Medicine2 - Complications Of Cancer Treatment Lecture

Complications of Cancer Treatment

A 40 year old premenopausic female was referred for adjuvant chemotherapy of Stage II B (T2 N1Mo) Estrogen Receptor negative her-2-neu 2+ (FISH) Invasive Ductal Carcinoma of the left breast. She had a left sided Modified Radical Mastectomy three weeks ago.

What information should be disclosed to her when you see her during consultation? A. B. C. D. E.

Diagnosis Stage of her disease Options for treatment Complications of treatment All of the above

Adverse Reactions to Cancer Treatment

Non-hematologic toxicities •Nausea & vomiting •Oral •Gastrointestinal •Pulmonary •Cardiac •Hair loss •Gonadal dysfunction •Second cancers •Miscellaneous Adverse reactions

Hematologic toxicities •Anemia •Leukopenia Neutropenia •Thrombocytopenia

Adverse reactions

Hair loss • immense burden psychologically and physically • occurs within 2 to 3 weeks of chemotherapy treatment • normally resolves within 2 to 3 months after completion or cessation of chemotherapy Adverse reactions

Table 54.5-3: Therapeutic Interventions in Alopecia Decrease local delivery Scalp tourniquet Scalp hypothermia Protection of the hair bulb Topical minoxidil AS101 -Tocopherol Inhibitors of cyclin-dependent kinase Thiol solution Inactivate chemotherapy locally ImuVert Epidermal growth factor and fibroblast growth factor Topical cyclosporine Interleukin-1 Topical calcitriol Liposome-entrapped monoclonal antibody Pulsed electrostatic field

Adverse reactions Hair loss

Definitions • Nausea • Vomiting • Retching

Adverse reactions Nausea & vomiting

Emetic syndromes related to chemotherapy

• Acute

– occurring within the first 24 hours after administration of CT (usually within 1 to 2 hours) – generally most severe during the initial 4 to 6 hours.

• Delayed – occurring 24 or more hours after CT • range of 16 to 24 hours • maximal risk at 48 hours

– most commonly associated with cisplatin, carboplatin, cyclophosphamide, and doxorubicin

• Anticipatory – learned or conditioned response that typically occurs before, during, or after the administration of CT Adverse reactions Nausea & vomiting

Mechanisms • activation of the chemoreceptor trigger zone (CTZ) either directly or indirectly • peripheral stimulation of the gastrointestinal (GI) tract • vestibular mechanisms • cortical mechanisms • alterations of taste and smell. Adverse reactions Nausea & vomiting

Pathophysiology • CTZ located in the area postrema of the brain • can be reached by emetogenic chemicals via the cerebrospinal fluid or the blood • release of various neurotransmitters that activate the vomiting center dopamine, serotonin, histamine, norepinephrine, apomorphine, neurotensin, angiotensin II, vasoactive intestinal polypeptide, gastrin, vasopressin, thyrotropinreleasing hormone, leucine-enkephalin, and substance P

• 5-hydroxytryptamine [serotonin (5-HT)] receptors are particularly important in the pathophysiology of acute vomiting • others may be more important in the pathophysiology of nausea and delayed Adverse reactions emesis.

Nausea & vomiting

Risk factors •prior exposure to chemotherapy •Chronic and heavy alcohol usage •heightened level of anxiety during the chemotherapy infusion •being prone to motion sickness •severe emesis during pregnancy Adverse reactions Nausea & vomiting

Pharmacologic agents • Selective 5-HT3 antagonists • Metoclopramide • Corticosteroids • Others: phenothiazines, butyrophenones, and cannabinoids • Adjuvants: Antianxiety agents Adverse reactions Nausea & vomiting

Table 54.1-2: Guidelines for Antiemetic Dosing Antiemetic

Dose: Acute Emesis

Dose: Delayed Emesis

5-Hydroxytryptamine type 3 receptor antagonists: administer once prechemotherapy Ondansetron

0.15 mg/kg IV or 8 mg IV

8 mg b.i.d. x 2–3 d

12–16 mg PO Granisetron

0.01 mg/kg IV or 1 mg IV 1 mg PO

Dolasetron

1.8 mg/kg IV or 100 mg IV 100–200 mg PO

Palonosetron

0.25 mg IV

Corticosteroid Dexamethasone

10–20 mg IV

High risk: 8 mg PO b.i.d. d 2–4 Moderate risk: 4–8 mg PO b.i.d. d 2–3

Dopamine antagonists Metoclopramide

2–3 mg IV prechemotherapy

0.5 mg/kg or 20–40 mg PO q.i.d d 2–5

Repeat 2 h postchemotherapy Prochlorperazine

10 mg IV or PO every 3–4 h p.r.n

Adverse reactions Nausea & vomiting

Radiation-Induced Nausea and Vomiting • related to the size of the radiation field, the dose per fraction, and the site of irradiation • exact mechanism of radiationinduced emesis remains unclear – Central – peripheral Adverse reactions Nausea & vomiting

