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EP-EMA
(GTD)
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.
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).
EP:
| etoposide | 150 mg /m² | IV | Day 1 |
| CISplatin | 75 mg /m² | IV * | Day 1 |
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(*In a clinical trial, it was given as 25 mg/m2 IV in 1000mL Nornal Saline over 4 hours for 3 doses) |
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| etoposide | 100 mg /m² | IV | Day 8 |
| methotrexate | 300 mg /m² | IV over 12 hours | Day 8 |
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Beginning 24 hours after the start of methotrexate, give leucovorin as follows:
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| leucovorin | 15 mg | PO | Every 6 hours x 4 doses |
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Day 8: |
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| DACTINomycin | 0.5 mg | IV | Day 8 |
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
High (D1)
Moderate (D8)
High
Other Supportive Care:
Also refer to CCO Antiemetic Recommendations.
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
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Worst Toxicity / Counts (x 109/L) in previous cycle |
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Worst Toxicity / Counts (x 109/L) in previous cycle |
CISplatin
(% previous dose)
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etoposide
(% previous dose)
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methotrexate
(% previous dose)
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dactinomycin (% previous dose)
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ANC <1.5
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Or
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Platelet < 100
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Hold * |
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Febrile Neutropenia
Or
ANC < 0.5 for ≥ 5-7 d
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Or
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Thrombocytopenic bleeding
Or
Platelets < 25
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Hold *, then 75% (consider GCSF for isolated neutropenia) |
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Grade 2 neurotoxicity /ototoxicity
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↓ 25% |
No change |
No change |
No change
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Grade 3 or 4 neurotoxicity/ototoxicity |
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Discontinue
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No change |
Discontinue if CNS neurotoxicity |
No change
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Grade 3 related organ / non-hematologic |
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*75% for suspect drug(s). if isolated mucositis related to methotrexate may consider doubling the dose of leucovorin prior to dose reduction |
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Suspected pneumonitis
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Hold, investigate appropriately and discontinue if confirmed |
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Grade 4 related organ / non-hematologic Hemolysis, optic neuritis, thromboembolism, severe hypersensitivity reactions, grade 3 or 4 ↑ LFTs Leucoencephalopathy, viral reactivation |
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Discontinue
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*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
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Bilirubin (µmol/L)
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Etoposide (% usual dose)
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Methotrexate (% usual dose)
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Dactinomycin (% usual dose)
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Cisplatin
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1-2 x ULN
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50
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Caution*
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Caution*
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No change
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>2 - 2.5 x ULN
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25
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Caution*
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50-66%
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>2.5 - 4 x ULN
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25
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75*
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>4 x ULN
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Discontinue
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Discontinue
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No change
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Renal Impairment
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Cisplatin (% usual dose)
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Etoposide % usual dose
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Methotrexate (% usual dose)
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Dactinomycin (% usual dose)
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>80
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No change
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No change
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100%
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No adjustment required
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>60-80
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No change
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No change
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60-75%
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>50-60
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75
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No change
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50-60%
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>30-50
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50
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75
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Discontinue
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15-30
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Discontinue
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75
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<15
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50, or discontinue
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Refer to etoposide, CISplatin, methotrexate, leucovorin, DACTINomycin drug monograph(s) for additional details of adverse effects
| Most Common Side Effects |
Less Common Side Effects, but may be |
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Refer to etoposide, CISplatin, methotrexate, leucovorin, DACTINomycin drug monograph(s) for additional details
Refer to etoposide, CISplatin, methotrexate, leucovorin, DACTINomycin drug monograph(s) for additional details
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
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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
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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 2020 Updated hyperlinks to dactinomycin drug monograph
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
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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.
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