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EVER

Cancer Type: Gastrointestinal, Neuroendocrine (GI)  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
Exceptional Access Program
    everolimus - For patients who have progressive, unresectable, well or moderately differentiated, locally advanced or metastatic pancreatic neuroendocrine tumors (PNET), with specific criteria
A - Regimen Name

EVER Regimen
Everolimus


Disease Site
Gastrointestinal - Neuroendocrine (GI)

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

Treatment of well-or moderately differentiated neuroendocrine tumours of pancreatic origin (PNET) in patients with unresectable, locally advanced or metastatic disease.  Funded for patients with ECOG 0-2 who have not progressed with sunitinib.  Health Canada indication limits to patients whose disease has progressed within the last 12 months.  Not indicated for carcinoid tumours.


Supplementary Public Funding

everolimus
Exceptional Access Program (everolimus - For patients who have progressive, unresectable, well or moderately differentiated, locally advanced or metastatic pancreatic neuroendocrine tumors (PNET), with specific criteria) (EAP Website)

 
B - Drug Regimen

everolimus
10 mg PO Daily

(Outpatient prescription in 2.5 mg, 5 mg or 10mg tablets)

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C - Cycle Frequency

CONTINUOUS TREATMENT

Until disease progression, no evidence of further response, or unacceptable toxicity.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal – No routine prophylaxis; PRN recommended

Other Supportive Care:

Manage stomatitis with non-irritant oral rinses. Antifungal agents should not be used unless an oral fungal infection has been diagnosed.

Consider the use of PJP prophylaxis when concomitant use of corticosteroids or other immunosuppressants are required

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.

Do not use for the treatment of carcinoid tumours. Patients in whom drug-drug interactions are likely (and who cannot discontinue the concomitant medication) may require dose modification (refer to Interactions section for details). Optimal glycemic/lipidemic control must be obtained prior to starting therapy.

Prophylaxis for PJP should be considered when concurrent use of corticosteroids or other immunosuppressive agents are required.

Dose levels: 10mg daily, 5mg daily, 5mg q2d

Dosage with toxicity

Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Non-infectious pneumonitis

If tolerable, maintain same dose.  Monitor and treat patient appropriately.

 
Consider hold until ≤ grade 1.   Rule out infection and then consider corticosteroids. 
Restart with 1 dose level ↓ .  Discontinue if no recovery within 4 weeks.

Hold until ≤ grade 1.  Rule out infection and then consider corticosteroids. 

Restart with 1 dose level ↓. 
Discontinue if grade 3 recurs.

Discontinue, investigate and treat patient appropriately.

Stomatitis
Hold until ≤ grade 1 and restart at same dose.
If recurs, hold until ≤ grade 1 and restart with 1 dose level ↓.
Hold until ≤ grade 1 and restart with 1 dose level ↓.
Metabolic events (e.g. hyperglycemia, hyperlipidemia)*

Maintain same dose. Monitor and start appropriate therapy.

Hold until ≤ grade 1 and restart with 1 dose level ↓.
Monitor and start appropriate therapy.
Other related non-hematologic toxicities
Maintain same dose if tolerable.
If intolerable, hold until ≤ grade 1 and restart at same dose.
If recurs, hold until ≤ grade 1 and restart with 1 dose level ↓.
Hold until ≤ grade 1 and restart with 1 dose level ↓.
Consider discontinuing if recurs.

* consider urgent therapy if hypertriglyceridemia due to risk of pancreatitis



Hepatic Impairment

Hepatic impairment (baseline and during treatment)

Everolimus dose (adults)
Mild (Child-Pugh class A)

7.5mg once daily. ↓ to 5mg daily if not well tolerated

Moderate (Child-Pugh class B)

5mg daily. ↓ to 2.5 mg daily if not well tolerated

Severe (Child-Pugh class C)

Use only when benefits outweigh risks, at 2.5 mg daily


Renal Impairment

No dose adjustment required.


 
F - Adverse Effects

Refer to everolimus drug monograph(s) for additional details of adverse effects


Most Common Side Effects 

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

  • Mucositis
  • Fatigue
  • Diarrhea
  • Rash
  • Nausea, vomiting
  • Anorexia
  • Fluid retention (may be severe)
  • ↑ LFTs
  • Pneumonitis (may be severe)
  • Myelosuppression ± bleeding, infection (may be severe, includes opportunistic infections)
  • Hyperglycemia
  • Hyperlipidemia
  • Nephrotoxicity
  • Cardiotoxicity
  • Hypersensitivity, including angioedema
  • Venous thromboembolism
  • Delayed wound healing
  • Hypertension
  • Rhabdomyolysis
  • GI obstruction
  • Pure red cell aplasia
 
G - Interactions
Refer to everolimus drug monograph(s) for additional details
 
H - Drug Administration and Special Precautions
Refer to everolimus 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 periodic
  • Fasting blood glucose and lipids; baseline and periodic (more frequent with concomitant use of drugs that can cause hyperglycemia)
  • Liver function tests; baseline and periodic
  • Renal function tests, electrolytes (including Ca, Mg and PO4), urinalysis; baseline and periodic
  • Clinical assessment of mucositis, fatigue, fluid retention, pulmonary toxicity, infection, rash, diarrhea, bleeding, thromboembolism, rhabdomyolysis; regular
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

  • Pulmonary function tests in patients with significant lung disease; baseline

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J - Administrative Information

Outpatient prescription for home administration


 
K - References

Everolimus drug monograph, Cancer Care Ontario.

Yao J, Shah, M, Tetsuhide I, et al. Everolimus for advanced pancreatic neuroendocrine tumours. N Engl J Med 2011; 364: 514-23.


June 2019 Updated emetic risk category


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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.