2
TB > 3.1 : Dose <= 50 mg/m2

Toxicity:

Leukopenia universal. Ptls common
Nausea common but not severe
Alopecia universal
Occasional mucositis
Hypersens rx (see above)
Sensory neuropathy (30-35%) at > 310 mg/m2
Myalgias/arthralgias (25%)
Rare seizures

Mix: 500cc. Must use special tubing and filter.

 

TEMOZOLOMIDE (Temodar)

Start 150 mg/m2/d x 5d. (See below for use with RT for brain metastases.)

Ck ANC and platelets day 22 and day 29 (day 1 of next cycle)

Based on lowest count either day:

ANC < 1 or platelets < 50: Hold until ANC > 1.5 and platelets > 100, and reduce dose by 50 mg/m2/d for next cycles
ANC 1-1.5 and platelets 50-100: Hold treatment until counts ok, but maintain dose.
ANC > 1.5 AND platelets > 100: Increase dose to or maintain at 200 mg/m2/d x 5 days.

When given with brain RT:

Give 75 mg/m2/day during RT up to 4 weeks, then 200 mg/m2/day x 5 days every 4 weeks. (JCO 20:3644, Sep 1, 2002). Versus RT alone, there was a better RR and recovery of neurological function.

 

TAXOTERE (Docetaxel)

 

TENIPSODE (VM-26, Vumon)

Topo II mediated double strand breaks. Causes cell cycle transit delay thru S phase and arrest at late S/G2.

Use: Refractory ALL, lymphoma, neuroblastoma, brain tumors

Dose:       50 mg/m2 in 50-100 NS IV/30min QD x 5

                160 mg/m2 in 250 NS IV/1h d1,3,5. Repeat q 3 wks

Precautions: Hypersens rxs usually resolve with interruption of in-fusion and can often be pre-vented with benadryl/HCT pretx. Hypotension alleviated by pro-longing infusion time. Possible vessicant.

Toxicity:

Counts
Occasional nausea
Alopecia
Occasional increased LFTs
Occasional hypersens rx with hives/flushing
Anaphylaxis uncommon
BP if infused too fast

 

THIOTEPA (Triethylenethiophosphoramide)

Alkylator similar to mustard

Use: superficial bladder, malignant effusions, breast, ovary, carcinomatous meningitis

Dose: 12 mg/m2 IVB q 3wks in comb with VBL+DOX for breast

30-60 mg in 40-50 cc H2O into bladder & retained 1hr. Repeat weekly for 3-6 wks, then q 3wks x 5 cycles.

25-30 mg/m2 in 50-100 NS as single intracavitary infusion.

Can also give intrathecal 12-15 mg BIW.

May repeat as tolerated by blood counts.

Toxicity:

Counts - nadir 2 wks; recovery by 4 wks
Dec counts may follow intracavirary/intravesicle chemo
Amenorrhrea/azoospermia

 

TOPOTECAN (Hycamtin)

Approved for SCLC, colon. A semisynthetic of alkaloid hydroxycamptothecin. A specific inhibitor of topoisomerase 1; results in lethal DNA damage during DNA replication.

Dose: 1.5mg/m2/d for 5 days q3wk

               dissolve in 150ml NS or

               conc. of 10mcg/ml-over 30 min.

Toxicity: neutro-,thrombo-,anemia, N/V, diarrhea, mucositis, alopecia, fever, flu, rash

 

TRETINOIN (VESANOID (R)) - ATRA

Indication: APL

Contra: Known hypersensitivity to retinoids or parabens (preservative)

Dose: 45 mg/m2/d divided BID. Treat for 30 days after CR or for 90 days, whichever comes first.

Supplied: 10mg caps.

WARNINGS:

RA-APL SYNDROME - Occurs in 25%. Fever/wt gain/pulmonary infiltrates on CXR/pleural or pericardial effusions. May occur with or without leukocytosis. Usually occurs during first month of treatment and has occurred after first dose! At first suggestion of syndrome, start dexamethasone 10mg IV q12h x 3d or until resolution of symptoms. Most pts do not require termination of ATRA during treatment of the syndrome.

