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Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.

A - Regimen Name

ECARBOX Regimen
Epirubicin-Carboplatin-Capecitabine (XELODA)®


Disease Site
Gastrointestinal
Esophagus
Gastric / Stomach


Intent
Palliative

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

An alternative to ECF for treatment of advanced (non-resectable; either locally advanced or metastatic) gastric, esophageal or gastroesophageal cancer, but not for squamous cell carcinomas.


Supplementary Public Funding

capecitabine
ODB - General Benefit (capecitabine)

 
B - Drug Regimen

EPIrubicin
50 mg /m² IV Day 1
CARBOplatin
AUC 5 IV Day 1
capecitabine
625 mg /m² PO BID* days 1 to 21

(*Total daily dose = 1250mg/m2/day; outpatient prescription in 150mg and 500mg tablets)

 

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C - Cycle Frequency

REPEAT EVERY 21 DAYS

For a maximum of up to 8 cycles unless disease progression or unacceptable toxicity occurs

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate + NK1 antagonist (Carboplatin AUC ≥ 5)
No routine prophylaxis for capecitabine


Febrile Neutropenia Risk:

Low

Other Supportive Care:

  • Topical emollients (e.g. hand creams, udder balm) may ameliorate the manifestations of hand-foot syndrome in patients receiving capecitabine.
  •  Supportive care should be provided, including loperamide for diarrhea.
 
E - Dose Modifications

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

Patients should be tested for DPD deficiency before starting treatment with capecitabine. Refer to the DPD Deficiency Guidance for Clinicians for more information.

In patients with unrecognized DPD deficiency, acute, life-threatening toxicity may occur; if acute grade 2-4 toxicity develops, treatment should be stopped immediately and permanent discontinuation considered based on clinical assessment of the toxicities.

 

Dosage with toxicity

Worst Toxicity Grade/
Counts (x 109/L) in Prior Cycle

Epirubicin (% previous dose)

Carboplatin Dose (% previous dose)

Capecitabine
Febrile Neutropenia
Thrombocytopenic bleeding
Grade 4 ANC ≥ 7 d
Hold, then ↓ 75%*
Hold, then ↓ 1 AUC*/#
 Refer to table below.

Cardiotoxicity**

Discontinue

No change

Grade 3 related non-hematologic/organ

Hold, then ↓ 75%* for suspect drug

Hold, then ↓ 1 AUC* for suspect drug

Grade 4 related non-hematologic/organ

Discontinue
  •  * Do not retreat until toxicity has recovered to ≤ grade 2, and platelets ≥ 100 x 109/L, and ANC ≥ 1.5 x 1009/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%.
  • # Use Egorin formula if isolated thrombocytopenia (See Appendix section).

 

Capecitabine:  Dose Modification:

Do not start treatment with capecitabine unless baseline neutrophil counts are ≥ 1.5 x 109/L and/or platelet counts of ≥ 100 x 109/L. Patients should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Supportive care should be provided, including loperamide for diarrhea. Doses should not be re-escalated if reduced for toxicity. Missed or omitted doses of capecitabine should not be replaced.

Dose modifications are mandatory for gastrointestinal, dermatological toxicity and hyperbilirubinemia.  Practitioner may elect not to reduce dose for other toxicities unlikely to become serious or life-threatening.

 

Toxicity

Action During a Course of Therapy

Dose Adjustment for Next Cycle   (% of starting dose)

 

 
Grade 1
 
 
Maintain dose level
 
Maintain dose level
 
Grade 2
1st appearance
2nd appearance
3rd appearance
4th appearance
 
 
 
Interrupt until resolved to grade 0-1
Interrupt until resolved to grade 0-1
Interrupt until resolved to grade 0-1 Discontinue treatment permanently
 
 
100%
75%
50%
--
 
Grade 3
1st appearance
2nd appearance
3rd appearance, OR any evidence of Stevens-Johnson syndrome or Toxic epidermal necrolysis
 
 
Interrupt until resolved to grade 0-1
Interrupt until resolved to grade 0-1
Discontinue treatment permanently
 
 
75%
50%
--
 
 
 
Grade 4
 
1st appearance, including SJS or TEN, OR cardiotoxicity OR
acute renal failure
 
 
 
 
2nd appearance

 

 

Discontinue permanently
                 OR
If physician deems it to be in the patient’s best interest to continue and no evidence of Stevens-Johnson syndrome or toxic epidermal necrolysis, interrupt until resolved to grade 0-1.
 

