Systemic Anticancer Therapies and the Role of Primary Care

■ THERAPY FOCUS

Systemic anticancer therapies and the role of primary care

SAMUEL W D MERRIEL AND WILLIE HAMILTON

Supporting cancer patients receiving systemic cancer therapies requires a multidisciplinary approach, and primary care plays a key role in identifying and managing the physical effects of treatment, providing psychosocial support and arranging specialist review. This article discusses the management of patients receiving systemic cancer therapies from a primary care perspective.

ancer therapeutics are complex, constantly evolving, and aim Cto prolong the life of a patient with cancer by cure, inducing remission, or by slowing disease progression. Cancer treatments can be delivered locally directly against the tumour (ie surgery or radiotherapy) or systemically (ie chemotherapy or hormone therapy). Systemic therapies have traditionally been administered intravenously in a hospital or day unit setting; however, many of the more recently discovered systemic cancer therapies are taken as oral medications. They also pose significant potential risks to a patient’s health through side-effects, immunosuppres- sion, and later development of secondary cancers. This article focuses on systemic cancer therapies from a primary care perspective, and briefly describes recent develop- ments and classifications of systemic therapies. Key consider- ations around monitoring, potential treatment harms and patient support are also discussed to inform the delivery of primary care for cancer patients receiving systemic therapies.

Systemic therapies The breadth of cancer treatments available continues to grow over time as new treatments move from the bench to the bedside and into clinical practice. New classes of cancer therapeutics, such as immunotherapy and targeted therapy, have improved cancer outcomes for patients with certain tumours that previously held very poor prognoses (eg metastatic malignant melanoma or lung adenocarcinoma). Table 1 shows the broad treatment types available, as well as some of the more common subtypes. The classes of systemic cancer therapies include:1-4 • Chemotherapy – medications delivered in a number of ways (oral, intravenous, topical, intramuscular, intracavitary) that inhibit the cell cycle, exploiting the fact that cancer cells generally divide more rapidly than normal cells. The non-specific nature of the treatments means that cells in tissue other than the cancer are

22 ❚ Prescriber October 2020 prescriber.co.uk Systemic anticancer therapies l THERAPY FOCUS ■

also affected, particularly more rapidly dividing cells such as localised prostate cancer. The length of hormone therapy treat- those in the skin and gut. The efficacy of chemotherapy is varia- ment for men can also vary, depending on the indication. It ble, and some cancers can become chemoresistant (where the could be delivered intermittently, or by depot injection, if the tumour cells have a reduced response to the therapy). man will be receiving it long-term. • Targeted therapy – treatments that target specific genes, cell signalling pathways, or proteins that are unique to cancer cells Chemotherapy or to the cellular environment that enables tumour growth to IV cytotoxics Anthracyclines (eg doxorubicin) occur. Targeted therapies provide benefit by affecting primarily Antibiotics (eg bleomycin) abnormal cancer cells, while minimising the effects on normal Platinum-based drugs (eg cisplatin) cells. These medications are most commonly administered orally, and are usually metabolised by the liver. Oral alkylating eg temozolomide, chlorambucil, • Immunotherapy – a range of treatments that enable or agents cyclophosphamide, lomustine, melphalan enhance the ability of the patient’s own immune system to identify and eliminate cancer cells within the body. This can be Oral eg capecitabine, hydroxycarbamide, achieved using several techniques, including vaccines, antibod- antimetabolites mercaptopurine, tioguanine, methotrexate ies and oncolytic viruses. • Hormone therapy – the development and progression of breast Targeted therapies cancer in women and prostate cancer in men is often influenced by hormones. There are some other cancer types (eg ovarian, Growth Inhibitors Tyrosine kinase inhibitors (eg imatinib) endometrial) that have a lesser, but still important, response to Proteasome inhibitors (eg bortezomib) the hormonal environment in the body. Hormone therapy can be mTOR inhibitors (eg everolimus) used for primary treatment of advanced/metastatic cancer, as Anti-VEGF eg bevacizumab an adjuvant to reduce the risk of recurrence, or neoadjuvantly to reduce tumour size prior to localised treatments. PARP inhibitors eg olaparib • Stem cell/bone marrow transplant – haematological cancers can be treated by eliminating a patient’s bone marrow with Biological therapy/immunotherapy intensive chemotherapy and other treatments, and then replac- ing it with their own (autologous) cells or another person’s Immune checkpoint Anti-programmed cell death protein 1 (anti-PD-1) (donor) cells. inhibitors (eg nivolumab) Anti-programmed death ligand 1 (anti-PD-L1) Prescribing in primary care (eg atezolizumab) Systemic cancer therapies are most often prescribed by secondary or tertiary care clinicians, and administered in inpatient Other monoclonal eg rituximab, trastuzumab and/or outpatient settings. Clear communication between antibodies oncology teams and primary care is vital to maintain accurate, contemporary records and to prevent drug-drug interactions CAR T-cell therapy eg axicabtagene ciloleucel, tisagenlecleucel from any new prescriptions initiated in primary care. These Hormone therapy interactions may reduce the effectiveness of the cancer treatment or induce unwanted side-effects. Androgen LHRH agonist (eg goserelin) Hormone therapies are often prescribed and administered deprivation therapy Non-steroidal anti-androgen (eg bicalutamide) in primary care for breast cancer in women and prostate cancer (ADT) Steroidal anti-androgen (eg cyproterone acetate) in men. They are usually commenced by the patient’s oncologist Androgen synthesis inhibitor (eg abiraterone acetate) or surgeon, and once the patient is stable, GPs are asked to continue the prescription and monitor treatment for these Selective estrogen- eg tamoxifen patients for a specified length of time. receptor modulators For women, hormone therapy has been shown to reduce (SERMs) breast cancer mortality and risk of recurrence.5 Tamoxifen is given as an adjuvant treatment for premenopausal women, with Aromatase eg anastrozole, letrozole, exemestane chemical or surgical ovarian suppression for high-risk women. inhibitors Postmenopausal women are often offered an aromatase inhibitor. A woman may be recommended to receive hormone ther- Stem cell or bone marrow transplant apy for 2–10 years, depending on the indication and other Autologous treatments given. For men, androgen deprivation can improve survival in the Donor adjuvant setting, and slow disease progression for advanced- stage cancers.6 Hormone therapy is not a primary treatment for Table 1. Categories of systemic cancer therapies, with examples prescriber.co.uk Prescriber October 2020 ❚ 23 ■ THERAPY FOCUS l Systemic anticancer therapies

