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A - Regimen Name

VAC Regimen
VinCRIStine-DOXOrubicin-Cyclophosphamide
(may be part of IE-VAC)


Disease Site
Sarcoma - Ewing's
Sarcoma - Soft Tissue

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
  • Ewing's sarcoma
  • Rhabdomyosarcoma
  • Other primitive neuroectodermal tumours, small round blue cell undifferentiated sarcoma, CIC-DUX4, BCOR sarcoma

 

 
B - Drug Regimen

vinCRIStine
1.5 mg /m² IV (maximum 2 mg) Day 1
DOXOrubicin

1

75 mg /m² IV Day 1
cyclophosphamide

2

1200 mg /m² IV Day 1

1Doxorubicin is omitted during radiation therapy.  Some studies split the dose of doxorubicin over 2 days. Give for a maximum of 5-6 cycles and then VC thereafter.

2 Prophylactic diuresis to reduce the incidence of cystitis is recommended.  Consider usage of Mesna, especially for younger patients or those with risk factors (e.g. previous radiation to the pelvic area). 

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C - Cycle Frequency

VAC*/ VC:  Repeat every 3 weeks

IE-VAC*/VC:  Used in an alternating schedule with ETOPIFOS for a total of 14 cycles given every 3 weeks (7 of each) in the absence of progression or unacceptable toxicity.

Intensified IE-VAC*/VC (for Ewing's sarcoma):  Used in an alternating schedule with ETOPIFOS for a total of 14 cycles (7 of each) given every 2 weeks. GCSF Prophylaxis is recommended with this regimen

*VAC for a maximum of 5-6 cycles then VC

Note that only patients less than 50 years old were included in the clinical trial by Womer et al. 

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

High

Other Supportive Care:

Also refer to CCO Antiemetic Summary

  • All patients should receive an appropriate hydration protocol according to local guidelines.
 
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.

More aggressive protocols, for example, those used with curative intent may allow re-treatment when ANC ≥ 0.75 x 109/L and platelets ≥75 x 109/L.

Dosage with toxicity

 

Worst Toxicity / Counts (x109/L) in previous cycle

 

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

Action (% previous dose)

ANC <1.5

OR

Platelet <  100

Hold *; consider G-CSF if repeated delay.

If recurs, may consider reducing doxorubicin and cyclophosphamide by 25%

Febrile Neutropenia

OR

ANC < 0.5 for ≥ 5-7 days

OR

Thrombocytopenic bleeding

OR

Platelets < 25

Hold *, then 75% or consider GCSF if isolated neutropenia. If recurs despite GCSF, reduce doxorubicin and cyclophosphamide by 25%

Cardiotoxicity**

 

 

OMIT doxorubicin (may substitute dactinomycin)

Neurotoxicity: Areflexia only

 

 

100% vincristine dose

Neurotoxicity:  Abnormal buttoning, writing, moderate motor neuropathy (± cranial)

 

 

 

Hold until recovery then restart at 50% vincristine dose

 

Severe motor neuropathy 

 

 

OMIT vincristine

Pneumonitis

 

 

Hold, investigate and if confirmed, discontinue regimen

 

Grade 3 related organ / non-hematologic

 

 

Hold until recovery* then 75% for suspect drug(s)

Grade 4 related organ / non-hematologic

 

 

Discontinue

 

Cystitis

 

 

Hold cyclophosphamide for macroscopic hematuria – consider mesna for next dose


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

 Doxorubicin is contraindicated in patients with severe hepatic impairment, and doses should be modified for mild-moderate impairment.

Bilirubin (µmol/L)

 

 

AST/ALT

Vincristine (% usual dose)

Doxorubicin (% Usual Dose)

Cyclophosphamide (% Usual dose)

1-2x ULN

 

 

50%

50%

100%

2-4x ULN

±

5-10 x ULN

25%

25%

Caution

4-10xULN

±

> 10 x ULN

25% or OMIT

OMIT

Caution

 


Renal Impairment

Creatinine Clearance (mL/min)

Vincristine

Doxorubicin

Cyclophosphamide (% of Dose)

> 50

No adjustment needed

No adjustment needed

100%

10 - 50

75%

< 10

Use with extreme caution or discontinue

 

Dosage in the elderly:

  • Older patients may have more neurotoxicity with vincristine. No dose modification is routinely required with doxorubicin and cyclophosphamide, but they should be used with caution.

 

Children:

  • Dose adjustment of cyclophosphamide may be required.
  • At higher risk of secondary leukemia from doxorubicin.  Children and adolescents are at an increased risk of developing delayed cardiotoxicity (up to 15 years after treatment).  Females may have a higher risk than males.  Increased monitoring is required.

