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AC-PACL(W); AC-PACL(W)+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 - Adjuvant Treatment for HER2_neu-Overexpressing Primary 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(W) Regimen
ADRIAMYCIN ® (DOXOrubicin)-Cyclophosphamide then PACLitaxel Weekly
AC-PACL(W)+TRAS Regimen
ADRIAMYCIN ® (DOXOrubicin)-Cyclophosphamide then PACLitaxel Weekly 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

Neo-adjuvant or adjuvant therapy in breast cancer. Weekly paclitaxel after AC chemotherapy improves overall survival and disease-free survival as compared to 3-weekly paclitaxel.
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 - Adjuvant Treatment for HER2_neu-Overexpressing Primary 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

AC: (x 4 cycles)

DOXOrubicin
60 mg /m² IV Day 1
cyclophosphamide
600 mg /m² IV Day 1

Repeat Every 21 Days 

THEN

PACLITAXEL Weekly:  (x 12 doses)

PACLitaxel
80 mg /m² IV Day 1

Repeat Every 7 Days 

For patients with HER2 positive tumours, Trastuzumab may be given for one year, starting concurrently with paclitaxel or after 12 weekly cycles of paclitaxel:

trastuzumab
8 mg /kg IV loading dose Day 1, cycle 1 only

THEN,

trastuzumab
6 mg /kg IV maintenance dose Every 21 Days

 

Alternative chemotherapy schedule:

AC: (x 4 cycles)

DOXOrubicin
60 mg /m² IV Day 1
cyclophosphamide
600 mg /m² IV Day 1

Repeat Every 14 Days 

THEN

PACLITAXEL Weekly:  (x 12 doses)

PACLitaxel
80 mg /m² IV Day 1

Repeat Every 7 Days

 

Alternative Trastuzumab schedule:

trastuzumab
4 mg /kg IV loading dose Day 1, cycle 1 only

THEN,

trastuzumab
2 mg /kg IV maintenance dose Weekly (Q7 Days)
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C - Cycle Frequency

AC X 4 cycles then weekly Paclitaxel (Taxol®) X 12 doses

Q3 Weeks or Weekly Trastuzumab:  Refer to TRAS (Breast - Adjuvant) regimen for details.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

High (AC)
Low (Paclitaxel)


Febrile Neutropenia Risk:

Low

AC(Q3W)-PACL(W)


High

AC(Q2W)-PACL(W):  Use G-CSF prophylaxis for patients at high risk of febrile neutropenia. See G-CSF recommendations.


Other Supportive Care:

• Paclitaxel: Patients should be pretreated with a corticosteroid as well as an antihistamine and a H2 Blocker. For example:

  • Dexamethasone 10mg IV 30 minutes before Paclitaxel
  • Diphenhydramine 50mg IV 30 minutes before Paclitaxel
  • Ranitidine 50mg IV 30 minutes before Paclitaxel

Also refer to CCO Antiemetic Summary

 
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.

Suggested Dose Levels:
Doxorubicin: 60 mg/m², 45 mg/m², 30 mg/m²
Cyclophosphamide: 600 mg/m², 450 mg/m², 300 mg/m²
Paclitaxel: 80 mg/m², 60 mg/m², 40 mg/m²

Toxicity Type / Counts x 109/L

 

Toxicity Type / Counts x 109/L

Doxorubicin*

 

Cyclophosphamide*

Paclitaxel*

 

ANC < 1.5

Or

Platelet < 100 

Hold*

Hold*

Hold*

Febrile Neutropenia

Or

ANC < 0.5

Hold* and ↓ 1 dose level or GCSF

Hold* and ↓ 1 dose level or GCSF

Hold* and ↓ 1 dose level or GCSF

Grade 3 neurotoxicity

 

 

100%

100%

↓  1 dose level *

Other Grade 3 non-hematologic

 

 

↓  1 dose level*

↓  1 dose level*

↓  1 dose level*

Grade 4 non-hematologic

 

 

Discontinue

Discontinue

Discontinue

* Major organ toxicity should have recovered to ≤ grade 2, ANC to ≥ 1.5 x 109/L and platelets ≥ 100 x 109/L prior to retreatment.



Hepatic Impairment

Bilirubin *

Doxorubicin
(% previous dose)

Cyclophosphamide

Paclitaxel
(% previous dose)

1-2 X ULN

50%

No adjustment required

Caution

2-4 X ULN

25%

  Caution

75%

> 4 X ULN

OMIT

  Caution

50% or OMIT

*Consider dose reduction for doxorubicin and paclitaxel for severe increase(s) in transaminases.

 

 

 


Renal Impairment

Creatinine Clearance (mL/min)

Doxorubicin

Cyclophosphamide
(% previous dose)

Paclitaxel

>30 – 50

No adjustment required

100%

No adjustment required

10 – 30

50 – 75%

<10

50% or OMIT


 
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
  • Myelosuppression ± infection
  • Fatigue
  • Stomatitis and diarrhea
  • Neurotoxicity
  • Hypersensitivity reactions (paclitaxel)
  • Myalgia and arthralgia
  • Alopecia
  • Cystitis
  • Cardiotoxicity (may be severe)
  • Increased LFTs, bilirubin
  • Rash (may be severe)
  • Pneumonitis, pulmonary fibrosis
  • SIADH
  • DIC, hemolytic uremic syndrome, renal failure
  • Secondary leukemia
  • Venous/arterial thromboembolism
  • Abnormal ECG, cardiac failure, acute MI
  • Pancreatitis, GI perforation, typhlitis, obstruction
 
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

 
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

  • CBC; baseline and before each cycle
  • Liver function tests; baseline and before each cycle
  • Renal function tests and urinalysis; baseline and before each cycle
  • Cardiac function tests (echocardiogram or MUGA scan) and examination especially with risk factors (including prior therapy with epirubicin, mitoxantrone, or other cardiotoxic drug), or a cumulative doxorubicin dose of > 450 mg/m2; baseline and regular
  • Blood pressure and pulse rate monitoring during paclitaxel infusion; baseline and as clinically indicated
  • Clinical toxicity assessment, including GI toxicity, cardiotoxicity, local toxicity, cystitis, hypersensitivity, neurotoxicity, musculoskeletal effects; at each visit
  • 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(W)
AC: 1 to 1.5 hours; Paclitaxel: 2 hours
AC-PACL(W)+TRAS
AC: 1 to 1.5 hours; Paclitaxel: 2 hours; TRAS: First cycle - 1.5 hours; Subsequent cycles - 0.5 hour
Pharmacy Workload (average time per visit)
AC-PACL(W)
20.888 minutes
AC-PACL(W)+TRAS
23.31 minutes
Nursing Workload (average time per visit)
AC-PACL(W)
51.542 minutes
AC-PACL(W)+TRAS
56.542 minutes
 
K - References

Doxorubicin, cyclophosphamide, paclitaxel and trastuzumab drug monographs, Cancer Care Ontario.

Henderson IC, Berry 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; 21(6): 976-83.

Romond EH, Perex EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. NEJM 2005; 353(16) 1673-84.

Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. NEJM 2008; 358(16): 1663-71.


PEBC Advice Documents or Guidelines

February 2018 edited paclitaxel to weekly x 12 doses


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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.
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