Part 2. Imatinib for Gastrointestinal Stromal Tumors
(GISTs) (continued)
Discussion
In this section we summarize the findings of the
review in terms of answering the key questions initially posed, and then
discuss the clinical and research implications of these data.
Prior to the advent of imatinib, unresectable or metastatic GIST had an
exceptionally poor prognosis.5,16 Single-agent
doxorubicin, single-agent ifosfamide or combination chemotherapy including
these agents were the standard of care since GIST
was treated in the same manner as any other sarcoma of soft tissues, although
response rates were exceedingly low and short-lived, and generally indicative
of the ineffectiveness of any conventional chemotherapy approach.31,32 Importantly, these chemotherapeutic studies were done
in an era when it was hard to differentiate GIST from other soft tissue sarcomas
(STS), so the reported response rates are for the entire group of tumors
rather than GIST specifically.16 With the discovery
of CD117 and the KIT or PDGFRA tyrosine kinase proteins on the surface of
most GISTs, it became possible to designate any
individual STS as GIST or as some other histopathologic subtype of STS. The
use of imatinib for CD 117 positive advanced GISTs quickly followed. Efficacy
and tolerability have only been compared with historical norms from studies
of the more general advanced STS therapy of single-agent doxorubicin, single-agent
ifosfamide, or combination chemotherapy. Head-to-head comparisons
are not available. Given the great improvements in efficacy
witnessed in the phase II and III studies, it is unlikely that head-to-head
studies would be conducted or would be ethical. More recent
analyses are starting to evaluate the role of imatinib in the adjuvant and
neo-adjuvant settings, but this work is early and the role of imatinib in
these peri-surgical settings remains unclear.
1. In patients with GIST, what is the effect of imatinib compared
to doxorubicin and ifosfamide on overall survival, disease free survival,
time to progression, CR, PR, and quality of life?
There is consistent convincing evidence from high
quality phase II and III studies that imatinib for unresectable or metastatic
GIST yields complete response (CR) rates of 0-6 percent,
partial response (PR) rates of 45-67 percent,
and stable disease (SD) rates of 19-47 percent,
with an overall response rate (CR + PR) of 49-71 percent. This
is substantially better than historical response rates of 15-34 percent (median
26 percent) for single agent doxorubicin and 7-38 percent (median 26 percent) for
single agent ifosfamide (studies of general STS).31 Experts argue that these comparative efficacy
rates are high, noting that the GIST-subgoup within the studies of all
STS had response rates in the 0-5 percent range.68,5 Exact estimates are difficult
to determine due to the historical difficulty with distinguishing GIST
from other STS prior to the advent of CD117.
Data from the Verweij, et al. (2004) study49 provides the most complete estimates of survival. One-year
overall survival (OS) with imatinib can be estimated at 85 percent and
2-year OS at 72 percent; 2-year progression-free
survival (PPS) with imatinib can be estimated at 44-50 percent depending upon the imatinib dose. The most widely
reported survival estimates from earlier STS studies are from a phase III
trial of combination chemotherapy with doxorubicin, dacarbazine, ifosfamide,
and mesna (MAID) vs. doxorubicin and decarbazine for advanced STS.37 In
that study, 1-year OS is approximately 45-50 percent for both groups (estimated
from Kaplan-Meier graphs) and 2-year OS is approximately 25-30 percent
%; 2-year PFS was approximately < 5 percent. In the NICE
systematic review of non-imatinib treatments for advanced GIST, OS was
72 percent (18-100 percent) at 1 year, 40 percent (30-66 percent) at
2 years, and 16 percent (0-40 percent) at 3 years.16 The interventions reviewed were heterogeneous
including novel chemotherapeutics and/or standard sarcoma chemotherapy
regimens; studies included patients with GISTs and a broad range of other
histopathologic subtypes of STS. In the Bramwell, et al. meta-analysis
of randomized trials of doxorubicin-containing regimens for advanced STS
overall, median survival ranged from 7.3-12.7 months and OS was not reported.32
The conventional tumor response criteria of CR
and PR represent the conventional goal in oncology to eliminate the tumor
to the greatest extent possible in an effort to ultimately improve patient
outcomes and survival. Recently there is an evolving change
to this convention. Current studies suggest that if
targeted therapy stabilizes disease, it may prolong survival despite failure
of the tumor to shrink sufficiently to show a response according to conventional
criteria.69 In essence the tumor is changed into
a more chronic disease, quiescent until resistance occurs.
