Supportive care in cancer

Cancer is a complex medical condition, with numerous subtypes, which leads to uncontrolled proliferation of abnormal cells that have the potential to metastasize to different areas in the body. Many cancer treatments aim to inhibit cancer cell growth and kill cancer cells, which may also negatively impact normal cells, particularly cells that are rapidly dividing. Supportive care in cancer includes interventions that mitigate the adverse effects of cancer and cancer treatment, including physical, psychosocial and spiritual considerations for patients.1 This article addresses common supportive care topics such as chemotherapy-induced nausea and vomiting, skeletal complications of cancer, immune-related adverse events of cancer therapy, and cancer pain management for adult patients who are receiving oral and/or intravenous (IV) cancer drug therapy. Chemotherapy-induced nausea and vomiting (CINV) When chemotherapy molecules circulate in blood, they are detected by the chemoreceptor trigger zone, which activates the vomiting centre in the medulla region of the brainstem to induce nausea and vomiting. This complex process involves the release and activation of multiple neurotransmitters and receptors, including dopamine, serotonin and 5-hydroxytryptamine (5-HT3) receptors, and substance P and its neurokinin-1 (NK1) receptor.2-4 Peripheral vagal afferent nerve activation of cholecystokinin in the gastrointestinal tract also contributes to CINV.2-4 There are four main types of CINV: 1) acute (which occurs within the first 24 hours of chemotherapy administration, 2) delayed (which occurs at least 24 hours after chemotherapy administration), 3) breakthrough (which occurs anytime throughout the dosing intervals of antinausea medications during the acute and/or delayed phases), and 4) anticipatory nausea and vomiting (which is a conditioned response that occurs in anticipation of receiving chemotherapy due to poor control of CINV previously).2-4 Chemotherapy agents have varying potential to induce CINV, if prophylactic antiemetics are not used. They can be highly emetogenic (greater than 90% likelihood of causing CINV), moderately emetogenic (30%–90% likelihood of causing CINV), have low emetogenicity (10%–29% likelihood of causing CINV) or be minimally emetogenic (< 10% likelihood of causing CINV).2-5 The goal of CINV management is to ensure patients do not experience any nausea or vomiting during any cycle of chemotherapy.2-5 It is much easier to prevent CINV than it is to treat it. The choice of drug therapy for the prevention and treatment of CINV depends on the emetogenic potential of chemotherapy and the type of CINV the patient is at risk for or is experiencing.2-5 Table 1 provides examples of antiemetic regimens used for management of CINV, which can be utilized as general guidance and not in place of appropriate clinical judgement in specific patient care scenarios, while considering type and duration of cancer therapy, patient age, comorbidities, renal/hepatic function, drug interactions, and potential for QTc prolongation.5 Skeletal complications of cancer Cancer cells may rarely form in the bone or may more commonly metastasize from the primary (original) cancer site to other areas in the body, including the bone. This can lead to complications, such as hypercalcemia, bone pain, pathological fractures and spinal cord compression.6-9 In the bone, cancer cells can adversely affect osteoblast and osteoclast activity, while altering calcium regulation, and cause increased bone resorption. The most common types of cancer that may lead to bone metastasis include thyroid, breast, lung, kidney, ovarian, prostate and melanoma. Patients with multiple myeloma (cancer of plasma cells) are also at risk for bone complications, as their cancer may directly affect the bone marrow and cause skeletal erosions.6-9 Skeletal complications of cancer are investigated by evaluating the patient’s signs and symptoms, including free/ionized serum calcium level, confusion, fatigue, dehydration, polydipsia, anorexia, nausea, constipation, polyuria, myopathy and pain, as well as imaging (X-ray, bone scan/CT/PET/MRI) and a bone marrow biopsy.6-9 Cancer-related hypercalcemia and skeletal complications are managed through supportive care measures and drug therapy. Supportive care includes symptomatic management and hydration, while drug therapy includes treatment with bisphosphonates or denosumab.6-9 Figure 1 provides a therapeutic approach for managing bone complications due to cancer.10 Immune-related adverse events of cancer therapy As cancer therapy evolves from traditional chemotherapy to include more targeted therapies and biologic agents, we recognize the important role that the immune system plays in getting rid of cancer cells. As such, immunotherapy, such as checkpoint inhibitors (e.g., pembrolizumab), have become a pertinent component of treatment for many types of cancer, including head and neck cancer, nonsmall cell lung cancer, kidney cancer, bladder cancer, melanoma and lymphoma.11,12 These medications target T-lymphocyte-associated antigen 4 (CTLA-4) and/or programmed cell death protein-1 (PD-1) and/or programmed cell death ligand-1 (PD-L1) receptors, thus enhancing T cell cytotoxic activity against cancer cells.12 Overactivation of T cells can lead to