Israel Medical Association Journal

The introduction of novel targeted therapies into the clinic in recent years has had a considerable impact on the management of several neoplastic diseases – such as gastrointestinal stromal tumors, hepatocellular carcinomas and renal cell carcinomas – considered until recently refractory to systemic therapies. We describe here two such novel biological agents, sunitinib and sorafenib, as a paradigm of the successful clinical application of new concepts. Sunitinib and sorafenib are small molecule tyrosine kinase inhibitors that target vascular endothelial growth factor receptor, platelet-derived growth factor receptor, C-Kit and others. Both agents are administered orally; sunitinib is typically given in cycles for 4 consecutive weeks with 2 weeks off, while sorafenib is given continually. Side effects occur in most patients, similar for both agents; they may affect several systems and organs but are mostly mild and easily manageable, rarely requiring discontinuation of the drug. However, these toxicities require prompt attention and intervention. The most frequently observed effects are hypertension, nausea, anorexia, asthenia and cutaneous manifestations; cardiac abnormalities may include congestive failure. Sunitinib, and markedly less frequently sorafenib, may cause thyroid gland dysfunction, mainly hypothyroidism. Antitumor activity has been shown for renal cell carcinoma in pivotal trials, for sunitinib as first-line treatment and for sorafenib in previously treated patients as second-line. Sunitinib is now approved as second-line therapy for patients with GIST[1] refractory to imatinib; sorafenib has resulted in a significant prolongation in median survival in patients with hepatocellular carcinoma. Ongoing clinical trials will further define the spectrum of these agents' antitumor activity, their role in combination with other drugs, as well as their optimal dose and schedule of administration.

Background: Gastrointestinal stromal tumors are the most common mesenchymal neoplasms of the human gastrointestinal tract.

Objectives: To review our accumulated experience using surgery to treat gastrointestinal stromal tumors.

Methods: We reviewed all patient charts and histological diagnoses of leiomyomas, leiomyosarcomas, leiomyoblastomas and schwannomas. Only tumors that displayed c-kit (CD117) immunopositivity were defined as GISTs[1].

Results: The study group comprised 40 female and 53 male patients (age 26–89 years); 40.9% of the tumors were classified as malignant, 39.8% as benign, and 19.4% as of uncertain malignancy. Fifty-six GISTs were located in the stomach (60.2%), 29 in the small bowel (31.2%), 4 in the duodenum (4.3%), 2 in the colon (2.1%) and 2 in the rectum (2.1%). Incidental GISTs were found in 23.7% of our patients. Mean overall survival time for malignant gastric GISTs was 102.6 months (95% confidence interval 74.2–131.1) as compared to 61.4 months mean overall survival for malignant small bowel GISTs (95% CI[2] 35.7–87) (P = 0.262). The mean disease-free survival period for patients with malignant gastric GISTs was 97.5 months (95% CI 69.7–125.2) as compared to only 49.6 months (95% CI 27.4–71.7) for patients with small bowel malignant GISTs (P = 0.041).

Conclusions: We found a high percentage of incidental GISTs. Gastric GISTs are more common than small bowel GISTs. Patients with malignant gastric GISTs have a significantly better prognosis than patients with malignant small bowel GISTs. A statistically significant correlation was found between age and malignant potential of the GIST.

Background: The diagnosis of gastrointestinal stromal tumors is based on documentation of c-KIT and platelet-derived growth factor-alpha receptors or specific c-KIT mutations. Before the diagnosis of GIST[1] was possible, all cases had been classified as sarcomas or benign tumors.

Objectives: To identify cases of GIST formerly diagnosed as abdominal or retroperitoneal mesenchymal tumors.

Methods: We reviewed the archive material on all surgical cases diagnosed as gastrointestinal related malignant mesenchymal tumors or GIST in our medical center during the last decade (1995–2004).

Results: Sixty-eight cases of retroperitoneal soft tissue sarcoma were identified. Thirty-eight were reconfirmed to be GIST, 19 were newly diagnosed as GIST (the hidden cases), 8 cases were re-diagnosed as mesenchymal tumors, and 3 cases of sarcoma remained sarcomas. Of all the GIST tumors, c-KIT-positive and PDGFRα[2]-positive tumors were more characteristic of primary gastric tumors, while c-KIT-positive and PDGFRα-negative tumors were found in the colorectal area. The c-KIT-negative and PDGFRα-positive cases were of gastric origin.

Conclusions: Any c-KIT-negative malignant mesenchymal mass located near the proximal gastrointestinal tract should also be stained for PDGFRα to differentiate between GIST and other soft tissue sarcomas. Practically, formerly diagnosed abdominal or retroperitoneal soft tissue sarcomas should be reviewed to identify patients with misdiagnosed GIST and thereby avoid future unnecessary and ineffective chemotherapy.