The role of imatinib in other clinical settings
is still unclear. Clearly, complete surgical resection is
still the therapy of choice in patients with primary presentation of limited
GIST in whom the disease can be completed resected without unacceptable
functional morbidity.3,16 It is unknown whether pre-operative (so-called "neo-adjuvant")
imatinib can make complete resection more feasible and recent studies are
just starting to address this question (Table 5). The role
of adjuvant imatinib for resected GISTs at high risk of recurrence is also
unknown, but is being addressed by a large, prospective, placebo-controlled
clinical trial sponsored by the U.S. NCI that is ongoing (ACOSOG trial Z9001). Meta-analysis
of adjuvant doxorubicin-containing regimens for general STS suggest that
they improve recurrence rates but not overall survival;28 subsequent studies of adjuvant ifosfamide-containing regimens
suggest the same.29
Quality of life outcomes have been poorly studied. The
only reported relevant findings were from one study;46 patients receiving imatinib had demonstrable improvement
in performance status with only 42 percent of patients fully functional
at baseline and 64 percent fully functional 4 months after initiation of
imatinib.
2. In
patients with GIST, what is the effect of imatinib compared to doxorubicin
(Adriamycin) and ifosfamide on adverse effects, tolerability, and compliance
with treatment?
Imatinib has far fewer adverse effects (any grade and grade 3/4) compared
with single-agent doxorubicin or ifosfamide. Imatinib's most
common side effects are edema, nausea and diarrhea, which are rarely grade
3 or 4. Any grade 3 or 4 side effects occur in ≤36 percent
of patients at the 600 mg daily dose or lower and hemorrhagic or hematologic
effects occur in ≤8 percent. At 800 mg daily, 30-50 percent
of patients will have grade 3 or 4 toxicities, which are primarily hemorrhagic
or hematologic effects. Compliance with treatment was not reported.
Doxorubicin’s most concerning toxicities are its cardiotoxicity, nausea/vomiting,
mucositis, and myelosuppression. In the Bramwell, et al. meta-analysis
of randomized trials of doxorubicin-containing regimens for advanced GIST,
toxicities were variably reported and included severe hematologic 28-53 percent
and moderate/severe nausea/vomiting 2-42 percent.32 At
total doxorubicin doses < 400 mg/m2 the incidence
of congestive heart failure (CHF) is 0.14 percent.70 The
incidence of CHF increases as the cumulative dose increases; at total doses
of 550 mg/m2 the incidence is 7 percent and at 700 mg/m2 the
incidence is 18 percent. Ifosfamide’s most frequently reported
toxicities include bladder toxicity, nephrotoxicity, nausea/vomiting myelosuppression,
and neurotoxicity. Summary toxicity data were not identified
in the literature; grade 3-4 toxicity from individual studies varied widely
with increasing rates as doses increased. For example,
Antman, et al. reported neurotoxicity in 19 percent of
patients who received 2g/m2 x 4 days,34 and van Oosterom, et al. reported up to 63 percent with grade 3/4 leukopenia at 3 g/m2 x 4 days.35 In the MAID combination, the incidence of
severe life-threatening toxicities includes the following: leucopenia
(89 percent), granulocytopenia (79 percent), thrombocytopenia (26 percent), anemia (22 percent),
nausea/vomiting (19 percent), mucositis
(9 percent), neurotoxicity (6 percent), and diarrhea (4 percent).37 Life-threatening cardiotoxicity due to doxorubicin
was not seen in the MAID phase III trial. Further, these chemotherapeutic
agents also have the inconvenience and increased cost of requiring parenteral
(intravenous) administration directly under the supervision of an oncologist
and treating nurse.
3. What patient or tumor characteristics distinguish treatment
responders from non-responders and have potential to be used to target
therapy?
There was little consistency in studies seeking to
identify possible prognostic factors. No factor was evaluated
in more than two studies. The most relevant predictors of response
relate to the mechanism of action of imatinib. Patients with
GIST (presumably expressing CD117) are more likely to respond to imatinib
than patients with other STS.48 Patients with identified
c-kit mutations, especially those on exons 11 and 9, are less likely to progress
on imatinib and have longer overall survival.47,59 These
findings are striking, since c-kit mutations including those on exons 11
and 9 lead to the more malignant GIST phenotype when imatinib is not used.12,17-21
Radiological predictors suggestive of response
may be useful for prognostication and tailoring therapy. In
particular, early response on PET scan at day 8 predicts clinical response
to imatinib.61 In the highest quality study of two
similar studies, PET was more sensitive than CT at determining tumor response
and combined PET-CT was most sensitive.62 A second
study of lower quality contradicted the finding of PET vs. CT. Other
clinical predictors were varied, unrelated to the mechanism of action of
imatinib, and uncorroborated.
