ADVERSE EFFECTS OF ADVERSE EFFECTS OF

ANTIANTI--CANCER CANCER

CHEMOTHERAPYCHEMOTHERAPYCHEMOTHERAPYCHEMOTHERAPY

Section of Medical OncologySection of Medical Oncology

College of MedicineCollege of Medicine--Philippine General HospitalPhilippine General Hospital

University of the PhilippinesUniversity of the Philippines

Principles of Cancer ManagementPrinciples of Cancer Management

�� Be certain that the diagnosis of cancer is correct. Be certain that the diagnosis of cancer is correct. Treatment of cancer cannot be started until Treatment of cancer cannot be started until histological proof of malignancy is availablehistological proof of malignancy is available

�� Cancer therapy goals are to cure or to control Cancer therapy goals are to cure or to control the disease or to palliate the symptoms of the the disease or to palliate the symptoms of the the disease or to palliate the symptoms of the the disease or to palliate the symptoms of the patient with minimal functional and structural patient with minimal functional and structural impairment.impairment.

�� The 1The 1stst decision is the most important decision is the most important determination of success in cancer treatment determination of success in cancer treatment and this should be a multiand this should be a multi--modal effort.modal effort.

Combined Modality Approach Combined Modality Approach

to Cancer Managementto Cancer Management

Cancer ChemotherapyCancer Chemotherapy

�� The use of drugs in the management of the cancer The use of drugs in the management of the cancer patient; patient;

�� May involve the use of:May involve the use of:�� Cytotoxic agents Cytotoxic agents –– drugs usually attach rapidly dividing cellsdrugs usually attach rapidly dividing cells�� Hormonal therapies Hormonal therapies –– can be hormones or antican be hormones or anti--hormones, used hormones, used

against hormoneagainst hormone--sensitive tumorssensitive tumorsagainst hormoneagainst hormone--sensitive tumorssensitive tumors�� Additive (e.g., prednisone in lymphoma)Additive (e.g., prednisone in lymphoma)�� Ablative (e.g., antiAblative (e.g., anti--estrogens tamoxiphen in breast cancer)estrogens tamoxiphen in breast cancer)

�� Immunologic drugs Immunologic drugs –– biologic response modifiers, natural biologic response modifiers, natural cellular products (e.g., monoclonal, vaccine, adaptive cellular products (e.g., monoclonal, vaccine, adaptive immunotherapy)immunotherapy)

�� Gene therapy Gene therapy –– use of tumor celluse of tumor cell--targeted cytokine Gene targeted cytokine Gene TransferTransfer

�� Effects are usually systemic in natureEffects are usually systemic in nature�� Can be used in combinationCan be used in combination

SITES OF ACTION OF CYTOTOXIC AGENTSSITES OF ACTION OF CYTOTOXIC AGENTS

Antibiotics

Antimetabolites

S

Cytotoxic agents exert their effect primarily on Cytotoxic agents exert their effect primarily on

cell multiplication and tumor growth. cell multiplication and tumor growth.

Most agents affect macromolecular synthesis Most agents affect macromolecular synthesis

and function (DNA, RNA, protein)and function (DNA, RNA, protein)

S

(2-6h)G2

(2-32h)

M

(0.5-2h)

Alkylating agents

G1

(2-∞h)

G0

Vinca alkaloids

Mitotic inhibitors

Taxoids

CellCell--Cycle Nonspecific DrugsCycle Nonspecific Drugs

CLASSCLASS TYPETYPE AGENTAGENT

AlkylatingAlkylating Nitrogen mustard Nitrogen mustard NitrosureaNitrosurea

MelchlorethamineMelchlorethamine

CarmustineCarmustine

LomustineLomustineLomustineLomustine

SemustineSemustine

•Effective even if cells in Go or outside cell cycle

Cell CycleCell Cycle--Specific DrugsSpecific Drugs

CLASSCLASS TYPETYPE AGENTAGENT

AlkylatingAlkylating Nitrogen mustardNitrogen mustard

AlkylsulfonateAlkylsulfonate

TriazineTriazine

Chlorambucil, Cyclophosphamide, Chlorambucil, Cyclophosphamide,

MelphalanMelphalan

BusulfanBusulfan

DacarbazineDacarbazine

Metal saltMetal salt Cisplatin, CarboplatinCisplatin, Carboplatin

Natural Natural productproduct

AntibioticAntibiotic Dactinomycin, Daunorubicin, Dactinomycin, Daunorubicin, Doxorubicin, IdarubicinDoxorubicin, Idarubicin