RAPIDLY EVOLVING LEUKOCYTOSIS - During treatment 40% of pts will develop rapidly evolving leukocytosis. Pts who present with WBC > 5x10-9/L have an increased risk of higher WBC--> risk of life-threatening complications. Some docs routinely add full dose chemo to ATRA if present with high WBC or if begin to develop. Indication to this: Present with WBC > 5; present lower, but rises to >6 by day 5; or >10 by day 10; or >15 by day 28.

TERATOGENIC - known teratogen. BE SURE YOUNG WOMAN IS NOT PREGNANT! Needs 2 forms of contraception during therapy and for 1 month following.

Adverse Reactions:

Headche 86%
Ocular disorders 17%
Fever          83
Alopecia       14
Dry skin       77
Skin changes   14
Bone pain      77
Changed visual acuity 6
N/V            57
Bone inflammation 3
Rash           54
Vis field defects  3
Mucositis      26
Malaise 66
Pruritis       20
Shivering      63
Sweating       20
DIC            26
Vision dist    17
Renal insuff   11

Tretinoin is >95% bound in plasma. Cleared by liver and kidneys. Altered by CytoP450, but no known drug interactions that are clinically impt, altho theoretically possible.

 

V: vinblastine (Velban), vincristine

 

VINBLASTINE (VLB, Velban)

Mitotic inhibition with reversi-ble metaphase arrest due to action on microtubular and spindle contractile proteins.

Use:        Testicular, gestational trophoblastic, kidney, breast, lymphomas

Dose:

4-18 mg/m2 IV Weekly
6 mg/m2 d1,15 (as part of ABVD)
4.5 mg/m2 IV d1 q 3wk with DOX & thiotepa for breast

Precautions: Give as slow push; avoid extravasation.

Toxicity:

Counts (not too bad on platelets)
Mild-mod nausea
Extravasation may --> tissue damage. Infiltrate with 1-6 ml of hyaluronidase (150u/ml).
Mild alopecia
Stomatitis-occasional severe
Neurotoxicity: Constipation, Parasthesias, peripheral neuropathy, jaw pain, (Neurotox less freq than VCR)
Transient hepatitis – uncommon
Depression, headache, seizures, orthostatic BP – rare

 

VINCRISTINE (VCR, Oncovin)

Same mechanism as VLB.

Dose: 1-2 mg/m2 (max 2.0-2.4 mg) IV weekly

Pharm: Liver excretion. In liver disease, isn't excreted --> severe toxicity.

Precautions:

Avoid extravasation
Cumulative neurotoxicity-do neuro exam before each dose if significant liver disease
Stool softeners good idea

Toxicity:

Counts - mild and rarely significant
Nausea NOT a problem unless paralytic ileus
Alopecia
Extravasation --> local damage
Dose-dependent and dose-limiting neurotox: parasthesias, DTRs, Peripheral neuro, Ileus, constipation
Uric acid <-- tumor lysis
SIADH (rare)
Jaw pain (uncommon)

 

X: Xeloda

Z: Zinecard, Zanosar

 

ZINECARD (dexrazoxane)

Cardioprotectant for use with doxorubicin. May work by interfering with Fe-mediated free radical generation thought, in part, to be responsible for anthracycline-induced cardiomyopathy.

Indicated in pts with breast ca who have reached cumulative dose of 300 mg/m2 of dox.

Dose: 10x doxorubicin dose (eg, 500mg/m2 for 50mg/m2 dox). Should be given slow IVB 30 min prior to dox.

Toxicity: Adverse effects seen were probably due to FAC except for pain on injection.