immune-related adverse events (irAEs) for patients. These present as autoimmune conditions that can affect any organ in the body, including the pituitary and thyroid glands (hypopituitarism, hypo/hyperthyroidism, thyroiditis), heart (myocarditis), lungs (pneumonitis), stomach (gastritis), intestine (diarrhea, enterocolitis), kidneys (nephritis), liver (hepatitis) and skin (rash, pruritus, dermatitis), and can be life-threatening.11-14 Although these irAEs often occur during the first three months of therapy, they may occur at any time, including after treatment discontinuation.11-14 Treatment of moderate–severe irAEs includes withholding immunotherapy, followed by referral to a specialist and prompt initiation of high-dose glucocorticoids (e.g., prednisone 1–2 mg/kg/day orally or methylprednisolone 1–2 mg/kg/day IV) for several weeks, until such time that the patient’s symptoms are well-controlled.11,13,14 For patients experiencing uveitis, iritis or episcleritis, the use of glucocorticoid eye drops (e.g., prednisolone acetate 1% or dexamethasone 0.1%, 1–2 drops in the affected eye(s) 4 times daily) is recommended.14-16 While some patients require long-term immunosuppressive therapy, others benefit from the resolution of their irAEs and may not need ongoing immunosuppressive therapy. Although most patients respond well to glucocorticoid therapy, some experience steroid-refractory irAE, and are at an increased risk for complications and mortality. These patients are often managed with nonsteroidal immunosuppressive agents, such as cyclophosphamide, mycophenolate mofetil, IV immune globulin or monoclonal antibodies, such as infliximab, which target tumour necrosis factor alpha (TNF-α), a proinflammatory cytokine.13,14 Preventive strategies for irAEs are currently being investigated and include identification of predictive biomarkers for irAEs, improvement of the gut microbiome, and understanding the role of human leucocyte antigen (HLA) genes in regulating immune responses.11,13 Cancer pain Up to 70% of patients with cancer experience pain.17,18 Factors contributing to cancer pain include advanced disease, infiltration of cancer cells into bone and other tissues, release of inflammatory mediators, and cancer complications such as obstruction, perforation, fracture, infection, hemorrhage or thrombosis.19-21 Cancer pain can be either acute or chronic.19,21 Acute cancer pain may be due to diagnostic procedures (e.g., a biopsy), mechanical interventions (e.g., placement of stents), surgery, chemotherapy infusion (e.g., phlebitis) and/or treatment-related side effects (e.g., oral mucositis).19,21 Chronic cancer pain may be due to disease activity/complications, progression (e.g., bone metastases) and/or treatment-related adverse effects, such as neuropathic pain (e.g., oxaliplatin-induced peripheral neuropathy).19,21 When evaluating cancer pain, it is crucial to capture a thorough disease and medication history from the patient, and to analyze the location (e.g., local, regional, multifocal), type (e.g., nociceptive: sharp, aching, throbbing; neuropathic: radiating, shooting, burning, tingling; referred: pain experienced away from site of origin), severity (e.g., mild, moderate, severe and/or “on a scale of 0–10”), duration, and exacerbating/mitigating factors that may lead to breakthrough/incident pain.19-21 This information would assist with identifying specific causes of cancer pain, which can lead to more successful treatment and improvement in the patient’s quality of life. Cancer pain is managed through a variety of pharmacological interventions, depending on individual patient circumstances, pain type and cause, frequency, severity and duration.17-19,21-23 Table 2 provides examples of treatment options for cancer pain. Oral methadone is an additional therapeutic option for refractory cancer pain, including nociceptive and neuropathic pain. Given its long and unpredictable half-life, autoinducible hepatic metabolism, potential for arrhythmias/QTc prolongation and drug interactions, it should be prescribed by experienced pain and palliative care providers.17,22 Fentanyl transdermal patch, which is more potent than morphine, may also be considered for patients with moderate–severe chronic and stable cancer pain, including those with swallowing difficulties, intractable nausea/vomiting or poor adherence.18,22 Its slow-release formulation must be avoided for acute pain syndromes or in opioid-naïve patients.22,24 It should be prescribed by experienced providers. Additional therapeutic interventions for refractory cancer pain include the use of parenteral ketamine or lidocaine in the hospital setting.25,26 Other modalities that may alleviate cancer pain include interventional (e.g., neural blockade), rehabilitative (e.g., exercise), psychological (e.g., cognitive behavioural therapy), neurostimulation (e.g., transcranial) and integrative therapies (e.g., acupuncture).17,19,27 Pharmacist’s role Pharmacists play an important role in the provision of supportive care for patients with cancer and in monitoring for the effectiveness and safety of drug therapy. By following up regularly with patients, pharmacists can detect persistent signs and symptoms (e.g., ongoing pain and nausea), while identifying and resolving drug therapy problems through comprehensive medication