AC+PEMB

Cancer Type

Breast

Intent

Neoadjuvant

Regimen Category

Evidence-Informed

Funding Program

New Drug Funding Program

Drugs in Regimen

pembrolizumab , DOXOrubicin , cyclophosphamide

A - Regimen Name

AC+PEMB Regimen

ADRIAMYCIN ® (DOXOrubicin)-Cyclophosphamide-Pembrolizumab

Disease Site

Breast

Intent

Neoadjuvant

Regimen Category

Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR). Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.

Rationale and Uses

For neoadjuvant treatment of high-risk triple negative breast cancer (TNBC)

AC+PEMB is given as either the first or second phase of various chemotherapy backbone options (AC-PACL, AC-PACL(W), or CRBPPACL(W)-AC).

Supplementary Public Funding

pembrolizumab
New Drug Funding Program (Pembrolizumab - Previously Untreated High-Risk Early-Stage Triple Negative Breast Cancer) (NDFP Website )

B - Drug Regimen

pembrolizumab

^1,2

2 mg /kg

IV (max 200 mg)

Day 1

DOXOrubicin

60 mg /m²

Day 1

cyclophosphamide

600 mg /m²

Day 1

¹Dosing based on NDFP funding criteria. Refer to NDFP form for alternative pembrolizumab dosing schedule (4 mg/kg IV q6 weeks).

²Give pembrolizumab before chemotherapy when given on the same day.

C - Cycle Frequency

REPEAT EVERY 21 DAYS

For 4 cycles unless disease progression or unacceptable toxicity occurs.

Neoadjuvant AC-PACL with Pembrolizumab (AC+PEMB x 4 cycles, then PACL+PEMB or PACL(W)+PEMB x 4 cycles):

Refer to PACL+PEMB or PACL(W)+PEMB for details on the second neoadjuvant treatment phase.

Neoadjuvant CRBPPACL(W)-AC with Pembrolizumab (CRBPPACL(W)+PEMB x 4 cycles, then AC+PEMB x 4 cycles):

Refer to PEMB for the adjuvant pembrolizumab monotherapy phase.

D - Premedication and Supportive Measures

Antiemetic Regimen:

High

Also refer to CCO Antiemetic Recommendations.

Febrile Neutropenia Risk:

Low

(AC-PACL)

Moderate

(CRBPPACL(W)-AC)

Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.

Premedication for pembrolizumab (prophylaxis for infusion reactions):

Routine pre-medication is not recommended.
May consider antipyretic and H1-receptor antagonist in patients who experienced a grade 1-2 infusion reaction.

Other Supportive Care:

Avoid the use of corticosteroids or immunosuppressants before starting treatment. Corticosteroids may be used as premedication (e.g. antiemetic) when given with chemotherapy.

E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated.

Dosage with toxicity

Worst Toxicity Type / Counts (x 10⁹/L) in Prior Cycle	Doxorubicin (% previous dose)	Cyclophosphamide (% previous dose)
Febrile Neutropenia, or Thrombocytopenic bleeding, or Grade 4 ANC ≥ 7 d	75%*
Cardiotoxicity **	Discontinue	Caution
Grade 3 related non-hematologic / organ	75% for suspect drug(s). *
Grade 4 related non-hematologic / organ	Discontinue

_{* Retreat when toxicities have recovered to ≤ grade 2, platelets ≥ 100 x 10⁹/L, and ANC ≥ 1.5 x 10⁹/L.}

_{**including any signs and symptoms of heart failure, greater than 10% decline in LVEF to below the lower limit of normal, a greater than 20% decline in LVEF from any level, or LVEF ≤ 45%.}

Pembrolizumab:

Healthcare professionals should also consult the most recent pembrolizumab product monograph for additional information.
There are no dose reductions for pembrolizumab. Doses are either delayed or discontinued with toxicity.