 

 

DRUGS THAT CAUSE ABNORMAL CLOTTING

TTP

MitoC
Bleo
Cisplat
Cyclosporine

Lower fibrinogen:

DIC
Liver disease
Congenital
L-asp

 

EMETOGENIC POTENTIAL OF CHEMOTHERAPY AGENTS (PRN)

Acute Risk, Delayed Emesis

MINIMAL (< 10% risk. Use prn antiemetics only)

Asparaginase
Interferon
Chlorambucil
Leuprolide
Cladribine
Paclitaxel
Oral CTX
Pegasparaginase
Floxuridine
Vinblastine
5FU < 1000mg/m2
Vincristine
Goserelin
Vinorelbine

LOW (10-30% risk. Use Decadron 10-20 mg po/iv)

Bleomycin
Hydrea (1000-6000 mg/m2)
AraC < 20 mg/m2
MTX < 250 mg/m2
DOX < 20 mg/m2
Mitomycin
5FU >= 1000 mg/m2
Mitoxantrone 10-14 mg/m2
Taxotere 60-100 mg/m2
Gemcitabine 1000 mg/m2
Irinotecan 125 mg/m2
Topotecan 1.5 mg/m2

MILD (30-60% risk. Use Zofran 16mg + Decadron 10-20mg)

Aldesleukin
DOX 20-45mg/m2
Altretamine
Etoposide
CBDCA <300mg/m2
Ifos < 1200mg/m2
CTX 750 mg/m2
MTX 250-1000mg/m2
AraC 20-250mg/m2
Mitotane

MODERATE (60-90% risk. Use Kytril 1mg IV or 2mg po + Decadron 10-20mg)

CBDCA 300-1000mg/m2
DOX > 45mg/m2
Carmustine <200mg/m2
Idarubicin
CDDP <70 mg/m2
Ifos 1200-3000mg/m2
CTX 750-1000 mg/m2
Lomustine <60mg/m2
AraC 250-1000mg/m2
MTX > 1000mg/m2
Dacarbazine<500mg/m2
Pentostatin
DNR >75mg/m2
Procarbazinie 100mg/m2

HIGH (>90% risk. Use Kytril 1mg IV or 2mg po + Decadron 10-20mg)

CBDCA > 1000mg/m2
Dactinomycin
Carmustine>200mg/m2
Ifos > 3gm/m2
CDDP > 70mg/m2
Lomustine >60 mg/m2
CTX >1000mg/m2
Mechlorethamine
AraC >1000mg/m2
Melphalan >140mg/m2
Dacarbazine>500mg/m2
Streptozocin

COMBINATIONS:

A combination of two drugs equals one step above highest single agent. Example: Low + Mild = Moderate. Combining three raises potential to 2 classes: Example: Mild + Mild + Mild = High.

Addition of any number of agents from Class I does not change the calculated class.

Note: If dose granisetron on wt basis, use 10 mcg/kg iv

DELAYED ANTIEMETIC REGIMEN

Zofran 8 mg BID x 4 days plus
Decadron 4 mg BID x 4 days
(NEJM 342:1554, 5/00)

OR

Decadron 8 mg po/iv x 2 days, taper to 4 mg bid x 2 days, plus
Compazine Spansule 15mg po bid x 2 days plus
Benadryl 50 mg po q 4h prn restlessness

               OR

Decadron 8mg po/iv bid x 2 days, taper to 4mg bid x 2 days plus
Reglan 30mg po/iv QID x 2 days plus
Benadryl 25-50mg po q4h prn restlessness

"Magic Bullet" -- "metodiphenodex"

10 mg Reglan + 10 mg dexamethasone + 10 mg Benadryl
Given as suppository q4h as needed

 

EXTRAVASATION ANTIDOTES

Doxorubicin, Daunorubicin

Apply ice 20 min QID x 3 days elevate

Topical DMSO - apply to area twice the size of injury, and allow to air dry. (DMSO is an antioxidant that neutralizes free radicals.)

Mitomycin

Injury can be similar to DOX. Usually treat with wide local excision, but some have infiltrated with pyridoxine, using a volume equal to that of the extravasated mitomycin.

Vinca drugs

Can cause painful, non-healing ulcers. Not clear what best management is, but manufacturer recommends local heat and local injection of hyaluronidase (300 unit vial - add 1-2cc NS and infiltrate "liberally."

Nitrogen Mustard

Mix 4cc 10% Thiosulfate in 6cc sterile water. Inject into extravasation site in excess of the amt of mustard extravasated.

After any extravasation, if pain persists > 2-3 days with conservative management, get surgical consult.
 

