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Breast neoadjuvant/adjuvant AC (DOXOrubicin and CYCLOPHOSPHamide) three weekly and pembrolizumab (part 2)

Treatment must be initiated and supervised by specialist physicians experienced in the treatment of cancer using immunological agents. Before commencing immunotherapy treatment in any patient, clinicians should have an understanding of the immune-related adverse events (irAEs) associated with immunotherapy treatment and their management.

Check for clinical trials in this patient group. Link to Australian Clinical Trials opens in a new tab or window website

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Cycle 1 to 4

Drug Dose Route Day
Pembrolizumab 200 mg * IV infusion 1
DOXOrubicin ** 60 mg/m2 IV 1
CYCLOPHOSPHamide 600 mg/m2 IV infusion 1
Pegfilgrastim 6 mg Subcut 2

Cycle 5 to 13

Drug Dose Route Day
Pembrolizumab 200 mg * IV infusion 1

* Pembrolizumab alternative dosing schedule of 400 mg every 42 days may be considered.1, 2

** The clinical trial allowed epirubicin as an alternative, at a dose of 90 mg/m2 on day 1.r

Note: Cycle 5 to 13 is given following surgery. In the trial surgery occurred 3-6 weeks following the completion or early discontinuation of the treatments in the neoadjuvant phase.

Frequency:
21 days 
Cycles:
13 (4 cycles of AC and pembrolizumab, followed by surgery, then 9 cycles of pembrolizumab alone)
Notes:

In the first few months after the start of immunotherapy, some patients can have a transient tumour flare (termed 'pseudo progression' or an immune response). This may manifest as growth of existing lesions or the development of new lesions prior to later tumour regression. While this is rare, (~5%), continuing treatment and performing a second scan 4 to 6 weeks later to confirm progression may be considered, particularly if the patient is believed to be deriving clinical benefit.

Radiation recall has been observed with PD1 inhibitors, consideration should be given to the timing when starting this treatment after a prolonged course of radiation therapy.

Drug status:

Doxorubicin and cyclophosphamide are on the PBS general schedule opens in a new tab or window

Pembrolizumab is PBS authority opens in a new tab or window

Cost:
~ $7,890 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, growth factor support etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 to 4

Day 1
Netupitant 300 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with palonosetron) 
Palonosetron 0.5 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone 12 mg (PO) 60 minutes before chemotherapy*
Pembrolizumab 200 mg (IV infusion) in 50 mL sodium chloride 0.9% over 30 minutes **
DOXOrubicin 60 mg/m2 (IV) over 5 to 15 minutes
CYCLOPHOSPHamide 600 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
Day 2
Pegfilgrastim 6 mg (Subcut) inject subcutaneously on day 2 at least 24 hours after chemotherapy

Cycle 5 to 13

Day 1
Pembrolizumab 200 mg (IV infusion) in 50 mL sodium chloride 0.9% over 30 minutes **

*Note: the full dose of dexamethasone on day 1 may not be required and may be reduced to 8 mg at the clinician's discretion. Dexamethasone 4 to 8 mg on days 2 to 4 may be required for those with risk factors for delayed nausea and vomiting. Link to ID 7 Prevention of anti-cancer induced nausea and vomiting

** Pembrolizumab alternative dosing schedule of 400 mg every 42 days may be considered.1, 2

Frequency:
21 days 
Cycles:
13 (4 cycles of AC and pembrolizumab, followed by surgery, then 9 cycles of pembrolizumab alone)

Cycle 1 to 4

Drug Dose Route Day
Pembrolizumab 200 mg * IV infusion 1
DOXOrubicin ** 60 mg/m2 IV 1
CYCLOPHOSPHamide 600 mg/m2 IV infusion 1
Pegfilgrastim 6 mg Subcut 2

Cycle 5 to 13

Drug Dose Route Day
Pembrolizumab 200 mg * IV infusion 1

* Pembrolizumab alternative dosing schedule of 400 mg every 42 days may be considered.1, 2

** The clinical trial allowed epirubicin as an alternative, at a dose of 90 mg/m2 on day 1.r

Note: Cycle 5 to 13 is given following surgery. In the trial surgery occurred 3-6 weeks following the completion or early discontinuation of the treatments in the neoadjuvant phase.

Frequency:
21 days 
Cycles:
13 (4 cycles of AC and pembrolizumab, followed by surgery, then 9 cycles of pembrolizumab alone)
Notes:

In the first few months after the start of immunotherapy, some patients can have a transient tumour flare (termed 'pseudo progression' or an immune response). This may manifest as growth of existing lesions or the development of new lesions prior to later tumour regression. While this is rare, (~5%), continuing treatment and performing a second scan 4 to 6 weeks later to confirm progression may be considered, particularly if the patient is believed to be deriving clinical benefit.

Radiation recall has been observed with PD1 inhibitors, consideration should be given to the timing when starting this treatment after a prolonged course of radiation therapy.

