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AC-PACL; AC-PACL+TRAS

Cancer Type: Breast  Intent: Neoadjuvant, Adjuvant
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Paclitaxel - Adjuvant Treatment for Breast Cancer
New Drug Funding Program
    Paclitaxel - Neoadjuvant Treatment for Non-Metastatic Breast Cancer
New Drug Funding Program
    Trastuzumab (Biosimilar) - Adjuvant Treatment for Breast Cancer
Evidence Building Program
    Trastuzumab (EBP) - Adjuvant Treatment for Breast Cancer
Evidence Building Program
    Trastuzumab (EBP) - Adjuvant Treatment for Breast Cancer Supplemental
A - Regimen Name

AC-PACL Regimen
ADRIAMYCIN ® (DOXOrubicin)-Cyclophosphamide then PACLitaxel
AC-PACL+TRAS Regimen
ADRIAMYCIN ® (DOXOrubicin)-Cyclophosphamide then PACLitaxel and Trastuzumab


Disease Site
Breast

Intent
Neoadjuvant
Adjuvant

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
Neoadjuvant treatment for non-metastatic breast cancer (inoperable locally advanced, inflammatory or to downsize tumour pre-surgery) or Adjuvant therapy for node-positive and high risk node-negative breast cancer patients.
Trastuzumab may be used concurrently with paclitaxel or after completion of paclitaxel in: 
  • high-risk (node-positive or negative with tumour > 1cm) HER-2 positive breast cancer
  • or small tumours (≤1 cm, node negative) in HER-2 positive breast cancer as part of the evidence building program

Supplementary Public Funding

PACLitaxel
New Drug Funding Program (Paclitaxel - Adjuvant Treatment for Breast Cancer)

PACLitaxel
New Drug Funding Program (Paclitaxel - Neoadjuvant Treatment for Non-Metastatic Breast Cancer)

trastuzumab
New Drug Funding Program (Trastuzumab (Biosimilar) - Adjuvant Treatment for Breast Cancer)

trastuzumab
Evidence Building Program (Trastuzumab (EBP) - Adjuvant Treatment for Breast Cancer)

trastuzumab
Evidence Building Program (Trastuzumab (EBP) - Adjuvant Treatment for Breast Cancer Supplemental)

 
B - Drug Regimen

Note: Different trastuzumab products are not interchangeable.

 

AC: (x 4 cycles)

DOXOrubicin

(Round to nearest 1mg)
60 mg /m² IV Day 1
cyclophosphamide

(Round to nearest 10mg)
600 mg /m² IV Day 1

THEN

PACLITAXEL (Taxol®): (x 4 cycles)

PACLitaxel

(Round to nearest 3mg)
175 mg /m² IV over 3 hours Day 1
For patients with HER2 positive tumours,  Trastuzumab may be given for one year, starting either concurrently with Paclitaxel or after 4 cycles of Paclitaxel:
trastuzumab

Refer to TRAS (Breast - Adjuvant) regimen for details.

 

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C - Cycle Frequency

REPEAT EVERY 21 DAYS

AC X 4 cycles then Paclitaxel (Taxol®) X 4 cycles

Trastuzumab: Refer to TRAS (Breast Adjuvant) regimen for details.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

High (AC)
Low (Paclitaxel)


Febrile Neutropenia Risk:

Low

Other Supportive Care:

  • Paclitaxel: Patients should be pretreated with a corticosteroid as well as an antihistamine and a H2 Blocker.
  • For example:
  • Dexamethasone 20mg PO 12 & 6 hours or 20mg IV 30 minutes before Paclitaxel administration
  • Diphenhydramine 50mg IV 30 minutes before Paclitaxel administration
  • Ranitidine 50mg IV 30 minutes before Paclitaxel administration
 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations are in use at some centres.

 

Dosage with toxicity

Hematologic Toxicities:  See Appendix 6 for general recommendations.