TOXICITY BY ORGAN SYSTEM

CARDIAC

Acute MI or Spasm:               5FU, CDDP, VCR, VBL

Arrythmias: IL2, Amsacrine (VT), Taxol (bradycardia/heart block), DOX,DNR (prolonged QT int with VT)

CHF: DOX, DNR @ >550 mg/m2 cum, DHAD @ >100-140 mg/m2 cum, CTX @ > 100-200 mg/kg over 2 days (hemorrhagic myocarditis and pericarditis, necrosis)

Other: Busulfan (endocardial fibrosis), IFN (exacerbates underlying disease), IL2 (capillary leak), Mito-C (damage similar to RT)

RENAL

CDDP     : damages prox & distal tubules, may also vasoconstriction, lytes, dose-related (50-200 mg/m2)

CBDCA: high doses similar to CDDP

CTX:       >50 mg/kg hemorrhagic cystitis, tubular injury, water retention

IFF: 1.2 g/m2/d same as CTX

Carmustine: >1.2 gm/m2 cum --> glomerular sclerosis, tubular atrophy, interstitial fibrosis

SZN: cumulative & dose-related toxicity, tubular atrophy proteinuria (early sign), interstitial nephritis

MTX: not nephrotoxic, but toxic in renal disease bec of excrection

Mito-C: >30 mg/m2 cum renal insuff, HUS

LIVER

Hepatotox usually reversible with d/c of offending agent

Typically see centrilobular damage with increased enzymes

L-Asparaginase --> diffuse fatty liver, decreased vit-K factors
Nitrosoureas and 6-MP --> increased enzymes
Methotrexate --> portal fibrosis, cirrhosis after cumulative dose of 1.5 gm
Mithromycin --> decreased vit-K factors at 30 mcg/kg or after 10 doses
Dacarbazine --> hepatocellular necrosis, hepatic vein thrombosis

NEURO

Tubulin binders, inclu Taxol, dose-dependent peripheral neuropathy that is usually reversible with d/c of drug.

Heavy metals (CDDP) both central & peripheral neurotox. Can see paresthesias, vibratory/proprioceptive loss, seizures, ototoxicity

Purine nucleosides - serious central damage at high doses

MTX > 12mg/m2 IT --> acute meningitis, arachnoiditis, paraplegia, leukoencephalopathy

Ara-C > 100mg/m2 IT -->     necrotizing leukoencephalopathy

5FU --> Acute cerebellar syndrome

VCR --> Cranial n motor neuropathy; symmetric sensorimotor peripheral neuropathy

CDDP --> Ototoxicity, peripheral neuropathy

DCF (High dose) --> Seizure, coma

Fludarabine --> Delayed cortical blindness, coma, peripheral neuropathy

Ifos --> Somnolence, confusion, coma

IFN --> mental status, dizzines, parasthesias

IL2 --> same as IFN

Taxol --> peripheral neuropathy

PULMONARY

Earliest manifestation usually nonspecific cough. Can be idiosyncratic or hypersensitivity rx. May be worsened by XRT

Interstitial Pneumonitis:

Bleomycin > 400u cum dose fibrosis, cough, fine rales, TLC, dose & age related
Mito-C
Carmustine >1 gm/m2 cum --> delayed pulm fibrosis
CTX (High dose) --> interstitial fibrosis
Chlorambucil
Melphalan
High dose MTX
Fludarabine

Pulmonary Edema

Ara-C in conventional doses

Other: Busulfan --> bronchopulm dysplasia, fibrosis onset delayed months to yrs

GASTROINTESTINAL

All can nausea/vomiting

Ones below also cause:

MTX --> ulceration
5FU --> bloody diarrhea
CTX --> diarrhea
DOX --> mucositis
Hydroxyurea --> mucositis
Ara-C --> mucositis
VCR --> dose-related constipation, abdominal cramps, adynamic ileus

HEMATOLOGIC

Most --> severe WBC suppression except:

CDDP
Hydroxyurea
Mitoxantrone
Mito-C
VBL

Delayed nadirs/recovery: Busulfan, Nitrosoureas, DTIC (sorta), Carbo (sorta), Mitomycin C

 

PREVENTION OF TAXOL NEUROPATHY AND RADIATION ESOPHAGITIS

Glutamine 10 gm QID x 5d p Taxol
Supplied: 480 gm bottle of powder

 

GLEEVEC (imatinib, STI-571)

Action: Protein-tyrosine kinase inhibitor (TKI) that inhibits the BCR-ABL tyrosine kinase. Inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Ph chromosome positive CML. It is not entirely selective. It also inhibits the receptor tyrosine kinases for PDGF and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events.