Drug status:

Doxorubicin and cyclophosphamide are on the PBS general schedule opens in a new tab or window

Pembrolizumab is PBS authority opens in a new tab or window

Cost:
~ $7,890 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, growth factor support etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 to 4

Day 1
Netupitant 300 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with palonosetron) 
Palonosetron 0.5 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone 12 mg (PO) 60 minutes before chemotherapy*
Pembrolizumab 200 mg (IV infusion) in 50 mL sodium chloride 0.9% over 30 minutes **
DOXOrubicin 60 mg/m2 (IV) over 5 to 15 minutes
CYCLOPHOSPHamide 600 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
Day 2
Pegfilgrastim 6 mg (Subcut) inject subcutaneously on day 2 at least 24 hours after chemotherapy

Cycle 5 to 13

Day 1
Pembrolizumab 200 mg (IV infusion) in 50 mL sodium chloride 0.9% over 30 minutes **

*Note: the full dose of dexamethasone on day 1 may not be required and may be reduced to 8 mg at the clinician's discretion. Dexamethasone 4 to 8 mg on days 2 to 4 may be required for those with risk factors for delayed nausea and vomiting. Link to ID 7 Prevention of anti-cancer induced nausea and vomiting

** Pembrolizumab alternative dosing schedule of 400 mg every 42 days may be considered.1, 2

Frequency:
21 days 
Cycles:
13 (4 cycles of AC and pembrolizumab, followed by surgery, then 9 cycles of pembrolizumab alone)

Indication:

  • neoadjuvant/adjuvant treatment for operable triple negative breast cancer.

Patient population:

  • clinical stage II to III non-inflammatory invasive breast cancer
  • triple negative

Precautions:

If any of these conditions are present, clinical judgement should be used and individual cases discussed with an expert in the field as indicated:

  • significant autoimmune disease (e.g. myasthenia gravis, inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, autoimmune ocular disease)
  • organ transplantation
  • previous history of viral hepatitis
  • HIV/acquired immune deficiency syndrome (AIDS)
  • previous radiation to the lungs.
Venous access required

IV cannula (IVC) or central venous access device (CVAD) is required to administer this treatment.

Read more about central venous access device line selection
Emetogenicity HIGH

Suggested default antiemetics have been added to the treatment schedule, and may be substituted to reflect institutional policy.

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 every 6 hours when necessary.

Read more about preventing anti-cancer therapy induced nausea and vomiting
Cumulative lifetime dose of anthracyclines

Cumulative doses should take into account all previous anthracyclines received during a patient’s lifetime (i.e. daunorubicin, doxorubicin, epirubicin, idarubicin and mitoxantrone). 

Criteria for reducing the total anthracycline cumulative lifetime dose include:

  • patient is elderly
  • prior mediastinal radiation
  • hypertensive cardiomegaly
  • concurrent therapy with high dose cyclophosphamide and some other cytotoxic drugs (e.g. bleomycin, dacarbazine, dactinomycin, etoposide, melphalan, mitomycin and vincristine).

Baseline clinical assessments include echocardiogram (ECHO) or gated heart pool scan (GHPS) and electrocardiogram (ECG) evaluation.

Patients with normal baseline cardiac function (left ventricular ejection fraction (LVEF) > 50%) and low risk patients require LVEF monitoring when greater than 70% of the anthracycline threshold is reached or if the patient displays symptoms of cardiac impairment. Post-treatment cardiac monitoring is recommended for patients who have received high levels of total cumulative doses of anthracyclines at the clinician's discretion.

Read more about cardiac toxicity associated with anthracyclines
Immune-related adverse events (irAEs)

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. Management of irAEs is largely based on expert opinion and consensus guidelines.

Examples of irAEs with high risk of mortality include:

  • cardiac toxicity: myocarditis
  • musculoskeletal toxicity: myositis
  • neurological toxicity: encephalitis, Guillain-Barré syndrome, myelitis, myasthenia gravis
  • pulmonary toxicity: pneumonitis
  • skin toxicity: Stevens-Johnson syndrome, toxic epidermal necrolysis.

Examples of irAEs in order of frequency include:

  • Common
    • endocrinopathies: thyroid dysfunction
    • gastrointestinal toxicity: diarrhoea
    • musculoskeletal toxicity: arthralgia, myalgia
    • skin toxicity: rash, erythema, pruritus
  • Less common
    • endocrinopathies: hypophysitis, type I diabetes mellitus
    • gastrointestinal toxicity: colitis
    • musculoskeletal toxicity: inflammatory arthritis
    • ocular toxicity: dry eye
    • renal toxicity
    • skin toxicity: vitiligo
  • Rare
    • endocrinopathies: primary adrenal insufficiency
    • gastrointestinal toxicity: pancreatitis
    • haematological toxicity
    • musculoskeletal toxicity: vasculitis
    • ocular toxicity: uveitis, iritis.

Proactive monitoring, patient self-monitoring and early reporting of adverse events is critical. Treatment interruptions/discontinuation, consultation with specialist and administration of corticosteroids and/or supportive care is required to minimise the risk of death.

