MANAGEMENT OF ADVERSE EFFECTS

OF CANCER CHEMOTHERAPY

CANCER

An abnormal growth of cells which tend

to proliferate in an uncontrolled way and,

in some cases, to metastasize (spread).

CLASSIFICATION OF ANTICANCER DRUGS

CELL CYCLE SPECIFIC AGENTS

CELL CYCLE NON SPECIFIC AGENTS

GENERAL ADVERSE EFFECTS OF ANTICANCER DRUGS1. Immediate ADR: Nausea, Vomiting

2. Myelosuppression

3. Mucositis

4. Alopecia

5. Teratogenicity

SYSTEMIC ADVERSE EFFECTS OF ANTICANCER DRUGS

• Veno occlusive disease of the liver

• Hemorrhagic cystitis

• Nephrotoxicity

• Neurotoxicity

• Pulmonary toxicity

• Cardiotoxicity

• Hand Foot syndrome

• Tumour Lysis syndrome

VENO OCCLUSIVE DISEASE OF THE LIVER

• Non thrombotic obliteration of small intrahepatic veins by subendothelial fibrin.

• Associated with congestion; necrosis of centrilobular hepatocytes.

• Result of bone marrow transplantation with high doses of chemotherapeutic agents esp. alkylating agents (Busulfan, Carmustine).

VENO OCCLUSIVE DISEASE OF THE LIVER

• Resultant vascular engorgement hepatomegaly; ascites.

• If acute phase does not reverse fibrosis of veins; atrophy of centrilobar hepatocytes.

• Characterized by painful hepatomegaly, jaundice, ascites, unexplained weight gain.

DEFIBROTIDE• Large, single stranded polydeoxyribonucleotide.

• Has antithrombotic, anti-ischemic, anti-inflammatory, thrombolytic properties.

• Binds to vascular endothelium, modulates platelet activity, promotes fibrinolysis, decreases thrombin generation and activity.

HAEMORRHAGIC CYSTITIS• Lower urinary tract infection characterized by dysuria,

hematuria and hemorrhage.

• Side effect of cyclophosphamide; ifosfamide.

• Incidence- 2-40%

• Onset of hematuria- 48 hours after Rx.

HAEMORRHAGIC CYSTITIS•Metabolite- acrolein excreted in the urine bladder edema and

hemorrhage.

• Chronic fibrosis; decreased capacity and trabeculations.

•More prevalent in dehydrated pts. Hence Rx should include-• Hydration• Foley catheter- for immediate drainage of bladder.• Continuous bladder irrigation to hasten acrolein clearance from

bladder.

MESNA• 2- Mercaptoethane sulfonate

• Binds to acrolein creates stable thioester compounds decreases bladder toxicity.

• Coadministered with cyclophosphamide/ Ifosfamide

• Orally/IV

MESNA

• Pt on cyclophosphamide may not develop HC;

• But there is life time risk of developing bladder cancer.

•MESNA decreases the risk.

NEPHROTOXICITY• Cisplatin induced- 20%

• Kidneys accumulate cisplatin to a greater degree;

• Concentration of drug in proximal tubular epithelial cells 5 times the serum concentration nephrotoxicity.

• Proximal tubular injury Oxidative stress Inflammation Vascular injury.

AMIFOSTINE• An inactive prodrug; converted into an active thiol by

dephosphorylation.

• Actions• free radical scavenging;

• DNA protection and repair acceleration;

• induction of cellular hypoxia.

AMIFOSTINE

• 200mg/m2 slow IV push over 3 minutes.

• Can be administered subcutaneously as well.

NEUROTOXICITY

PULMONARY TOXICITY•Major limitation of bleomycin Rx.

• Incidence- 10%

• Potential determinant of bleomycin toxicity Bleomycin hydrolase enzyme responsible for metabolizing bleomycin to non toxic molecules.

PULMONARY TOXICITY•Pulmonary toxicity involves-

• Bronchiolitis Obliterans with Organizing Pneumonia

• Eosinophilic Hypersensitivity

• Interstitial pneumonitis progressing to fibrosis (most

common)

PULMONARY TOXICITY• Pathogenesis-• Oxidative damage

• Relative deficiency of the deactivating enzyme bleomycin hydrolase

• Genetic susceptibility

• Elaboration of inflammatory cytokines.

• Effect on fibrinolytic system present- alters balance b/w fibrin deposition and fibrinolysis on alveolar surface fibrin deposition.

PULMONARY TOXICITY• Develops gradually during Rx or upto 2 years after

discontinuation.

• Symptoms- Exertional dyspnea, non productive cough, tachypnea, cyanosis.

• On physical examination- End inspiratory bibasilar crepitation's/rhonchi.

TREATMENT• Bleomycin should be discontinued in all pts with

documented or suspected pulmonary toxicity.

• Rx- Glucocorticoids.

• 0.75-1mg/kg Prednisone is prescribed.

• Dose tapered after 4-8 weeks over an additional 4-6 months.

TREATMENT

• Short term improvement seen in 50-70% patients.

• Symptoms may relapse due to tapering of therapy.

CARDIOTOXICITY• Commonly caused by Anthracyclines.

• Pyrimidine analogues- capecitabine acute chest pain with evidence of ischemia.

CARDIOTOXICITY• Cardiotoxicity due to anthrayclines can occur at any point

during Rx or later.

• Acute cardiotoxicity-

• Occurs immediately/ weeks after Rx.