Taken together, these data suggest that the
patients most likely to get benefit from imatinib are those with c-kit mutations,
especially those on exons 11 or 9. Early response PET may be
a good indicator of overall treatment effect.
Current State of Clinical Use
Imatinib is quickly becoming the standard of
care for unresectable and/or metastatic GIST worldwide. A recent
National Comprehensive Cancer Network (NCCN) 2004 Task Force Report and Guideline
advocated its use3, as does the NICE systematic review.16 The
NCI clinical guide at www.cancer.gov does not recommend imatinib or other specific
therapy for recurrent/metastatic GIST currently; 30 experts argue
that this guideline is out of date and does not represent current clinical
care. According to the NCCN, baseline
CT with or without PET is advocated, with three monthly reassessments to
evaluate response to therapy. Imatinib is started at a minimum
dose of 400 mg daily; dose escalation can be considered for tumor progression
or disease recurrence. The NCCN recommends imatinib as the
only chemotherapy for primary, metastatic, postsurgical adjuvant, or progressive
recurrent treatment. The use of imatinib in the post-operative
adjuvant setting remains the focus of ongoing clinical research studies.
The optimal dose continues to be unclear. The
current FDA indication is for 400–600 mg daily.43 The randomized phase II trial of 400 mg vs.
600 mg daily does not show clear benefit of one dose over another.43,46 In the randomized phase III trial of 400 mg
vs. 800 mg, there was a trend (in the U.S./Canadian trial) or a statistically
significant increase (in the European/Australasian trial) in progression-free
survival but not overall survival with the higher imatinib dose. However,
the higher dose had significantly more adverse effects.71,72,73,54 Patients on the lower dose were able to cross over to the
higher dose when disease progressed and some anti-tumor activity was seen
in these crossover patients.49,50
Current phase III studies are investigating the
question of 400 mg vs. 800 mg daily further and the option for intermittent
dosing. Early analyses of the two dosing levels suggest that
the two doses have equal efficacy, and that increasing to the higher
dose in the setting of tumor progression at the lower dose is possible.53,54 In the trial of continuous vs. intermittent dosing,
patients are provided continuous imatinib for the first year (dose unknown)
and then randomized to continue the imatinib or stop the imatinib and resume
it in the setting of tumor progression.52 It is
too early to interpret the results from this study. Based
on current information, the current dosing plan of 400 mg daily on an uninterrupted
schedule and then increasing to 800 mg daily in the setting of progressive
tumor appears to be a rational strategy.
Additional clinical trials are underway to determine whether adjuvant imatinib
for one, two or three years post-resection will impact progression-free survival.74
Forthcoming
Evidence and Implications for Future Research
Understanding of the role of imatinib in GIST is quickly evolving. At
the American Society of Clinical Oncology (ASCO) meeting in June 2005, 19
abstracts included information specifically about imatinib for the treatment
of GIST. Published ASCO abstracts were reviewed to develop
a horizon view of emerging data and upcoming clinical trials. Of
the 19 abstracts, 3 were case reports,75-77 3 were retrospective
reviews78-80, and 2 focused on radiographic issues81,82 and
therefore excluded from this discussion. Eleven abstracts were
fully reviewed.
Three abstracts present information from the S0033 Phase III trial of 400
mg vs. 800 mg of imatinib for the management of advanced GIST.83-85 A
total of 746 participants were randomized in this study. On
the 400mg arm (N=350), 62 percent had at least one dose delay and 10 percent
had at least one dose reduction unusually due to side effects such as rash,
edema, or gastrointestinal hemorrhage.83 On the
800 mg arm, 56 percent had at least one dose delay and 44 percent had at
least one dose reduction due to edema, nausea, and fatigue. Crossover
from 400 mg to 800 mg was allowed for non-responders at the lower dose. This
occurred in 112 patients with 23 percent having at least one dose delay and
16 percent one dose reduction (data available on 77 of 112 crossover patients). Pathological
data and tumor response information were available for 414 participants.84 Patients
with KIT positive GIST (N=377) and KIT negative GIST (N=14) had similar response
rates and PFS at 2 years (KIT+ 49 percent, KIT- 43 percent). Patients
with non-GIST histology (N=16) had substantially poorer outcomes with 13
percent PFS at 2 years. Median survival for GIST patients had
not been reached at the time of the abstract analysis; median survival for
non-GIST patients was 8 months. Unblinded results of this RCT
are pending. Among KIT+ GIST patients, 86 percent had KIT mutations
and 1 percent had PDGFRA mutations, with an overall mutation frequency of
87 percent.85 Patients with the exon 11 mutant KIT
isoform were more likely to have an objective response (OR) to imatinib (OR=67
percent) than those with the exon 9 mutation (OR=40 percent) or no mutation
(OR=39 percent, p=0.0022). There was also a trend toward better
overall survival for patients with the exon 11 mutation. Current
analyses of S0033 suggest that there are differential rates of toxicity for
400 mg vs. 800 mg, that crossover to higher dose imatinib is feasible when
patients progress on the 400 mg dose, that imatinib is efficacious for both
KIT+ and KIT- GIST but not tumors other than GIST, and that patients with KIT exon
11 mutations have the best prognosis.