Read more about the management of immune-related adverse events (irAEs)
Baseline investigations

Consider ECG and troponin at baseline. There is no clear evidence regarding the efficacy/value of baseline ECG or troponin in patients receiving immune checkpoint inhibitor therapy. Some cancer specialists obtain baseline testing, and others continue this through the initial period of therapy. Consider urinalysis at baseline, particularly in patients with additional risk factors for developing immune-related acute kidney injury.
Growth factor support

G-CSF (short or long-acting) is available on the PBS for chemotherapy induced neutropenia depending on clinical indication and/or febrile neutropenia risk.  

Access the PBS website opens in a new tab or window
Biosimilar drug

Read more about biosimilar drugs on the Biosimilar Awareness Initiative opens in a new tab or window page
Blood tests

FBC, EUC, eGFR, LFTs, serum cortisol, TFTs and BSL at baseline.

Repeat FBC, EUC, eGFR, LFTs and BSL prior to each cycle. Check TFTs every 4-6 weeks during treatment and every 12 weeks as indicated after finalising treatment. Consider checking serum cortisol every 4-6 weeks during treatment and every 12 weeks as indicated after finalising treatment. 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.

Read more about immunotherapy blood test monitoring recommendations.
Hepatitis and HIV

Hepatitis screening is recommended in all patients who are to receive 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), detectable human immunodeficiency virus (HIV) viral load or acquired immune deficiency syndrome (AIDS).
Vaccinations

Live vaccines are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease.
Live vaccines are not recommended for patients receiving immunotherapy. Caution is advised with inactivated vaccines, particularly the influenza vaccine.

For more information about vaccinations in people with cancer refer to the Australian Immunisation Handbook opens in a new tab or window.
Effects of cancer treatment on fertility

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive potential 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. Limited evidence supports that immune checkpoint inhibitor-related hypogonadism due to orchitis and hypophysitis can impact fertility. Immune checkpoint inhibitors can cause fetal harm when given to pregnant women. A pregnancy test should be considered in females of reproductive potential if sexually active. It is important that all patients of reproductive potential use effective contraception whilst on therapy and after treatment finishes. There is very limited evidence to provide guidance regarding contraception timelines. Some studies have demonstrated PD-1 receptor occupancy for greater than 9 months after anti-PD-1 therapy (Brahmer et al., 2010). As a result, some cancer specialists advise using contraception for at least six months or even as long as two years after treatment finishes.

Read more about the impact of cancer treatment on fertility opens in a new tab or window

Link to Brahmer et al., 2010 opens in a new tab or window
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) opens in a new tab or window unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Immune checkpoint inhibitor dose modifications

  • Dose reduction is not recommended
  • No dose adjustment is required in the elderly or mild hepatic impairment. Immune checkpoint inhibitors have not been studied in patients with moderate to severe hepatic impairment.

Management of immune-related adverse events (irAEs)

Link to Management of immune-related adverse events (irAEs)

Chemotherapy dose modifications

Note: All dose reductions are calculated as a percentage of the starting dose

Haematological toxicity
ANC x 109/L (pre-treatment blood test)
0.5 to less than 1.0 Delay treatment until recovery and consider adding G-CSF for subsequent cycles
less than 0.5 Delay treatment until recovery and consider adding G-CSF for subsequent cycles
If patient is already on G-CSF, consider reducing doxorubicin and cyclophosphamide by 25% for subsequent cycles
Febrile neutropenia Delay treatment until recovery and consider adding G-CSF for subsequent cycles
If patient is already on G-CSF, consider reducing doxorubicin and cyclophosphamide by 25% for subsequent cycles
Platelets x 109/L (pre-treatment blood test)
75 to less than 100 Refer to local institutional guidelines; it is the view of the expert clinicians that treatment should continue if patient is clinically well
50 to less than 75 Delay treatment until recovery
less than 50 Delay treatment until recovery and consider reducing doxorubicin and cyclophosphamide by 25% for subsequent cycles
Kidney dosing recommendations 
  • Suggested dose modifications are based on the International Consensus Guideline on Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).
  • Where one or more drugs in a protocol is recommended to be avoided, consider using a clinically appropriate alternative treatment protocol instead.
  • Before dose adjusting or omitting a drug, consider treatment intent.
  • In kidney replacement therapy consult a multidisciplinary team consisting of oncology/haematology with nephrology and/or clinical pharmacology for the management of dosing. 
  • For complete information on individual drug recommendations please review the individual drug monograph in the ADDIKD guideline.
eGFR
(mL/min/1.73m2)		 Cyclophosphamide Doxorubicin Pembrolizumab
≥ 60

Full dose

Full dose

Full dose
45 - 59

Full dose

Full dose 

Full dose
30 - 44

Full dose 

Full dose 

Full dose 
15 - 29

Full dose

Potential for increased risk of adverse events

Full dose

Full dose 
< 15
(without kidney replacement therapy)

Consult a multidisciplinary team consisting of oncology/haematology with nephrology and/or clinical pharmacology for the management of dosing.

