Dr. Mehwesh Taj M.B.B.S (Dow),F.C.P.S(Med) Assistant Prof.

& Consultant Clinical Haematologist CPSP Approved supervisor Clinical Haematology N.I.B.D

Treating cancer with chemical agents Major role in cancer therapy Used to cure and increase survival time Some selectivity for killing cancer cells over normal cells Normal cells most affected: the skin, hair, intestinal tissues, spermatocytes, and blood-forming cells

Carcinoma Sarcoma

Lymphoma Leukemia

Epithelium Mesenchymal tissue: bone, soft tissue Lymphoid tissue Hematopoietic cell

INCREASED EFFICACY

ACTIVITY
Different mechanisms of action Different mechanisms of resistance

SAFETY
Compatible side effects

Antimetabolites Antitumor antibodies Alkylating agents Antimitotic agents Topoisomerase inhibitors Miscellaneous agents Combination chemotherapy

Alkylating agents:
busulfan, nitrosoureas, cyclophosphamide,

chlorambucil, melphalan, mechlorethamine,

Antimetabolites:
methotrexate, 5-fluorouracil, nucleoside

analogues

Anthracyclines:
doxorubicin, epirubicin

Antimicrotubule agents:
vinca alkaloids, taxanes

Platinum analogues:
cisplatin, carboplatin

Topoisomerase II inhibitors:
etoposide, tenoposide

Topoisomerase I inhibitors: camptothecins Antibiotics: bleomycin, dactinomycin

The Cell Cycle

DNA synthesis Antimetabolites

DNA

Alkylating agents

DNA transcription

DNA duplication

Intercalating agents

Mitosis

Spindle poisons & Microtuble Stablizers

Mucositis

Alopecia

Pulmonary fibrosis Nausea/vomiting

Diarrhea
Cystitis Sterility Myalgia

Cardiotoxicity
Local reaction Renal failure

Myelosuppression
Phlebitis

Neuropathy

Seen with high rate of infusion of certain drugs also more common with new MONOCLONAL ANTIBODY agents ie RITUXIMAB Infusion of these agents may take several hours Fever, hypotension, asthma like reactions, pain Premedicate or treat with Dexamthasone, Benadryl, Panadol May have to stop infusion temporarily If serious, may have to discontinue agent

Infiltrating surrounding tissue blistering May be delayed 6-12 hr Severe necrosis Absent of blood return

Local inflammatory reaction Intact blood return Short-term injury

Antineoplastic drugs Amsacrine Cisplatin (concentrations 0.5 mg/mL) Dactinomycin Daunorubicin Docetaxel (rare) Doxorubicin Epirubicin Idarubicin Mechlorethamine Mitomycin Oxaliplatin (rare) Paclitaxel (rare) Streptozocin Trabectedin Vinblastine Vincristine Vindesine Vinorelbine

Arsenic trioxide Bleomycin Bortezomib Carboplatin/Carmustine Cisplatin* Cladribine Cyclophosphamide Dacarbazine* Docetaxel Etoposide Fluorouracil/Floxuridine Gemcitabine Ifosfamide Liposomal daunorubicin/doxorubicin Mitoxantrone Oxaliplatin Paclitaxel Thiotepa Topotecan

Select recent, large IV access with good back flow Fore-arm->dorsum->wrist->anticubital Avoid sclerosis, thrombosis, or scar sites butterfly needle or plastic cannula should be secured to the skin with transparent tap Check patency Diluted chemo should be infused with free flowing DW or NS Central venous catheter..

Stop the infusion immediately. Do not flush the line Avoid applying pressure to the affected site. Elevate the affected extremity. The catheter/needle should be left in place to attempt to aspirate fluid from the extravasated area and to facilitate the administration of an antidote to the local area, if available Otherwise catheter/needle can be removed after attempted aspiration of fluid.

Topical application of ice or cold packs is recommended for extravasation of all vesicant or irritant drugs except the vinca alkaloids (vincristine, vinblastine, vinorelbine) and epipodophyllotoxins such as etoposide. Cold application worsens the ulceration Local heating is thought to result in localized vasodilation and increased blood flow, thereby enhancing drug removal

Local injection of sodium thiosulfate for extravasations of mechlorethamine, dacarbazine and cisplatin Topical application of dimethylsulfoxide (DMSO) for anthracycline extravasation A single subcutaneous injection of DMSO for mitomycin extravasation, followed by topical application Local injection of hyaluronidase has been recommended for extravasations of vinca alkaloids, paclitaxel, epipodophyllotoxins, and ifosfamide Systemic administration of dexrazoxane following anthracycline extravasation

Anthracycline extravasation-IV,SC or ID administration of corticosteroids at the site have all been recommended Corticosteroids may worsen the skin damage from etoposide or vinca alkaloids, and they are specifically contraindicated in these situations.