reviews. Combination of cancer treatments with supportive care medications may put patients at risk for additional adverse events, such as confusion, drowsiness, respiratory depression, QT prolongation, constipation and falls, and lead to pharmacokinetic (e.g., CYP450 induction/inhibition) and pharmacodynamic (e.g., increased risk of bleeding) interactions.28 Pharmacists can educate patients and healthcare professionals about medication optimization, prevent/minimize adverse events and drug interactions, and improve medication adherence, while facilitating timely access to affordable medications. Summary Cancer and its treatment are associated with significant complications, requiring timely initiation of supportive care, to alleviate patients’ signs and symptoms and improve their quality of life. Pharmacists, as medication experts, are in a great position to enable supportive care optimization for patients with cancer, while monitoring for potential adverse drug reactions and interactions. Shirin Abadi (sabadi@bccancer.bc.ca) is the Pharmacy Clinical and Education Coordinator at BC Cancer, in Vancouver, BC, and a clinical professor at the University of British Columbia. She has reviewed the literature on supportive care in cancer and has given presentations on this topic. References: National Cancer Institute. NCI dictionary of cancer terms: supportive care. (accessed May 3, 2023). Tilleman JA. Chemotherapy-induced nausea and vomiting. US Pharm 2018;43(2):2-5. Navari RM, Aapro M. Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med 2016;374:1356-67. Rao KV, Faso A. Chemotherapy-induced nausea and vomiting: optimizing prevention and management. Am Health Drug Benefits 2012;5(4):232-40. Den Brok W. BC Cancer guidelines for prevention and treatment of chemotherapy-induced nausea and vomiting in adults. BC Cancer Protocol Summary SCNAUSEA 2022:1-8. (accessed May 5, 2023). Subbiah V, West HL. Bone complications in patients with cancer. JAMA Oncology 2016;2(5):695. Seccareccia D. Cancer-related hypercalcemia. Can Fam Physician 2010;56:244-6. Tsukamoto S, Kido A, Tanaka Y, et al. Current overview of treatment for metastatic bone disease. Curr Oncol 2021;28:3347-72. Tsuzuki S, Park SH, Eber MR, et al. Skeletal complications in cancer patients with bone metastases. Int J Urol 2016;23(10):825-32. Van Poznak C, Clemons M. Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors. UpToDate. December 20, 2022. (accessed May 5, 2023). Conroy M, Naidoo J. Immune-related adverse events and the balancing act of immunotherapy. Nat Commun 2022;13(392):1-4. Weinmann SC, Pisetsky DS. Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors. Rheumatology 2019;58:vii59-67. Choi J, Lee SY. Clinical characteristics and treatment of immune-related adverse events of immune checkpoint inhibitors. Immune Netw 2020;20(1):e9-30. Savage K. BC Cancer protocol summary for management of immune-mediated adverse reactions to checkpoint inhibitor immunotherapy. BC Cancer Protocol Summary SCIMMUNE 2022: 1-15. (accessed May 5, 2023). Shahzad O, Thompson N, Clare G, et al. Ocular adverse events associated with immune checkpoint inhibitors: a novel multidisciplinary management algorithm. Ther Adv Med Oncol 2021;13:1-12. Yu-Wen Zhou, Qian Xu, Yan Wang, et al. Immune checkpoint inhibitor-associated ophthalmic adverse events: current understanding of its mechanisms, diagnosis, and management. Int J Ophthalmol 2022;15(4):646-56. Chapman EJ, Edwards Z, Boland JW, et al. Practice review: evidence-based and effective management of pain in patients with advanced cancer. Palliat Med 2020;34(4):444-53. World Health Organization. WHO guidelines for the pharmacological and radiotherapeutic management of cancer pain in adults and adolescents. Geneva; 2018. Licence: CC BY-NC-SA 3.0 IGO. Gress KL, Charipova K, Kaye AD, et al. An overview of current recommendations and options for the management of cancer pain: a comprehensive review. Oncol Ther 2020;8:251-9. Haroun R, Wood JN, Sikandar S. Mechanisms of cancer pain. Front Pain Res 2023;3:1030899. doi: 10.3389/fpain.2022.1030899. Portenoy RK, Dhingra LK. Overview of cancer pain syndromes. UpToDate. February 21, 2022. (accessed May 8, 2023). Portenoy RK, Mehta Z, Ahmed E. Cancer pain management with opioids: optimizing analgesia. UpToDate. January 24, 2023. (accessed May 8, 2023). Portenoy RK, Ahmed E, Keilson YY. Cancer pain management: role of adjuvant analgesics (coanalgesics). UpToDate. December 16, 2022. (accessed May 8, 2023). Weaver JM. Multiple risks for patients using the transdermal fentanyl patch. Anesth Prog 2014;61:1-2. Lee J, Currow D, Lovell M, et al. Lidocaine for neuropathic cancer pain (LiCPain): study protocol for a mixed-methods pilot study. BMJ Open 2023;13:e066125. doi:10.1136/bmjopen-2022-066125. Chong PH, Yeo ZZ. Parenteral lidocaine for complex cancer pain in the home or inpatient hospice setting: a review and synthesis of the evidence. J Palliat Med 2021;24(8):1154-60. Strada EA, Portenoy RK. Rehabilitative and integrative therapies for pain in patients with cancer. UpToDate. December 23, 2022. (accessed May 8, 2023). Miranda V, Fede A, Nobuo M, et al. Adverse drug reactions and drug interactions as causes of hospital admission in oncology. J Pain Symptom Manage 2011;42:342-53.

Supportive care in cancer

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