Full dose

Full dose
Consider if immune-related adverse event. See Management of immune-related adverse events (irAEs)
Hepatic impairment
Hepatic dysfunction
Consider if immune-related adverse event. See Management of immune-related adverse events (irAEs)
Mild Reduce doxorubicin by 25%
Moderate Reduce doxorubicin by 50%
Severe Omit doxorubicin
Mucositis and stomatitis
Grade 2 Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose for subsequent cycles as follows:
1st occurrence: No dose reduction
2nd occurrence: Reduce doxorubicin and cyclophosphamide by 25%
3rd occurrence: Reduce doxorubicin and cyclophosphamide by 50%
4th occurrence: Withhold chemotherapy
Grade 3 or Grade 4 Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose for subsequent cycles as follows:
1st occurrence: Reduce doxorubicin and cyclophosphamide by 50%
2nd occurrence: Withhold chemotherapy
Diarrhoea
Grade 2 Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose for subsequent cycles as follows:
1st occurrence: No dose reduction
2nd occurrence: Reduce doxorubicin and cyclophosphamide by 25%
3rd occurrence: Reduce doxorubicin and cyclophosphamide by 50%
4th occurrence: Withhold chemotherapy
Grade 3 or Grade 4 Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose for subsequent cycles as follows:
1st occurrence: Reduce doxorubicin and cyclophosphamide by 50%
2nd occurrence: Withhold chemotherapy

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources: 

For more information see References & Disclaimer.

Cyclophosphamide
  Interaction Clinical management
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Increased toxicity of cyclophosphamide possible due to increased conversion to active (and inactive) metabolites Avoid combination or monitor for cyclophosphamide toxicity
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Reduced efficacy of cyclophosphamide possible due to decreased conversion to active (and inactive) metabolites Avoid combination or monitor for decreased clinical response to cyclophosphamide
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney function closely
Amiodarone Possible additive pulmonary toxicity with high-dose cyclophosphamide (i.e. doses used prior to stem cell transplant; 60 mg/kg daily or 120 to 270 mg/kg over a few days) Avoid combination or monitor closely for pulmonary toxicity
Allopurinol, hydrochlorothiazide, indapamide Delayed effect. Increased risk of bone marrow depression; probably due to reduced clearance of active metabolites of cyclophosphamide Avoid combination, consider alternative antihypertensive therapy or monitor for myelosuppression
Ciclosporin Reduced efficacy of ciclosporin due to reduced serum concentration Monitor ciclosporin levels; adjust dosage as appropriate; monitor response to ciclosporin
Suxamethonium Prolonged apnoea due to marked and persistent inhibition of cholinesterase by cyclophosphamide Alert the anaesthetist if a patient has been treated with cyclophosphamide within ten days of planned general anaesthesia
Doxorubicin
  Interaction Clinical management
Cardiotoxic drugs (eg. bevacizumab, calcium channel blockers, propranolol, trastuzumab etc.) Increased risk of doxorubicin-induced cardiotoxicity Avoid combination or monitor closely for cardiotoxicity
Cyclophosphamide Sensitises the heart to the cardiotoxic effects of doxorubicin; also, doxorubicin may exacerbate cyclophosphamide induced cystitis Monitor closely for cardiotoxicity and ensure adequate prophylaxis for haemorrhagic cystitis when combination is used
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs etc.) Additive nephrotoxicity Avoid combination or monitor kidney function closely
Glucosamine Reduced efficacy of doxorubicin (due to induction of glucose-regulated stress proteins resulting in decreased expression of topoisomerase II in vitro) The clinical effect of glucosamine taken orally is unknown. Avoid combination or monitor for decreased clinical response to doxorubicin
CYP2D6 inhibitors (e.g. SSRIs (esp. paroxetine), perhexiline, cinacalcet, doxepin, flecainide, quinine, terbinafine, ritonavir etc.) Increased toxicity of doxorubicin possible due to reduced clearance Monitor for doxorubicin toxicity
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of doxorubicin possible due to reduced clearance Monitor for doxorubicin toxicity
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John's wort etc.) Reduced efficacy of doxorubicin possible due to increased clearance Monitor for decreased clinical response to doxorubicin
Pembrolizumab
No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. Since pembrolizumab is cleared from the circulation through catabolism, no metabolic drug-drug interactions are expected.
  Interaction Clinical management
Immunosuppressants (inc. corticosteroids) Reduced efficacy of both immunosuppressants and pembrolizumab possible due to pharmacodynamic interaction

It is recommended that patients requiring corticosteroids prior to treatment receive the lowest possible dose (preferably no greater than 10 mg prednisolone or equivalent steroid per day). Once started on pembrolizumab the use of corticosteroids to treat immune related adverse events (irAEs) does not appear to impact the clinical response to pembrolizumab. In patients requiring ongoing corticosteroids post management of an irAE, the dose should be as low as possible.