Pharmacology: Metabolized by CYP3A4 (a cytochrome P450 enzyme), so other drugs may interact: ketoconazole, simvastatin, phenytoin and other antiepiletics, decadron, cyclosporine, Coumadin, et al.

Indications: For patients with CML – any phase – who fail IFN therapy.

Trial Results: In Chronic Phase CML patients who had failed IFN treated with 400 mg QD, 88% got complete hematologic response (CHR). 49% got major cytogenetic response. 30% got cytogenetic CR (CCR). In Accelerated Phase patients 28% got CHR, 11% no evidence of leukemia (NEL), and 24% returned to chronic phase. 14% got CCR. I patient in Blast Crisis 19% returned to chronic phase, 7% achieved either CHR or NEL. 5% got CCR.

Dose:

Chronic Phase CML: 400 mg QD (supplied as 100 mg caps)
Accelerated Phase or Blast Crisis: 600 mg QD

Precautions:

- Fluid retention and edema (increased risk in patients > 65 years old)
- GI irritation: Take with food and glass of water
- Heme: Check cbc weekly x 4, then q 2 wks x 2, then as indicated
- Liver: increased enzymes

Dose Modifications:

ANC < 1 or Plt < 50 in a patient with Chronic Phase CML: Stop drug until ANC > 1.5 and Plt count > 75. Resume at 400 mg QD dose. If problem recurs, hold drug again, then resume at 300 mg QD.

ANC < 0.5 or Plt < 10 in a patient with Accelerated Phase or Blast Crisis: Check marrow to see whether cytopenia is related to drug or leukemia. If due to drug, reduce dose to 400 mg. If cytopenia persists, reduce further to 300 mg. If cytopenia persists 4 wks, stop drug until ANC > 1 and plt 20+, then resume at 300 mg.

 

ANTIBODIES

Alemtuzumab, Cetuximab, Rituximab

 

CETUXIMAB

For refractory colon cancer

 

CAMPATH (Alemtuzumab)

Recombinant Ab directed against CD52 that is expressed on the surface of normal and malignant B and T lymphocytes, NK cells, monocytes, macrophages, and tissues of the male reproductive system. Campath leads to antibody-dependent lysis of leukemic cells following cell surface binding.

Half life = 12 days.

Overall RR = ~30%. CR = 1%.

Indicated for patients who fail fludarabine. Contraindicated in patients with known sensitivity, HIV+, or serious infections.

Adverse reactions: Hematologic, Infusion reactions, Infections (need PCP prophylaxis).

ADMINISTRATION: Start at 3 mg QD IV/2 hours. When tolerated, increase to 10 mg IV/2 hr QD, then if no reaction, 30 mg IV/2hr TIW for up to 12 weeks. Most patients can reach the 30 mg dose by 3-7 days. Do NOT give more than 30 mg per dose or 90 mg per week!

Premeds: Tylenol, Benadryl 50 mg. May also use hydrocortisone 200 mg if any events.

Prophylaxis: Bactrim DS BID TIW, Famvir 250 mg BID. Continue for 2 months after therapy is completed or until the CD4 count in > 200, whichever occurs later.

Dose Modifications: First ANC < 250 or Platelet count < 25 --> Hold drug until ANC > 500 and platelet count > 50. Resume at same dose. If delay is 7+ days, resume at 3 mg dose and work back up to 30 mg dose the same as at the start.

For second occurrence of ANC < 250 or platelet < 25 --> Hold drug. When ANC > 500 and platelet > 50, resume at 10 mg dose. If delay is 7+ days, resume at 3 mg and escalate only to 10 mg.

For third occurrence, discontinue Campath permanently.

 

DARBEPOETIN (Aranesp)

 

Starting in renal failure patients: Start with 0.45 mcg/kg weekly. Titrate to maintain Hb < 12.

