Imatinib treatment interruption after 3 years results in rapid relapse, with a median progression-free survival of only 9 months, in patients with advanced gastrointestinal stromal tumours (GIST). These results published in The Lancet Oncology, show that 3 years of treatment with imatinib does not totally eliminate cancer-initiating cells, enabling the disease to recur after treatment stops. Thus, imatinib treatment should be given continuously unless patients experience unacceptable toxicity.

Most GIST patients experience significant tumour shrinkage after beginning treatment with imatinib, and 2-year overall survival has increased from 25% to 75% since its introduction. However, more than half of patients develop resistance after about two years. Additionally, some patients with stable disease, believing their disease to be totally controlled or cured, do not comply fully with treatment. Whether imatinib treatment interruption could have an effect on progression-free and overall survival in patients with non-progressive advanced GIST is not known.

In 2007, the phase III BFR14 trial showed that imatinib interruption after 1 year of treatment was associated with a high risk of tumour progression, a median of 6.1 months after interruption, without affecting time to secondary resistance (the risk of progression after reintroduction of imatinib) and overall survival. But whether treatment interruption could be beneficial at later time points is unknown.

In this study, the French Sarcoma Group examined the effects of imatinib interruption in GIST patients with non-progressive disease after 3 years of treatment. 50 patients were randomly assigned to continuous or interrupted treatment, 25 in each group. Patients were assessed every 3 months with CT scans.

The median time to disease progression was 9 months after randomisation in the interruption group and was not reached in the continuation group.

After a median 35 months follow-up, 2–year progression-free survival was 16% in the interruption group compared to 80% in the continuous treatment group.

The authors say: “There was further tumour control in all cases after the reintroduction of imatinib, and the time to secondary resistance to imatinib was similar in the two groups, which shows that imatinib interruption neither prevents nor promotes the emergence of imatinib resistance in GIST cells.”

However, they conclude: “3 years of treatment with imatinib are not sufficient to eliminate the remaining dormant GIST cells and cure patients with metastatic GIST…Discontinuation of imatinib is not recommended outside clinical trials unless patients experience significant toxic effects.”

In an accompanying comment, Michael Heinrich from Portland VA Medical Center, USA, says that these findings support the need for continuous treatment: “Interruption of treatment is associated with a fairly rapid repopulation of differentiated cancer cells from an underlying intact population of stem and progenitor cells…Therapies that can eradicate the initiating stem cells are needed for the cure that eludes current treatment with tyrosine-kinase inhibitors.”


Source: Lancet Oncology