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CRBPPACL

Cancer Type: Gynecologic, Ovary  Intent: Adjuvant
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Paclitaxel in Combination with Platinum - First Line - Advanced Ovarian Fallopian Tube or Primary Peritoneal Carcinoma
A - Regimen Name

CRBPPACL Regimen
PACLitaxel-CARBOplatin


Disease Site
Gynecologic - Ovary

Intent
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

First-line postoperative treatment for stage II-IV epithelial ovarian cancer, fallopian tube or primary peritoneal cancers

 

 


Supplementary Public Funding

PACLitaxel
New Drug Funding Program (Paclitaxel in Combination with Platinum - First Line - Advanced Ovarian Fallopian Tube or Primary Peritoneal Carcinoma)

 
B - Drug Regimen

PACLitaxel
175 mg /m² IV Day 1
CARBOplatin
AUC 5 to 6 IV Day 1

Adjust Carboplatin dose to AUC target (using Calvert formula) as outlined in "Other Notes" section.

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C - Cycle Frequency

REPEAT EVERY 21 DAYS

For a usual total of 6 cycles unless disease progression or unacceptable toxicity occurs

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate + NK1 antagonist (Carboplatin AUC ≥ 5)

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.

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
  • diphenhydramine 50mg IV 30 minutes before paclitaxel
  • ranitidine 50mg IV 30 minutes before paclitaxel
 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and may be considered.

 

Dosage with toxicity

Suggested Dose Levels:

Dose Level

Carboplatin

Paclitaxel (mg/m2)

0

AUC 6

175

-1

AUC 5

160

-2

AUC 4

135

 

Worst toxicity in previous cycle

Carboplatin (% previous dose)

Paclitaxel (% previous dose)*

Febrile neutropenia;

Grade 4 ANC ≥ 5-7 days OR

No change

Consider adding G-CSF and continue current dose

OR ↓ 1 dose level

Neutropenia as defined above AND platelets < 100 for > 7d,

grade 4 thrombocytopenia OR thrombocytopenic bleeding

↓ 1 dose level

Consider adding G-CSF and continue current dose

OR ↓ 1 dose level

Grade 3 neurotoxicity OR other toxicity

↓ 1 dose level

↓ 1 dose level

Grade 4 neurotoxicity OR other toxicity;

Discontinue

Discontinue

Any grade cystoid macular edema

No Change

Hold and investigate; refer patient promptly to an ophthalmic examination. Discontinue if confirmed

*Patients should not be retreated with paclitaxel until neutrophils ≥ 1.5 x 109/L and platelet counts ≥ 100 x 109/L and other toxicity has recovered to ≤ grade 2



Hepatic Impairment

No dose adjustment required for carboplatin.

Bilirubin
Dose
1. If Bilirubin 2-4 x ULN
Give MAXIMUM dose of Paclitaxel 135mg/m2
2. If Bilirubin > 4 x ULN
OMIT Paclitaxel dose or
Give MAXIMUM dose of Paclitaxel 50mg/m2

Renal Impairment

  • As creatinine clearance changes, adjust dosage of carboplatin using the Calvert Formula. See "Other Notes" section.

  • Modification for paclitaxel not required.


Dosage in the Elderly

  • No adjustment required , but elderly patients are more at risk for severe toxicity paclitaxel.

  • Caution should be exercised and dose reduction considered as elderly patients may have more severe myelosuppression and neuropathy with carboplatin.

 


 
F - Adverse Effects

Refer to PACLitaxel, CARBOplatin 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
  • Peripheral neuropathy
  • Myelosuppression ± infection, bleeding (may be severe)
  • Musculoskeletal pain
  • Nausea, vomiting
  • Hypersensitivity
  • Abnormal electrolytes
  • ↑ LFTs
  • Nephrotoxicity
  • Fatigue
  • Edema
  • Mucositis
  • Constipation
  • Diarrhea (may be severe)
  • Hearing impairment
  • ECG changes
  • Arrhythmia, cardiac failure
  • Arterial / venous thromboembolism
  • Rash
  • Radiation recall reaction
  • GI obstruction / perforation
  • Hemolytic uremic syndrome
  • Pancreatitis
  • Injection site reaction
  • Secondary malignancy
  • Autonomic, cranial neuropathy
  • Encephalopathy
  • Cystoid macular edema
  • Seizure
  • Pneumonitis
 
