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A - Regimen Name

MVAC(HD) Regimen
Methotrexate-VinBLAStine-ADRIAMYCIN ® (DOXOrubicin)-CISplatin (high dose / dose dense)


Disease Site
Genitourinary - Bladder / Urothelial

Intent
Neoadjuvant
Adjuvant
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

For the treatment of transitional cell carcinoma of the bladder or urothelium

 
B - Drug Regimen

methotrexate

(Round to nearest 2.5 mg)
30 mg /m² IV Day 1
vinBLAStine

(Round to nearest 0.1 mg)
3 mg /m² IV Day 2

 

 

DOXOrubicin

(Round to nearest 1 mg)
30 mg /m² IV Day 2
CISplatin

(Round to nearest 1 mg)
70 mg /m² IV Day 2
filgrastim
240 mcg /m² Subcut Days 4 to 10
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C - Cycle Frequency

REPEAT EVERY 14 DAYS

Until disease progression or unacceptable toxicity or 3 to 4 cycles in neoadjuvant/adjuvant settings

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal (D1)
High (D2)


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 are in use at some centres.

Dosage with toxicity

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

 

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

methotrexate
(% previous dose)
vinBLAStine
(% previous dose)
DOXOrubicin
(% previous dose)
Cisplatin (% 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%

ANC ≥ 1.5
And
Platelet ≥ 100
 
100%
Cardiotoxicity**
 
 
 

No change

No change

Discontinue

No change

Grade 2 neurotoxicity /ototoxicity
 
 

No change

Consider dose reduction

No change

↓ 25%

Grade 3 or 4 neurotoxicity/ototoxicity
 
 

No change

Discontinue

No change

Discontinue

Grade 3 related organ / non-hematologic 

 

 
 

*75% for suspect drug(s)

 

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

 

 

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

methotrexate

(% previous dose)

vinBLAStine

(% previous dose)

DOXOrubicin

(% previous dose)

Cisplatin (% previous dose)

Grade 4 related organ / non-hematologic

Leucoencephalopathy, hepatic fibrosis, viral reactivation,   Hemolysis, optic neuritis, arterial thromboembolism, severe hypersensitivity reactions

 
 
Discontinue
 
Suspected Pneumonitis
 
 

Hold, investigate appropriately and discontinue if confirmed

*Do not start new cycle until toxicities have recovered to ≤ grade 2 (grade 1 for neurotoxicity), platelets ≥ 100x109/L, and ANC≥ 1.5x109/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
 
AST/ALT
methotrexate
(% previous dose)
vinBLAStine
(% previous dose)
DOXOrubicin
(% previous dose)
Cisplatin
(% previous dose)
1-2 x ULN
 
 
Caution
 50%
 50%
No adjustment required
 
 
>2-4 x ULN
 OR
2-4 x ULN
 75%
 25%
 25%
>4 x ULN
 OR
>4 x ULN
 Discontinue
Discontinue
 Discontinue

Renal Impairment

Creatinine clearance (mL/min)

Methotrexate (% usual dose)

Cisplatin (% previous dose)

Vinblastine and Doxorubicin

80
75%
100%

No change

 
 
 
 
60
60%*
75%
50
50%*
75%
30-50
Discontinue
50%
<30
Discontinue
Discontinue

* Less conservative dose modifications could be considered for low dose regimens (<50mg/m2)


 
F - Adverse Effects
Refer to methotrexate, vinBLAStine, DOXOrubicin, CISplatin, filgrastim 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
  • Diarrhea
  • Myelosuppression ± infection, bleeding (may be severe)
  • Nausea, vomiting
  • Rash (may be severe)
  • ↑ LFTs (may be severe)
  • Alopecia
  • Nephrotoxicity (may be severe)
  • Electrolyte abnormalities
  • Neurotoxicity and ototoxicity (may be severe)
  • Arterial thromboembolism
  • Venous thromboembolism
  • Hypersensitivity
  • GI perforation
  • Pancreatitis
  • Secondary malignancies
  • Cardiotoxicity
  • Vesicant
  • SIADH
  • Photosensitivity
  • Pneumonitis
  • Arrhythmia
  • Hemolytic uremic-syndrome, vasculitis
  • Raynaud's
  • Hemolysis
 
G - Interactions
Refer to methotrexate, vinBLAStine, DOXOrubicin, CISplatin, filgrastim drug monograph(s) for additional details
 
H - Drug Administration and Special Precautions

Refer to methotrexate, vinBLAStine, DOXOrubicin, CISplatin, filgrastim drug monograph(s) for additional details

 
I - Recommended Clinical Monitoring

Recommended Clinical Monitoring

  • CBC; baseline and regular
  • Electrolytes, including magnesium, phosphate and calcium; baseline and regular
  • Liver function tests; baseline and regular
  • Renal function tests; baseline and regular
  • Clinical toxicity assessment (infection, bleeding, nausea/vomiting, mucositis, neurotoxicity, cardiotoxicity, ototoxicity, local toxicity, pulmonary, skin, CNS); at each visit
  • Cardiac function tests (Echo, RNA and/or MUGA scans) for all patients with cardiac risk factors; baseline
  • Cardiac tests for all patients with cardiac risk factors (including prior trastuzumab or patients at or above the threshold doxorubicin cumulative dose levels (400mg/m2 for q21 day schedules and 550mg/m2 for weekly schedules); periodic
  • Audiogram; as clinically indicated
  • 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 hour, Day 2: 4-5 hours
Pharmacy Workload (average time per visit)
22.93 minutes
Nursing Workload (average time per visit)
49.167 minutes
 
K - References

Blick C, Hall P, Pwint T, et al.  Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) as neoadjuvant chemotherapy for patients with muscle-invasive transitional cell carcinoma of the bladder. Cancer  2012;118(16):3920-7

Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 2006;42(1):50-4.

Sternberg CN, de Mulder PHM, Schornagel JH, et. al. Randomized Phase III Trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol No. 30924. J Clin oncol 2001;19(10):2638-46.


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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.
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