Treatment

Surgery represents the mainstay of treatment in patients with localized, resectable GISTs with positive effects on long term survival. The goal of surgery is to obtain radical resection of tumour mass. In fact, surgical margins status as well as other clinico-pathological parameters (such as mitotic index and tumour size) influence GIST patients’ outcome. A median overall survival of 46 months vs 10 months is respectively reported in cases of complete or incomplete surgical resection.
Surgical techniques are strongly related to tumour size and site. When the tumour is small and easily resectable, a laparoscopic approach is feasible. Otherwise, laparotomy and demolition surgery is mandatory in order to effectively manage the tumour mass.
Lymphnode metastasis of gastrointestinal stromal tumours is unusual (0%-15%). Unlike gastric adenocarcinomas, routine lymphadenectomy is not recommended unless there is macroscopic suspicion for lymphnode metastasis.
In any case, surgeons are required to handle the tumour mass with care during surgical resection in order to avoid peritoneal spreading (which in turn can lead to recurrence).
However, even after complete surgical resection, relapse is a common event (range 7-24 months) and only 10% of patients are disease free after a long follow-up. Since metastases could appear even 20 years after the first diagnosis, a lifelong follow-up represents the only way to rapidly detect relapses or metastases.
The most common sites of recurrence are liver (65%) and peritoneum (20%), whilst nodes (6%), bones (6%) and lung (2%) are rarely affected.
In the case of liver metastases, the patient could undergo a new surgical resection and numerous study have demonstrated good results (OS of 90%, 58% and 30% at 1, 3 and 5 years, respectively) especially in patients with few, small-sized liver metastases, with an interval time between the primary tumour and liver metastasis of greater than 2 years and in patients in which major liver resection (≥ lobe) was achieved. Nevertheless a new recurrence after complete hepatic resection was observed in a high percentage of patients (almost 90%).
Recurrences on peritoneal surfaces could easily be removed, but a second recurrence in these cases is expected in almost 100% of patients.
Until a few years ago, there was no chance of treatment for metastatic or unresectable GIST and the median OS was <1 year with a survival rate at 5 years less than 35%. Surgery was only performed in cases of emergency (tumour’s rupture, digestive bleeding, intestinal occlusion) or for palliative purposes.
The advent of imatinib mesylate has radically changed the clinical approach to GIST and the exceptional results obtained in the treatment of advanced disease suggested that it could be successfully employed even in neoadjuvant setting. Imatinib is a small molecule with the property to inhibit several tyrosine kinases (TKs), including KIT and PDGFR-alfa. Imatinib treatment obtains an objective response rate (partial response or stable disease) of 81.6% in a median time of 13 weeks. It is usually well tolerated, only mild or moderate adverse events (AEs) have been observed: periorbital and widespread oedema, nausea, diarrhoea, musculoskeletal pain, fatigue, skin rash, abdominal pain. Serious AEs, like GI or intra-abdominal bleeding, are rare (5% of patients) and generally occur in cases of voluminous masses.
Although the majority of patients affected by GIST dramatically respond to imatinib mesylate, there is a little subset of patients (5%) that exhibits primary resistance to imatinib and many patients (14%) acquire this resistance after several months (with a median of about 2 years) of drug administration (secondary resistance). Molecular mechanisms seem to be responsible for these events. Patients whose tumour expressed an exon 11 mutation were much more likely to have a partial response with imatinib (83.5%) than patients with exon 9 mutant isoform protein (47.8% of PR, P=0.0006) and than patients with no detectable KIT mutation (0.0% of PR, P<0.0001). Also PFS was significantly better for patients with exon 11 mutation than for patients with exon 9 mutation (P<0.0001) and than patients without KIT mutation (P<0.0001).
OS for the entire population at 19 months was 85%, but patients with exon 11 mutant KIT isoform had better survival compared to patients with mutation in the exon 9 (P=0.0034) and patients with no KIT mutation (P<0.0001). In conclusion, the type of KIT mutation in advanced GISTs is predictive of response to imatinib therapy and it is very important to select patients who are responsive to imatinib and patients who are at high risk for early treatment failure.
Another mechanism of resistance can be represented by gene amplification and consequently receptor over-expression. In this case, it is possible to obtain a response to treatment, using higher doses of imatinib, while when the resistance is due to mutations in the enzymatic site, new treatments with different drugs are required. Considering the primary and secondary resistance to imatinib, a second generation of TK inhibitors has been developed.
Sunitinib is an oral multitargeted TK inhibitor with antiangiogenetic properties, that has been tested in patients with advanced GIST after failure of imatinib because of resistance or intolerance. The percentages of response obtained in patients treated with Sunitinib, were 7% of partial response as the best response, 58% of stable disease and 19% of progressive disease. Therapy was reasonably well tolerated: AEs (fatigue, diarrhoea, rash and skin discolouration, stomatitis, hand-foot syndrome, nausea and hypertension) were generally mild to moderate in intensity and easily managed by dose reduction, dose interruption or standard supportive medical treatments.
In particular, sunitinib administered to patients with GIST associated to KIT mutation in exon 9, that are typically resistant to imatinib, showed relatively higher rates of response and clinical benefit.
After confirmed progression on sunitinib, a prospective
placebo-controlled randomised trial proved that regorafenib, at
the dose of 160 mg daily for 3 every 4 weeks, is able to significantly prolong PFS. This therapy, as it becomes routinely available, is therefore standard for the third-line targeted therapy of patients progressing on or failing to respond to imatinib and sunitinib.
There is controlled evidence that patients who have already progressed on imatinib may benefit when re-challenged with the same drug. Likewise, there is evidence that maintaining
treatment with an anti-tyrosine kinase agent, even in the case of progressive disease, may slow down progression as opposed to stopping it (if no other option is available at the time). Therefore, re-challenge or continuation treatment with an antityrosine kinase agent to which the patient has already been exposed is an option in patients with progression.