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A - Regimen Name

 

CISPDOXOETOPMTTN Regimen
CISplatin-DOXOrubicin-Etoposide-Mitotane

 

 

Disease Site
Endocrine - Adrenal

 

 

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 patients with metastatic or locally advanced unresectable adrenocortical carcinoma, who have good performance status, no prior radiation or chemotherapy treatment (except adjuvant mitotane) and have no brain metastases. A phase III clinical trial has shown significantly higher response rate and progression-free survival, but similar overall survival and toxicity compared to streptozocin-mitotane.

 

 
B - Drug Regimen

 

DOXOrubicin
 
40 mg /m²IVDay 1
etoposide
 
100 mg /m²IVDays 2, 3, and 4
CISplatin
 
40 mg /m²IVDays 3 and 4
mitotane
 
1 to 4 gPODaily as tolerated, start 1 week before chemotherapy *
(This drug is not currently publicly funded for this regimen and intent)
*(Outpatient prescription in multiples of 500 mg tablets; to reach mitotane blood level of 14-20 mg/L)
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C - Cycle Frequency

 

REPEAT EVERY 28 DAYS

• Cisplatin-Doxorubicin-Etoposide: For a usual maximum of 6 cycles, or until disease progression in the absence of unacceptable toxicity

• Mitotane: Until disease progression or unacceptable toxicity occurs

 

 
D - Premedication and Supportive Measures
 
Antiemetic Regimen:

Moderate (Mitotane: Adjust according to symptoms)

Other Supportive Care:

  • Supplement with replacement cortisone (glucocorticoid) and fludrocortisone (mineralocorticoid) (See mitotane drug monograph.)
  • Standard regimens for Cisplatin premedication and hydration should be followed. Refer to Cisplatin monograph.

Also refer to CCO Antiemetic Summary

 
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.

 

Dosage with toxicity

 

Worst Toxicity / Counts (x 109/L) in previous cycle

 

Worst Toxicity / Counts (x 109/L) in previous cycle

DOXOrubicin
(% previous dose)
CISplatin
(% previous dose)
etoposide
(% previous dose)
Mitotane
(% previous dose)
Febrile Neutropenia
 
Or
 
ANC < 0.5 for ≥ 5-7 d
Or
Thrombocytopenic bleeding
 
Or
Platelets < 25
 Hold *, then 75%
No change
Cardiotoxicity**
 
 
Discontinue

No change

Grade 2 neurotoxicity /ototoxicity

 
 

No change

75%

No change

Caution

Grade 3 or 4 neurotoxicity/ototoxicity 

 
 
No change
Discontinue

No change

Hold* or discontinue

Grade 3 related organ / non-hematologic
 
 
*75% for suspect drug(s)
Grade 4 related organ / non-hematologic

Hemolysis, optic neuritis, arterial thromboembolism, severe hypersensitivity reactions

 
 
Discontinue
 

*Do not start new cycle until toxicities have recovered to ≤ grade 2, platelets ≥ 100 x 109/L, creatinine ≤ grade 1 and ANC ≥ 1.5 x 109/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%.

 

 

Hepatic Impairment

Bilirubin
Cisplatin
Doxorubicin (% previous dose)
Etoposide (% previous dose)
Mitotane^ (% previous dose)
1-2 x ULN
No change
50%
50%
50%
>2 – 4 x ULN
25%*
25%
25%
> 4 x ULN
Discontinue*
Discontinue
Discontinue
* Consider 75% dose reduction or OMIT dose for severe increases in LFTs (i.e. > 5 x ULN)
^ suggested – no specific recommendations found
 

Renal Impairment

Creatinine clearance

Doxorubicin

Cisplatin (% previous dose)

Etoposide (% previous dose)

Mitotane*
>45-60

No adjustment required

75%
100%
75-100%
>30-45
50%
75%
75%
15-30
Discontinue
75%
75%
<15
Discontinue
Discontinue

50% or discontinue

*suggested - no specific recommendations found
 
F - Adverse Effects

Refer to DOXOrubicin, CISplatin, etoposide, mitotane drug monograph(s) for additional details of adverse effects

 

Most common side effects

Less common but may be severe or life-threatening

  • Nausea, vomiting
  • Anorexia
  • Diarrhea
  • Alopecia
  • Nephrotoxicity (may be severe)
  • Neurotoxicity/ototoxicity (may be severe)
  • Myelosuppression +/- infection, bleeding (may be severe)
  • Fatigue
  • Somnolence
  • Increased LFTs (may be severe)
  • Abnormal electrolyte(s)
  • Adrenal insufficiency
  • Rash (may be severe)

·          

  • Arterial thromboembolism
  • Cardiotoxicity, arrhythmia
  • Hemolytic uremic syndrome, vasculitis
  • Secondary malignancies
  • Hypersensitivity
  • Raynaud’s
  • Hemolysis
  • Vesicant
  • Venous thromboembolism
  • Pneumonitis
 
G - Interactions

Refer to DOXOrubicin, CISplatin, etoposide, mitotane drug monograph(s) for additional details

 
H - Drug Administration and Special Precautions

Refer to DOXOrubicin, CISplatin, etoposide, mitotane 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 regular
  • Liver function tests; baseline and regular
  • Renal function tests; baseline and regular
  • Electrolytes, including magnesium, phosphate and calcium; baseline and regular
  • Cardiac tests for all patients with cardiac risk factors (including prior trastuzumab or patients at or above the threshold dose levels (doxorubicin 400mg/m2 for q21 day schedules and 550mg/m2 for weekly schedules); baseline and periodic
  • Clinical toxicity assessment (infection, bleeding, mucositis, adrenal insufficiency, cardiotoxicity, thromboembolism, GI, nausea/vomiting, local toxicity, infusion reactions, neurotoxicity, ototoxicity); 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
Day 1: 0.5 to 1 hour; Day 2: 1-2 hours; Day 3-4: 3-4 hours
Pharmacy Workload (average time per visit)
13.384 minutes
Nursing Workload (average time per visit)
47.917 minutes
 
K - References
Berruti A, Terzolo M, Sperone P, et al. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocrine-Related Cancer 2005; 12: 657–66.
 
Berruti A, Terzolo M, Pia A, et al. Mitotane Associated with Etoposide, Doxorubicin, and Cisplatin in the Treatment of Advanced Adrenocortical Carcinoma. Cancer 1998; 83: 2194–200.
 
Cisplatin, doxorubicin, etoposide and mitotane drug monographs, Cancer Care Ontario.

Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med 2012;366(23):2189-97.

October 2017 added not publicly funded under drug regimen (mitotane)

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L - Other Notes
Mitotane causes adrenal suppression; it is important to maintain adequate replacement of both the glucocorticoid and mineralocorticoid steroids throughout Mitotane treatment, and possibly after Mitotane is discontinued.
 
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.