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Chemotherapy for osteosarcoma in patients < 40 years


Medical editor Kirsten Sundby Hall MD
Oncologist
Oslo University Hospital

General

The treatment protocol is very intensive, has high toxicity and risk for developing delayed side effects in multiple organs, and requires precise monitoring. The treatment is given only at regional sarcoma centers.
The Scandinavian countries participate in multinational treatment protocols  (Europa, USA). According to the last protocol EURAMOS-I protocol the patients were  randomized based on the histological examination of the operation specimen. Poor responders have a worse prognosis than patients with a good histological response The protocol tests the benefit of modification/intensifying postoperative chemotherapy for patients with poor histological reponse. and addition or not of maintenance therapy with pegylated interferon-alfa in good responders. The protocol was closed June 30th, 2011. Short treatment arm is standard treatment until a new protocol is available.

Indications

  • Osteosarcoma in patients ≤ 40 years, any site, metastasis or not

Goal

  • Cure the disease
  • Limb-saving surgery

Preparation

Examinations before start of treatment

  • X-ray of tumor/thorax
  • MRI of tumor
  • CT of thorax
  • Biopsy
  • Check of:
    • kidney function
    • heart function
    • hearing
    • liver
  • Sperm banking/ovarial tissue freezing (under development)
  • Insertion of VAP

Preoperative examinations

  • X-ray of tumor/thorax
  • MRI of tumor
  • CT thorax
  • Biopsy
  • Check of:
    • kidney function
    • heart function
    • hearing
    • liver
Organ functions are checked regularly but at varying intervals for different treatment plans.

Implementation

Duration

In total about 30 weeks


Growth factor support


Growth factor support is given after all courses except for methotrexate.

Metastases

Operation for metastases occurs between weeks 11-30.

Follow-up

Conclusion of treatment

  • X-ray of tumor/thorax
  • MRI of tumor
  • Examine:
    • kidney function
    • heart function
    • hearing
    • liver function
VAP is removed about 6 weeks after the last chemotherapy cycle.

Side effects and delayed complications

Nutrition

Nutritional problems may occur in patients undergoing this treatment. It may be caused by nausea, vomiting, mucositis, diarrhea, dry mouth, pains, constipation, and changes in senses of smell and taste. Many will need intravenous nutrition. Good nutritional guidance is important.

Mucositis

Mucositis, both in the mouth and other mucous membranes, often occurs when the white blood count are at nadir. Soreness in the mouth for individuals. Sore mucous membranes in the mouth are not only an entrance for bacteria but can also be painful. Prophylactic mouth hygiene is performed during the entire treatment.

Nausea

Nausea improves after 1-2 days after the end of treatment. Some patients have lasting problems, often with multi-factorial etiology.

Hair loss

Hair loss usually occurs 2-3 weeks after the start of chemotherapy treatment; the hair falls off in tufts.

Bone marrow toxicity

Leucopenia and thrombocytopenia occur regularly between treatment courses. Measurement of hemoglobin, white blood cells, and thrombocytes is carried out routinely twice per week. For intercurrent febrile neutropenia, one should avoid using kidney-toxic antiobiotics due to the risk of additive kidney damage in combination with cisplatin and high-dose ifosfamide. This applies for up to one year after treatment is concluded. Transfusion of thrombocytes may be necessary, especially at the conclusion of treatment.

Kidney injury

Kidney injury can occur in the form of tubular and glomerular damage. Tubular damage appears to be reversible while the duration of reduction of glomerular function is more uncertain.


Hypomagnesemia

Hypomagnesemia is a result of cisplatin-induced damage of reabsorption in the kidney tubuli and can be increased by ifosfamide. Serum levels >0.5 mmol/l can be asymptomatic. Serious symptoms (twitches, seizures, arythmias, circulation collapse) can be triggered by medications causing additional magnesium loss (for example aminoglycosides). Hypomagnesemia can last many years and a long-term peroral magnesium supplement may be needed.

Ototoxicity

Ototoxicity with irreversible hearing loss in high frequency sounds and tinnitus has previously occurred in 30-40% of patients as a complication from cisplatin treatment. Recent protocols call for cisplatin as a long-term infusion which is reported to reduce ototoxicity drastically.

CNS-toxicity

CNS toxicity can occur during high-dosage ifosfamide and is characterized by somnolence, confusion, nightmares, changes in facial expressions, and in the most severe cases, seizures. The status is reversible after discontinuation of the ifosfamide infusion and a special antidote (methylene blue) is used both for treatment and as prophylaxis.

Cardiotoxicity

Cardiotoxicity of clinical importance occurs rarely (1-2%) with the actual dose (cumulative dose less than or equal to 450 mg/m2) and the administration method for (long-term infusion lasting at least 4 hours) doxorubicin.

Infertility

Infertility in men is a normal complication especially with the combination of ifosfamide, cisplatin, and doxorubicin. For patients in the appropriate age, freezing of sperm is recommended. Female egg production is also influenced, however currently, freezing of female eggs is under testing in Norway and is not routinely offered.

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