Supportive care options for cancer

Managing side effects associated with chemotherapy and radiation therapy

Chemotherapy drugs are extensively used in clinic as one of the main cancer treatments and can be administered alone or as an adjuvant therapy. Chemotherapy interferes with and inhibits DNA, RNA and protein synthesis, often in the S phase of the cell cycle, leading to cell death. Radiation therapy is commonly used in conjunction with chemotherapy and has a similar mode of action, causing damage to DNA strands and resulting in cell death.

Although these therapies have drastically improved the survival of patients, they are notorious for causing severe side effects that ultimately limit the amount that can be tolerated and thus treatment efficacy

Drugs commonly used for chemotherapy include¹:

• Platinum-based agents (cisplatin, oxaliplatin, carboplatin)
• Taxanes (paclitaxel, docetaxel)
• Fluoropyrimidines (5-fluorouracil, capecitabine)
• Vinca alkaloids (vinblastine, vinorelbine, vincristine, vindesine)

Guideline recommendations for managing the side effects of chemotherapy and radiation therapy

Thrombosis

In this video, Dr Gary Lyman discusses the challenges of treating thrombosis in patients with cancer.

Venous thromboembolism (VTE) is a major complication of thrombosis. Anticoagulants are used for VTE prevention and treatment include unfractionated heparin (UFH), low molecular weight heparins (LMWHs), fondaparinux (a synthetic indirect inhibitor of activated factor Xa), vitamin K antagonists (VKAs) and more recently, direct oral anticoagulants (DOACS)^2-7. Choice of anticoagulant is determined by considerations such as bleeding risk, patient preference and potential drug interactions^3-7. LMWH is the preferred treatment choice in those at high risk of bleeding, while for patients at low risk of bleeding, DOACs (apixaban or rivaroxaban) are preferred^3-7. Caution should be exercised when prescribing DOACS to people with gastrointestinal or genitourinary tract cancers because of an increased risk of bleeding^3-7. If apixaban, rivaroxaban or LMWHs are contraindicated or unsuitable, alternatives such as dabigatran, UFH, fondaparinux or a VKA can be considered⁴.

Treatment is recommended for at least 3–6 months, or for as long as the cancer is active, the patient remains on cancer therapy or remains at high risk of recurrent VTE^4,5. The ASH 2021 guidelines suggest indefinite anticoagulant treatment for the long-term prevention of VTE may be considered if the benefits outweigh the risks⁴.

Learn more about the management of cancer-associated thrombosis

Nausea and vomiting

In this video, Dr Lyman highlights the guideline recommended management strategies for nausea and vomiting caused by cancer treatments.

The risk of chemotherapy-induced nausea and vomiting (CINV) for each patient should be ascertained based on the type of treatment (Table 1) and predisposing factors such as gender, type of cancer and age. A useful tool recommended by the Multinational Association of Supportive Care in Cancer (MASCC) and the European Society for Medical Oncology (ESMO) for predicting CINV risk can be found at www.riskcinv.com.

Table 1. Emetogenic risk of anticancer treatments (Adapted)⁸.

Management of CINV depends on the emetogenic potential of the anticancer therapy that a patient is taking (high-risk: emesis documented in >90% of patients; moderate-risk: emesis documented in 30-90% of patients; low-risk: emesis documented in 10–30% of patients; minimal-risk: emesis documented in <10% of patients^9,10.

High emetic risk

The American Society of Clinical Oncology (ASCO) guidelines recommend adults treated with cisplatin and other high-emetic-risk drugs be offered a 4-drug combination of a neurokinin-1 (NK1) receptor antagonist, a 5-hydroxytrytamine 3 (5-HT₃) receptor antagonist (ondansetron, granisetron), dexamethasone (DEX) and olanzapine on day 1 of treatment. DEX and olanzapine should be continued on days 2–4¹⁰. ESMO and MASCC guidelines recommend a single prophylactic dose of 5-HT₃ + DEX + NK1 before chemotherapy for acute emesis in high-risk patients, with the addition of olanzapine in instances of delayed-onset emesis⁹.

For high-emetic risk radiation therapy, a 2-drug combination of a 5-HT₃ receptor antagonist and DEX is recommended before each fraction and on the day after each fraction³

Moderate emetic risk

Adults treated with moderate-emetic risk anti-neoplastic treatments (excluding carboplatin) should be offered a 2-drug combination of a 5-HT₃ receptor antagonist and DEX (day 1)^9,10. ASCO further states that patients treated with cyclophosphamide, doxorubicin, oxaliplatin and other moderate-emetic-risk drugs known to cause delayed CINV may be offered DEX on days 2–3¹⁰.

