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A - Regimen Name

CAPE(RT) Regimen
Capecitabine


Disease Site
Gastrointestinal - Colorectal

Intent
Neoadjuvant

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

For the neo-adjuvant treatment of rectal cancer.


Supplementary Public Funding

capecitabine
ODB - General Benefit (capecitabine) (ODB Formulary)

 
B - Drug Regimen

capecitabine
825 mg /m² PO BID*

(Outpatient prescription in 150 mg and 500 mg tablets; *Total dose 1650 mg/m2/day)

 

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C - Cycle Frequency

Either on days of radiation (5 days per week) OR continuously (7 days per week) during radiotherapy (single cycle).

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal


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. 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

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 (% 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, TENS, OR
cardiotoxicity OR acute renal failture
 
 
 
 
 
 
2nd appearance OR any occurrence of confirmed leukoencephalopathy

 

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%
 
 
 
 
 
--

 

 

Hematological Toxicities: 

Modify according to protocol by which patient is being treated; if no guidelines available, refer to Appendix 6 for general recommendations. Hold capecitabine during a treatment cycle in the presence of grade 3 or 4 hematologic toxicity.



Hepatic Impairment

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.


Renal Impairment

Moderate renal impairment results in an increase in severe toxicity.
 

Creatinine Clearance (mL/min)

% of starting dose

51-80

100 % with close monitoring

30-50

75 % (use with caution)

<30

CONTRAINDICATED


Dosage in the Elderly

No dose adjustment for the starting dose is required, but patients should be closely monitored and dose modification should be performed as described above. Older patients are more susceptible to the effects of fluoropyrimidine-based therapies with increased grade 3 / 4 adverse effects, especially when used in combination.

 


 
F - Adverse Effects

Refer to capecitabine 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

  • Hand-foot syndrome
  • Diarrhea (may be severe)
  • Nausea, vomiting
  • Mucositis
  • Increased LFTs (may be severe)
  • Fatigue
  • Abdominal pain
  • Cardiotoxicity
  • Venous thromboembolism
  • Arterial thromboembolism
  • Hypersensitivity
  • Myelosuppression +/- infection, bleeding
  • Leukoencephalopathy
  • GI perforation, obstruction
  • Idiopathic thrombocytopenic purpura
  • Eye disorders
  • Renal failure

 

 

 

 
G - Interactions

Refer to capecitabine drug monograph(s) for additional details


  • Avoid concomitant administration with sorivudine or analogues given increased risk of capecitabine toxicity (may be fatal). Wait 4 weeks after sorivudine treatment before starting capecitabine.
  • Avoid concomitant administration with phenytoin as capecitabine may increase phenytoin levels.
  • Avoid leucovorin as this may increase capecitabine toxicity.
  • Caution and monitor PT/INR when administered with warfarin; capecitabine increases warfarin exposure.
  • Avoid concomitant administration of antacids; these may increase capecitabine exposure.
  • Caution and monitor when administered with docetaxel; increased toxicity in elderly observed.
 
H - Drug Administration and Special Precautions

Refer to capecitabine drug monograph(s) for additional details


Administration:

  • Doses are given orally approximately 12 hours apart, within 30 minutes after the end of a meal. 
  • If a capecitabine dose is missed, skip this and give the next dose at the usual time. Missed or omitted doses should not be replaced.
  • Store tablets at 15ºC to 30ºC in the original package.

Contraindications:

  • Patients who have a known hypersensitivity to capecitabine, its excipients, or 5-fluorouracil
  • Patients with severe renal impairment (CrCl <30 mL/min)
  • Patients with known near or complete absence of DPD (dihydropyrimidine dehydrogenase) deficiency
  • Concomitant use with sorivudine or related analogues (i.e. brivudine) (see Interactions)
  • Contains lactose and should not be used in patients with hereditary galactose/glucose/lactase disorders.

Other Warnings/Precautions:

  • Use with caution in patients with risk factors for dehydration, pre-existing renal dysfunction, and on nephrotoxic agents
  • Use with caution in patients with a history of cardiovascular disease as well as patients taking anticoagulants
  • Use with extreme caution in patients with partial DPD deficiency
 
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 at each visit
  • Renal function tests; baseline and regular
  • INR or PT; baseline and regular if on anticoagulants
  • Clinical toxicity assessment for diarrhea, dehydration, infection, stomatitis, rash, hand-foot syndrome, cardiac, hepatic and neurotoxicity; at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

  • Liver function tests; baseline and regular (if severe organ failure suspected)

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J - Administrative Information

Outpatient prescription for home administration


 
K - References
Capecitabine drug monograph, Cancer Care Ontario.
 
Clinical Pracitice Guidelines in Oncology (NCCN Guidelines).  Colon Cancer.  Version 3.2015.  NCCN.org
 
De Paoli, A, et al. Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study. Ann Oncol 2006;17:246-51.
 
Dunst J, Debus J, Rudat V et al. Neoadjuvant Capecitabine Combined with Standard Radiotherapy in Patients with Locally Advanced Rectal Cancer: Mature Results of a Phase II Trial. Strahlenther Onkol 2008;184(9):450-6.
 
Dupuis O, Vie B, Lledo G et al. Preoperative treatment combining capecitabine with radiation therapy in rectal cancer: a GERCOR Phase II Study. Oncology 2007;73(3-4):169-76
 
Hofheinz R, Wenz F, Post S, et al: Capecitabine (Cape) versus 5-fluorouracil (5-FU)-based (neo)adjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC): Long-term results of a randomized, phase III trial. 2011 ASCO Annual Meeting. Abstract 3504. Presented June 4, 2011.
 
Roh MS, Yothers GA, O’Connell MJ, et al: The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum: NSABP R-04. 2011 ASCO Annual Meeting. Abstract 3503. Presented June 4, 2011. 

April 2018 updated capecitabine funding to general benefit


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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.