•Broad-spectrum agent capable of affecting any cell so long as it is within the cell cycle, regardless of phase

PhasePhase--Specific DrugsSpecific Drugs

PHASE OF PHASE OF GREATEST GREATEST ACTIVITYACTIVITY

ACTIVITYACTIVITY TYPETYPE AGENTAGENT

Gap 1 (G1)Gap 1 (G1) Natural productNatural product

HormoneHormone

EnzymeEnzyme

CorticosteroidCorticosteroid

AsparaginaseAsparaginase

PrednisonePrednisone

DNA synthesis DNA synthesis (S)(S)

AntimetaboliteAntimetabolite Pyrimidine Pyrimidine

Folinic acidFolinic acid

PurinePurine

Cytarabine, FUCytarabine, FU

MethotrexateMethotrexate

ThioguanineThioguanine

Gap 2 (G2)Gap 2 (G2) Natural productNatural product AntibioticAntibiotic Bleomycin, EtoposideBleomycin, EtoposideGap 2 (G2)Gap 2 (G2) Natural productNatural product AntibioticAntibiotic

Topoisomerase II Topoisomerase II

inhibitioninhibition

Microtubule Microtubule

polymerization & polymerization &

stabilizationstabilization

Bleomycin, EtoposideBleomycin, Etoposide

PaclitaxelPaclitaxel

MitosisMitosis Natural productNatural product Mitotic inhibitionMitotic inhibition Vinblastine, Vinblastine, Vincristine, VindesineVincristine, Vindesine

•Drug is effective only in certain phase(s) of the cell cycle.

Aim of AntiAim of Anti--Cancer Drug TherapyCancer Drug Therapy

AIM OF COMBINATION THERAPYAIM OF COMBINATION THERAPY

INCREASED EFFICACYFavorableFavorable ResponseResponse

Different mechanisms of action Compatible side effects

Different mechanisms of resistance

ACTIVITYACTIVITY SAFETYSAFETY

Risk from ChemotherapyRisk from Chemotherapy

�� Second malignanciesSecond malignancies –– attributable to genetic damage from attributable to genetic damage from chemotherapychemotherapy

�� Studies of patients in CR following combination chemotherapy for Studies of patients in CR following combination chemotherapy for Hodgkin’s disease have indicated the following:Hodgkin’s disease have indicated the following:�� Chemotherapy alone or chemotherapy plus radiation therapy seems Chemotherapy alone or chemotherapy plus radiation therapy seems

more likely to predispose to secondary acute leukemia than radiation more likely to predispose to secondary acute leukemia than radiation therapy alonetherapy alonePeak incidence of the onset of secondary acute leukemia is between 3 Peak incidence of the onset of secondary acute leukemia is between 3 �� Peak incidence of the onset of secondary acute leukemia is between 3 Peak incidence of the onset of secondary acute leukemia is between 3 and 9 years following previous chemotherapy, with a declining and 9 years following previous chemotherapy, with a declining frequency thereafterfrequency thereafter

�� Certain drugs, including alkylating agents, procarbazine, and Certain drugs, including alkylating agents, procarbazine, and nitrosureas, appear to have more leukemogenic potential than other nitrosureas, appear to have more leukemogenic potential than other drugs; this increases expectations that appropriate modifications of drugs; this increases expectations that appropriate modifications of current combination chemotherapy may decrease the likelihood of this current combination chemotherapy may decrease the likelihood of this complicationcomplication

�� Risk of secondary leukemia rises with increasing patient age at the time Risk of secondary leukemia rises with increasing patient age at the time of treatment especially cover 40 years of ageof treatment especially cover 40 years of age

Risks from ChemotherapyRisks from Chemotherapy

�� Drug toxicityDrug toxicity�� The therapeutic index, or relationship between the therapeutic The therapeutic index, or relationship between the therapeutic

benefit and toxicity, is relatively small for many anticancer drugs benefit and toxicity, is relatively small for many anticancer drugs –– i.e., the anticancer drug’s optimal therapeutic dose oftentimes i.e., the anticancer drug’s optimal therapeutic dose oftentimes borders on its toxicity dose.borders on its toxicity dose.

