Venous access required
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IV cannula (IVC) or central venous access device (CVAD) is required to administer this treatment.
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Hypersensitivity/infusion related reaction
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High risk with carboplatin. Hypersensitivity risk increases with number of cycles of carboplatin.
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Premedication
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Starting 5 to 7 days prior to the first cycle of chemotherapy
Hydroxocobalamin (Vit B12) 1000 micrograms intramuscularly and repeat once every 3 cycles;
Folic acid 500 micrograms PO once daily continuously until 21 days after the last dose of pemetrexed.
Starting 1 day prior to each cycle of chemotherapy,
Dexamethasone (for skin rash prophylaxis) 4 mg PO twice daily - administer the day before, the day of and the day after chemotherapy
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Emetogenicity MODERATE
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Suggested default antiemetics have been added to the treatment schedule, and may be substituted to reflect institutional policy.
Carboplatin AUC > 4 is classified by MASCC/ESMO 2016 Antiemetic Guidelines 2016 and ASCO Antiemetic Guidelines 2017 as having moderate emetogenicity.
However, a NK1 receptor antagonist and a 5HT3 receptor antagonist in combination with dexamethasone are available on the PBS for primary prophylaxis of carboplatin induced nausea and vomiting.
Note: a steroid has been included both as an antiemetic and premedication for hypersensitivity in this protocol.
Ensure that patients also have sufficient antiemetics for breakthrough emesis:
Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR
Prochlorperazine 10 mg PO or 12.5 mg IV every 6 hours when necessary.
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Immune-related adverse events (irAEs)
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Immune-related adverse events (irAEs) can occur early and escalate quickly in patients receiving immune checkpoint inhibitors. irAEs can also occur after discontinuation of treatment. Fatalities have been reported.
Examples of irAEs include arthritis, colitis, endocrinopathies, Guillain-Barré syndrome, haemolytic anaemia, hepatitis, hypophysitis, myositis, nephritis, nerve paresis, autoimmune neuropathy, pancreatitis, rash, pneumonitis, uveitis, vasculitis.
irAEs that carry a high risk of mortality include myocarditis, encephalitis, pneumonitis and hepatitis.
Proactive monitoring, patient self-monitoring and early reporting of adverse events is critical. Treatment interruptions and administration of corticosteroids and/or supportive care is required to minimise the risk of death.
See individual irAEs listed below for more information.
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Skin toxicity
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Immune-related skin rash has been observed in patients receiving immune checkpoint inhibitor therapy.
Monitor for rash, erythema and pruritus (unless an alternate aetiology has been identified).
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Thyroid toxicity
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Immune-related thyroid disorders are common (hypothyroidism and hyperthyroidism) and can occur at any time during immune checkpoint inhibitor therapy.
Monitor patients for changes in thyroid function and clinical signs and symptoms of thyroid disorders.
Isolated hypothyroidism may be managed with replacement therapy, without treatment interruption, and without corticosteroids.
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Hypophysitis
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Immune-related hypophysitis has been observed in patients receiving immune checkpoint inhibitor therapy.
Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and secondary adrenal insufficiency) and exclude other causes of hypophysitis.
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Diabetes
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Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients receiving immune checkpoint inhibitor therapy.
Monitor patients for hyperglycaemia or other signs and symptoms of diabetes. Exclude other causes of diabetes.
Initiate insulin replacement as needed. Monitor blood sugar levels to ensure appropriate insulin replacement is achieved.
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Gastrointestinal toxicity
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Immune-related diarrhoea and colitis have been observed in patients receiving immune checkpoint inhibitor therapy, in some cases these adverse events have been severe.
Patients should be monitored for symptoms of increased frequency of bowel movements, change in the consistency of the stool, diarrhoea, abdominal pain, mucus in stools, haematochezia, and constitutional symptoms (fever, fatigue, weight loss). Exclude other causes of diarrhoea or colitis.