Monitor for signs of organ rejection in transplant recipients.
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney function closely
NK-1 antagonist e.g. aprepitant, fosaprepitant, netupitant
  Interaction Clinical management
Dexamethasone Increased effects/toxicity of dexamethasone due to inhibition of its metabolism via CYP3A4

Reduce dose of antiemetic dexamethasone by approximately 50% when adding a NK-1 antagonist. For protocols that already recommend a NK-1 antagonist, the dose reduction of antiemetic dexamethasone has already been taken into account.

If dexamethasone is part of the chemotherapy protocol, dose reduction as per the product information is not routinely recommended in clinical practice and no additional dexamethasone is required for antiemetic cover. 
Warfarin

Reduced anticoagulant efficacy of warfarin due to increased clearance (aprepitant induces CYP2C9). *Note interaction only applicable to aprepitant/ fosaprepitant

INR should be monitored in the 2 week period, particularly at 7 to 10 days following the administration of aprepitant/ fosaprepitant
Combined oral contraceptive Reduced contraceptive efficacy due to increased clearance. *Note interaction only applicable to aprepitant/ fosaprepitant Alternative non-hormonal methods should be used during and for 1 month after stopping aprepitant/ fosaprepitant
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of NK-1 antagonist possible due to increased clearance Avoid combination or monitor for decreased antiemetic effect. Consider using an alternative antiemetic regimen
CYP3A4 inhibitors (e.g. azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of NK-1 antagonist possible due to reduced clearance Avoid combination or monitor for increased adverse effects of NK-1 antagonist (e.g. headache, hiccups, constipation)
Drugs metabolised by CYP3A4 (e.g. etoposide, imatinib, irinotecan, midazolam, paclitaxel, vinblastine, vincristine etc.) Increased effects/toxicity of these drugs possible due to inhibition of CYP3A4 by NK-1 antagonist Avoid combination or monitor for increased toxicity especially with orally administered drugs
General
  Interaction Clinical management
Warfarin Anti-cancer drugs may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

Interaction with both CYP3A4 and P-gp inhibitors /inducers.

DOAC and anti-cancer drug levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).

Apixaban: avoid concurrent use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window inhibitors. If treating VTE, avoid use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window  inhibitors.

Dabigatran: avoid combination with strong P‑gp opens in a new tab or window inducers and inhibitors.

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin Anti-cancer drugs can damage the lining of the intestine; affecting the absorption of digoxin. Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics Both altered antiepileptic and anti-cancer drug levels may occur, possibly leading to loss of efficacy or toxicity. Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the anti-cancer therapy.
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia. Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update opens in a new tab or window

eviQ provides safe and effective instructions on how to administer cancer treatments. However, eviQ does not provide every treatment delivery option, and is unable to provide a comprehensive list of cancer treatment agents and their required IV line giving set/filter or address chemical compatibilities related to IV drug preparation and administration. There may be alternative methods of treatment administration, and alternative supportive treatments that are also appropriate. Please refer to the individual product information monographs via the TGA opens in a new tab or window and Australian Injectable Drugs Handbook opens in a new tab or window websites for further information.

eviQ is currently updating the way information is presented in the administration section, if you notice any discrepancies please let us know, via feedback@eviq.org.au.

Day 1

Approximate treatment time: 3 hours

Any toxicity may require dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

Anti-cancer drug patient assessment tool prior to each day of treatment.

Immunotherapy patient assessment prior to each treatment.

Prime IV line(s) with sodium chloride 0.9%.

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Verify dexamethasone taken or administer as prescribed.

Pembrolizumab

Administer pembrolizumab:
  • a low protein binding 0.2 micron to 5 micron in-line or add-on filter must be used
  • attach a second IV line via a luer lock connector as close as possible to the site of injection 
    • this may be required in case of a hypersensitivity reaction.
  • via IV infusion over 30 minutes
  • observe for infusion-related reactions
  • flush with 50 mL of sodium chloride 0.9%
  • do not co-administer other drugs through the same infusion line. 
Mild or moderate infusion-related reaction:
  • decrease the rate of infusion and monitor closely 
  • give any further doses with close monitoring
  • premedication with paracetamol and an antihistamine should be considered for further doses.
Severe infusion reaction:
  • stop infusion immediately 
  • medical officer review
  • permanently discontinue pembrolizumab.

Doxorubicin

Extravasation of a vesicant is a medical emergency. Monitor for signs of extravasation throughout administration.

Administer doxorubicin (vesicant):
  • over 5 to 15 minutes
    • via a minibag OR
    • by IV bolus via a side port of a freely flowing IV infusion
  • flush with ~150 mL of sodium chloride 0.9%.
Potential adverse events:
  • potential for flare reaction during administration of doxorubicin (facial flushing and red streaking along the vein), stop infusion and exclude extravasation before continuing at a slower rate of infusion
  • although rare, cardiac arrhythmias may occur during or immediately after doxorubicin administration, if sudden onset of dyspnoea, palpitations or irregular pulse occurs, stop administration and obtain urgent medical officer review.