Patients receiving moderate-emetic-risk radiation therapy should be offered a 5-HT₃ receptor antagonist before each fraction, with or without DEX, for the first 5 fractions⁹.

Low emetic risk

Patients treated with low-emetic-risk treatments should be offered a single dose of a 5-HT₃ receptor antagonist or a single 8-mg dose of DEX before treatment^9,10.

Patients undergoing low-emetic-risk radiation therapy to the brain should be offered breakthrough DEX therapy. Patients who are treated with radiation therapy to the head and neck, thorax, or pelvis should be offered breakthrough therapy with a 5-HT₃ receptor antagonist, DEX, or a dopamine-receptor antagonist³.

Diarrhoea

Diarrhoea is a common side effect of various neoplastic treatments and can be classified as uncomplicated or complicated¹¹.

To ascertain the severity of diarrhoea, it should first be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE)¹²

Uncomplicated diarrhoea

Grade 1 or 2 diarrhoea with no other complications may be classified as ‘uncomplicated’ and managed conservatively with oral hydration and loperamide (4 mg to start, and then 2 mg every 4 hours or after each loose stool)¹¹. Skin barrier creams should be used to prevent skin irritation caused by increased faecal contact¹¹.

Patients with complicated diarrhoea, which includes mild-to-moderate diarrhoea accompanied by moderate-to-severe cramping, nausea and vomiting, cognitive decline, fever, sepsis, neutropenia, bleeding or dehydration, require hospitalisation for closer monitoring and evaluation¹¹.

Complicated diarrhoea

Management of complicated diarrhoea involves intravenous rehydration fluids, antibiotics and subcutaneous octreotide at a starting dose of 100–150 µg three times a day. If the patient is severely dehydrated, octreotide can be administered intravenously at a dose of 25–50 µg/h. The dose can be rapidly escalated up to 500 µg subcutaneously until the diarrhoea is controlled. Additional evaluations to be performed include a complete blood count, electrolyte profile and a stool work-up investigating the presence of blood, Clostridium difficile, Salmonella, Escherichia coli, Campylobacter and infectious colitis¹¹.

Constipation

Best practice for management of constipation is a balance between prevention, self-care, and oral and rectal laxative therapy. Self-care strategies include increasing fluids, dietary fibre intake and mobility¹³.

Management with oral laxatives is an essential part of care planning, the two most recommended class of laxative being osmotic and stimulant laxatives¹³

Other classes of laxatives, including bulk-forming laxatives, detergent/stool softener and liquid paraffin, are generally not recommended over osmotic and stimulant laxatives, especially in cases of advanced cancer¹³.

Suppositories and enemas are the recommended first-line therapy where there is faecal impaction and/or where oral laxatives have failed to relieve constipation¹³.

Mucositis

Oral and gastrointestinal (GI) mucositis caused by high-dose chemotherapy and/or radiation continues to be an important clinical problem. A number of recommendations have been made for the prevention and treatment of oral mucositis as follows¹⁴ :

• 30 minutes of oral cryotherapy to prevent oral mucositis in patients receiving bolus 5-fluorouracil chemotherapy
• Recombinant human keratinocyte growth factor-1 (KGF-1/palifermin) to prevent oral mucositis in patients receiving high-dose chemotherapy and total body irradiation
• Patient-controlled analgesia with morphine to treat pain due to oral mucositis
• Benzydamine mouthwash to prevent oral mucositis in patients with head and neck cancer receiving moderate-dose radiation therapy (up to 50 Gy), without concomitant chemotherapy

Guideline recommendations for prevention and treatment of GI mucositis include¹⁵:

• The use of intravenous amifostine in patients receiving radiation therapy
• Subcutaneous octreotide twice daily to treat diarrhoea secondary to mucositis induced by standard- or high-dose chemotherapy if loperamide is ineffective

Neutropenia

Watch Dr Lyman discuss guideline recommended management of febrile and non-febrile neutropenia following cancer treatment.

Most patients undergoing chemotherapy and radiation therapy will develop neutropenia, which is characterised by an absolute neutrophil count (ANC) of <500 cells/µL following treatment¹⁵.

