Essentials. Oncology Practise Essentials. Oncology Basics. Tutorial 5. Toxicity of Chemotherapy Agents

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Gregory Price
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Toxicity of This tutorial reviews the common clinical toxicities of chemotherapy gastrointestinal, dermatological, secondary malignancies, and infertility and their treatment and management.

2 Toxicity of This tutorial reviews the common clinical toxicities of chemotherapy gastrointestinal, dermatological, secondary malignancies, and infertility and their treatment and management. Goals and Objectives Classify common side effects of chemotherapy. Describe the causes of chemotherapy-induced nausea and vomiting. Describe the pharmacologic treatments for chemotherapy-induced nausea and vomiting. Identify the causes of chemotherapy-induced diarrhea, constipation and oral mucositis. Describe the causes of chemotherapy-induced dermatologic toxicity, secondary malignancies and infertility. 58

3 Side effects of chemotherapy Generally, chemotherapy is administered at the maximum tolerated dose based on a doseresponse relationship. The higher the dose, the more effectively the tumour burden is reduced despite toxicity and patient discomfort. The organ systems and tissues most susceptible to the toxic effects of chemotherapy are those comprised of rapidly dividing cells (e.g. bone marrow, epithelial lining of the gastrointestinal tract and oral mucosa, hair follicles, gonads). this nature is generally reversible and not cumulative. Other organ systems such as the heart and lungs are also subject to the toxic effects of chemotherapy these toxicities are usually cumulative and irreversible. Sterility and secondary malignancies may also be dose-dependent and irreversible. Classification of Side Effects Side effects of chemotherapy can be classified according to the time of onset and symptoms: Immediate (hours to days) such as nausea, vomiting, diarrhea and extravasation Early (days to weeks) such as alopecia and neuropathy Delayed (weeks to months) such as pulmonary toxicity Late (months to years) such as secondary malignancies, sterility and cardiomyopathy Most cancer institutions use standardized objective criteria, such as the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, to grade toxicities and ensure patient assessment is consistent. Toxicities of chemotherapy are often graded on a scale of 0 to 4, with 0 indicating no toxicity and 4 indicating the most severe manifestations of a specific toxicity. For example: Grade 1 neutropenia refers to a reduction in neutrophil counts to x 10 9 cells/l which usually permits further treatments Grade 4 neutropenia refers to neutrophil counts of < 0.5 x 10 9 cells/l which require holding further treatment until blood counts recover Several factors influence patient risk for chemotherapy-related side effects including age, pharmacokinetic factors (absorption, metabolism, and excretion), previous chemotherapy or radiation therapy, nutritional status, type of cancer, medical history, and other medications. Dose-limiting toxicity is a term commonly used when referring to chemotherapy toxicity. This term refers to a drug-related adverse effect that, if severe enough, would necessitate a delay or discontinuation of therapy. 59 acpho.org

4 Gastrointestinal Toxicity Nausea and Vomiting Nausea and vomiting are chemotherapy s most commonly reported side effects, and often cause patients the most distress and anxiety. If this toxicity is not managed effectively, it can lead to poor compliance, lack of willingness for continued treatment, as well as anorexia and extreme fatigue. Pathogenesis Vomiting is caused by activation of the vomiting center (VC) in the lateral reticular formation of the brain stem medulla, which sends efferent signals to effector organs (abdominal muscles, diaphragm, stomach, and esophagus). The VC is triggered in at least four different ways, by: Peripheral visceral vagal afferents Chemoreceptor trigger zone (CTZ) Vestibular apparatus Cortical psychogenic pathways Of these, the most important mechanism in chemotherapy-induced nausea and vomiting involves the peripheral visceral vagal afferents and the neurotransmitter serotonin. Chemoreceptors in the splanchnic (visceral) plexus of the upper gastrointestinal tract are stimulated in the presence of irritants, sending messages along vagal afferents through the tenth cranial nerve, which reaches the VC. Severing the tenth cranial nerve in animal models has been shown to delay cisplatininduced emesis as well as reverse emesis due to gastrointestinal irritation. The CTZ, located in the postrema area of the fourth ventricle, lies outside the blood brain barrier. It is, therefore, directly exposed to circulating noxious drugs and neurotransmitters. Numerous neurotransmitter receptors are located in the vomiting center, CTZ and GI tract, including cholinergic, histaminic, dopaminergic, opiate, serotonergic, neurokinin, and benzodiazepine receptors. Chemotherapeutic agents trigger the process of emesis by stimulating one or more of these receptors. Effective antiemetics are able to antagonize the emetogenic receptors. Chemotherapy agents are classified according to emetogenic potential. The table below indicates the incidence of nausea and vomiting without the use of antiemetic therapy. Minimal Mild Moderate High < 30% 30-60% 60-90% > 90% 60 acpho.org