Summary of Principles of Management or immune-related adverse effects (iRAEs)
- Immune-related adverse effects (irAEs) are different in their presentation, onset and duration compared to conventional chemotherapy. Patient and provider education is essential.
- Initial irAE presentation can occur months after completion of treatment and affect multiple organs.
- Dose escalation or reduction is not recommended.
- If no other cause can be identified (such as infection), any new symptom should be considered immune-related and prompt treatment initiated.
- Organ-specific system-based toxicity management is recommended.
Refer to CCO's Immune Checkpoint Inhibitor Toxicity Management Guideline for detailed descriptions of Immune-related toxicities and their management.

Management of Infusion-related reactions

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

Anthracyclines (Doxorubicin):

Grade	Management	Re-challenge
1 or 2	Stop or slow the infusion rate. Manage the symptoms.	Consider pre-medications and administering at a slower infusion rate.
3 or 4	Stop treatment. Aggressively manage symptoms.	Re-challenge is discouraged, especially if vital symptoms have been affected. Consider desensitization if therapy is necessary.

Pembrolizumab:

Grade

Management

Re-challenge

1 or 2

Stop or slow the infusion.
Manage the symptoms.

Restart:

No specific recommendations can be made at this time.

Consider re-challenge with close monitoring and pre-medications (antipyretic and H1-receptor antagonist).

3 or 4

Stop the infusion.
Aggressively manage symptoms.

Discontinue permanently (do not re-challenge).

Hepatic Impairment

Refer to CCO's Immune Checkpoint Inhibitor Toxicity Management Guideline for detailed descriptions for immune-related hepatitis management with pembrolizumab.

Bilirubin		AST/ALT	Cyclophosphamide	Doxorubicin
Bilirubin		AST/ALT	(% of previous dose)
1-2 x ULN	AND	< 2x ULN	100%	50%
2-4 x ULN	OR	2-4x ULN	Caution	25%
>4 x ULN	OR	>4 x ULN	Caution	Discontinue

Renal Impairment

Refer to CCO's Immune Checkpoint Inhibitor Toxicity Management Guideline for detailed descriptions for immune-related nephritis management with pembrolizumab.

Creatinine Clearance (mL/min)	Cyclophosphamide	Doxorubicin
Creatinine Clearance (mL/min)	(% of previous dose)
>30-50	100%	100%
10-30	50-75%	100%
<10	50% or OMIT	100%

F - Adverse Effects

Refer to pembrolizumab, DOXOrubicin, cyclophosphamide drug monograph(s) for additional details of adverse effects

Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

Alopecia
Myelosuppression ± infection, bleeding (May be severe)
Nausea, vomiting
Mucositis

Anorexia
Fatigue
Graft-versus-host disease (GVHD)

Diarrhea
Rash, pruritus
Phlebitis
Immunosuppression
Musculoskeletal pain
ECG changes

↑ LFTs
Cardiotoxicity
Hemorrhagic Cystitis
Rash
Hypothyroidism
Arrhythmia
Hyperthyroidism
Leukemia (secondary)
Pneumonitis (May be severe)
Eye disorders
Hyperglycemia
Adrenal insufficiency
Encephalitis
Guillain-Barre syndrome
Hemolytic anemia
Hypopituitarism
Infusion related reaction (May be severe)
Myelitis
Nephritis
Nephrotoxicity
Pancreatitis
Pericarditis
Sarcoidosis
Vasculitis
Abdominal pain
Aplastic anemia
Arterial thromboembolism
Bladder fibrosis
Conjunctivitis
Constipation
Cystitis
Cytokine release syndrome
Delayed wound healing
Dizziness
Dysgeusia
Estrogen deprivation symptoms
Fluid retention (including effusions)
Flushing
GI hemorrhage
Hand-foot syndrome
Headache
Hemolytic uremic syndrome
Hemophagocytic lymphohistiocytosis
Hypersensitivity
Hyperuricemia
Injection site reaction
Myocarditis
Nail disorder
Neurotoxicity
Other
Other
Other
Photosensitivity
Posterior reversible encephalopathy syndrome (PRES)
QT interval prolonged
Radiation recall reaction
Rhabdomyolysis
Secondary malignancy
SIADH
Skin discolouration
Skin hyperpigmentation
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Tumour lysis syndrome
Urine discoloration
Veno-occlusive disease
Venous thromboembolism
Visual disorders
Watering eyes