Patients with neutropenia are highly susceptible to infection and require careful monitoring for fever, chills and sweat¹⁶

The most dangerous complication of neutropenia is febrile neutropenia. ASCO, ESMO and the Infectious Diseases Society of America (IDSA) recommend using the MASCC febrile neutropenia risk calculator to pre-emptively manage this condition^15,17,18. A MASCC score of ≤20 indicates high risk, while a score of ≥21 indicates low risk¹⁷. The prophylactic use of antimicrobials to prevent febrile neutropenia is discouraged by ESMO, ASCO and the European Organisation for Research and Treatment of Cancer (EORTC)¹⁶.

Febrile neutropenia

Febrile neutropenia (FN) is defined as a one-time oral temperature of >38.3°C or a sustained temperature of >38°C (100.4°F) for ≥1 hour in a patient who has an ANC of <500 cells/μL¹⁵. FN can be ef­fectively pre­vent­ed by administering granulocyte colony-stimulating factors (G-‍CSFs), but this is only suggested for pa­tients with a >20% risk of de­vel­op­ing FN and in those with se­ri­ous comor­bidi­ties and/‍or aged >60 years¹⁵. Several meta-analyses indicate that primary prophylaxis with G-CSF (filgrastim) reduces the risk of FN by at least 50%^19,20.

Initial management should include taking a detailed medical history, including past infections with antibiotic-resistant organisms. A full-body examination looking for infection entry points should be performed, as well as routine investigations including^15,16:

• ur­gent blood test­ing to as­sess bone mar­row, renal and liver func­tion
• co­ag­u­la­tion screen
• C-‍re­ac­tive pro­tein
• blood cul­tures in­clud­ing cul­tures from in­dwelling intravenous catheters
• uri­nal­y­sis and cul­ture
• spu­tum mi­croscopy and cul­ture
• stool mi­croscopy and cul­ture
• skin le­sion assessment (aspirate/‍biopsy/‍swab)
• chest ra­dio­graph

ESMO recommends use of a risk assessment algorithm to determine the appropriate management approach (Figure 1). In patients at high risk of FN, treatment with intravenous broad-spectrum antibiotics is recommended^15,16. Oral antibacterial therapy can be commenced for some patients at low risk of FN, namely those who^15,16:

• are haemodynamically stable
• do not have acute leukaemia or evidence of organ failure
• do not have pneumonia, an indwelling venous catheter or severe soft tissue infection

The majority of FN cases can be resolved with prompt empirical therapy, with tailored antibacterial therapy if the type of infection is known¹⁶.

Figure 2. ESMO algorithm of response assessment (Adapted¹⁶). ANC, absolute neutrophil count; IV, intravenous; MASCC, Multinational Association of Supportive Care in Cancer.

Monotherapy and combination therapy have equivalent efficacy; however, high-risk patients may benefit more from a ß-‍lactam an­tibi­ot­ic in com­bi­na­tion with an amino­gly­co­side¹⁶. Clinical assessment and follow-up may be required every 2–4 hours in severe cases, while daily assessment of fever trends, bone marrow and renal function is recommended until the patient is afebrile for at least 24 hours^15,16.

Chemotherapy-induced thrombocytopenia (CIT)

Official guidelines have not codified a response to CIT, and there are few studies to describe the appropriate approach. While platelet transfusion remains the cornerstone of managing CIT, a synthesis of the available data on management practices is as follows^21,22:

• Identify and treat any other underlying cause of thrombocytopenia (stop antibiotics, treat infections, and control coagulopathy)
• Reduce chemotherapy dose, frequency or alter the chemotherapy regimen
• Platelet transfusion support can be used if maintenance of chemotherapy dose intensity is vital for response or survival, and is indicated if the patient is bleeding or to prevent major bleeding if platelet counts are less than 10x10⁹/L (<20x10⁹/L if febrile)
• Recombinant interleukin-11 (oprelvekin) is the only approved treatment for CIT, however its use is limited due to adverse effects
• Thrombopoetin receptor agonists (TPO-RAs), such as romiplostim and eltrombopag, increase platelet production and have both been approved for immune thrombocytopenia
• Antifibrinolytic agents such as ε-aminocaproic acid or tranexamic acid have been used in some thrombocytopenic cancer patients to improve haemostasis when platelet transfusions do not work

Fatigue

In this video, Dr Lyman discusses guideline recommended approaches to managing fatigue in cancer patients.

Management of cancer-related fatigue includes an initial screening for contributing factors such as sleep disturbance and anaemia²³. Management interventions include exercise (a mixture of aerobic, strength and flexibility exercises), cognitive behavioural therapy and pharmacological management with psychostimulants such as methylphenidate and dexamphetamine²³.

