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Drug therapy of soft tissue sarcoma of the abdomen and pelvis

Chemotherapy is administered to a  limited degree for abdominal sarcomas, but the benefit has not been clearly documented yet. Pre- and postoperative chemotherapy is administered for small round cell sarcoma (Ewing's sarcoma, rhabdomyosarcoma, desmoplastic small round-cell tumors, and mesenchymal chondrosarcoma.

The tyrosine kinase inhibitor imatinib (Glivec®), has shown a dramatic effect on inoperable and/or metastasizing GISTs (gastrointestinal stromal tumor). Objective responses are observed in approximately 60% and the disease stabilizes in approximately 20%. Approximately 50% of patients with advanced GIST live after 5 years of imatinib use.

Imatinib

All medical treatment of Gists should take place in close collaboration with Regional Sarcoma Centers. Proper diagnosis and treatment require cooperation between surgeon, oncologist, radiologist and pathologist. The Sarcoma Centers are mainly responsible for the treatment plan.

The majority of GISTs (>80%) have active mutations in KIT, which code for the tyrosine kinase enzyme. The mutation status for KIT is important to predict the response of treatment with the tyrosine kinase inhibitor, imatinib. Primary mutations occur in exon 9, 11, 13, or 17. Most mutations (approximately 70%) occur in exon 11, but 10-20% of the mutations are found in exon 9. Exon 9 mutations are seen most frequently in the small intestine and rarely in the stomach.

The recommended start dosage of imatinib is 400 mg daily. The dosage may be increased to 800 mg daily at progression or in case of a KIT mutation in exon 9. It is recommended to follow international guidelines for treatment of GIST when treating this patient group. 

The benefit of imatinib after removal of the primary tumor (adjuvant) is examined in multiple studies in both Europe and the US. Norway has participated in a study through the Scandinavian Sarcoma Group and the German Sarcoma Group where the effect of 1 and 3-year treatment with imatinib 400 mg was compared. The results from this study show better effect with 3 years of treatment. Therefore, 3 years of adjuvant treatment, with 400 mg imatinib daily, is recommended for patiens with certain tumor risk factors.  

The side effects of imatinib are usually moderate: edema, nausea, diarrhea, dermatitis, and fatigue. Tumor bleeding is shown in approximately 5% and can be fatal. Interactions with medications which metabolize in the liver via CYP3A4 are known, and simultaneous use of paracetamol (acetominophen) and warfarin should be avoided.

Patients where a positive effect of imatinib is not observed (primary or secondary resistance) or who experience unacceptable side effects, may be offered a next-generation tyrosine kinase inhibitor, sunitinib. This drug was registered in Norway in 2007. The effect is a combination of tyrosine kinase and angiogenesis inhibition. In 98 GIST patients with progression on imatinib, objective response/stable illness was reported for more than 6 months in 54% of the patients.

Patients with mutation in exon 9 usually respond better to sunitinib than to imatinib primarly. 

Sunitinib is available in capsules and the dosage is 50 mg/daily for 28 days followed by a two week break. Some patients tolerate 37,5 g daily better, without break.

One should be aware of the most serious side effects: hypothyroidism, palmar or plantar erythema, hypertension and heart failure. Less serious side effects are fatigue and symptoms from the gastrointestinal tract, from skin and mucous membranes.

In the Sarcoma Centers in Norway other tyrosine kinase inhibitors are under testing for GISTs, which has progressed during treatment with imatinib and sunitinib.

Preoperative imatinib treatment is an option to mutilating surgery or when there is a risk of tumor rupture. A mutation analysis of the tumor tissue should be performed in advance. These patiens should be treated at a Regional Sarcoma Center. 

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