Cyclophosphamide

Administer cyclophosphamide:
  • via IV infusion over 30 to 60 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%.
Potential adverse events:
  • rapid infusion can cause dizziness, rhinitis, nausea and perioral numbness, if symptoms develop slow infusion rate.

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Continue safe handling precautions until 7 days after completion of drug(s).

Discharge information

Growth factor support - as/if prescribed, and arrangements for administration.

Patient information

Ensure patient receives protocol patient information sheet.

Neoadjuvant chemotherapy (breast cancer) - ensure patient receives the Chemotherapy before breast cancer surgery (neoadjuvant chemotherapy) patient information sheet.

eviQ provides safe and effective instructions on how to administer cancer treatments. However, eviQ does not provide every treatment delivery option, and is unable to provide a comprehensive list of cancer treatment agents and their required IV line giving set/filter or address chemical compatibilities related to IV drug preparation and administration. There may be alternative methods of treatment administration, and alternative supportive treatments that are also appropriate. Please refer to the individual product information monographs via the TGA opens in a new tab or window and Australian Injectable Drugs Handbook opens in a new tab or window websites for further information.

eviQ is currently updating the way information is presented in the administration section, if you notice any discrepancies please let us know, via feedback@eviq.org.au.

Day 1

Approximate treatment time: 60 minutes

Any toxicity may require delay of treatment and review by medical officer before commencing treatment.

Check for adverse events during previous treatment. 

Immunotherapy patient assessment prior to each treatment.

Prime IV line(s) with sodium chloride 0.9%.

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Administer antiemetics if required.

Pembrolizumab

Administer pembrolizumab:
  • a low protein binding 0.2 micron to 5 micron in-line or add-on filter must be used
  • attach a second IV line via a luer lock connector as close as possible to the site of injection 
    • this may be required in case of a hypersensitivity reaction.
  • via IV infusion over 30 minutes
  • observe for infusion-related reactions
  • flush with 50 mL of sodium chloride 0.9%
  • do not co-administer other drugs through the same infusion line. 
Mild or moderate infusion-related reaction:
  • decrease the rate of infusion and monitor closely 
  • give any further doses with close monitoring
  • premedication with paracetamol and an antihistamine should be considered for further doses.
Severe infusion reaction:
  • stop infusion immediately 
  • medical officer review
  • permanently discontinue pembrolizumab.

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Discharge Information

Patient information

Ensure patient receives protocol patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

There can be an overlap between the immune-related and chemotherapy-related adverse events with this treatment. Immune-related adverse events (irAEs) can escalate quickly and close monitoring of the patient is required. Immune-related symptoms symptoms should improve promptly after the introduction of immunosuppressive therapy. If this does not occur review the diagnosis and seek further specialist advice. Refer to the Management of immune related adverse events document for further information. 

Immune related adverse events
Cardiotoxicity

Cardiotoxicity is a rare but serious side effect, which may manifest as asymptomatic reduction in left ventricular ejection fraction (LVEF), arrhythmia, cardiomyopathy, myocarditis, pericarditis, cardiac fibrosis, hypertension, cardiac ischaemia, congestive heart failure (CHF) and cardiac arrest.

Read more about Management of immune related adverse events.
Gastrointestinal toxicity

Colitis, diarrhoea or more bowel movements than usual; blood or mucous in stools; dark, tarry, sticky stools; abdominal pain or tenderness.

Upper gastrointestinal tract inflammation including gastritis, duodenitis and oesophagitis can occur less commonly. Symptoms include nausea, vomiting, dysphagia, odynophagia, haematemesis and abdominal pain.

Read more about Management of immune related adverse events
Haematological toxicity

Autoimmune haemolytic anaemia (AIHA), acquired thrombotic thrombocytopenic purpura (TTP), aplastic anaemia (AA), immune thrombocytopenia (ITP), acquired haemophilia (AH), haemolytic uremic syndrome (HUS) and lymphopenia are rare but potentially serious immune-related adverse events associated with immunotherapy treatment.

Read more about Management of immune related adverse events.
Hepatotoxicity

Transaminase and total bilirubin elevation, jaundice, severe nausea or vomiting, pain on the right side of the abdomen, drowsiness, dark urine, bleeding or bruising more easily than normal, anorexia.

Read more about Management of immune related adverse events.
Musculoskeletal toxicity

Inflammatory arthritis, temporal arteritis, arthralgia, myalgia, synovitis, vasculitis, polymyalgia-like syndrome and myositis.

Read more about Management of immune related adverse events.
Neurological toxicity

Aseptic meningitis, myasthenia gravis, Guillain-Barre syndrome, encephalitis, meningeal symptoms, optic neuritis, neuropathy and acute inflammatory demyelinating polyneuropathy are infrequent but potentially serious immune-related adverse events associated with immunotherapy treatment.

