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The Role of Imatinib Following Complete Resection of Primary Gastrointestinal Stromal Tumors
imatinib in the adjuvant setting is based on its demonstrated efficacy
Table 1: Survival Rates at Median Follow-up of Four Years
and tolerability in patients with unresectable and/or metastatic GIST, and
its potential benefit in an earlier and minimal residual status, particularly
Year of Follow-up Overall Survival (%) Recurrence-free Survival (%)
in patients at higher risk of relapse.
19994
29773
3961
American College of Surgeons
Oncology Group Trials
Source: DeMatteo et al., 2008.
35
The American College of Surgeons Oncology Group (ACOSOG) evaluated
Table 2: Recurrence-free Survival at the One-year Mark
the relative benefits of adjuvant imatinib therapy in patients who have
Recurrence-free Survival Tumor Size
undergone complete gross resection of primary GIST in two clinical trials. 3–6cm 6–10cm >10cm
Imatinib arm 100% 96% 96%
American College of Surgeons Oncology Group Z9000
Placebo arm 95% 80% 67%
This was a single-arm, open-label, multicenter, phase II study.
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Patients
Significant difference p=0.011 p=0.041 p<0.0001
recruited to the study had primary KIT-positive primary GIST, with a high
Source: DeMatteo et al., 2008.
37
risk for recurrence (tumor size ≥10cm, tumor rupture, or fewer than five The preliminary results of this trial have been published based on 713
peritoneal metastases). They were required to undergo complete gross patients. In the imatinib arm, one-year RFS was 98% compared with
resection of the primary GIST. Imatinib 400mg/day was given orally for 83% in the placebo arm, with a statistically proven absolute benefit of
one year, beginning within 84 days of resection. The patients planned 16%. The early results of this trial indicated that imatinib can improve
follow-up is for up to 10 years. The trial is closed to accrual and RFS following complete gross resection of the GIST. No difference
preliminary data have been presented in abstract form, based on 107 in OS between the two treatment arms was observed. However,
evaluable patients. These early data suggest that imatinib was well- the study was underpowered to demonstrate this difference and the
tolerated by all patients. The study indicated that imatinib can prolong cross-over design allowed those patients on placebo to receive
recurrence-free survival (RFS) and is associated with improved OS imatinib on recurrence. Imatinib therapy was well-tolerated in most
compared with historical controls (see Table 1). patients. This phase III trial also indicated that the higher-risk patients
benefited the most (see Table 2).
When imatinib treatment was discontinued, patients with exon 9
mutations quickly relapsed (0% RFS at two years), while those with exon Implications of the American College of
11 mutations experienced a lower rate of recurrence (62% RFS at three Surgeons Oncology Group Trials
years).
35
This indicates a link between the type of tumor mutation and Based on the preliminary data from the ACOSOG trials, the National
the rate of recurrence. In the metastatic setting, it has been shown that Comprehensive Cancer Center Network (NCCN) treatment guidelines
a high dose of imatinib 800mg/day can lead to a significantly superior for adjuvant therapy in GISTs have been updated.
7
These guidelines
PFS rate in GIST patients with exon 9 mutations compared with a lower now indicate that imatinib should be considered post-operatively in
imatinib dose of 400mg/day.
36
Thus, an interesting question for future the adjuvant setting for patients who have undergone complete
clinical trials would be to evaluate whether a higher imatinib dose or a resection for primary GIST. In December 2008, the FDA approved
longer treatment duration in the adjuvant therapy of GIST patients with imatinib for the adjuvant treatment of adult patients following
a mutation in exon 9 may prove to be more efficacious. Some light may complete gross resection of KIT-positive GIST, with a recommended
be shed on this matter when the mutational status of the patients on dose of 400mg/day.
Z9000 and Z9001 are published and compared with the recurrence data.
The early data from the ACOSOG trials are promising, but there are
American College of Surgeons Oncology Group Z9001 still some areas of adjuvant imatinib therapy that need further
This is a recently completed randomized, double-blind, placebo- investigation. Although the trials have shown that imatinib can delay
controlled, cross-over, multicenter phase III study.
37
The main entry recurrence, it is currently unknown whether they can indefinitely
criteria were tumor size ≥3 cm and KIT-positive primary GIST with either prevent recurrence. The four- and five-year follow-up results for the
intermediate or high risk for recurrence. Patients were required to RFS rates from the ACOSOG Z9001 trial are highly anticipated as
undergo a complete gross resection of the sarcoma. Patients were then they would shed some light on this area. The other areas that need
randomized to receive either oral imatinib 400mg/day or oral placebo to be further evaluated include the optimal duration of post-
once daily for one year. During the treatment phase, if there was operative adjuvant imatinib therapy and the impact of adjuvant
recurrence treatment assignment was unblinded and patients on imatinib therapy on OS.
placebo were given the option of receiving therapy with imatinib. Patients
already receiving imatinib were given the option of increasing their dose Duration of Adjuvant Imatinib Treatment
to 800mg/day. The primary end-point was RFS for a follow-up period of While the data from the ACOSOG trials currently support one year of
10 years. The anticipated patient accrual for this trial was halted therapy with imatinib, the optimal duration of adjuvant treatment has
prematurely on the recommendation of an independent data monitoring not yet been determined. The Radiation Therapy Oncology Group
committee. This recommendation was based on a planned interim (RTOG) 0132/ACRIN 6665 showed that 83% of GIST patients (median
analysis that showed that a statistical difference had been achieved for tumor size 9cm) achieved PFS at two years of adjuvant imatinib
the primary study end-point of RFS, favoring the treatment arm. therapy. Although imatinib therapy was stopped two years after
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