Aromatase inhibitors taken in patients with non-cancer-related risk factors for VTE. There are a number of important health impacts and side- effects • Endometrial cancer – any patients on tamoxifen with features experienced by women receiving hormone therapy that prescrib- of possible endometrial cancer, such as abnormal vaginal ers need to be aware of and to mitigate where possible.5 bleeding, should be promptly investigated due to an increased Aromatase inhibitors (eg letrozole) can have the following effects: risk of these cancers. • Osteoporosis and bone fractures – oestrogen deficiency leads to • Ocular pathology – tamoxifen increases the risk of cataracts increased bone resorption, putting women treated with an aro- and other ocular pathologies that can affect vision. Patients matase inhibitor at increased risk of osteoporotic fractures. exhibiting any visual symptoms should be assessed in primary Baseline bone density measurement using dual-energy X-ray care and/or by the patient’s optometrist. absorptiometry (DEXA) is advised, and repeat monitoring depends on the woman’s menopausal status and treatment regimen.7 All Androgen-deprivation therapy

women should aim for at least 800IU vitamin D3 and 1200mg Androgen-deprivation therapy (ADT) for men with prostate can- total calcium in their diet per day. Postmenopausal women and cer can have physical and psychological effects, including the premenopausal women undergoing ovarian suppression should following:8 be recommended osteoporosis treatment (eg zoledronic acid). • Osteoporosis – though this is a less recognised health issue for • Sexual dysfunction – oestrogen deficiency can also lead to vag- older men relative to women, reduced bone mineral density can initis, dyspareunia, recurrent cystitis and decreased libido. Sexual occur in men receiving ADT. Baseline bone density monitoring dysfunction is often a complex issue that is under-reported, would ideally be performed. Men should also be advised to con-