 

Converting from Epoetin: If patient was receiving erythropoietin more than once a week, give Aranesp weekly. If patient was receiving erythropoietin once a week, then can give the Aranesp every two weeks.

 

The conversion formula is: Darbepoetin Units = (EpoUnitsPerWeek/2500)*6.25

 

 

GEFITINIB (IRESSA)

 

On May 5, 2003 the Food and Drug Administration (FDA) approved gefitinib (Iressa*, AstraZeneca) 250 mg tablets as monotherapy treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of both platinum-based and docetaxel chemotherapies.  Gefitinib is not recommended for use in combination with chemotherapy.

 

Gefitinib was evaluated in a multicenter United States clinical trial in patients with advanced non-small cell lung cancer.  Patients were entered after disease progression or intolerable toxicity associated with at least two prior chemotherapy regimens, including both a platinum and docetaxel. One hundred forty-two evaluable patients received gefitinib at a dose of either 250 mg/day or 500mg/day.  Approximately 75% had adenocarcinoma histology (alone or mixed with squamous cell histology).  Partial tumor responses occurred in 15 of 142 evaluable patients for a response rate of 10.6% (95CI: 6-16.8%) overall. Responses occurred in 9 of 66 patients receiving 250 mg/day (13.6%) and in 6 of 76 patients receiving 500 mg/day (7.8%). Median duration of response was 7.0 months (range 4.6 -18.6+ months).

 

Two large controlled randomized trials in the first-line treatment of non-small cell lung cancer showed no benefit from adding gefitinib to doublet, platinum-based chemotherapy. 

 

In the patients who received Iressa monotherapy for treatment of NSCLC, the most common adverse drug reactions reported were diarrhea (sometimes associated with dehydration), rash, acne, dry skin, nausea, vomiting, and pruritis. These events generally occurred within the first month of therapy and usually were mild to moderate. Cases of interstitial lung disease

(ILD) have been observed in patients receiving gefitinib at an overall incidence of about 1%, and approximately 1/3 of the cases have been fatal. (The reported incidence of ILD was about 2% in the Japanese post-marketing experience and about 0.3% in approximately 23,000 patients treated with gefitinib in a US expanded access program and about 1% in the studies of first-line use in NSCLC [but with similar rates in both treatment and placebo groups]). In the event of acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever), gefitinib therapy should be interrupted and a prompt investigation of these symptoms should occur.  If interstitial lung disease is confirmed, gefitinib should be discontinued and the patient treated appropriately.

 

The approved dose for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies is one 250 mg tablet once a day with or without food.  Higher doses do not give a better response and cause increased toxicity.

 

This indication is approved on the basis of objective response rate under accelerated approval provisions.  Randomized controlled clinical trials will be performed to evaluate whether gefitinib treatment is associated with clinical benefit, such as improved survival or symptom improvement. Gefitinib received fast-track designation and priority review.

 

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at www.fda.gov/cder/foi/label/2003/021399lbl.pdf.

 

PEMETREXED (ALIMTA)

As 2nd line therapy ORR was same as Taxotere (9%) with similar MS (8 months) in NSCLC, but was less toxic.

 

500 mg/m2 IV over 10 minutes Q3 weeks

 

Premed:

Folate 1 mg daily beginning 1-2 weeks prior to starting chemotherapy until 3 weeks after last dose of pemetrexed.

Vitamin B12  1,000 mcg IM 1-2 weeks before pemetrexed and Q 9 weeks (every third cycle) until after discontinuation.

Decadron 4 mg BID on day before, day of, and day after pemetrexed to prevent skin rash.

 

Mechanism: Antifolate drug with multiple targets. Inhibits TS, DHFR and glycinamide ribonucleotide formyl transferase.

Toxicities: Hematologic, rise in ALT

 

ABRAXANE (albumin-bound paclitaxel)

 

260 mg/m2 IV over 30 minutes every 3 weeks

 

OR

 

100 mg/m2 IV over 30 minutes weekly.

 

Does not need premedication.

Main toxicities are hematologic and neurological.

Hold if develops Grade 3 neuro symptoms (impaired function). May resume if resolves to Grade 1-2.