A long-term follow-up of the imatinib mesylate treatment for the patients with recurrent gastrointestinal stromal tumor (GIST): the liver metastasis and the outcome

Gastrointestinal stromal tumor (GIST) accounts for approximately 1% to 3% of all the gastrointestinal tract neoplasms and 5% to 6% of all the mesenchymal tumors (sarcomas) [1, 2]. GIST expresses mutant protein-tyrosine kinase KIT (CD117), which results in constitutive activation of the KIT receptor tyrosine kinase [3, 4].

Surgical operation, as the first-line treatment, has been the most effective method for the resectable GIST. Most of the chemotherapy agents and radiation have failed to treat GIST [5]. About 80% of the patients have the tumor recurrence or/and metastasis after the radical operation, and the most common site of the metastasis is the liver [6, 7]. Before the imatinib mesylate was used, another resection had to be performed to remove the relapsed tumor when GIST recurred after the first radical surgery. Unfortunately, the outcome was still rather poor, and the patients could only achieve a median survival of about 15 months even if they had undergone another surgical operation [8, 9]. If the relapsed tumor could not be removed, the patient would have a much worse prognosis.

Imatinib mesylate, a small-molecule orally bioavailable drug, is able to inhibit KIT. Imatinib mesylate has proved to be the most active agent for advanced GIST [10, 11]. A long-term follow-up phase II study on the imatinib mesylate treatment for the patients with advanced GIST has revealed a response rate of 68% and a median overall survival time of 58 months [12]. A recent study has also proved the advantages of the adjuvant treatment with imatinib mesylate in recurrent-free survival [13]. Not a few patients with recurrent GIST after surgery have used imatinib mesylate as a salvage therapy, but no sufficient data about those patients are available. More than half of the recurrent GIST cases have liver metastasis. Liver involvement was always considered as a bad prognostic factor in solid tumors, but whether liver metastasis could influence the outcome of the recurrent GIST treated with imatinib mesylate has not been clear yet. The present study was focused on whether imatinib mesylate could prolong the survival of the patients who had the recurrent GIST after the first radical operation and whether the liver metastasis could influence the effectiveness of imatinib mesylate treatment. In order to confirm the final outcome, we performed a long-term follow-up.

GIST is the most common sarcoma of the alimentary tract that has a high resistance to chemotherapy and radiation. It is now categorized as a spindle-cell or a mixed epithelioid neoplasm located in the gastrointestinal tract, presumably originated from the same progenitor cell with the interstitial cells of Cajal [15]. GIST expresses a KIT protein (CD117) as its characteristic, which establishes the diagnosis. Surgery is always the first choice of treatment for the localized, resectable GIST; unfortunately, half of the patients have a tumor recurrence within months [5, 16].

Liver was reported to be the most common site of the GIST metastasis. Over 60% of the patients were found to have a liver involvement during the disease process [6, 7]. Recurrence in the primary site and/or the other sites was also found whether or not accompanied by the liver metastasis. The liver metastasis was always regarded as an impressive poor prognostic factor in solid tumors, and the patients had a short survival for several months [17, 18]. The patients with a resectable liver-metastatic GIST had to undergo a second line localized resection or so-called cytoreductive surgery [19]. Imatinib mesylate was proved to have an impressive therapeutic effect on the patients with an advanced GIST. A good 2-year survival rate of 95.2% was found in the patients who had only a liver-metastatic GIST after the prior radical resection combined with the treatment of imatinib mesylate [20]. However, the relationship between the liver metastasis and the outcome of the imatinib mesylate treatment has rarely been studied. So, the present study was focused on whether the liver metastasis would influence the survival of the patients who were treated with imatinib mesylate.

Although the results from our previous study answers the above question to some extent. The present study further proved that imatinib mesylate was able to prolong the survival time of the patients who had suffered from recurrent GIST after the radical surgery. Our median follow-up for 39.5 months revealed that 21 patients were still alive, with a 3-year survival rate of 66.7% and a median overall survival of 48 months (95% CI: 37.0~58.9 months). Oral imatinib mesylate, instead of another palliative surgery, was the reasonable choice for the patients who had recurrent GISTs that can not be radically removed. The clinical data from the patients in the LG, the AG and the ALG group were comparable. The analysis showed that the patients in the three groups had a similar tumor-response rate, TTP and OS. In the LG group, 7 of the 10 patients who had only liver-metastatic GIST were still alive when the clinical data were evaluated. Those patients achieved the highest 3-year survival rate of 80% in the current study. Survival was not significantly affected by liver metastases when imatinib mesylate was warranted.

Edema and anemia, although mild and well tolerated, were the commonest adverse effects observed during this long-term imatinib mesylate treatment. No treatment-related death occurred.

Tumor's resistance to imatinib mesylate is still a major problem. An increase of the imatinib mesylate dose to 600 mg per day or a maximal dose of 800 mg per day is useful but its effectiveness only lasts for a short time. A change to another targeting agent, such as sunitinib, could improve the outcome [21]. In our study, for the economic reason, only 12 of the 26 patients (46.2%) who had tumor progression used an increased dose of imatinib mesylate, only 3 patients (11.5%) were given sunitinib. The tumor control rate achieved by the second-line therapy was 23.1% in our study. The median survival time was 5 months (range, 1~23 months) after the failure of the imatinib mesylate treatment of 400 mg per day.

The imatinib mesylate treatment could prolong the survival of the patients who have recurrent GIST after the radical surgery in spite of an existence of the liver metastasis. Survival was not significantly affected by liver metastasis when imatinib mesylate was warranted.