requiring a varied approach to help patients maintain their sexual sume at least 800IU vitamin D3 and 1200mg total calcium daily relationships. In addition to lubricants and dietary supplements, as part of their diet. The decision to commence bisphosphonate patients may benefit from psychosexual counselling. therapy will depend on a patient’s risk of osteoporotic fracture, • Musculoskeletal problems – arthralgia, myalgia, tendonitis and which can be calculated using the FRAX or QFracture scores. carpal tunnel syndrome have all been reported by patients receiv- • Sexual dysfunction – men on ADT commonly experience reduced ing aromatase inhibitors. Following discussion with the oncolo- libido and/or erectile dysfunction. A trial of a phosphodiesterase gist, switching to an alternative aromatase inhibitor may help type 5 (PDE5) inhibitor is recommended. Psychosexual counsel- alleviate symptoms. Usual primary care management of muscu- ling may be beneficial for some men, and referral to urology for loskeletal problems, such as anti-inflammatory drugs, exercise consideration of other erectile dysfunction treatments may be or possibly acupuncture may also prove to be of some benefit. warranted if there is no improvement in symptoms. • Cardiovascular disease risk – women with oestrogen deficiency • Hot flushes – vasomotor symptoms are common for men on are at increased risk of hypertension and hyperlipidaemia, poten- ADT, and can persist for years, even after completion of treat- tially raising their cardiovascular disease risk. Close monitoring ment. Medroxyprogesterone (20mg once daily) can be trialled and management of cardiovascular risk factors is needed. for 10 weeks initially to help manage symptoms. Cyproterone acetate (50mg twice daily for four weeks) is an alternative if Tamoxifen medroxyprogesterone is not effective or not tolerated. The more common adverse effects of tamoxifen, and other • Anaemia – ADT can result in a normocytic, normochromic anti-oestrogens, include the following:5 anaemia. Routine monitoring is not recommended, but this • Hot flushes – a very common side-effect of tamoxifen. effect should be considered if men become symptomatic (eg Conservative management includes loose, light clothing and exertional dyspnoea) or if an incidental anaemia is found. bed covers. Patients can be co-prescribed an SSRI or SNRI, but strong CYP2D6 inhibitors such as paroxetine or fluoxetine Problems relating to systemic cancer therapies should be avoided to prevent reducing the efficacy of tamoxifen. There are a number of potential drug-related problems to con- • Venous thromboembolism (VTE) – patients receiving anti-oestro- sider for patients taking systemic cancer therapies.9 The gens are at a two to three times higher risk of VTE, particularly in side-effect profile of each drug will vary, but there are some prolonged courses (more than five years). Caution should be side-effects that are common to many systemic cancer therapies. There are also some severe adverse effects of cancer Common, seldom Common, Uncommon, severe treatments that primary care professionals need to be aware of severe potentially severe and act on urgently (see Table 2). Fatigue Vomiting Venous thromboembolism Patients and their partners/carers can be empowered to mon- Nausea Diarrhoea Febrile neutropenia itor, manage, and report their symptoms with the provision of Mucositis Rash Tumour lysis syndrome good-quality treatment information, and symptom reporting tools. Constipation Pain Hyperuricaemia, renal An example of a traffic light symptom reporting tool can be found Hair loss Neuropathy failure on page 4 of the National Chemotherapy Board Good Practice Skin erythema Teratogenicity Guideline (see https://rcni.com/sites/rcn_nspace/files/ 10 Cardiomyopathy National_Chemotherapy_Board_good_practice_guideline.pdf). Drug interactions are a significant potential problem for Table 2. More common adverse effects of systemic cancer therapies cancer patients. Estimates of the prevalence of potential drug-

24 ❚ Prescriber October 2020 prescriber.co.uk Systemic anticancer therapies l THERAPY FOCUS ■