�� Therefore, astute surveillance for signs of toxicity, and adequate Therefore, astute surveillance for signs of toxicity, and adequate appreciation of techniques for controlling side effects and for appreciation of techniques for controlling side effects and for Therefore, astute surveillance for signs of toxicity, and adequate Therefore, astute surveillance for signs of toxicity, and adequate appreciation of techniques for controlling side effects and for appreciation of techniques for controlling side effects and for modifying doses when necessary, is a necessity.modifying doses when necessary, is a necessity.

�� In general, actively dividing cells are more susceptible to the In general, actively dividing cells are more susceptible to the effects of many antineoplastic drugs than noneffects of many antineoplastic drugs than non--dividing cells.dividing cells.

�� Therefore, toxicity is generally a reflection of varying degrees of Therefore, toxicity is generally a reflection of varying degrees of damage to actively dividing normal cells in the bone marrow, GI damage to actively dividing normal cells in the bone marrow, GI tract, hair follicles, and gonads.tract, hair follicles, and gonads.

Dose Modification in Kidney DysfunctionDose Modification in Kidney Dysfunction

Creatinine Creatinine Clearance Clearance (ml/min/(ml/min/

1.73)1.73)

Serum Serum Creatinine Creatinine

(mg/dl)(mg/dl)

BUNBUN Drug DosageDrug Dosage

PDD & PDD & STZSTZ

MTX*MTX* Others**Others**

>70>70 <1.5<1.5 <20<20 100%100% 100%100% 100%100%

7070--5050 1.51.5--22 2020--4040 50%50% 50%50% 75%75%7070--5050 1.51.5--22 2020--4040 50%50% 50%50% 75%75%

<50<50 >2>2 >40>40 -- 25%25% 25%***25%***

•When serum creatinine is the only parameter of kidney function available.

•Presence of proteinuria >3 g/L also suggest dosage variation

*Standard dose MTX; **BLM, VO-16, VM-26, L-PAM, CPA, IFO, PCZ, MMC, DIC, HEXA; ***Consider carefully each individual case

Dose Modification in Liver DysfunctionDose Modification in Liver Dysfunction% Brom% Brom--sulphalein sulphalein Retention* Retention*

(at 45)(at 45)

Serum Serum Bilirubin Bilirubin (mg/dl)(mg/dl)

OthersOthers Drug DosageDrug Dosage

ADR, EPI, ADR, EPI, other other

anthracyclinesanthracyclines

Others**Others**

<9<9 <1.2<1.2 <2 x N<2 x N 100%100% 100%100%

99--1515 1.21.2--33 22--5 x N5 x N 50%50% 75%75%

>15>15 >3>3 >5 x N>5 x N 25%25% 50%50%

*BSP is infrequently determined for the risk of allergic reactions

** MTX, CCNU, BCNU, MeCCNU, VC, VLB, VDS, MMC, VP-16. VM-26, DIC. CPA should be given at proportionally increased dosages; use preparably other alkylating agents

Common Side EffectsCommon Side Effects

�� HormonotherapyHormonotherapy

�� Fluid retention, Fluid retention, thromphephlebitis, thromphephlebitis, hypercalcemia, hypercalcemia, gynecomastia, nausea, gynecomastia, nausea,

�� ImmunotherapyImmunotherapy

�� Skin reactions, fluSkin reactions, flu--like like symptoms, allergic symptoms, allergic reactions, liver toxicity, reactions, liver toxicity, nausea and vomiting, nausea and vomiting, gynecomastia, nausea, gynecomastia, nausea,

vomiting, increased vomiting, increased BP, thromboBP, thrombo--embolism, visual embolism, visual disturbances, appetite disturbances, appetite and weight increase, and weight increase, psychosis, …psychosis, …

nausea and vomiting, nausea and vomiting, hypotension, hypotension, tachycardia, …tachycardia, …

Common Side Effects of Common Side Effects of Cytotoxic ChemotherapyCytotoxic Chemotherapy