Toxicity Type / Counts x 109/L

 

Toxicity Type / Counts x 109/L

Doxorubicin
(% previous dose)

 

Cyclophosphamide
(% previous dose)
Paclitaxel
(% previous dose)

ANC <1.5

Or

Platelet <  100

Hold *

Febrile Neutropenia, or
Grade 4 ANC ≥ 7 d 

Or

Thrombocytopenic bleeding

 

Hold* then 75%

(or consider GCSF – for isolated neutropenia)

ANC ≥ 1.5

And

Platelet ≥ 100

100%

Toxicity Type / Counts x 109/L   Toxicity Type / Counts x 109/L Doxorubicin
(% previous dose)
Cyclophosphamide
(% previous dose)
Paclitaxel
(% previous dose)

Grade 3/4 Neurotoxicity

 

 

Not applicable

80%*

Grade 3 related organ

 

 

*75% for suspect drug(s). If cardiotoxicity, follow recommendations in doxorubicin and paclitaxel drug monographs.

Grade 4 related organ

 

 

 Discontinue 

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



Hepatic Impairment

Bilirubin

 

AST/ALT

Cyclophosphamide

Doxorubicin

Paclitaxel

(% of previous / mg/m2)

1-2 x ULN

and/ or

-

100%

50%

100%

2-4 x ULN

2-4x ULN

Caution

25%

135mg/m2

>4 x ULN

>4 x ULN

Caution

Discontinue

50mg/m2 or OMIT


Renal Impairment

Creatinine Clearance (mL/min)

Cyclophosphamide

Doxorubicin

Paclitaxel

(% of previous)

>30-50

100%

100%

100%

10-30

50-75%

100%

100%

<10

50% or OMIT

100%

100%


 
F - Adverse Effects

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


Refer to trastuzumab drug monograph for adverse effect details (not listed below).

 

Most Common Side Effects 

Less Common Side Effects, but may be
Severe or Life-Threatening

  • Nausea and vomiting
  • Cystitis
  • Myelosuppression ± infection
  • Stomatitis and diarrhea
  • Peripheral neuropathy
  • Hypersensitivity reactions (Paclitaxel)
  • Myalgia and arthralgia
  • Alopecia

·       Cardiotoxicity

·       Secondary leukemia/malignancies

·       Arterial/Venous Thromboembolism

·       Pneumonitis

·       SIADH

·       DIC, Hemolytic Uremic Syndrome

·       Rhabdomyolysis

·       Pancreatitis, GI obstruction, perforation

 
G - Interactions
Refer to DOXOrubicin, cyclophosphamide, PACLitaxel drug monograph(s) for additional details
 
H - Drug Administration and Special Precautions

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


Note: Different trastuzumab products are not interchangeable.

 
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.

Recommended Clinical Monitoring

  • Clinical toxicity assessment (including stomatitis, cardiotoxicity, local toxicity, cystitis, hypersensitivity, neuropathy, musculoskeletal, infection or diarrhea); at each visit
  • CBC before each cycle
  • Baseline and regular liver function tests
  • Baseline and regular renal function tests and urinalysis
  • Cardiac examination especially with risk factors (including prior therapy with Epirubicin, Mitoxantrone, or other cardiotoxic drug), or a cumulative doxorubicin dose of > 450 mg/m2
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Approximate Patient Visit
AC-PACL
AC: 1 to 1.5 hours; Paclitaxel: 5 hours
AC-PACL+TRAS
AC: 1 to 1.5 hours; Paclitaxel: 5 hours; TRAS: First cycle - 1.5 hours; Subsequent cycles - 0.5 hour
Pharmacy Workload (average time per visit)
AC-PACL
24.613 minutes
AC-PACL+TRAS
29.158 minutes
Nursing Workload (average time per visit)
AC-PACL
55.75 minutes
AC-PACL+TRAS
65.75 minutes
 
K - References

Henderson IC, Beryy D, Demetri G, Cirrincione C, et al. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol, 2003 Mar15;21(6):976-83

Tan-Chiu E, Yothers G, Romond EH, et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, Human Epidermal Growth Factor Receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol. 2005; 23(31): 7811-9.


PEBC Advice Documents or Guidelines

December 2019 Updated NDFP form and biosimilar information in Drug Regimen and Drug Administration and Special Precautions sections.


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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.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.