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CAPECISP+TRAS

Cancer Type: Gastrointestinal, Esophagus, Gastric / Stomach  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Trastuzumab (Biosimilar) - Advanced Gastric, Gastroesophageal, or Esophageal Cancer
ODB - General Benefit
    capecitabine
A - Regimen Name

CAPECISP+TRAS Regimen
Capecitabine-CISplatin-Trastuzumab


Disease Site
Gastrointestinal - Esophagus
Gastrointestinal - 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

Palliative treatment of HER2-overexpressing (IHC3+ or IHC2+ confirmed by ISH) inoperable advanced (non-resectable; either locally advanced, recurrent or metastatic) adenocarcinoma of the stomach or the gastroesophageal junction, in patients with ECOG 0-2, a normal ejection fraction and who have not received previous systemic treatment for metastatic disease.


Supplementary Public Funding

trastuzumab
New Drug Funding Program (Trastuzumab (Biosimilar) - Advanced Gastric, Gastroesophageal, or Esophageal Cancer)

capecitabine
ODB - General Benefit (capecitabine)

 
B - Drug Regimen

Note: Different trastuzumab products are NOT INTERCHANGEABLE.
 

Trastuzumab Loading Dose:
 

trastuzumab

1

8 mg /kg IV Day 1, cycle 1 only

THEN, Trastuzumab Maintenance Dose:

trastuzumab
1
6 mg /kg IV Day 1, cycle 2 onwards

1In general, the dose of trastuzumab should be delayed if the chemotherapy cycle is delayed for scheduling convenience; if the delay is > 1 week, trastuzumab loading dose should be repeated.

AND

CISplatin
80 mg /m² IV Day 1
capecitabine
1000 mg /m² PO BID* Days 1 to 14

(*Total dose 2000 mg/m2/day)
(Outpatient prescription in 150mg and 500mg tablets)

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C - Cycle Frequency

REPEAT EVERY 21 DAYS

Cisplatin-Capecitabine: Up to 6 cycles unless evidence of disease progression or unacceptable toxicity occurs

Trastuzumab: Until evidence of disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

High
No routine prophylaxis for capecitabine

Other Supportive Care:

  • To prevent recurrence of infusion-associated reactions, acetaminophen and diphenhydramine may be given as pre-medication. Refer to trastuzumab drug monograph for full details.
  • Standard regimens for cisplatin premedication and hydration should be followed. Refer to cisplatin monograph
  • 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.

Also refer to CCO Antiemetic Recommendations.

 
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 could be considered.

Use capecitabine with extreme caution in patients with partial DPD deficiency; reduce the initial dose substantially, monitor frequently and adjust the dose for toxicity as recommended in the dosage with toxicity section. In patients with unrecognized DPD deficiency, acute, life-threatening toxicity may occur; discontinue if acute grade 2-4 toxicity develops.

Dosage with toxicity

Trastuzumab:

Dosage with myelosuppression: No adjustment required


Dosage with cardiotoxicity:

Product Monograph Recommendations

  • Trastuzumab should be held with a fall in LVEF (if LVEF falls ≥10 points from baseline and/or if LVEF falls to < 50%). Repeat LVEF in 3 weeks and consider discontinuing. Discontinue if clinically significant cardiac dysfunction or cardiac failure develops.

Canadian Consensus Guidelines

  • Discontinue if symptomatic.

 

Management of trastuzumab therapy in adjuvant breast cancer patients with asymptomatic decreases in LVEF (Mackey et al 2008):

Relationship of LVEF to Lower Limit of Normal (LLN)

Trastuzumab dose modification

based on asymptomatic LVEF decrease from baseline

≤ 10 percentage points

10-15 percentage points

≥ 15 percentage points

Within facility’s normal limits

Continue

Continue

Hold and repeat MUGA/ECHO after 4 weeks

1-5% below LLN

Continue 1

Hold and repeat MUGA/ECHO after 4 weeks 1, 2

Hold and repeat MUGA/ECHO after 4 weeks 2, 3

≥ 6% below LLN

Continue and repeat MUGA/ECHO after 4 weeks 3

Hold and repeat MUGA/ECHO after 4 weeks 2, 3

Hold and repeat MUGA/ECHO after 4 weeks 2, 3

1 Consider cardiac assessment and starting ACEI therapy
2 After 2 holds, consider permanent trastuzumab discontinuation
3 Start ACEI therapy and refer to cardiologist

Trastuzumab - Dosage with other toxicity:

Toxicity
Action
Mild hypersensitivity reaction

↓ infusion rate (and/ or hold)  and use beta-agonists, antihistamines, antipyretics, and/or corticosteroids as appropriate. Consider premedication for next infusion.