SIDE EFFECTS OF CHEMOTHERAPYSIDE EFFECTS OF CHEMOTHERAPY

MucositisAlopecia

•Emesis

•Alopecia

•Skin necrosis/vesicants

•Renal tubular Nausea/vomiting

Diarrhea

Cystitis

Sterility

Myalgia

Neuropathy

Pulmonary fibrosis

Cardiotoxicity

Local reaction

Renal failure

Myelosuppression

Phlebitis

•Renal tubular necrosis

•Liver toxicity

•Pulmonary toxicity

•Gonadal damage

•Anaphylactoid

Bone Marrow SuppressionBone Marrow Suppression

�� Most BM stem cells are resting at any given time, and are recruited Most BM stem cells are resting at any given time, and are recruited into the mitotic pool following damage to more mature cells by into the mitotic pool following damage to more mature cells by chemotherapeutic agents.chemotherapeutic agents.

�� With most drugs, lowest peripheral granulocyte counts (nadir) are With most drugs, lowest peripheral granulocyte counts (nadir) are reached in ~ 8 to 10 days reached in ~ 8 to 10 days –– at this point, BM stem cell proliferation at this point, BM stem cell proliferation is at maximum.is at maximum.

�� If intervals between treatments can be extended to 17If intervals between treatments can be extended to 17--21 days, 21 days, most of the stem cells will have returned to the resting state and most of the stem cells will have returned to the resting state and

�� If intervals between treatments can be extended to 17If intervals between treatments can be extended to 17--21 days, 21 days, most of the stem cells will have returned to the resting state and most of the stem cells will have returned to the resting state and exposure to the antiexposure to the anti--tumor agents at this time will have minimal tumor agents at this time will have minimal effect on the stem cells.effect on the stem cells.�� Minimized by using intermittent schedules of cell cycle.Minimized by using intermittent schedules of cell cycle.�� CycleCycle--specific agents should be avoided at this point to reduce specific agents should be avoided at this point to reduce

hematopoietic damage hematopoietic damage –– if response of the tumor will permit such a if response of the tumor will permit such a drugdrug--free interval.free interval.

�� Some agents (nitrosureas) produce a biphasic suppression of Some agents (nitrosureas) produce a biphasic suppression of peripheral granulocytes (8peripheral granulocytes (8--10 days; 2710 days; 27--32 days). 32 days). �� Delay reDelay re--treatment until 6treatment until 6--8 weeks after8 weeks after

Bone Marrow SuppressionBone Marrow SuppressionTimes to recovery of peripheral granulocyte counts

following administration of pulse doses of anti-tumor drugs

Dose Variation Dose Variation –– Myelosuppressive RegimensMyelosuppressive Regimens

Nadir Nadir WBC/mm2WBC/mm2

Nadir PLT/mm2Nadir PLT/mm2 Dose to be Dose to be administeredadministered

>>4,0004,000 >>100,000100,000 Inc 1 level up Inc 1 level up (125%)(125%)

3,9003,900--3,0003,000 99,00099,000--75,00075,000 Same dose Same dose (100%)(100%)(100%)(100%)

2,9002,900--2,0002,000 74,00074,000--50,00050,000 Dec 1 level Dec 1 level down (75%)down (75%)

<2,000<2,000 <50,000<50,000 Dec 2 levels Dec 2 levels down (50%)down (50%)

•Blood count weekly until controlled.

•Treatment to be re-started following scheduled intervals (usually after 3-4 or 6 weeks) and/ or – if the treatment has been delayed upon hematological normalization.

ECOG Toxicity CriteriaECOG Toxicity Criteria

�� Grade 0 Grade 0 –– NoneNone

�� Grade 1 Grade 1 –– MildMild

�� Grade 2 Grade 2 –– ModerateModerate

Grade 3 Grade 3 –– SevereSevere�� Grade 3 Grade 3 –– SevereSevere

�� Grade 4 Grade 4 –– LifeLife--threateningthreatening

Hematologic ToxicityHematologic Toxicity

TOXICITY TYPETOXICITY TYPE GR 0GR 0 GR 1GR 1 GR 2GR 2 GR 3GR 3 GR 4GR 4

LeukoLeuko--peniapenia

WBC x WBC x 10001000

>>4.54.5 3.03.0--<4.5<4.5 2.02.0--<3.0<3.0 1.01.0--<2.0<2.0 <1.0<1.0

Neut x Neut x 10001000

>>1.91.9 1.51.5--<1.9<1.9 1.01.0--<1.5<1.5 0.50.5--<1.0<1.0 <0.5<0.5

ThromboThrombo-- Plt Plt >>130130 9090--<130<130 5050--<90<90 2525--<50<50 <25<25ThromboThrombo--cytopeniacytopenia

