You are using an outdated browser. We suggest you update your browser for a better experience. Click here for update.
Close this notification.
Skip to main content Skip to search
A - Regimen Name

EP-EMA Regimen
PLATINOL® (CISplatin)-Etoposide-Methotrexate-Actinomycin (Dactinomycin)


Disease Site
Gynecologic - Gestational Trophoblastic Disease

(GTD)


Intent
Curative

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 for patient with high risk (WHO≥7) GTD who has become refractory to EMA-CO chemotherapy (i.e. 2nd line therapy for the treatment of choriocarcinoma), and for the 1st line treatment of placental site trophoblastic tumours (PSTT).

 
B - Drug Regimen

EP:

etoposide
150 mg /m² IV Day 1
CISplatin
75 mg /m² IV * Day 1

(*In a clinical trial, it was given as 25 mg/m2 IV in 1000mL Nornal Saline over 4 hours for 3 doses)

EMA:

etoposide
100 mg /m² IV Day 8
methotrexate
300 mg /m² IV over 12 hours Day 8

 

Beginning 24 hours after the start of methotrexate, give leucovorin as follows:

 

leucovorin
15 mg PO Every 6 hours x 4 doses

Day 8:

DACTINomycin
0.5 mg IV Day 8
back to top
 
C - Cycle Frequency

REPEAT EVERY 14 DAYS

(EP and EMA are alternated at weekly intervals starting with EP)

Treatment continued for 2-4 courses after documentation of the first normal hCG level

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

High (D1)
Moderate (D8)


Febrile Neutropenia Risk:

High

Other Supportive Care:

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.

Dosage with toxicity

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

 

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

CISplatin
(% previous dose)
etoposide
(% previous dose)
methotrexate
(% previous dose)
dactinomycin (% previous dose)
ANC <1.5
Or
Platelet <  100

Hold *

 
Febrile Neutropenia
 
Or
 
ANC < 0.5 for ≥ 5-7 d
 
Or
Thrombocytopenic bleeding
 
Or
Platelets < 25

 Hold *, then 75%

(consider GCSF for isolated neutropenia)

Grade 2 neurotoxicity /ototoxicity
 
 

↓ 25%

No change

No change

No change

Grade 3 or 4 neurotoxicity/ototoxicity 

 
 
Discontinue

No change

Discontinue if CNS neurotoxicity

No change

Grade 3 related organ / non-hematologic

 
 
 

*75% for suspect drug(s). if isolated mucositis related to methotrexate may consider doubling the dose of leucovorin prior to dose reduction

Suspected pneumonitis
 
 

Hold, investigate appropriately and discontinue if confirmed

Grade 4 related organ / non-hematologic

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

Leucoencephalopathy, viral reactivation

 
 
Discontinue
 

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

Overdose or Severe Methotrexate Toxicity: Can be treated with prompt leucovorin rescue.   Acute, intermittent dialysis with a high-flux dialyzer has also been used. Hydration and urinary alkalinization may prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. There have been case reports of intravenous carboxypeptidase G2 use in cases of overdose to hydrolyze methotrexate to inactive metabolites and hasten clearance.



Hepatic Impairment

Bilirubin (µmol/L)
Etoposide (% usual dose)
Methotrexate (% usual dose)
Dactinomycin (% usual dose)
Cisplatin
1-2 x ULN
50
Caution*
Caution*
No change
>2 - 2.5 x ULN
25
Caution*
50-66%
>2.5 - 4 x ULN
25
75*
>4 x ULN
Discontinue
Discontinue
No change
*Consider reducing dose if LFTs >3 x ULN
 

Renal Impairment

Cisplatin (% usual dose)
Etoposide % usual dose
Methotrexate (% usual dose)
Dactinomycin (% usual dose)
>80
No change
No change
100%
No adjustment required
>60-80
No change
No change
60-75%
>50-60
75
No change
50-60%
>30-50
50
75
Discontinue
 
15-30
Discontinue
75
<15
50, or discontinue

 
F - Adverse Effects
Refer to etoposide, CISplatin, methotrexate, dactinomycin, leucovorin 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, vomiting
  • Alopecia
  • Nephrotoxicity
  • Neurotoxicity, ototoxicity (may be severe)
  • Diarrhea
  • Mucositis
  • Myelosuppression ± infection, bleeding (may be severe, includes opportunistic)
  • Anorexia
  • ↑ LFTs (may be severe)
  • Abnormal electrolytes
  • Rash (may be severe)
  • Hypotension
  • Hypersensitivity
  • Arterial thromboembolism
  • Arrhythmia
  • GI perforation
  • Hemolytic uremic syndrome, hemolysis
  • Leukoencephalopathy
  • Optic nerve disorder
  • Pancreatitis
  • Pneumonitis
  • Secondary malignancy
  • Seizure
  • Vasculitis
  • Veno-occlusive disease
  • Venous thromboembolism
 
G - Interactions
Refer to etoposide, CISplatin, methotrexate, dactinomycin, leucovorin drug monograph(s) for additional details
 
H - Drug Administration and Special Precautions

Refer to etoposide, CISplatin, methotrexate, dactinomycin, leucovorin 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
  • Electrolytes, including magnesium, sodium, potassium, phosphate and calcium.; baseline and regular 
  • Liver function tests; baseline and regular
  • Renal function tests; baseline and regular
  • Audiogram; as clinically indicated
  • Clinical toxicity assessment of infection, bleeding, GI (stomatitis, nausea/vomiting, diarrhea), skin, pulmonary, or CNS or peripheral neurotoxicity, ototoxicity, infusion reactions; at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

  • Lung function tests if pulmonary toxicity suspected
  • Hepatitis B and Hepatitis C infection testing; Baseline

back to top
 
J - Administrative Information

Approximate Patient Visit
Usually as inpatient
Pharmacy Workload (average time per visit)
43.501 minutes
Nursing Workload (average time per visit)
54.167 minutes
 
K - References

Dobson LS, Lorigan PC, COleman RE, et al. Persistent gestational trophoblastic disease: results of MEA (methotrexate, etoposide and dactinomycin) as first-line chemotherapy in high risk disease and EA (etoposide and dactinomycin) as second-line therapy for low risk disease.  Br J Cancer 2000;82(9):1547-52.

Newlands ES, Mulholland PJ, et al. Etoposide and cisplatin/etoposide, methotrexate, and Actinomycin D (EMA) for patients with high risk gestational trophoblastic tumors refractory to EMA/cyclophosmphamide and vincristine chemotherapy and patients presenting with metatstatic placental site trophoblastic tumours. J Clin Oncol 2000 Feb; 18(4) : 854-59.

Society of Gynecologists and Obstetricians of Canada Clinical Practice Guidelines: Gestational Trophoblastic Disease.

 

June 2019 Updated emetic risk category


back to top
 
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.