Moderate hypersensitivity reaction

Hold and use beta-agonists, antihistamines, antipyretics, and/or corticosteroids as appropriate; complete infusion at ↓ rate if possible. Use premedication for next infusion.

Severe hypersensitivity reaction or Pulmonary Toxicity

Hold and manage symptoms aggressively with beta-agonists, antihistamines, antipyretics, and/or corticosteroids.  Discontinue permanently and do not rechallenge

 

CISplatin:

Worst Toxicity in Previous Cycle

CISplatin Dose for next cycle*

Grade 4 platelets, grade 4 ANC ≥ 5 days, thrombocytopenic bleeding or febrile neutropenia

↓ 25%

Grade 2 neurotoxicity /ototoxicity

↓ 25%
Grade 3 or 4 neurotoxicity/ototoxicity
 
Discontinue
Worst Toxicity in Previous Cycle (Continued) CISplatin Dose for next cycle*

Other grade 3 non-hematologic/organ toxicity

↓ 25%
Other grade 4 non-hematologic/organ toxicity
Discontinue

Hemolysis, optic neuritis, arterial thromboembolism, severe hypersensitivity reactions, grade 3 or 4 ↑ LFTs

Discontinue

* Do not retreat until platelets ≥100 x 109/L, ANC ≥ 1.5 x 109/L, toxicity has recovered to ≤ grade 2 (grade 1 for neurotoxicity) and creatinine ≤ ULN.

Capecitabine:

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. 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%
--
Toxicity (Continued) Action During a Course of Therapy Dose Adjustment for Next Cycle   (% of starting dose)
 
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, TENS, 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%
 
 
 
 
 
 
--



Hepatic Impairment

No adjustment required for trastuzumab and cisplatin.

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

Renal Impairment

No adjustment required for trastuzumab.
 
 
Creatinine clearance (mL/min) Cisplatin (% previous dose) Capecitabine (% previous dose)
> 60 No change 100%; monitor closely
> 50-60 75%* 100%; monitor closely
30-50 50%* 75%; use with caution
10-<30 Discontinue* Discontinue
< 10 Discontinue* Discontinue

*Upon the discretion of the prescriber, less dose reduction may be suggested. 


 
F - Adverse Effects

Refer to trastuzumab, CISplatin, capecitabine drug monograph(s) for additional details of adverse effects


Most Common Side Effects 

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

  • Nausea and vomiting
  • Nephrotoxicity (may be severe)
  • Neurotoxicity (ototoxicity), electrolyte changes
  • Myelosuppression ± infection, bleeding (may be severe)
  • Cardiotoxicity (may be severe)
  • Mucositis, diarrhea, anorexia
  • Abdominal pain
  • Hand-foot syndrome
  • Fatigue
  • ↑ LFTs
  • Headache, musculoskeletal pain
  • Rash (may be severe); photosensitivity
  • Infusion-related reaction (may be severe)
  • GI obstruction/perforation
  • Seizures
  • Arterial thromboembolism
  • Venous thromboembolism
  • Raynaud’s
  • Arrhythmia
  • ITP
  • Pancreatitis
  • Pneumonitis
  • Hemolytic-uremic syndrome, hemolysis, vasculitis
  • Renal failure
  • Secondary malignancies
  • Injection site reaction
 
G - Interactions
Refer to trastuzumab, CISplatin, capecitabine drug monograph(s) for additional details
 
H - Drug Administration and Special Precautions

Refer to trastuzumab, CISplatin, capecitabine drug monograph(s) for additional details


NOTE: Different trastuzumab products are NOT-INTERCHANAGEABLE.

 

 
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 mucositis, nausea/vomiting, neurotoxicity, ototoxicity, cardiotoxicity, infection, bleeding, skin and pulmonary toxicity, diarrhea, dehydration, infusion reactions); at each visit
  • CBC; baseline and before each cycle
  • Electrolytes, including magnesium, sodium, potassium, phosphate and calcium; baseline and regular
  • Baseline and regular liver and renal function tests
  • Baseline and regular cardiac assessment, including evaluation of left ventricular function (Echocardiogram or MUGA scan); more frequent with asymptomatic reductions in LVEF, q3 months during treatment and then q6 months after trastuzumab discontinuation x 2 years
  • INR or PT; baseline and regular if on anticoagulants
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

  • Audiogram; baseline and periodic

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J - Administrative Information

Approximate Patient Visit
First cycle: 5 hours; Subsequent cycles: 3.5 hours
Pharmacy Workload (average time per visit)
40.176 minutes
Nursing Workload (average time per visit)
62.5 minutes
 
K - References

Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376(9742): 687-97.

Capecitabine, cisplatin and trastuzumab drug monographs, Cancer Care Ontario.


PEBC Advice Documents or Guidelines

November 2019 Updated NDFP forms and interchangeability information in Drug Regimen and Drug Administration and Special Precautions section 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.