Read more about Management of immune related adverse events.
Ocular toxicity

Eye pain, blurred vision, Uveitis/iritis, episcleritis, blepharitis, optic neuritis, tear duct stenosis, conjunctivitis, hyperlacrimation, watery or dry eyes and photophobia. 

Read more about Management of immune related adverse events.
Other endocrinopathies

Type 1 diabetes mellitus, hypophysitis, hypopituitarism and adrenal insufficiency are infrequent but potentially serious immune-related adverse events associated with immunotherapy treatment.

Read more about Management of immune related adverse events
Pulmonary toxicity

Radiographic changes, dyspnoea, new or worsening cough, hypoxia, tachycardia, chest pain or fever.

Read more about Management of immune related adverse events.
Renal toxicity

Increase in serum creatinine, oliguria, haematuria, peripheral oedema and anorexia.

Read more about Management of immune related adverse events.
Skin toxicity

Rash including full thickness, pruritus, skin blisters, ulceration and necrosis. Radiation recall can occur at site of previous radiation therapy. Symptoms include vesiculation, desquamation and ulceration of the skin.

Read more about Management of immune related adverse events
Thyroid toxicity

Thyroid toxicity is common with immune checkpoint inhibitors. Hypothyroidism is most frequent however hyperthyroidism can also occur.

Read more about Management of immune related adverse events

Chemotherapy immediate (onset hours to days)
Extravasation, tissue or vein injury

The unintentional instillation or leakage of a drug or substance out of a blood vessel into surrounding tissue. This has the potential to cause damage to affected tissue.

Read more about extravasation management
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Red-orange discolouration of urine

Pink/red/orange discolouration of the urine. This can last for up to 48 hours after some anthracycline drugs.
Flare reaction

Anthracycline flare reaction is caused by a localised allergic reaction. It is characterised by erythematous vein streaking, urticaria and pruritus which may occur during drug administration and is often associated with too rapid an infusion. Extravasation must be ruled out if flare occurs.
Taste and smell alteration

Read more about taste and smell changes
Bone pain

Bone pain, usually in the lower back or pelvis, associated with G-CSF.

Chemotherapy early (onset days to weeks)
Neutropenia

Abnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. 

Read more about immediate management of neutropenic fever
Thrombocytopenia

A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding.  

Read more about thrombocytopenia
Oral mucositis and stomatitis

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following anti-cancer treatment, radiation therapy to the head, neck or oesophagus, and high-dose chemotherapy followed by a blood and marrow transplant (BMT).

Read more about oral mucositis and stomatitis
Diarrhoea

Read more about treatment induced diarrhoea
Haemorrhagic cystitis

An inflammatory process, characterised by diffuse bladder mucosal inflammation resulting in haemorrhage. Patients are at risk following blood and marrow transplant (BMT) or treatment with cyclophosphamide, ifosfamide and/or radiation therapy.

Read more about haemorrhagic cystitis
Fatigue

Read more about fatigue
Photosensitivity

Increased sensitivity to ultraviolet (UV) light resulting in an exaggerated sunburn-like reaction accompanied by stinging sensations and urticaria.
Radiation recall

Erythematous or inflammatory skin reaction resembling severe sunburn at sites previously treated with radiation therapy can occur with certain anti-cancer drugs. Symptoms include vesiculation, desquamation and ulceration of the skin.

Read more about radiation recall

Chemotherapy late (onset weeks to months)
Anaemia

Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. 

Read more about anaemia
Alopecia

Hair loss may occur from all parts of the body. Patients can also experience mild to moderate discomfort of the hair follicles, and rarely pain as the hair is falling out.

Read more about alopecia and scalp cooling
Cognitive changes (chemo fog)

Changes in cognition characterised by memory loss, forgetfulness and feeling vague. This is also referred to as 'chemo brain' or 'chemo fog'.

Read more about cognitive changes (chemo fog) 
Nail changes

Hyperpigmentation, paronychia, onycholysis, splinter haemorrhage, pyogenic granuloma formation, subungual haematoma and subungual hyperkeratosis are some of the nail changes associated with anti-cancer drugs.   

Read more about nail toxicities

Chemotherapy delayed (onset months to years)
Menopausal symptoms

Irregular or absent periods, hot flushes, mood swings, sleep disturbance, night sweats, vaginal dryness, decreased libido and dyspareunia. This is caused by ovarian failure and may be temporary or permanent.
Cardiotoxicity

Anthracyclines are the most frequently implicated anti-cancer drugs associated with cardiotoxicity, which typically manifests as a reduction in left ventricular ejection fraction (LVEF), cardiomyopathy, or symptomatic CHF. Anthracycline induced cardiotoxicity has been categorised into acute, early-onset chronic progressive and late-onset chronic progressive and is usually not reversible. The risk of clinical cardiotoxicity increases with a number of risk factors including higher total cumulative doses. 