 


 
F - Adverse Effects

Refer to vinCRIStine, DOXOrubicin, cyclophosphamide drug monograph(s) for additional details of adverse effects


Most Common Side Effects 

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

  • Myelosuppression ± infection/bleeding (may be severe)
  • Nausea and vomiting
  • Alopecia
  • Constipation (may be severe)
  • Mucositis, diarrhea
  • Dysgeusia
  • Abdominal pain
  • Increased LFTs (may be severe)
  • Hand foot syndrome; rash
  • Skin hyperpigmentation
  • Neurotoxicity (may be severe)
  • Flu-like symptoms
  • Fatigue
  • Urine discolouration
  • Arterial thromboembolism
  • Venous thromboembolism
  • Cardiotoxicity
  • Arrhthymia
  • Secondary malignancies
  • Vesicant (vincristine, doxorubicin)
  • Photosensitivity
  • Hypersensitivity
  • Radiation recall reaction
  • Nephrotoxicity
  • SIADH
  • Pneumonitis
  • Pancreatitis
  • Cystitis

 

 
G - Interactions

Refer to vinCRIStine, DOXOrubicin, cyclophosphamide drug monograph(s) for additional details


  • All drugs in regimen may decrease absorption and effectiveness of digoxin and verapamil; use with caution and monitor levels
  • Avoid nifedipine as it may decrease vincristine excretion
  • Vincristine and doxorubicin may decrease phenytoin levels; monitor levels and adjust phenytoin dose as needed
  • CYP3A4 inducers may increase clearance and decrease efficacy of vincristine
  • Use ototoxic drugs with extreme caution due to an increased ototoxicity risk with vincristine
  • Avoid nephrotoxic drugs due to additive effects with cyclophosphamide
  • Barbiturates can decrease the therapeutic effects of doxorubicin.
  • Decreased absorption of quinolones is possible with doxorubicin and vincristine; caution with Ciprofloxacin as it may decrease efficacy of cylclophophamide
  • Doxorubicin causes zidovudine and stavudine to be less effective; avoid the combination
  • Avoid calcium channel blockers due to additive cardiotoxicity with doxorubicin
  • P-glycoprotein inhibitors should be used with caution as they increase doxorubicin exposure and toxicity
  • Lovastatin may cause increased rhabdomyolysis and renal failure with cyclophosphamide; avoid
  • Drugs that induce hepatic microsomal enzymes (especially 2B6, 2C9 and 3A4) decrease the activation of cyclophosphamide.  Drugs that inhibit hepatic microsomal enzymes increase the activation.  Use with caution and monitor for toxicity/efficacy
  • Increased and decreased warfarin effects have been reported with cyclophosphamide; monitor INR closely
  • Acute encephalopathy has been reported with metronidazole and cylcophosphamide

 

 
H - Drug Administration and Special Precautions

Refer to vinCRIStine, DOXOrubicin, cyclophosphamide 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 prior to each cycle
  • Liver function tests; baseline and prior to each cycle
  • Renal function tests; baseline and prior to each cycle
  • Urinalysis; baseline and regular
  • Cardiac function tests (Echo, RNA and/or MUGA scans) for all patients with cardiac risk factors; baseline and periodic
  • Clinical assessment of  neurotoxicity, GI (stomatitis, nausea/vomiting), infusion site reactions, cystitis, infection, bleeding, thromboembolism, skin, cardiac or pulmonary adverse effects; 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
2 hours
Pharmacy Workload (average time per visit)
36.054 minutes
Nursing Workload (average time per visit)
66.667 minutes
 
K - References

Arndt CA, Nascimento AG, Schroeder G, et al. Treatment of intermediate risk rhabdomyosarcoma and undifferentiated sarcoma with alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide. Eur J Cancer 1998;34:1224–1229.

Arndt CA, Hawkins DS, Meyer WH, et al.  Comparison of results of a pilot study of alternating vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide with IRS-IV in intermediate risk rhabdomyosarcoma: a report from the Children's Oncology Group.  Pediatr Blood Cancer 2008 Jan;50(1):33-6.

Cyclophosphamide, doxorubicin, and vincristine drug monographs, Cancer Care Ontario.

Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003 Feb 20;348(8):694-701. 

Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Grier HE. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004 Jul 15;22(14):2873-6.

Womer RB, West DC, Krailo MD, Dickman PS, Pawel BR, Grier HG, Marcus K, Sailer S, Healey JH, Dormans JP, Weiss AR.  Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma:  a report from the Children's Oncology Group.  J Clin Oncol. 2012 Nov 20; 30(33): 4148-54. 

July 2019 Updated hyperlink to vincristine drug monograph


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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.