Exploring Surgical Options for Imatinib-Treated Patients with Advanced GIST
Clinical Management of GIST
Helsinki and Barcelona 2003-Conference Highlights
Before the introduction of molecularly specific pharmacotherapy, surgery was the only effective treatment for GIST. Currently, it remains the treatment of choice for patients with primary resectable tumors. However, complete resection alone often does not result in cure. In 50% or more of patients who undergo potentially curative operations for GIST, local recurrences or metastases develop.1 In a large series of 200 GIST patients, 80 were able to undergo complete resection of all gross primary disease.2 Their overall 5-year survival rate was 54%, and their median survival time was 66 months (Figure 1).
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Figure 1 |
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Disease-specific
survival in patients
with primary GIST who
underwent complete |
The efficacy of imatinib in treating metastatic and unresectable GIST has prompted consideration of the potential role of this agent in improving the outcome of surgery and rendering more tumors operable. Encouraging results have already been seen in small studies, including one reported at the American Society of Clinical Oncology meeting in June 2003 by Hohenberger and coworkers, of Humboldt University and the University of Essen, Germany.3 These investigators gave imatinib to 112 GIST patients, 18 of whom eventually underwent resection of residual tumors. Complete (R0) resection was achieved in 7 of 8 patients whose tumors were responding to imatinib at the time of surgery and in 2 of 10 patients with progressive disease. The recommendation of these investigators was to evaluate initially inoperable patients who achieve a partial response during imatinib therapy for surgery as early as possible, while their disease is responsive or stabilized with treatment.
Additional experience with the combination of imatinib and surgery was presented at the CTOS meeting by Frits van Coevorden, MD, PhD, on behalf of his colleagues at the Netherlands Cancer Institute.4 These investigators examined 2 approaches to surgery in patients with advanced GIST: as a second-line intervention after neoadjuvant treatment with imatinib, and as a salvage modality for patients with relapsed disease after an initial response or stabilization induced by imatinib therapy. van Coevorden and colleagues studied 30 consecutive patients with locally advanced or metastatic GIST who were treated with imatinib. Eighteen patients (60%) achieved a partial response, according to RECIST; 8 (26%) had stable disease; 2 (7%) had disease progression; and 2 (7%) died of complications from perforation following massive tumor necrosis. Of the 26 initially responsive and stabilized patients, 6 underwent post-imatinib surgery because of residual tumor. Complete resection of down-staged, locally advanced, nonmetastatic GIST was achieved in 2 patients. The first patient had a gastric GIST with extensive invasion of surrounding tissue, including probable aortic involvement. The mass became smaller and better defined during imatinib therapy, allowing for surgical excision, and the patient had no evidence of disease at 15 months postoperatively. The second patient had a large tumor that did not show substantial change on CT scans evaluated by RECIST but was internally necrotic. Nine months after complete resection, the patient continued to be free of disease. Neither patient received ongoing therapy with imatinib postoperatively. The other 4 patients in van Coevorden and coworkers’ study who underwent surgery had salvage operations. GIST progression occurred in these patients, all of whom had metastatic disease, after initial imatinib induced responses or stabilization. In 3 cases, evaluation of specimens from the resected tumors demonstrated viable, CD117 (KIT)-positive residual GIST foci. All 4 patients had extensive GIST recurrence at 2 months postoperatively. The investigators noted that discontinuation of imatinib therapy for 2 to 4 weeks following surgery because of side effects may have played a role in these recurrences.
What role for combined modalities?
Like
Hohenberger and coworkers, the
Dutch investigators concluded
that neoadjuvant use of imatinib
is feasible and promising,
having facilitated complete
resection of locally advanced
GISTs with durable imatinib
responses in their study.
Salvage surgery in cases of
progression during imatinib
therapy might be considered, but
the results reported by van
Coevorden and colleagues suggest
that clarification of its role
requires further investigation.
The rapid postoperative
development of recurrent disease
in the “salvage” patients after
an interruption of imatinib
therapy for up to a month is
noteworthy in light of the
growing body of anecdotal
reports indicating risk of
disease acceleration if imatinib
is discontinued. The relapsed
patients who underwent salvage
surgery also had more extensive
disease than those with a
durable benefit from imatinib
who became disease-free after
complete resection of residual
tumor. What the results might
have been with early resumption
of imatinib administration after
salvage surgery, with
postoperative continuation of
imatinib in the patients who
received the drug in the
neoadjuvant setting, or with a
larger group of patients may be
indicated by other studies of
imatinib and surgery currently
under way.
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