CISPDOXO

¹ Various doses and schedules have been used in clinical trials.  Doxorubicin total dose may be split over 2 to 3 days. Alternate regimens administered doxorubicin as a bolus or a 4 hour infusion or cisplatin over 2, 4, or 24 hours on Day 1.

REPEAT EVERY 21 DAYS

For a usual total of 6 cycles unless disease progression or unacceptable toxicity occurs

Other Supportive Care:

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.

_{*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%.}

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

• Geriatric patients may be at higher risk of developing nephrotoxicity, ototoxicity/neurotoxicity or hematologic adverse effects with cisplatin.
• Use doxorubicin with caution.

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

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

• Avoid nephrotoxic and ototoxic drugs (i.e. aminoglycosides) due to additive effects.
• Concomitant use of renally excreted drugs (i.e. methotrexate) may decrease renal clearance and enhance toxicities of these drugs.  Avoid use, if possible.  If not possible, modify doses as necessary.
• Barbiturates can decrease the therapeutic effects of doxorubicin.
• Doxorubicin can cause decreased digoxin absorption; monitor patient and levels.
• May need to modify doses of quinolones due to decreased absorption with concomitant doxorubicin.
• Doxorubicin causes zidovudine and stavudine to be less effective; avoid the combination.
• Doxorubicin and cisplatin may decrease phenytoin levels; monitor levels and patient.
• Avoid sorafenib while on doxorubicin due to increased doxorubicin toxicity.
• Avoid calcium channel blockers due to additive cardiotoxicity with doxorubicin.
• P-glycoprotein inhibitors (cyclosporine, verapamil, quinidine) should be used with caution as they increase doxorubicin exposure and toxicity.

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

Administration

Cisplatin:

• Cisplatin is physically incompatible with any IV set, needle or syringe containing aluminum.
• Dilute in NS and administer IV according to local guidelines.
• All patients should receive adequate hydration and premedication for emesis, according to local guidelines.
• Oral hydration with 8 glasses of fluid per day is strongly encouraged on treatment day and for 1-2 days after cisplatin; if nausea and vomiting prevent oral hydration, the patient may need to return for more IV hydration.
• Hydration and diuresis for patients with pre-existing renal, cardiac, or diabetic history at discretion of physician.
• Adequate hydration and urinary output must be maintained for 24 hours following cisplatin treatment.
• Store unopened vials between 15°C to 25°C and protect from light. Do not refrigerate or freeze since precipitation will occur.

Doxorubicin:

• Slow push through sidearm of free flowing IV (5% Dextrose, Normal Saline). Depending on the dose volume and vein condition, administer the dose between 3 to 10 minutes to minimize thrombosis risk or extravasation.
• Do not admix with other drugs unless data are available; precipitates with fluorouracil and heparin.
• Avoid contact with alkaline solutions as this can lead to hydrolysis of doxorubicin
• Slow down injection rate if erythematous streaking or facial flushing occurs.
• If any signs or symptoms of extravasation occur, the injection or infusion should be immediately terminated and restarted in another vein. Any known or suspected extravasation should be managed promptly as per local guidelines.
• Store vials under refrigeration (2 to 8ºC) and protect from light.
   

Contraindications:

• patients with known hypersensitivity to platinum-containing compounds
• patients who have severe myelosuppression
• patients with pre-existing renal impairment and hearing impairment, unless the possible benefits of treatment outweigh the risks. 
• Doxorubicin is contraindicated in patients with a hypersensitivity to this drug or any of its components, other anthracyclines or anthracenediones (i.e. epirubicin, daunorubicin, mitoxantrone or mitomycin C), severe hepatic impairment, severe myocardial insufficiency, arrhthymias, history of cardiac disease or recent myocardial infarction, previous treatment with maximum cumulative doses of doxorubicin, other anthracyclines  (or anthracenediones)
   

Other Warnings/Precautions:

•  Avoid the use of live vaccines; use may result in serious infections in immunocompromised patients.
• Patients with pre-existing neuropathy or prior treatment with other neurotoxic drugs may have increased potential for neurotoxicity
   

Pregnancy/Lactation

• This regimen is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners while on treatment and after the last treatment dose. Recommended methods and duration of contraception may differ depending on the treatment. Refer to the drug monograph(s) for more information.
• Male patients should not donate semen while using cisplatin and up to 2 years after the last dose.
• Breastfeeding is not recommended during this treatment and after the last treatment dose. Refer to the drug monograph(s) for recommendations after the last treatment dose (if available).

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.

Recommended Clinical Monitoring

Bramwell VH, Burgers M, Sneath R, et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncology 1992; 10: 1579-91.

Bramwell VH, Steward WP, Nooij M, et al. Neoadjuvant chemotherapy with doxorubicin and cisplatin in malignant fibrous histiocytoma of bone: an European Osteosarcoma Intergroup Study. J Clin Oncology 1999; 17(10): 3260-69.

Cisplatin, doxorubicin drug monographs, Cancer Care Ontario.

EURAMOS-1 protocol. Children's Oncology Group, 2011.

Souhami RL, Craft AW, Van der Eijken JW, et al. Randomised trial of two regimens of chemotheray in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet 1997; 350: 911-17.

Lewis IJ, Nooij, MA, Whelan J, et al. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst 2007; 99: 112-28.

Lewis MJ, Dubois SG, Fligor B, et al. Ototoxicity in Children Treated for Osteosarcoma. Pediatr Blood Cancer 2009;52:387–91.

Zalupski MM, Rankin C, Ryan JR, et al.  Adjuvant Therapy of Osteosarcoma—A Phase II Trial (SWOG 9139). Cancer 2004; 100(4): 818-25.