• Presents as arrhythmias, ST and T wave abnormality.

CARDIOTOXICITY• Chronic cardiotoxicity-• Occurs in the 1st year following Rx.• LV dysfunction, QT dispersion.

• Late- onset cardiotoxicity-• Following a prolonged asymptomatic period.• Presents with heart failure 1 year- decades following

chemotherapy.

TREATMENT• Liposomal analogues-• Reduce drug toxicity

• Preserves antineoplastic effects by selectively perfusing into tumour tissue.

• 3 liposomal anthracyclines-• Liposomal Daunorubicin• Liposomal Doxorubicin• Pegylated Liposomal Doxorubicin.

TREATMENT• Cardioprotectants-• Dexrazoxane-• Decreases incidence and severity of cardiomyopathy.

• Recommended for usage if patient has taken-• >300mg/m2 doxorubicin• >500mg/m2 epirubicin

Who further require administration of these agents for advanced anthracyclin sensitive cancers.

HAND FOOT SYNDROME• Palmar plantar erythrodysesthesia; Palmar plantar erythema;

Acral erythema; Burgdoff’s Reaction.

• Incidence- 6-42%

• Occurs within first 6 weeks of Rx.

HAND FOOT SYNDROME•Drugs causing HFS-• 5- FU• Doxorubicin• Cytarabine• Cyclophosphamide• Vinorelbine• Docetaxel• Capecitabine (50%)

CLINICAL FEATURES• Paraesthesia in sock-glove distribution.

• Varying degrees of pain, tingling, dryness, erythema, scaling, swelling, vesciculations of hands and feet.

• Symptoms may evolve 24 hours to 10 months after Rx.

PREVENTION AND TREATMENT

• No standard therapy; Only symptomatic management.

• Prevention-

• Avoid exposure to source of heat.

• Avoid activities that cause unnecessary force/friction on the

feet.

• Avoid contact with harsh chemicals- laundry detergents.

TREATMENT• Dose reduction or cessation- symptoms resolve within 2-4

weeks of drug cessation.

• Pyridoxine- 50-300mg daily.

• Vasoconstrictive therapies- localized cooling of the acral areas decreases the amount of drug delivered to these areas.

TREATMENT• Topical moisturizing creams containing urea, salicylic acid,

ammonium lactate.

• Enhance moisture retention; Maintain hydration reducing further desquamation and decreasing infection risk.

TUMOUR LYSIS SYNDROME• Constellation of metabolic disturbances that follows

initiation of cancer Rx.

• Large number of neoplastic cells are killed rapidly release of intracellular ions and metabolic byproducts to systemic circulation.

• Usually occurs 48-72 hours after initiation of cancer Rx.

TUMOUR LYSIS SYNDROME• Clinically characterized by rapid development of

hyperuricemia; hyperkalemia; hyperphosphatemia; hypocalcemia and acute renal failure.

• Drugs causing TLS-• Paclitaxel• Fludarabine• Etoposide• Thalidomide.

CLINICAL FEATURES• Abdominal pain and distention.

• Urinary symptoms- dysuria, oliguria, flank pain, hematuria.

•Weakness, Paralysis,

TREATMENT• Allopurinol:

• Xanthine Oxidase Inhibitor.

• 600-900mg daily orally.

Synthesis of Uric acidRNA, DNA

PURINES

HYPOXANTHINE XANTHINE OXIDASE

XANTHINE XANTHINE OXIDASE

URIC ACID

MECHANISM OF ACTION OF ALLOPURINOL

RNA, DNA

PURINES

HYPOXANTHINE XANTHINE OXIDASE

XANTHINE XANTHINE OXIDASE

URIC ACID

RASBURICASE• Recombinant urate oxidase.

• Catalyzes conversion of poorly soluble uric acid to soluble allantoin.

• This effectively decreases plasma and urinary uric acid levels.

• 0.2mg/kg IV over 30 minutes.

TREATMENT• HYDRATION

• To correct electrolyte imbalance

• Increases intravascular volume increase in renal blood flow.

• Decreases concentration of solute in urine.

• Ideally begins 24-48 hours before Rx and continued for 48-72

hours later.

THANK YOU

REFERENCES• Goodman and Gillman Manual of Pharmacology and therapeutics

• Medscape

• Stubblefield M, Burstein H, Burton A, Custodio C, Deng G, Ho M et al. NCCN Task Force Report: Management of Neuropathy in Cancer. Journal of the National Comprehensive Cancer Network. 2009;7(5):6.

• Kouvaris J, Kouloulias V, Vlahos L. Amifostine: The First Selective-Target and Broad-Spectrum Radioprotector. The Oncologist. 2007;12(6):738-747.

• Volkova M, Russell R. Anthracycline Cardiotoxicity: Prevalence, Pathogenesis and Treatment. Current Cardiology Reviews. 2012;7(4):214-220.

• Reinert T, Baldotto C, Pereira Nunes, F, Souza Scheliga A. Bleomycin-Induced Lung Injury. Journal of Cancer Research. 2013;2013.

• Richardson P, Soiffer R, Antin J, Uno H, Jin Z, Kurtzberg J et al. Defibrotide for the Treatment of Severe Hepatic Veno-Occlusive Disease and Multiorgan Failure after Stem Cell Transplantation: A Multicenter, Randomized, Dose-Finding Trial. Biology of Blood and Marrow Transplantation. 2010;16(7):1005-1017.