Direct Treatment Related: chemotherapy

- acute - delayed

- anticipatory
- breakthrough N/V - refractory N/V

radiation therapy

Indirect Treatment Related: mucositis opiates antibiotics gastroparesis infection hyperacidity anorexia diarrhea pain anxiety

Chemical- direct mucosal injury to GIT (chemotherapy-induced: acute and delayed; opioids)

Vestibular
CNS -increased intracranial pressure, effects on mid-brain vomiting centers Visceral (direct disease-related sources, abdominal irradiation)

Starts within the first 24 hours after chemotherapy administration Majority of chemotherapeutic agents induce emesis approximately 13 hours following administration Most researched type of CINV Remains common despite dramatically improved protection

Pisters KMW, Kris MG. In: Principles and Practice of Supportive Oncology. Lippincott-Raven; 1998. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Ann Oncol 1998;9:811819.

Starts 24 hours or more after chemotherapy administration First defined with high doses of cisplatin but known to occur with other chemotherapy agents Carboplatin Cyclophosphamide Doxorubicin Epirubicin Anthracyclines Mechanism not known; appears to differ from acute emesis

Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins, 2001:28692880. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Ann Oncol 1998;9:811819.

No Delayed 76%
No Acute CINV Delayed 24%

Yes Acute CINV

No Delayed 20%

Delayed 80%

Worst nausea seen with cysplatin, High dose cyclophosphamide, Doxorubicin, Epirubicin, Prokinetics, Antiemetics, Lorazepam, Haloperidol, Steroids Diet (avoid fried, fatty foods) Smaller meals

Chemotherapy injure all rapidly dividing cells Presents with loss of taste, mouth sores, inflammation and sometimes sloughing of mucosa anywhere in GIT or Respiratory tract Oral complications seen to arise in 40% of patients receiving therapies Source of bacteriemia

Simple oral mucositis treated with mouth rinse/ice cubes Salt water gargles TOPICAL ANALGESIA ie xylocaine Systemic analgesia e.g IV morphine Nystatin Stomatitis cocktail/Magic mouthwash: 1:1:1 antacid solution containing aluminum hydroxide, magnesium hydroxide/viscous lidocaine/diphenhydramine(benadryl) Multivitamines,Zn

Heart burn/ gastritis Treated with regular use of PPI, Antacids, sucralfate Severe mucositis with esophagitis, diarrhoea, sloughing of mucosa need aggressive supportive measures including Bowel rest, IV fluids to maintain hydration and electrolyte imbalances TPN

 Chemotherpy induced mucosal injury causes

increased fluid secretion by the intestine. Seen in upto 45% of cases Risk factors include: known colitis, concomitant irradiation, Elderly, more frequently seen with GI malignancies Severe with 5-FU ,sometimes need Atropine

Usually self limiting Supportive management Fluids & Electrolytes Nutrition Avoid problem foods and drugs, soft diet Medication management Opioids Loperamide (imodium) more effective 4 mg stat then 2mg q4hrly till formed stools * Diphenoxylate(Lomotil) *(r/o infective diarrhoea/C.Diff)

If severe, Ocreotide (Sandostatin) Decreases fluid output from bowel 100mcg sc TID Growth hormone analogue-decreases all salivary gland secretions Side-effects include gall bladder problems, dysglycemia, hypothyroidism, bradycardia Antibiotics may be considered e.g if C.DIFF +ve oral metronidazole oral vancomycin oral CIPRO

 Alkylating agents
Cisplatin Ifosfamide Carmustine Carboplatin Malphalan

Antimetabolites
Methotrexate Gemcitabine

Other
Mitomycin C

Cisplatin

Fractionate dose Continuous IV Adequate hydration Use mannitol (increase urine volume) Prevent dehydration Amifostine Carboplatin substitute (not for all case esp in germ cell tumor

Metrotrexate
Adequate hydration Alkalinize of urine Leucovorin rescue

Ifosfamide/cycloph
Fractionated doses Hydration Monitor fluid retention

(body weight)

Agents
Ifosfamide, cyclophosphamide in high dose acrolein

accumulation in bladder

Clinical presentation
Onset : 2-3 days Hematuria, dysuria

Prevention
MESNA (2-merceptoethane sodium sulphonate) 100-160% of dose + adequate hydration 3L/sq m/day

Stop chemotherapy Hydration &diuresis Bladder irrigation 300-1000ml/h Cyctoscopy Adequate platelets Chemical agents e.g Alum, Formaline Selective embolization Surgical intervention etc