Acute radiation dermatitis

A standardised approach to management of acute radiation dermatitis (ARD) has been limited by the lack of high-quality evidence. To address this gap, in January 2023, MASCC conducted a systematic review of current evidence on interventions for prevention and treatment of ARD²⁴. This review included 235 studies, of which 149 were randomised controlled clinical trials; however, definitive recommendations could not be made on the basis of published evidence as there was considerable variability and insufficient high-quality evidence. A four-round Delphi consensus process was undertaken, therefore, to generate recommendations based on the opinions of 42 international ARD experts. Interventions were recommended if at least 75% consensus was reached²⁵.

The Delphi consensus process recommended six interventions for the prevention of ARD, including photobiomodulation therapy and silicone film (in breast cancer patients), polyurethane film, mometasone furoate, betamethasone and olive oil. For the management of ARD, foam dressings were recommended (Table 2)²⁵.

The study concluded that most interventions could not be recommended because there was insufficient evidence, conflicting evidence or lack of consensus to support use²⁵. This suggests the need for further research on the prevention and management of ARD. However, clinicians can consider implementing the recommended interventions in their practice until additional evidence becomes available.

Table 2. Delphi consensus recommendations for interventions to prevent or manage acute radiation dermatitis (²⁵). Note, recommended interventions are those with a consensus of ≥75%. Interventions with consensus of <75% could not be recommended.

Management of immune thrombocytopenia

Severity of thrombocytopenia induced by immunotherapy is graded according to platelet count, with management based on the grade of thrombocytopenia (Table 6)³⁹.

 Table 6. Management of thrombocytopenia according to grade of severity³⁹. IVIg, intravenous immunoglobulin.

Management of cardiovascular side effects

A range of cardiovascular (CV) side effects have been reported after treatment with immunotherapy, including myocarditis, pericarditis, arrhythmias and cardiomyopathy⁴⁰.

Myocarditis is one of the most common CV side effects and generally occurs within 4 weeks of immunotherapy initiation³⁹

For patients who develop new CV symptoms after onset of treatment, a full workup should be conducted including³⁹:

• electrocardiogram
• troponin
• B-type natriuretic peptide (BNP) or N-terminal-proBNP
• C-reactive protein
• viral titre
• echocardiogram with global longitudinal strain
• cardiac magnetic resonance imaging

If myocarditis is suspected, therapy should be withheld and high-dose corticosteroids (methylprednisolone 1000 mg/day followed by oral prednisone 1 mg/kg/day) should be initiated. Corticosteroids should be continued until resolution of symptoms and normalisation of troponin, left ventricular systolic function and conduction abnormalities³⁹.

Hypertension

Management of hypertension involves antihypertensive therapy, aiming to achieve a blood pressure (BP) of <140/90 mmHg. Discontinuation of treatment is recommended if systolic BP is >200 mmHg or diastolic BP >100 mmHg. Antihypertensive therapy includes angiotensin-converting enzyme (ACE) inhibitors and beta-blockers^39,40.

Management of endocrine side effects

The most common endocrine side effects associated with immunotherapy include hypothyroidism and adrenal insufficiency^35,39.

Hypothyroidism

Hypothyroidism is more common than hyperthyroidism and can be detected by routine blood tests for thyroid-stimulating hormone (TSH) and free thyroxine (FT4)^35,39. Once detected, routine monitoring should be done at baseline and before every infusion for 4–6 weeks whilst receiving treatment. Levothyroxine can be initiated for TSH levels above 10 mIU/L³⁹.

Adrenal insufficiency

Adrenal insufficiency is associated with inhibitors of the immune checkpoint programmed cell death protein 1 (PD-1) and its ligand PD-L1³⁵. Management depends on the clinical severity. Patients with mild signs and symptoms can be started on prednisone (5–10 mg daily); those with moderate symptoms should receive prednisone 20 mg daily³⁹.

Patients with suspected adrenal crisis should receive an immediate dose of 100 mg intravenous hydrocortisone plus fluid resuscitation with 2 L saline³⁹

Once clinically stable, maintenance oral therapy should be continued as previously described.

Management of diarrhoea

Diarrhoea occurs in roughly 20% of patients receiving anti-PD-1 therapy³⁵. Management of diarrhoea depends on severity, but in moderate cases treatment should be temporarily withheld until symptoms resolve³⁹. Corticosteroids (1 mg/kg/day) and loperamide can also be administered³⁹.