Read more about cardiac toxicity associated with anthracyclines

eviQ is currently updating the way information is presented in the evidence section to improve usability, consistency and facilitate easier update and maintenance. An updated evidence template is being implemented in a staged approach, first across new protocols, then existing protocols as they are reviewed. Find out more

The evidence supporting this protocol is provided by a phase III multicentre international randomised trial, KEYNOTE-522, which involved 1,174 patients, comparing the addition of pembrolizumab versus placebo in patients with high risk early stage (tumour stage T1c, nodal stage N1-2, or tumour stage T2-4, nodal stage N0-2) triple negative breast cancer receiving neoadjuvant chemotherapy.r

Between March 2017 to September 2018, 784 patients were randomised to receive pembrolizumab 200 mg every 3 weeks with chemotherapy and 390 patients randomised to receive placebo with chemotherapy. In the neoadjuvant phase, patients received four cycles of pembrolizumab or placebo once every 3 weeks plus paclitaxel 80 mg/m2 once weekly plus carboplatin AUC 5 once every 3 weeks or AUC 1.5 once weekly in the first 12 weeks, followed by four cycles of pembrolizumab or placebo plus doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 once every 3 weeks in the subsequent 12 weeks.

Following surgery (mastectomy or breast conservation, with sentinel lymph node sampling or axillary dissection) patients received radiation therapy if indicated, and pembrolizumab or placebo once every 3 weeks for up to nine cycles. Adjuvant capecitabine was not permitted in the study.

Patients who either completed or discontinued the first neoadjuvant treatment could start the second neoadjuvant treatment or undergo surgery, and those who completed or discontinued the second neoadjuvant treatment could undergo surgery.

The two primary end points were a pathological complete response (pCR), defined as pathological stage ypT0/Tis ypN0 at the time of definitive surgery, and event-free survival (EFS) in the intention-to-treat population. Secondary end points included overall survival (OS) among all patients and patients with PD-L1–positive tumours.

Efficacy

At the fourth interim analysis (median follow up 39.1 months), the pembrolizumab arm had a 37% reduction in EFS events. The 3-year EFS rate was 84.5% with pembrolizumab/chemotherapy compared with 76.8% with chemotherapy alone (hazard ratio [HR] = 0.63; 95% confidence interval [CI] 0.48 - 0.82; P < 0.001). Neoadjuvant pembrolizumab plus chemotherapy resulted in a significant increase in pCR rate (ypT0/Tis ypN0): 64.8% vs 51.2%, an absolute 13.6% improvement (P = 0.00055). OS data is immature.r

In prespecified exploratory subgroup analyses, the 3-year EFS benefit seen with pembrolizumab was independent of PD-L1 expression or achievement of pCR.

Pathological complete response according to pathological stager

© N Engl J Med 2022

Kaplan-Meier estimates of event free survival according to treatment groupr

© N Engl J Med 2022

Toxicityr

The safety profile of the pembrolizumab regimen was consistent with the known profiles of each regimen, and no new safety concerns were identified.

For the combined neoadjuvant and adjuvant phases, grade ≥3 treatment-related adverse events were observed in 77.1% of the pembrolizumab+chemotherapy arm and 73.3% of the chemotherapy alone arm.

Treatment-related toxicity led to death in four patients who received pembrolizumab and in one patient given chemotherapy alone.

Adverse eventsr

© N Engl J Med 2022

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Version 3

Date Summary of changes
28/08/2024

As per ASCO 2020 and MASCC/ESMO 2023 guidelines and consensus of the breast reference committee, detailed treatment schedule updated as follows:

  • Dexamethasone day 2, 3, 4 removed.
  • Footnote added "Dexamethasone 4 to 8 mg on days 2 to 4 may be required for those with risk factors for delayed nausea and vomiting."

Version number changed to V.3. 

Version 2

Date Summary of changes
19/07/2023

Protocol updated with ADDIKD guideline recommendations. New kidney dosing recommendation table added to dose modification section.

PDF of previous protocol.

Version number changed to V.2.
11/12/2023 Protocol reviewed electronically by Medical Oncology Reference Committee. Drug status updated to: pembrolizumab PBS authority. Indications note "Capecitabine and olaparib were not permitted in the trial" removed. Next review 2 years.
19/01/2024 Pembrolizumab alternative dosing schedule note added to overview and detail treatment schedule.
03/04/2024 Patient information side effects preamble updated to include examples of 'common, less common and rare' side effects following consensus at the immunotherapy and skin reference committee meeting held on 23rd of February 2024.
29/07/2024 Patient information 'your treatment' section updated to reflect alternative pembrolizumab dosing schedule.

Version 1

Date Summary of changes
05/08/2022 New protocol taken to Medical Oncology Reference Committee meeting
31/10/2022 Approved and published on eviQ. Review in 1 year.
03/02/2023

Edit made to "Patient population":

  • Dot point "triple negative defined by ER and PR expression 10% or less, AND HER-2 negativity (i.e. IHC 0 to 1+ OR FISH ratio less than 2.0 if IHC 2+ or IHC not performed)" changed to "triple negative".

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/4154

04 Jul 2025