High dose cytarabine cerebellar toxicity L-asparaginase drowsiness, stupor Cisplatin ototoxic, ataxia Etoposide Vinca alkaloid jaw pain,cranial nerve pulsies Procarbazine Metrotrexate acute arachnoiditis Oxaliplatin sensory neurotoxic (cold trigger symptom parathesia

Peripheral Neuropathy

Numbness Sense of touch is distorted- ordinary touch can be unpleasant or painful. Burning or prickling feeling without stimulus Decreased touch sensation Difficulty sensing the position, location, orientation, and movement of the body and its parts (Proprioception) Glove and stocking distribution

Seen commonly with Vincristine, Vinblastin and cisplatin Usually temporary Sometimes respond to dose alteration or stopping some drugs Gabapentine, Amityptyline, Carbamazapine may help in severe cases

Risk factor Cumulative dose: bleomycin, busulfan,BCNU Age: bleomycin Radiotherapy: bleomycin, busulfan, mitomycin, cyclophosphamide, doxorubicin, actinomycin Oxygen therapy: bleomycin, cyclophosphamide, mitomycin Prevention----Avoid risk factors, free radical scavanger, early detection Treatment----corticosteroids, diuretics

 Anthracyclines
Cyclophosphamide 5-FU

Trastuzumab (Herceptin)
Bevacizumab Cisplatinin (Platinol)

Congestive heart failure (mortality >20%) Risk factors

Life time Cumulative dose (> 450 mg/m2)

Dosing schedule- infusion lesser risk than bolus

Age (>65 or <4) Prior mediastinal irradiation Preexisting heart disease and arterial hypertension,

peripheral vascular disease Diabetes Gender (female)

Mild ECG abnormalities Arrhythmias (both supraventricular and ventricular) Heart block (including Mobitz type II second degree AV block and complete heart block), ventricular dysfunction High plasma brain natriuretic peptide (a marker of increased cardiac filling pressures and heart failure) Pericarditis-myocarditis syndrome (particularly with mitoxantron)

In adults, chronic anthracycline-related cardiotoxicity typically presents early, within one year after termination of chemotherapy. The peak time for the appearance of symptoms of heart failure is about three months after the last anthracycline dose Mortality in these early series was high (60 percent);

Avoiding anthracyclines Lowering cumulative dose Lowering peak dose 2nd generation anthracyclines (Idarubicin, epirubicin, mitoxantrone) Early detection of subclinical cardiotoxicity (Echocardiography) Oxygen free radical scavengers vit.E, C, Liposomal encapsulation Dexrazoxane ACE inhibitors and Beta blockers

 Local cutaneous reaction

after chemotherapy Seen on palms, finger, soles 2-12 days after chemo Tingling, burning of palms, hand, feet Pain, peeling Resolution in 7-14 days after stopping medication

Common in high dose therapy, prolonged infusion, liposomal forms Agents Capecitabine Cytarabine Docetaxel Daunorubicin Doxorubicin(liposomal) 5-FU (infusion) MTX

Management
Dose reduction Topical wound care, cold cream base & emollients

Pain management
Steroid creams Pyridoxine Avoid heat and pressure, avoid tight fitting shoes

Anthracyclins Etoposide Cyclophosphamide Taxanes Ifosphamide Vindesine Vinorelbine Topotecan

Myelosuppression

Febrile neutropenia Anemia Bleeding -Thrombocytopenia

Febrile neutropenia
Monitor fever (>38.5 C) ANC < 1.0 x 109 /L

Anemia
Hb < 10 g/dL

Antibiotics/antifungal/ antiviral prophylaxis (CSF prophylaxis) Blood transfusion (Epoitin alpha)

Thrombocytopenia
Platelet < 20,000 / mm3

Platelet transfusion

Multiple white bands in the nails, representing periods of growth arrest

Rash
Avoid sun, heat & humidity Use mild soaps Water based sun screens/other products Topical and/oral antibiotics Topical and/or oral antihistamines Cool compresses Petroleum jelly, silver sulfadiazine ointment for ulcerative lesions

Malignancy diagnosis can be overwhelming The discussion of treatments and adverse effects can also be overwhelming Anxiety, depression, fatigue related to diagnosis and treatments LOTS of information regarding treatments

Gaining Control by giving up control.

(Dr. B. Rotella)

Daily routine goes upside down Changing work routinemissing work for weeks, months or permanently Income changes

The inability to forget is infinitely more devastating than the inability to remember.
Mark Twain

Hard to forget some of the stressful times one goes through Getting through months of chemotherapy is very difficult task Just surviving each day step by step Need a team approach, social worker, supportive care coordinators etc