drug interactions for cancer patients receiving systemic therapy Risk factors for drug interactions range from 17–46%.11,12 These drug interactions particularly affect older cancer patients, who are more likely to have multi- • Older age ple co-morbidities and take multiple long-term medications. • Polypharmacy Risk factors for drug interactions are listed in Table 3. These • Low body weight risks re-emphasise the importance of clear communication • Renal impairment between primary care and oncology teams to ensure anyone • Haematological cancer prescribing a new medication for a cancer patient is clear on • Multiple medical co-morbidities what systemic therapies they are receiving and what their regu- • Longer hospital stays lar medications are. • History of adverse drug reactions Each type of systemic cancer therapy has its own known • Intake of highly protein-bound drugs drug-drug interactions, as well as potential interactions with 13 over-the-counter (OTC) medications, alternative therapies, and Table 3. Risk factors for drug interactions. From Campen et al. (2017) foods. There are some more common potential drug-drug interactions to be aware of when prescribing in primary care:13,14 References • Cytochrome P450 inhibitors/inducers – Drugs that competi- 1. Cancer Research UK. Treatment for cancer. Available from: https:// tively inhibit (eg ciprofloxacin) or induce (eg phenytoin) www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment. cytochrome P450 binding sites can have an impact on the effi- 2. Philip L, et al. Exploring common drug interactions with oral oncology cacy and safety of a number of oral and intravenous systemic agents. Pharm Today 2018;24(4):44–5. 3. Oiseth SJ, Aziz MS. Cancer immunotherapy: a brief review of the cancer therapies, including tyrosine kinase inhibitors, selective history, possibilities, and challenges ahead. J Cancer Metastasis Treat estrogen receptor modulators (SERMs) and ADT agents. 2017;3(10):250–61. • Gastric acid suppressants – H2-antagonists (eg ranitidine) and 4. Padma VV. An overview of targeted cancer therapy. Biomedicine proton pump inhibitors (PPIs, eg omeprazole) alter the gastric 2015;5(4):1–6. pH, which can affect the absorption and bioavailability of oral 5. Awan A, Esfahani K. Endocrine therapy for breast cancer in the pri- systemic cancer therapies. If a patient is symptomatic and mary care setting. Curr Oncol 2018;25(4):285–91. needs acid suppression, taking these medications at least two 6. Abraham J, Staffurth J. Hormonal therapy for cancer. Medicine hours before or after their oral cancer treatment may reduce (Baltimore) 2011;39(12):723–7. their impact on drug absorption. 7. Reid DM, et al. Guidance for the management of breast cancer treat- • Anticoagulants – Some oral systemic cancer therapies, such ment-induced bone loss. Cancer Treat Rev 2008;34(Suppl. 1):S3–18. 8. Noonan EM, Farrell TW. Primary care of the prostate cancer survivor. as ibrutinib (a tyrosine kinase inhibitor), can increase the INR Am Fam Physician 2016;93(9):764–70. and cause bleeding. Patients taking oral anticoagulants (eg 9. Jaehde U, et al. Minimising treatment-associated risks in systemic warfarin) for other indications, such as atrial fibrillation, will cancer therapy. Pharm World Sci 2008;30(2):161–8. need careful assessment of the risks and benefits of both treat- 10. Oakley C, et al. National Chemotherapy Board Good Practice ments, and close monitoring. Guideline: Promoting early identification of systemic anti-cancer thera- • QTc prolongation – A number of targeted therapies are known pies side effects – two approaches. September 2016. Available from: to cause QTc prolongation (eg sorafenib, sunitinib), perhaps https://rcni.com/sites/rcn_nspace/files/National_Chemotherapy_ provoking serious arrhythmias. Prescribers giving long-term (eg Board_good_practice_guideline.pdf amitriptyline) or short-term (eg clarithromycin) medications that 11. Ramos-Esquivel A, et al. Potential drug-drug and herb-drug interac- can also affect the QT interval need to be aware of the possibil- tions in patients with cancer: a prospective study of medication surveil- lance. J Oncol Pract 2017;13(7):e613–22. ity of drug-drug interaction and prolongation of the QT interval. 12. Van Leeuwen RWF, et al. Prevalence of potential drug-drug interactions in cancer patients treated with oral anticancer drugs. Br J Cancer Optimising primary care for cancer patients 2013;108(5):1071–8. Supporting cancer patients receiving systemic cancer therapies 13. Campen CJ, et al. Managing drug interactions in cancer therapy: a optimally requires a multidisciplinary approach that includes guide for the advanced practitioner. J Adv Pract Oncol 2017;8(6):609–20. primary care. The treatment journey for these patients can have 14. Conde-Estévez D. Targeted cancer therapy: interactions with other physical, psychological, social and emotional effects. Some medicines. Clin Transl Oncol 2017;19(1):21–30. patients will recover from treatment with the cancer in remission or cured, but many will need further treatment with curative Declaration of interests intent or for palliation if there is disease progression in spite of Samuel Merriel is supported by the CanTest Collaborative, which treatment. Primary care plays a key role in identifying and man- is funded by Cancer Research UK (C8640/Q37A23385). Willie aging physical effects of treatment, providing psychosocial sup- Hamilton is co-director of CanTest, and was clinical lead in the port and arranging specialist review where needed. Regular and NICE Guideline Development group, which formulated NG12. accurate communication is critical to ensure all professionals involved in the patient’s care are informed of current and Dr Samuel W D Merriel is a GP and Clinical Senior Research planned treatments, and to avoid preventable adverse drug Fellow at the University of Exeter and Professor Willie Hamilton is reactions. Professor of Primary Care Diagnostics at the University of Exeter prescriber.co.uk Prescriber October 2020 ❚ 25