5 Nausea and vomiting are further classified as: Acute (within one to two hours post-chemotherapy) Delayed (> 24 hours post-chemotherapy) Breakthrough (occurs during antiemetic therapy) Anticipatory (occurs as a conditioned response prior to receiving chemotherapy) Drug-related risk factors for development of chemotherapy-induced nausea and vomiting include: Emetogenicity of the drug Combination chemotherapy regimens High doses Rapid rate of infusion (shorter infusions have a greater peak effect) Patient-related risk factors include: Previous lack of success in managing chemotherapy-induced emesis Women and children (compared to men) Susceptibility to motion sickness History of chronic alcohol use may be a negative risk factor as this makes CTZ less sensitive Pharmacological Antiemetic Agents Serotonin (5-HT3) receptor antagonists: These agents selectively block serotonin type 3 receptors on vagal afferents and the CTZ. They are indicated in the prevention of acute emesis in moderate and highly emetogenic protocols. All agents are comparable in efficacy and are synergistic with steroids. Examples of 5-HT3 receptor antagonists include ondansetron and granisetron. Substance P/Neurokinin 1 receptor antagonists: Substance P is a peptide neurotransmitter in the neurokinin (NK) family with the preferred receptor being the NK1 receptor. The acute phase of chemotherapy-induced nausea and vomiting is believed to involve both serotonin and substance P, but the delayed phase is mediated mainly by substance P. Aprepitant (oral formulation) and fosaprepitant (IV formulation) are substance P/NK1 receptor antagonists used to prevent acute and delayed chemotherapy-induced nausea and vomiting. It can augment the antiemetic effects of 5-HT3 receptor antagonists and steroids. Aprepitant is a substrate and a moderate inhibitor of CYP3A4, and has the potential for numerous drug interactions. 61 acpho.org

6 Dopamine antagonists: All of these agents block dopamine receptors on the CTZ. Examples include phenothiazines (e.g. prochlorperazine), substituted benzamides (i.e. metoclopramide), and butyrophenones (e.g. haloperidol). Dopamine antagonists are used in mild, moderate and highly emetogenic chemotherapy protocols. Antihistamines: Dimenhydrinate may be added on an as-needed basis to control acute symptoms. Steroids: The mechanism of action of steroids in the prevention of nausea is not clearly understood. Dexamethasone is the most commonly used agent in this class. Steroids can be used in combination with other agents for highly and moderately emetogenic chemotherapy, or used alone for mildly emetogenic chemotherapy. Benzodiazepines: These agents possess anxiolytic, sedative, and antiemetic properties. They are useful in combination with other antiemetic agents, particularly in the prevention of anticipatory nausea and vomiting. Lorazepam is the most commonly used agent. Cannabinoids: Dronabilone and nabilone are synthetic cannabinoids possessing entiemetic and appetite-stimulant properties. These agents are not commonly used, and only considered when other regimens do not provide the desired efficacy. Antiemetic Therapy The treatment goal of antiemetic therapy should be no or mild nausea, and no vomiting. Achieving this goal is a challenge, especially with highly emetogenic chemotherapy such as cisplatin (doses > 50 mg/m 2 ). The prevention and treatment of anticipatory nausea is also challenging because the underlying mechanism is unclear. The more a patient experiences emesis throughout treatment, the more difficult it is to control. It is, thus, imperative to prevent and control chemotherapy-induced nausea and vomiting early in the treatment course to achieve successful patient outcomes. The emetogenic potential of a chemotherapy protocol should be known, with consideration that: Emetogenicity is additive with combination therapy (i.e. two moderately emetogenic agents in combination is more emetogenic than either agent alone). Emetogenic potential may decrease or increase over the course of treatment (patients may need more aggressive antiemetic treatment on the last day of a three-day etoposide/cisplatin lung protocol). 62 acpho.org