Oral Complications • chemotherapy- and radiation therapy–related stomatitis and associated oropharyngeal pain • xerostomia • oral infection • oral chronic graft-versus-host disease (cGVHD) Adverse reactions Oral complications

Table 54.2-1: Patient- and Treatment-Related Risk Factors for Stomatitis Patient-related Age older than 65 y or younger than 20 y Gender Poor oral health and hygiene Periodontal diseases Microbial flora Chronic low-grade mouth infections Salivary gland secretory dysfunction Herpes simplex virus infection Inability to metabolize chemotherapeutic agent effectively Poor nutritional status Exposure to oral stressors such as alcohol and smoking Ill-fitting dental prostheses Treatment-related Radiation: dose, schedule Chemotherapy: drug, dose, schedule Myelosuppression Neutropenia Immunosuppression Reduced secretory immunoglobulin A Oral care during treatment

Adapted from Barasch A, Peterson DE 1999 Dodd MJ, Miaskowski C, Shiba GH, et al, 2003

Infections: bacterial, viral, fungal Use of antidepressants, opiates, antihypertensives, antihistamines, diuretics, and sedatives Impairment of renal and/or hepatic function Protein or calorie malnutrition, and dehydration Xerostomia

Adverse reactions Oral complications

Chemotherapy induced stomatitis • 40% of chemotherapy patients develop stomatitis • approximately 50% of these patients develop severe painful lesions requiring treatment modification or parenteral analgesia • patients undergoing BMT have high incidence rates of stomatitis of more than 60% Adverse reactions Oral complications

Chemotherapy induced stomatitis • asymptomatic erythema • progresses from solitary, white, elevated desquamative patches that are slightly painful to large, contiguous, pseudomembranous, painful lesions Adverse reactions Oral complications

Radiation Therapy–Induced Stomatitis • universal when radiation therapy includes the oropharyngeal area • severity dependent on – type of ionizing radiation – volume of irradiated tissue – dose per day – cumulative dose – duration of radiotherapy Adverse reactions Oral complications

Graft versus Host Disease • an alloimmune condition derived from an immune attack mediated by donor T cells recognizing antigens expressed on normal tissues • 80% of patients who have extensive cGVHD have some sort of oral involvement Adverse reactions Oral complications

Oral cGVHD • presents with – tissue atrophy and erythema – lichenoid changes (hyperkeratotic striae, patches, plaques, and papules) – pseudomembranous ulcerations occurring typically on buccal and labial mucosa and the lateral tongue, angular stomatitis – xerostomia Adverse reactions Oral complications

Prevention & Treatment • Pretreatment oral/dental stabilization – to eliminate sites of oral infection and trauma – provide adequate cleaning – encourage appropriate oral hygiene

• Frequent oral cavity assessment is necessary to capture clinical signs before, during, and after the treatment time course • Pain management Adverse reactions Oral complications

Prevention & Treatment • Sialogogues – Pilocarpine • side effects of glaucoma, cardiac problems, and sweating

• Amifostine (Ethyol) – 200 mg/m2 as a 3-minute IV infusion 15 to 30 minutes before each fraction of radiation

• Oral hygiene regimens – reduce colonization and proliferation of oral pathogens – water or saline Adverseatreactions – daily fluoride application with brushing teeth least Oral complications three times daily.

Prevention & Treatment • Direct Cytoprotectants:Sucralfate – Not efficacious in 5FU induced or radiation induced stomatis but patients reported less pain

• Benzydamine – nonsteroidal agent with analgesic, anesthetic, antiinflammatory, and antimicrobial properties – efficacious for both stomatitis and radiation therapy–induced stomatitis

• Steroid mouthwashes • Allopurinol

Adverse reactions Oral complicatons

The physician recommended the following regimen for adjuvant chemotherapy: 4 cycles of Doxorubicin + Cyclophosphamide followed by 4 cycles of Paclitaxel with Trastuzumab for one year and radiation to the chest wall and axilla

What particular toxicities should he watch out for? A. B. C. D. E.