G - Interactions

Refer to pembrolizumab, DOXOrubicin, cyclophosphamide drug monograph(s) for additional details

Avoid use of calcium channel blockers (e.g. verapamil) or bevacizumab with doxorubicin due to additive cardiotoxicity.
Avoid anthracycline-based therapy for up to 28 weeks after stopping trastuzumab.
Avoid using stavudine or zidovudine with doxorubicin.
Monitor serum digoxin levels when used with doxorubicin; levels may decrease.
Monitor serum phenytoin levels when used with doxorubicin; levels may decrease.
Avoid concurrent alcohol use with cyclophosphamide; may ↑ cyclophosphamide-induced nausea and vomiting; reduced anti-tumour activity has been observed in animal studies
Caution with use of CYP3A4 inhibitors and cyclophosphamide; avoid grapefruit for 48 hours before and on day of cyclophosphamide.
Use of systemic corticosteroids or immunosuppressants should be avoided prior to starting pembrolizumab because of potential interference with efficacy. They can be used to treat immune-mediated reactions after starting the drug.

H - Drug Administration and Special Precautions

Refer to pembrolizumab, DOXOrubicin, cyclophosphamide drug monograph(s) for additional details

Administration

DOXOrubicin

Slow push through sidearm of free flowing IV (5% Dextrose, Normal Saline). Depending on the dose volume and vein condition, administer the dose between 3 to 10 minutes to minimize thrombosis risk or extravasation.
Do not admix with other drugs unless data are available; precipitates with fluorouracil and heparin.
Avoid contact with alkaline solutions as this can lead to hydrolysis of doxorubicin.
Slow down injection rate if erythematous streaking or facial flushing occurs.
If any signs or symptoms of extravasation occur, the injection or infusion should be immediately terminated and restarted in another vein. Any known or suspected extravasation should be managed promptly as per local guidelines and should include application of ice to the affected area.
Store vials under refrigeration (2 to 8ºC) and protect from light

Cyclophosphamide

Oral hydration is strongly encouraged; for IV cyclophosphamide: 2-3 L of fluid/day. Poorly hydrated patients may need more IV hydration. Inadequate total hydration may result in dose-related hemorrhagic cystitis.
Patients should be encouraged to empty their bladder frequently to minimize dwell times.
Morning administration of cyclophosphamide is recommended, to decrease the amount of drug dwelling in the bladder overnight.
Consider usage of mesna with high dose therapy of cyclophosphamide (>1 g/m²).

For IV infusion, may reconstitute cyclophosphamide with sodium chloride 0.9% or sterile water for injection and further dilute as follows:

Dose Dilution volume

≤ 1000 mg 100 mL sodium chloride 0.9% or dextrose 5%

> 1000 mg 250 mL sodium chloride 0.9% or dextrose 5%

Do not reconstitute or dilute with benzyl alcohol-containing solutions (ie. Bacteriostatic sodium chloride), since it may catalyse the decomposition of cyclophosphamide or cause toxicity in infants
Avoid the use of aluminum-containing preparation and administration equipment, since darkening of aluminum and gas production have been reported

Store unopened vial in the original packaging at room temperature, away from heat, light or moisture

Pembrolizumab

Dilute in 0.9% sodium chloride or D5W to final concentration of 1 to 10 mg/mL; mix by gentle inversion.
Administer over 30 minutes using sterile, non-pyrogenic, low protein-binding 0.2 to 5 micron in-line or add-on filter.
Administer pembrolizumab before chemotherapy, if given on the same day.
Do not co-administer other drugs through the same infusion line.
Unopened vials should be stored under refrigeration (2 to 8^oC). Protect from light. Do not freeze.

