2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Table 1. Risk Criteria for Relapse after Primary Surgery for GIST
Author
No. Patients
Initial
used for decision making since this design is unable to
exclude major selection bias. This is best exemplified by the
study of Li and colleagues 14 who compared a group of 56
patients self-selected for 3 years of treatment with imatinib
postsurgery to a group of self-selected patients that rejected
the offer of postoperative imatinib. The latter control
group 14 performed much worse than the control group in
either of the two prospectively randomized studies that will
be discussed. Here, I will therefore not discuss the other
performed nonrandomized studies.
Adjuvant Imatinib: Randomized Studies
Three randomized phase III studies on the adjuvant use of
imatinib have now been performed (Table 3), two of which
have been published, either as a full paper 15 or abstract. 16
DeMatteo and colleagues, through ACOSOG (trial Z9001) 15
performed a randomized phase III, double-blind, placebocontrolled
trial in patients after complete resection of a
primary GIST at least 3 cm in diameter and positive for the
KIT protein by immunohistochemistry. Seven hundred
seventy-eight patients were registered, but because of randomization
problems only 713 were formally randomly assigned
to either 400 mg imatinib daily (359 patients) or
placebo (354 patients) daily for 1 year. Patients and investigators
were blinded to the treatment group. Cross-over to
or re-treatment with imatinib was allowed in case of tumor
recurrence. The primary endpoint was RFS. Accrual in this
study was terminated early on recommendation of the Independent
Data Monitoring Committee (IDMC) because the
trial results crossed the interim analysis efficacy boundary
for RFS. The intention to treat analysis is taken for the
purpose of this review.
At a median follow-up of 19.7 months, 70 patients (20%) in
the placebo group as compared with 30 (8%) in the imatinib
group had tumor recurrence or had died. Imatinib significantly
improved 1-year RFS compared with placebo (98% vs.
83%; HR: 0.35, p � 0.0001). Overall survival, however, was
fully identical in both arms up to 48 months. 15
A later analyses of the trial by mutation subtype held up
KEY POINTS
No. Patients
Validation Criteria
Gold 9 127 360 Size, site, mitotic rate
Joensuu 4 2,560 920 Size, site, mitotic rate, rupture, gender
● Validated models for postsurgery risk assessment are
now available.
● Adjuvant therapy aims to improve survival.
● Adjuvant imatinib given for 3 years at a daily dose of
400 mg improves overall survival in patients at high
risk of relapse.
● Evidence is currently based on relatively limited
numbers.
● Data from future studies should be used when available,
to re-evaluate the evidence for adjuvant imatinib
use.
660
Table 2. Suggested Aims for Adjuvant Treatment
Internet lay sites: Adjuvant treatment is aimed to improve overall treatment
outcome, and together with the initial treatment forms the curative therapy
Oncoline: Adjuvant systemic drug therapy is given after primary local treatment
with the aim to eradicate possible occult metastases and increase cure rates
ASCO guidelines: Adjuvant systemic therapy is aimed to improve clinically
meaningful outcomes (i.e., disease-free survival, overall survival, quality of life,
and toxicity) when compared with and/or added to other therapies
NCCN guidelines: No definition of the aim of adjuvant therapies given
ESMO guidelines: Aim differs per tumor type. Mostly disease-free survival
Abbreviations: ASCO, American Society of Clinical Oncology; NCCN, National
Comprehensive Cancer Network; ESMO, European Society of Medical Oncology.
the statistically significant difference in RFS after 2 years
for patients with KIT exon 11 and PDGFRA mutations
(excluding PDGFRA D842V), but not for KIT wild-type and
exon 9 mutations. 17 A further update is expected this summer.
The SSG and the German Working Group on Medical
Oncology (Arbeitsgemeinschaft Internistische Onkologie)
have recently reported results of a smaller (400 patients)
randomized controlled trial comparing adjuvant imatinib for
3 years with adjuvant imatinib for 1 year, both at a daily
dose of 400 mg, in high-risk GIST. 16 At a median follow-up
of 54 months, 42% of patients in the 1-year treatment group
had GIST recurrence, compared with 25% of patients in the
3-year treatment group. 16 In the intention to treat analysis
at 3 years, the RFS for the 3 years of imatinib therapy was
87% compared with 60% for those given the drug for 1 year,
which translated into 66% and 48%, respectively, at 5 years
(HR: 0.46; 95% CI [0.32, 0.65]; p � 0.0001). 16 At 3 years the
OS in patients with 3 years of imatinib therapy was similar
to the OS in those with 1 year of imatinib (96% and 94%,
respectively), while at 5 years these numbers were 92% and
82% (HR: 0.45; 95% CI [0.22–0.89]; p � 0.019). 16 Although
statistically the analysis was robust, we still should realize
that because of the relatively small size of the study the
difference in OS is based on seven more patients dying in the
1-year treatment group. Death due to GIST occurred in 14
patients (7%) in the 1-year group and in 7 (4%) in the 3-year
group. The numbers at 5 years were even smaller and at
that point the difference is based on three events.
The third study, which has not yet been reported, is also
the largest study, accruing 908 patients and coordinated by
EORTC, in an intergroup setting with the Austral-Asian
Gastro-Intestinal Tumor Group, the French Sarcoma Group
(FSG), the Italian Sarcoma Group, and the Grupo Espanola
Investigaciones Sarcomas. This study randomly selected
patients at intermediate or high risk of relapse to either
receive no further adjuvant therapy or 2 years of daily
imatinib at 400 mg. The primary endpoint was overall
survival. The study was closed to accrual in October 2008
Table 3. Randomized Studies on Adjuvant Imatinib in GIST
Group Randomization
JAAP VERWEIJ
No. of
Patients
Ineligible
(%)
ASCOSOG 1 yr 400 mg dd versus control 713 9.1
SSG 1 yr 400 mg dd versus 3 yr 400 mg dd 400 9.8
EORTC 2 yr 400 mg dd versus control 908 NR
Abbreviations: ACOSOG, American College of Surgical Oncology Group; dd,
daily dose; SSG, Scandinavian Sarcoma Group; EORTC, European Organisation
for Research and Treatment of Cancer; NR, not yet reported.