7 A number of treatment algorithms exist for chemotherapy-induced nausea and vomiting: American Society of Clinical Guidelines for Antiemetics (see Multinational Association of Supportive Care in Cancer Antiemetic Guidelines (see www. mascc.org) BC Cancer Agency Guidelines for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults (see SupportiveCare/default.htm) CancerCare Ontario Recommendations for the Prevention and Treatment of Nausea and Vomiting Related to Cancer Chemotherapy (see Diarrhea The epithelial lining of the gastrointestinal tract (GIT) has rapid cellular turnover (replaced every three to five days) and is, therefore, susceptible to acute toxic effects of chemotherapy. While any chemotherapeutic agent can potentially cause diarrhea, the worst offenders are: irinotecan, capecitabine, fluorouracil, methotrexate, cytarabine, and high-dose chemotherapy prior to stem cell transplant. Diarrhea can be so severe with irinotecan that it is the dose-limiting toxicity for this drug. The mechanism by which chemotherapy causes diarrhea is not clearly understood. It is thought that chemotherapy agents exert a direct toxic effect on epithelial cells which leads to an inflammatory response with prostaglandin release, resulting in secretory diarrhea. Continuous infusions cause more diarrhea than short infusions. Other causes of diarrhea must also be considered, including: Graft versus host disease (GVHD) in allogeneic stem cell transplants (the GIT is one of the most common sites of attack) Secretory tumours such as in carcinoid syndrome Concomitant medications Bowel surgery The management of diarrhea includes hydration, nutritional support, anti diarrheal agents and sometimes dose reductions. 63 acpho.org

8 Constipation Although not a common side effect of chemotherapy, constipation can occur with vinca alkaloids, as a manifestation of the neurotoxic, autonomic effects. Constipation is often the first sign of neurotoxicity with vincristine and can be prevented with the regular use of a stimulant laxative. Constipation is also a major problem for cancer patients treated with opioids for cancer-related pain or serotonin (5-HT3) receptor antagonists for chemotherapy-induced nausea and vomiting. Oral Mucositis Due to the rapid turnover of the epithelial lining of the GIT, mucositis is a common toxicity associated with chemotherapy. It can range in severity from mild inflammation to bleeding ulcers. Mucositis usually presents five to seven days after chemotherapy, during the neutrophil nadir, when the immune system is most vulnerable. Risk factors include the use of continuous chemotherapy infusions and radiation therapy. Chemotherapy agents most commonly associated with mucositis include anthracyclines, fluorouracil, capecitabine, methotrexate, mechlorethamine, and stem cell transplant conditioning. Several therapies are available for the prevention and treatment of oral mucositis, all with varying degrees of effectiveness and all failing to demonstrate efficacy consistently in clinical trials. Strategies to minimize the effects of chemotherapy-induced mucositis include: Good dental hygiene Using a soft-bristled toothbrush Chewing on ice chips 30 minutes prior to chemotherapy for regimens that do not include oxaliplatin. Ice chips with oxaliplatin can induce an unusual sensory neuropathy called pharyngo-laryngeal dysesthesia where patients feel difficulty breathing, when their breathing is actually normal. Rinsing with club soda or sodium bicarbonate in water three to four times daily Decreasing solid oral intake and replacing solids with nutritional liquid supplements Avoiding commercial mouthwash When mucositis is complicated by an infection or when patients are at high risk of infection, antiviral agents may be used. Some commercial mouthwash and rinses may be beneficial these products may contain nystatin for oral candidiasis, chlorhexidine for gram-positive bacterial infections, hydrocortisone to reduce inflammation, and anesthetics (e.g. lidocaine and benzydamine) to relieve pain. Avoid mouthwash containing high alcohol content as these products may worsen symptoms. Analgesics may be required for pain control. 64 acpho.org

9 Dermatological toxicity Alopecia Hair follicles possess rapidly dividing cells and are, therefore, susceptible to the toxic effects of chemotherapy. Scalp hair is the most commonly affected area, as this hair generally grows most rapidly. Eyebrows, eyelashes, and other more slowly growing facial and body hair can also be affected by highly toxic agents such as taxanes, cyclophosphamide, and anthracyclines. Although reversible, alopecia can be a devastating toxicity for some patients. For this reason, it is important to forewarn patients of this risk so esthetic interventions can be made if desired. Chemotherapy agents most commonly associated with alopecia include: vincristine, anthracyclines, irinotecan, cyclophosphamide, topotecan, etoposide, docetaxel and paclitaxel. Dose, dosing interval, route, pharmacokinetics and combination drug therapy also play a role in predicting the degree of hair loss (e.g. oral cyclophosphamide causes less hair loss than intravenous cyclophosphamide). Categories include: Minimal hair loss < 25% of hair Moderate hair loss 25 to 50% Severe hair loss > 50% Unfortunately, there is no proven safe and effective preventative measures for alopecia. Patient counseling should cover: The risk for developing alopecia The severity of alopecia associated with the chemotherapy regimen The rationale for its occurrence The fact that it is reversible in most cases and may grow back differently in texture and colour (colour change is rare, but hair may grow back curly when previously straight, or thicker than before). Recommendations: Use soft-bristled hair brushes, mild shampoos, and satin pillow cases to decrease friction, and protect the head from sun to avoid sunburn. 65 acpho.org