 Discontinue permanently

 
 
 
Discontinue
OR
 
50%
 
 
 
 
Not applicable

 
 



Hepatic Impairment

Epirubicin is contraindicated in patients with severe hepatic impairment, especially with elevated bilirubin. Consideration should be given to dose modification for patients with severe increases in transaminases.  

Capecitabine:  In patients with mild to moderate hepatic impairment, exposure is increased but no dose adjustment is necessary, although caution should be exercised. Use dose modification table above for increases in bilirubin. The use of capecitabine in patients with severe hepatic impairment has not been studied.

Bilirubin (µmol/L)

 

AST/ALT

 Epirubicin (% usual dose)

Carboplatin Capecitabine

1-2 x ULN

or

2-4 x ULN

50%

No change Use capecitabine dose modification table above

2-4 x ULN

or

> 4 x ULN

25%

> 4 x ULN

 

omit

Omit


Renal Impairment

Creatinine Clearance (ml/min)

Epirubicin (% previous dose)

Carboplatin (% previous dose)

Capecitabine (% previous dose)
51 - 80 No change No change 100 % with close monitoring

30 - 50

Use Calvert or Chatelut formula

 

75% (use with caution)
21 - 29 CONTRAINDICATED

< 20

Adjust dose with severe renal impairment (creatinine > 440 μmol/L)

Discontinue

 


 
F - Adverse Effects

Refer to EPIrubicin, CARBOplatin, capecitabine drug monograph(s) for additional details of adverse effects


Most common adverse effects        
Less common adverse effects, but may be severe or life-threatening
  • Alopecia
  • Hand-foot syndrome (may be severe)
  • Mucositis
  • Diarrhea (may be severe), abdominal pain
  • Nausea, vomiting
  • Myelosuppression +/- bleeding, infection
  • Fatigue
  • ↑ LFTs (may be severe)
  • Ototoxicity
  • Nephrotoxicity
  • Electrolyte abnormalities
  • Cardiotoxicity
  • Hypersensitivity
  • Arterial thromboembolism
  • Venous thromboembolism
  • Rash
  • Radiation recall reaction
  • Neuropathy
  • GI obstruction, perforation
  • Hemolytic uremic syndrome, ITP
  • Pneumonitis
  •  Secondary malignancy
 
 
G - Interactions

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

 
H - Drug Administration and Special Precautions

Refer to EPIrubicin, CARBOplatin, capecitabine 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 regular
  • Renal function tests; baseline and regular including electrolytes
  • Cardiac function tests (Echo, RNA and/or MUGA scans) for all patients with cardiac risk factors or cumulative epirubicin doses > 650mg/m2; baseline and periodic
  • INR and/or PT; Baseline and regular if on anticoagulants
  • Clinical toxicity assessment for neurotoxicity, ototoxicity, hypersensitivity, bleeding, infection, GI, cardiac and skin 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
1 hour
Pharmacy Workload (average time per visit)
27.365 minutes
Nursing Workload (average time per visit)
65.833 minutes
 
K - References

Capecitabine, epirubicin, carboplatin drug monographs, Cancer Care Ontario.

Cunningham D , Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008 Jan 3;358(1):36 - 46.

Cunningham D, Allum WH, Stenning SP, et al. Perioperative Chemotherapy versus Surgery Alone for Resectable Gastroesophageal Cancer. N Engl J Med 2006; 355: 11-20.

 


April 2023 Updated DPD deficiency information in the Dose Modifications section


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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)

Egorin Formula

Previously Untreated Patients-

     DOSE (mg/m²) =      317 [{ [(pre - nadir)/ pre]100 - 82.1} X (BSA / Cr Cl)] + 447

Previously Treated Patients-

     DOSE (mg/m²) =      317 [{ [(pre - nadir)/ pre]100 - 92.4} X (BSA / Cr Cl)] + 447

  • Pre = pretreatment platelet count
  • Nadir = platelet nadir desired
  • BSA = Body Surface Area
  • Cr Cl = Creatinine Clearance

(Egorin MJ, Van Echo DA, Tiping SJ, et al, Pharmacokinetics and dosage reduction of carboplatin in patients with impaired renal function. Cancer Res, 1984; 44: 5432-5438)

 
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.