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

Contraindications

Patients who have a hypersensitivity to these drugs or any of their components, other anthracyclines or anthracenediones (i.e. epirubicin, daunorubicin, mitoxantrone or mitomycin C)
Persistent myelosuppression induced by chemotherapy or radiation, severe immunosuppression
Severe hepatic or renal impairment, or urinary outflow obstruction
Severe myocardial insufficiency, arrhythmias or history of cardiac disease or recent myocardial infarction
Previous treatment with maximum cumulative doses of doxorubicin, other anthracyclines or anthracenediones
Patients with active infection, particularly varicella zoster infection

Warnings/ Precautions

Avoid the use of live or live-attenuated vaccines; use may result in serious infections in immunocompromised patients. Reduced immunogenicity may occur with use of inactivated vaccines
Exercise caution in patients with adrenal insufficiency
Pembrolizumab may cause serious immune-mediated reactions affecting multiple organ systems, including GI, hepatic, renal, respiratory, endocrine and others. Use with caution and monitor closely in patients with pre-existing conditions such as colitis, hepatic impairment, respiratory or endocrine disorders, such as hypo or hyperthyroidism or diabetes mellitus.
Use caution when driving or operating machinery since cyclophosphamide may produce symptoms of vasomotor ataxia (e.g. dizziness, blurred vision, etc.).

Pregnancy/ Lactation

This regimen is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners while on treatment and after the last treatment dose. Recommended methods and duration of contraception may differ depending on the treatment. Refer to the drug monograph(s) for more information.
Breastfeeding is not recommended during this treatment and after the last treatment dose. Refer to the drug monograph(s) for recommendations after the last treatment dose (if available).
Fertility Effects:
- DOXOrubicin: Yes; may be partially reversible
- Cyclophosphamide: Yes; Sperm-banking before treatment should be considered
- Pembrolizumab: Unknown

I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.

Recommended Clinical Monitoring

CBC; Baseline and before each cycle
Liver function tests; Baseline and before each cycle
Renal function tests; Baseline and before each cycle
Electrolytes; Baseline and as clinically indicated
Blood glucose; Baseline and as clinically indicated
Thyroid function tests; Baseline and as clinically indicated
Blood cortisol (for TNBC in neoadjuvant setting); Baseline, prior to surgery, and as clinically indicated
Urinalysis; Baseline and as clinically indicated
Cardiac function tests (Echo, RNA and/or MUGA scans) for all patients with cardiac risk factors (including prior trastuzumab or patients at or above threshold dose levels); Baseline and as clinically indicated
Clinical toxicity assessment for fatigue, infection, thromboembolism, bleeding, injection site reactions, infusion-related and immune-mediated reactions, hyperuricemia, GI effects (e.g. stomatitis, nausea, vomiting) cystitis, cardiac, pulmonary, ocular, endocrine, musculoskeletal, dermatologic and neurologic effects ; At each visit
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

ECGs; As clinically indicated
INR; for patients on warfarin; Baseline and as clinically indicated
Pulmonary function tests; As clinically indicated

J - Administrative Information

Approximate Patient Visit

2 hours

Pharmacy Workload (average time per visit)

39.814 minutes

Nursing Workload (average time per visit)

57.333 minutes

K - References

BC Cancer Protocol Summary for NEOAdjuvant Therapy for Triple Negative Breast Cancer Using Carboplatin and Weekly PACLitaxel Followed by DOXOrubicin and Cyclophosphamide. June 14, 2021.

CADTH Reimbursement recommendation - Pembrolizumab: For the treatment of adult patients with high-risk early-stage triple negative breast cancer. September 2022.

Cyclophosphamide drug monograph, Ontario Health (Cancer Care Ontario)

Doxorubicin drug monograph, Ontario Health (Cancer Care Ontario)

Loibl S, O’Shaughnessy J, Untch M et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 2018; 19(4): 497–509.

Pembrolizumab drug monograph, Ontario Health (Cancer Care Ontario)

Schmid J, Cortes L, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020;382:810-21.

Schmid P, Cortes J, Dent R, et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med 2022;386:556-67.
DOI: 10.1056/NEJMoa2112651

Sikov WM, Berry DA, Perou CM et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: cALGB 40603 (Alliance). J Clin Oncol 2015; 33(1): 13–21.

September 2026 Expanded to full regimen monograph.

M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph. Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
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Last Updated: July 31, 2026

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