Plt Plt x1,000, x1,000,

000000

>>130130 9090--<130<130 5050--<90<90 2525--<50<50 <25<25

AnemiaAnemia Hgb Hgb g/100mLg/100mL

>>1111 <9.9<9.9 <9.5<9.5 Req BTReq BT SeriousSerious

HemorrhageHemorrhage NoneNone MinimalMinimal Mod, not Mod, not debidebi--

DebiliDebili--tatingtating

SeriousSerious

Fever/ Infection/ Allergy ToxicityFever/ Infection/ Allergy Toxicity

TOXICITY TOXICITY TYPETYPE

GR 0GR 0 GR 1GR 1 GR 2GR 2 GR 3GR 3 GR 4GR 4

FeverFever <37.5oC<37.5oC <38oC<38oC >38oC>38oC >>40oC; 40oC; ChillsChills

Fever/ Fever/ HypotensionHypotension

Fever felt to be caused by drug allergy Fever felt to be caused by drug allergy –– grade as allergy; grade as allergy; fever due to infection fever due to infection –– grade under infection onlygrade under infection onlyfever due to infection fever due to infection –– grade under infection onlygrade under infection only

InfectionInfection NoneNone No active No active RxRx

Req active Req active RxRx

DebilitatiDebilitatingng

SeriousSerious

AllergyAllergy NoneNone Transient Transient rash; drug rash; drug

fever fever (<38oC)(<38oC)

Urticaria; Urticaria; drug fever drug fever (>38oC)(>38oC)

Serum Serum sickness; sickness; bronchobroncho--spasm; spasm;

Req. Req. parenteparente--ral medsral meds

AnaphylaxisAnaphylaxis

Skin & Mucosa ToxicitySkin & Mucosa ToxicityTOXICITY TOXICITY

TYPETYPEGR 0GR 0 GR 1GR 1 GR 2GR 2 GR 3GR 3 GR 4GR 4

SkinSkin NormalNormal Transient Transient erythema; erythema; pigmenpigmen--tation; tation; atrophyatrophy

VesiculatiVesiculation; subon; sub--

epidermal epidermal fibrosisfibrosis

UlceraUlcera--tion; tion;

necrosisnecrosis

atrophyatrophy

Mucosa/ Mucosa/ StomatitisStomatitis

NoneNone SorenessSoreness UlcersUlcers--can eatcan eat

Ulcers Ulcers ––cannot cannot

eateat

AlopeciaAlopecia NoneNone Mild Mild ModerateModerate SevereSevere

Local IV site/ Local IV site/ ExtravasationExtravasation

NoneNone PainPain Pain + Pain + PhlebitisPhlebitis

UlceraUlcera--tiontion

GIGI--Hepatic ToxicityHepatic ToxicityTOXICITY TYPETOXICITY TYPE GR 0GR 0 GR 1GR 1 GR 2GR 2 GR 3GR 3 GR4GR4

Nausea & Nausea & VomitingVomiting

NoneNone NauseaNausea N&V N&V controllablecontrollable

Vomiting Vomiting intractableintractable

DiarrheaDiarrhea NoneNone No No dehydehy--

drationdration

DehyDehy--drationdration

Grossly Grossly bloodybloody

HepaticHepatic SGOTSGOT <1.5 <1.5 1.51.5--2 2 2.12.1--5 x nl5 x nl >5 x nl>5 x nlHepaticHepatic SGOTSGOT <1.5 <1.5 x nlx nl