Cardiotoxicity Neurotoxicity Pulmonary toxicity Hypersensitivity reactions All of the above

Cardiotoxicity • Mediastinal radiation • Drugs – Anthracyclines • Doxorubicin

– – – – – –

Mitoxantrone Cyclophosphamide Ifosfamide Paclitaxel Docetaxel 5-fluorouracil

• Monoclonal antibodies: trastuzumab Adverse reactions

Acute Anthracycline induced cardiotoxicity • rare, but reversible • presents as a myocarditis, with or without pericarditis • may result in transient congestive heart failure (CHF)/arrhythmias

Adverse reactions Cardiac

Delayed Anthracycline induced cardiotoxicity • irreversible, dilated cardiomyopathy • presents clinically as – – – – – – –

fatigue dyspnea on exertion orthopnea sinus tachycardia S3 gallop rhythm pedal edema/pleural effusions elevated jugular venous distention Adverse reactions Cardiac

Risk factors for Cardiomyopathy • Cumulative dose – 5% risk is seen • • • •

450 900 935 223

mg/m2 mg/m2 mg/m2 mg/m2

for for for for

doxorubicin daunorubicin epirubicin idarubicin

• Cofactors – mediastinal irradiation – older (particularly older than 70 years) or younger (younger than 15 years) age – coronary artery disease (CAD), other valvular or myocardial conditions – hypertension

Adverse reactions Cardiac

Diagnosis • compare baseline with serial left ventricular function studies using radionuclide imaging or echocardiography, or both

Adverse reactions Cardiac

Pulmonary Toxicity: Clinical Presentation

• dyspnea • nonproductive cough or a cough productive of small amounts of pinkish sputum • fever is unusual • signs of pulmonary involvement are minimal • occasionally, moist rales, a pleural friction rub, or evidence of pleural fluid may be heard over the area of Adverse reactions irradiation

Chemotherapeutic agents associated with pulmonary toxicity Chemotherapeutic agent Bleomycin

Incidence

Mitomycin

3–14%

Carmustine (BCNU)

20–30%

Methotrexate

2–8%

Paclitaxel

3–10% (acute hypersensitivity)

up to 10%

•Rare: Busulfan,Cyclophosphamide,Chlorambucil,Melphalan,Docetaxel

Adverse reactions Pulmonary

Mechanisms • direct toxic effect on alveolar epithelial cells • induction of an inflammatory immunologic response • endothelial cell injury or activation causing capillary leak syndrome Adverse reactions Pulmonary

Radiation Pneumonitis • 5% to 15% of patients receiving highdose external-beam radiation for treatment of lung cancer • Factors that can add to the development of radiation pneumonitis – concomitant chemotherapy – previous irradiation – withdrawal of steroids Adverse reactions Pulmonary

Neurotoxicity • Vinca alkaloids • Cisplatin , Oxaliplatin • Thalidomide • Cytarabine • Ifosfamide • Methotrexate • Paclitaxel , docetaxel

Adverse reactions

Vincristine Neurotoxicity • Axonal injury with relative preservation of the myelin sheath • Peripheral, central or autonomic nervous system • most common and initial manifestations – depression of the deep tendon reflexes Adverse reactions Neurotoxicity – paresthesias of the distal extremities

Vincristine Neurotoxicity • Motor dysfunction and gait disorders are initially manifested as lower extremity weakness • Cranial nerves may be affected and cause ophthalmoplegia and facial palsy • Toxicity to the parasympathetic nervous system is manifested by constipation and difficult micturition • Autonomic neuropathy can also produce orthostatic hypotension (which can be symptomatic or clinically silent) and erectile and ejaculatory dysfunction Adverse reactions

Hypersensitivity reactions • l-Asparaginase produces hypersensitivity reactions in 10% to 20% of patients – polypeptide of bacterial origin, displaying multiple antigenic sites that can stimulate production of immunoglobulin E (IgE) or other immunoglobulins – acute onset of wheezing, pruritus, rash, angioedema, extremity pain, agitation, and hypotension

Adverse reactions

Hypersensitivity reactions • Paclitaxel – Frequency : 5% – Cremophor EL excipient used to maintain solubility of paclitaxel – most often (more than 70% of the time) occur with the first drug dose suggests a nonimmunologic mechanism

• Docetaxel

Adverse reactions

Hypersensitivity to Taxanes

• clinical manifestations of type I hypersensitivity reaction – bronchospasm and wheezing, agitation, chest and back pain, rash, angioedema, and hypotension – onset is usually within minutes of starting a drug infusion – even very small drug doses are capable of initiating a reaction • apparent hypersensitivity that may be delayed in onset is pulmonary infiltrates typical of a hypersensitivity pneumonitis that may either Adverse reactions resolve spontaneously or after corticosteroid therapy

Prophylaxis vs. Hypersensitivity • Infusion over 1 to 3 hours • Premedication with corticosteroids and antihistamines

Adverse reactions

Hepatotoxicity • direct effect of either the parent drug or a metabolite • acute event • serum hepatic enzymes rise as cellular damage occurs • fatty infiltration & cholestasis may occur as the toxic effect Adverse reactions progresses.