Clinical signs of peritonism should be immediately acted upon given the risk of bowel perforation.
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Pulmonary toxicity
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Immune-related pneumonitis has been observed in patients receiving immune checkpoint inhibitor therapy.
Monitor patients for signs and symptoms of pneumonitis (e.g. new or worsening cough, shortness of breath, or chest pain). If pneumonitis is suspected, evaluate with radiographic imaging (e.g. High Resolution CT) and exclude other causes of pneumonitis.
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Hepatotoxicity
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Immune-related hepatitis has been observed in patients receiving immune checkpoint inhibitor therapy.
Monitor patients for signs and symptoms of hepatitis (e.g. abnormal LFTs, jaundice, dark urine, severe nausea and vomiting, pain on the right side of the abdomen) and exclude other causes.
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Neurological toxicity
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Rare but serious immune-related neurological events including neuropathies, encephalitis, aseptic meningitis, meningeal symptoms, Guillain-Barre syndrome and myasthenia gravis-like symptoms have been observed in patients receiving immune checkpoint inhibitor therapy.
Monitor for signs and symptoms of motor or sensory neuropathies and muscle weakness.
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Renal toxicity
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Immune-related nephritis and renal dysfunction have been observed in patients receiving immune checkpoint inhibitor therapy, in some cases the adverse events have been severe.
Monitor patients for changes in renal function (e.g. elevated serum creatinine, haematuria, decrease in urine output) and exclude other causes of nephritis.
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Rheumatological toxicity
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Arthralgia and myalgia have been reported in patients receiving immune checkpoint inhibitor therapy. Although rare, polymyositis can also occur.
Monitor patients for symptoms of arthralgia and myalgia. Moderately strong analgesia and corticosteroid therapy may be required in some patients
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Blood tests
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FBC, EUC, LFTs, serum cortisol, TFTs and BSL at baseline.
Repeat FBC, EUC, LFTs and BSL prior to each cycle and serum cortisol and TFTs alternate cycles. N.B for CTLA4 containing regimens – repeat serum cortisol and TFTs prior to each cycle containing CTLA 4 drug. Check lipase and amylase if symptomatic of pancreatitis.
In the absence of suspicion of immune related adverse events less frequent monitoring may be applicable, according to institutional guidelines. Evidence for the frequency of routine blood testing with immunotherapies varies within published studies and guidelines.
Recalculate carboplatin dose if significant change in weight and/or creatinine.
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Hepatitis and HIV
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Hepatitis screening is recommended in all patients who are to receive immune checkpoint inhibitors, however the value of hepatitis and HIV screening is unknown and many trials no longer require screening prior to commencing immune checkpoint inhibitors.
Immunotherapy is associated with inflammatory adverse reactions resulting from increased or excessive immune activity and patients are at risk of developing autoimmune hepatitis. It should be used with caution in patients who have a history of chronic hepatic infections (hepatitis B and C) and human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS).
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Vaccinations
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The safety of having vaccinations during treatment is unknown. Patients in the clinical trial were allowed to receive inactivated vaccines (e.g. inactivated influenza vaccine) but live vaccines (e.g. BCG, MMR, zoster and varicella vaccines) were typically not permitted.
Caution: in patients receiving combination ipilimumab and nivolumab there have been reported cases of fatal myocarditis, myositis and rhabdomyolysis shortly after administration of the influenza vaccine. Whilst a causative relationship to the use of influenza vaccine has not been demonstrated, caution is advised.
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Effects of cancer treatment on fertility
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Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive age prior to commencing treatment.
Studies to evaluate the effects of immune checkpoint inhibitor therapy on fertility have not been performed. Therefore, the effect on male and female fertility is unknown, however, immune checkpoint inhibitors can cause fetal harm when given to pregnant women. It is important that females of reproductive potential and males use effective contraception whilst on therapy and for at least 4 months post last dose of therapy.
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