G - Interactions

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


  • Caution and monitor with nephrotoxic drugs (i.e. aminoglycosides)

  • Caution and monitor INR in patients receiving warfarin

  • Caution and monitor phenytoin levels in patients receiving phenytoin

  • Caution and monitor with CYP3A4 and 2C8 inhibitors and inducers

  • Avoid if possible, or caution with radiation given increased risk of radiation pneumonitis

 
H - Drug Administration and Special Precautions

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


Administration

Carboplatin:

  • Mix in 100mL to 250mL bag (5% Dextrose or Normal Saline); infuse IV over 15 to 60 minutes.

  • Incompatible with sets, needles or syringes containing aluminum – leads to precipitation and loss of potency.

  • Protect from light.

Paclitaxel:

  • Use non-PVC equipment, including 0.22 micron in-line filter, in order to minimize patients’ exposure to DEHP leaching from PVC bags or sets; infuse over 3 hours.

  • Dilute in 500-1000 mL Normal Saline or 5% Dextrose, in a final concentration of 0.3-1.2 mg/mL.

  • Excessive shaking, agitation, or vibration may induce precipitation and should be avoided.

  • Precipitation may rarely occur with infusions longer than 3 hours.

 

Contraindications:

  • Patients who have a hypersensitivity to platinum-containing compounds, paclitaxel or other drugs formulated in Cremophor EL (polyethoxylated castor oil)

  • Patients with severe renal impairment

  • Patients with severe baseline neutropenia (<1.5 x 109/L; < 1 x 109/L for patients with AIDS-related Kaposi’s) or bleeding tumours

 

Warnings/precautions:

  • Patients with abnormal renal function or who are receiving concomitant nephrotoxic drugs

  • Patients who have received extensive prior treatment, have poor performance status and those over 65 years of age

  • Severe arrhythmias may occur during infusion; patients should be appropriately managed and undergo continuous ECG monitoring during subsequent infusions. Congestive heart failure (including LVEF decrease) has been reported in patients who have received other chemotherapy agents, especially anthracyclines.

  • Paclitaxel contains ethanol, and is administered with agents such as antihistamines which cause drowsiness. Patients should be cautioned regarding driving and the use of machinery.

 

Pregnancy/lactation:

  • Carboplatin and paclitaxel are not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.

  • Breastfeeding is not recommended.

  • Fertility Effects:

    • Carboplatin: Unknown

    • Paclitaxel: Yes

 
I - Recommended Clinical Monitoring

Recommended Clinical Monitoring

  • CBC; baseline and before each cycle

  • Blood pressure and pulse rate monitoring during paclitaxel infusion, cardiac monitoring with prior arrhythmia

  • Liver function tests; baseline and regular

  • Renal function tests; baseline and regular, including electrolytes

  • Clinical assessment of thromboembolism, bleeding, nausea and vomiting, infection, musculoskeletal, ototoxicity, neurologic (sensory), hypersensitivity and flu-like symptoms; regular

  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Approximate Patient Visit
5-6 hours
Pharmacy Workload (average time per visit)
30.383 minutes
Nursing Workload (average time per visit)
59.833 minutes
 
K - References

Carboplatin and paclitaxel  drug monographs, Cancer Care Ontario.

du Bois A, Luck HJ, Meier W, Adams HP, Mobus V, Costa S, et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 2003;95:1320-30.

Kwon JS, Elit L, Finn M et al. A comparison of two prophylactic regimens for hypersensitivity recations to paclitaxel. Gynecol Oncol 2002 Mar; 84(3): 420-5.

Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 2003;21:3194-200.

The International Collaborative Ovarian Neoplasm (ICON) Group. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet 2002; 360:505-15.

May 2019 Updated emetic risk category


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L - Other Notes

Calvert Formula

DOSE (mg) = target AUC X (GFR + 25)

  • AUC = product of serum concentration (mg/mL) and time (min)
  • GFR (glomerular filtration rate) expressed as measured Creatinine Clearance or estimated from Serum Creatinine (by Cockcroft and Gault method or Jelliffe method)

(Calvert AH, Newell DR, Gumbrell LA, et al, Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol, 1989; 7: 1748-1756)

 
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.