Causes of Enzymatic Abnormalities • hepatic metastases • viral hepatitis • drugs administered for other therapeutic purposes (e.g., antiemetics) Adverse reactions

Table 54.8-3: Antitumor Agents That Cause Hepatotoxicity High potential for hepatotoxicity L-Asparaginase

Interferons (in high doses)

Cytarabine

Methotrexate (long-term therapy)

Gemtuzumab ozogamicin

Streptozocin

High potential for hepatotoxicity with high doses Busulfan

Dactinomycin

Carmustine (BCNU)

Methotrexate

Cyclophosphamide

Mitomycin

Cytarabine Occasional irreversible hepatotoxicity Busulfan (in high doses)

Gemcitabine

Carmustine (in high doses)

Methotrexate

Cytarabine

Mitomycin

Dacarbazine Isolated instances of hepatotoxicity Dacarbazine

6-Mercaptopurine

Chlorambucil

Pentostatin

Hydroxyurea

6-Thioguanine

Interferons (in low doses)

Vincristine

Adverse reactions

Drugs most likely to cause enzyme abnormalities • • • • • • • • • •

l-asparaginase carmustine in high doses cytarabine dactinomycin etoposide levamisole in combination with 5-FU 6-mercaptopurine methotrexate in high doses streptozocin vincristine. Adverse reactions

Nephrotoxicity • Manifestations range from rise in creatinine level or mild proteinuria to ARF requiring dialysis

Adverse reactions

Table 54.8-2: Antitumor Agents That Cause Nephrotoxicity High potential for nephrotoxicity Aldesleukin (interleukin-2)

Ifosfamide

Azacitidine

Methotrexate (in high doses)

Cisplatin

Mitomycin

Gallium nitrate

Streptozocin

Azotemia without nephrotoxicity L-Asparaginase

Dacarbazine

Occasional irreversible nephrotoxicity Cisplatin

Lomustine (CCNU)

Gallium nitrate

Mitomycin

Fludarabine

Pentostatin

Ifosfamide

Streptozocin

Interferons Isolated instances of nephrotoxicity Carboplatin

6-Mercaptopurine

Gemcitabine

Methotrexate (in low doses)

Adverse reactions

Cisplatin renal toxicity • dose related • cumulative • manifested primarily by a decrease in the glomerular filtration rate – clinically approximated by increases in the serum creatinine level and decreases in creatinine clearance

• electrolyte abnormalities such as hyponatremia and hypomagnesemia Adverse reactions

Prophylaxis for cisplatin nephrotoxicity • Hydration with normal saline – high chloride level inhibits cisplatin hydrolysis in the tubules which adds to the nephrotoxicity protection effect of diuresis

• Mannitol is also used to enhance diuresis • Monitor renal function & Adverse reactions electrolytes

Vascular toxicity • Veno-occlusive Disease • thrombotic microangiopathy with hemolytic uremic syndrome • venous or arterial thrombosis • vascular ischemia (involving cerebral, myocardial, or extremity arterial vessels) Adverse reactions

Gonadal Dysfunction Table 54.6-1: Impact of Cancer and Cancer Therapy on the Reproductive System Tumor

Direct gonadal involvement Reproductive tract involvement Hypothalamic and pituitary involvement Concern about heritability of cancer susceptibility

Surgery

Removal of gonad Genital mutilation Failure of emission and retrograde ejaculation Impotence and loss of orgasm

Radiotherapy or chemotherapy

Germ cell depletion Loss of gonadal hormones Mutagenic changes in germ cells Teratogenic effects on fetus

Chemotherapy

Seminal transmission of drug

Radiotherapy (cranial)

Loss of gonadotropic hormones

Adverse reactions

Gonadal dysfunction in men • After cytotoxic treatment, sperm count diminishes with a time course that depends on the sensitivities of the different spermatogenic cells and their kinetics of maturation to sperm • loss of germ cells has secondary effects on the hypothalamic-pituitary-gonadal axis Adverse reactions

Gonadal dysfunction in women

• temporary amenorrhea

– may occasionally last several years – often a result of direct ovarian damage, which causes loss of maturing follicles or failure of follicular recruitment – alternative causes: stress, malnutrition, or weight loss alter hypothalamic activity and estrogen metabolism Adverse reactions – age independent

Gonadal dysfunction in women • permanent amenorrhea – may begin during chemotherapy or subsequently, after several years of oligomenorrhea – dramatically and continuously increases with age at treatment

Adverse reactions

Second cancers • Not all second cancers are due to therapy • Other causes: – host influences • genetic susceptibility • immunodeficiency

– – – –

common carcinogenic influences clustering of risk factors diagnostic surveillance chance event Adverse reactions

Second cancers • Radiation induced – Leukemia – Breast cancer – Lung cancer

• Chemotherapy related – AML • Alkylating agents • Topoisomerase II inhibitors Adverse reactions