1.51.5--2 2

x nlx nl

2.12.1--5 x nl5 x nl >5 x nl>5 x nl

Alk POAlk PO <1.5 <1.5 x nlx nl

1.51.5--2 2

x nlx nl

2.12.1--5 x nl5 x nl >5 x nl>5 x nl

BilirubinBilirubin <1.5 <1.5 x nlx nl

1.51.5--2 2

x nlx nl

2.12.1--5 x nl5 x nl >5 x nl>5 x nl

ClinicalClinical PrecomaPrecoma HepaHepatic tic

comacoma

Neurologic ToxicityNeurologic ToxicityTOXICITY TOXICITY

TYPETYPEGR 0GR 0 GR 1GR 1 GR 2GR 2 GR 3GR 3 GR 4GR 4

PeripheralPeripheral NoneNone Decr. Decr. DTRs; mild DTRs; mild

parespares--thesia/ thesia/

constipaconstipa--tiontion

Abs DTRs; Abs DTRs; Severe Severe parespares--thesia/ thesia/

constipaconstipa--tion; mild tion; mild weaknessweakness

Disabling Disabling sense sense loss; loss;

severe PN severe PN pain; pain;

obstipaobstipa--tion; tion;

Resp. dysf Resp. dysf due due

weakness; weakness; obstipaobstipa--tion tion

req surg; req surg; paralysisparalysis

weaknessweakness tion; tion; weakness; weakness;

bladder bladder dysf’ndysf’n

CNSCNS NoneNone Mild Mild anxiety/ anxiety/

depressiondepression/headache; /headache;

lethargylethargy

Sev anxiety; Sev anxiety; mod mod

depression/ depression/ HA; HA;

somnolencesomnolence; tremor; ; tremor;

mild hypermild hyper--activityactivity

Confused Confused or manic. or manic.

Sev Sev depressiodepressio

n/HA; n/HA; cord dysf; cord dysf; confined confined to bedto bed

Seizure; Seizure; suicidal; suicidal;

comacoma

NephroNephro--Urinary ToxicityUrinary ToxicityTOXICITY TYPETOXICITY TYPE GR 0GR 0 GR 1GR 1 GR 2GR 2 GR 3GR 3 GR 4GR 4

CreatinineCreatinine <<1.21.2 1.31.3--2.02.0 2.12.1--4.04.0 >4.0>4.0 UremiaUremia

ProteinuriaProteinuria NegNeg 1+1+ 2+2+--3+3+ 4+4+

HematuriaHematuria NegNeg MicroMicro-- GrossGross-- Gross Gross ObstrucObstrucHematuriaHematuria NegNeg MicroMicro--C+C+

GrossGross--C+C+

Gross Gross +clots+clots

ObstrucObstructivetive

UTI UTI –– grade under infection; grade under infection;

Hematuria due to thrombocytopenia Hematuria due to thrombocytopenia –– grade under grade under hemorrhagehemorrhage

Pulmonary ToxicityPulmonary ToxicityTOXICITY TYPETOXICITY TYPE GR 0GR 0 GR 1GR 1 GR 2GR 2 GR 3GR 3 GR 4GR 4

PFTPFT NormalNormal 2525--50% 50% dec in dec in

DLco or DLco or VC; mild VC; mild

sxsx

>50% >50% dec in dec in Dco or Dco or

VC; mod VC; mod sxsxsxsx sxsx

CLINICALCLINICAL Mild sxMild sx Mod sxMod sx Severe Severe sx; sx;

intermitintermittent O2tent O2

Assisted Assisted vent. or vent. or contincontin--uous O2uous O2

Pneumonia is considered infection, unless due to Pneumonia is considered infection, unless due to pulmonary changes directly induced by pulmonary changes directly induced by treatmenttreatment

Cardiac ToxicityCardiac Toxicity

TOXICITY TOXICITY TYPETYPE

GR 0 GR 0 GR 1GR 1 GR 2GR 2 GR 3GR 3 GR 4GR 4

CardiacCardiac NormalNormal STT STT changes; changes;

sinus sinus tachy tachy

Atrial Atrial arrhytharrhyth

mia; mia; unifocal unifocal

Mild Mild CHF; CHF;

MultiMulti--focal focal

Severe Severe or or

refract refract CHF; CHF; tachy tachy

>110 at >110 at restrest

unifocal unifocal PVCsPVCs

focal focal PVCs; PVCs;

PericarPericar--ditisditis

CHF; CHF; ventriventri--cular cular

tachy; tachy; tamtam--

ponadeponade