10 Hypersensitivity Hypersensitivity reactions to chemotherapy can be local or systemic. Local toxicities occurring at or around the site of injection include rash, urticaria, erythema, phlebitis, pain and vein discolouration. Systemic hypersensitivity reactions include bronchospasm, angioedema, hypotension, generalized rash, pruritis, dermatitis, and a variety of other symptoms. Drugs most commonly associated with hypersensitivity reactions include: taxanes, bleomycin and monoclonal antibodies. Extravasation Extravasation is the escape of a drug from a vein to the surrounding tissue during intravenous administration, either by leakage or direct infiltration. The extent of morbidity depends on the drug, its concentration, the degree of extravasation, and whether the treatment for extravasation was delayed. Policies and procedures for drug administration generally provide guidance on the prevention and treatment of this complication. Causative Agents are Classified as Irritants and Vesicants Irritants are drugs that often produce a local venous response with or without a skin reaction. Effects of irritants are short term, and do not cause tissue necrosis. Irritant drugs include cisplatin (volume < 20 ml and concentrations < 0.5 mg/ml), dacarbazine, docetaxel, doxorubicin (liposomal), etoposide, fluorouracil, ifosfamide, mitoxantrone (may rarely act as a vesicant), paclitaxel, streptozocin and teniposide. Vesicants are drugs that produce a reaction so severe that plasma escapes from the extracellular space, forming blisters and tissue necrosis. Vesicant drugs include melphalan, carmustine, oxaliplatin, nab-paclitaxel, dactinomycin, mitomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, cisplatin (volume > 20 ml and concentrations > 0.5 mg/ml), mechlorethamine, vinblastine, vincristine and vinorelbine. Dimethylsulfoxide (DMSO) 99% topical solution may be used for the treatment of anthracyclineinduced extravasation. Dexrazoxane can be used for anthracycline-induced extravasation. Treatment should be initiated as soon as possible and within the first six hours post-extravasation. It is administered by IV infusion daily for three days. 66 acpho.org

11 Hand and Foot Syndrome Also known as palmar-plantar erythrodysesthesia (PPE), hand and foot syndrome can cause the palms of the hands and the soles of the feet to develop dryness, redness, numbness and tingling. In more severe cases, it can progress to swelling, blistering and severe pain. Agents that most commonly cause hand and foot syndrome are capecitabine, liposomal doxorubin, and continuous 5-fluorouracil infusions. Sorafenib and sunitinib can cause a type of hand and foot syndrome that may cause hyperkeratosis, in addition to the previously mentioned PPE symptoms. These symptoms usually appear in the first few cycles of therapy, but can also appear later in the course of therapy. Measures to prevent PPE include: Applying moisturizer to the hands and feet Avoiding hot water Avoiding activities that apply pressure to the skin of the hands and feet, including wearing tightfitting shoes or gardening activities. Note that gardening may also introduce bacteria that can complicate PPE. Secondary Malignancies Secondary malignancies are a long-term toxicity of cancer chemotherapy with presentation years to decades after completion of treatment. The most commonly implicated drugs are: Alkylating agents (chlorambucil, cyclophosphamide, ifosfamide, dacarbazine, procarbazine, mechlorethamine, and melphalan) Topoisomerase II inhibitors (etoposide, teniposide, doxorubicin, epirubicin and mitoxantrone) The risk for secondary malignancies from many other chemotherapy agents is still largely unknown because it requires long-term follow-up. The most common presenting secondary malignancies are acute myelogenous leukemia and myelodysplastic syndromes. Solid tumours as a secondary malignancy occur more commonly after treatment with radiation than with chemotherapy. 67 acpho.org

12 Infertility Infertility is another late effect of chemotherapy. In men, anticancer agents produce severe oligospermia or azoospermia, which may lead to infertility. Serum testosterone levels are rarely affected. The recovery of spermatogenesis after completion of chemotherapy is not predictable. Men who have received combination chemotherapy sustain more long-lasting adverse effects on fertility than do men who have received single-agent treatment. Age, total dose, duration of therapy and type of drug are other variables. In women, chemotherapy can cause amenorrhea, vaginal epithelial atrophy, and menopausal symptoms. Younger patients are more resistant to the effects on the ovaries. Again, the recovery of fertility is unpredictable. Alkylating agents appear to exert profound and consistently detrimental effects on reproductive function. Less is known about other agents such as doxorubicin, taxanes and platinum compounds. 68 acpho.org

Managing Adverse Events in the Cancer Patient. Learning Objectives. Chemotherapy-Induced Nausea/Vomiting

Managing Adverse Events in the Cancer Patient Lisa A Thompson, PharmD, BCOP Assistant Professor University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences Learning Objectives Describe