The BFR14 study is a phase III trial of the French Sarcoma Group evaluating
continuous vs. interrupted imatinib for the management of advanced GIST;
two abstracts regarding this trial were presented.86,87 Patients
who were progression-free after one year were randomized to either discontinue
imatinib until evidence of further progression or to continue imatinib until
evidence of progression. Thus far, 198 patients have been enrolled
in the study and 58 patients were free from progression at one year and therefore
randomized. This study is ongoing and final results are pending,
however at the time of the ASCO abstract, 66 percent of patients in the interrupted
treatment plan arm had progressed vs. 15 percent of patients who received
uninterrupted imatinib (median follow up 21 months, p < 0.0004 for difference
in PFS).87 Imatinib reintroduction allowed tumor
control in 79 percent of patients. One year OS rates were similar
(89 percent vs 87 percent, p = 0.46). Evaluation for predictors
of OS and PFS among enrolled participants demonstrated that elevated lymphocyte
count (HR 1.25, 95 percent CI 1.04-1.49), CD34 negative phenotype (HR 5.18,
95 percent CI 1.98-13.6), and performance status > 1 (HR 5.32, 95
percent CI 1.75-16.2) independently predicted OS while liver metastases ((HR
0.40, 95 percent CI 0.20-0.83) and CD34 positive phenotype (HR 0.45, 95 percent
CI 0.22-0.93) independently predicted higher PFS.86 Current
analyses of BFR14 suggest that PFS is poorer when imatinib is interrupted,
but that reintroduction of the drug allows further tumor control in the majority
of patients, thus far without a difference in overall survival.
ACASOG Z9000 is a phase II evaluation of adjuvant imatinib at 400 mg for
1 year in patients with primary high risk GIST following complete resection.88 Data
on 106 evaluable patients who had been in the study for at least one year
were presented in one ASCO abstract (median age 58, 67 percent male). Toxicity
profiles were similar to other studies of imatinib; nineteen (18 percent)
patients did not complete therapy either due to toxicity (N=6) or withdrawal
of consent (N=12). This study is ongoing with survival outcomes
pending. The current assessment of Z9000 is that adjuvant imatinib
is well tolerated.
A phase II efficacy study including 7 patients with unresectable advanced
GIST treated with imatinib 400 mg daily at Oncology Hospital “Siglo XXI”
IMSS (Mexico) demonstrated an overall response rate of 72 percent.89 One
patient achieved a complete response. Average follow up was
9 months (range 5-10).
In addition to the predictors of response and survival described in the
S0033 and BFR14 trials, there were three other abstracts addressing predictors
of response. In an analysis of 15 advanced GIST patients treated
with imatinib at 400 mg daily, PDGFR overexpression (N=10 of 15) predicted
shorter time to progression (p=0.02).90 In an analysis
of 68 cases of advanced GIST, p53 mutations were identified in 12 cases (18
percent). Two-year OS was better in p53 mutation negative patients
than p53 positive patients (89 percent vs. 75 percent, p=0.0156).91 In
an analysis of 55 resected GIST patients, survival was predicted by size
of the tumor mass (tumor <5cm with 3-year OS 86 percent and >5cm 66
percent, p=0.023) and mitotic activity (<10 mitoses per high power field
3-year OS=90 percent, >10 OS=64 percent, p=0.0368).92 In
this study, patients with a deletion or insertion of KIT exon 11 had poorer
3-year OS of 35 percent vs. 64 percent for all other patients (p=0.0383). These
findings contradict those of the S0033 study where exon 11 mutations predicted
better survival.85 Overall, molecular predictors
analyses presented at ASCO suggest that KIT status does not affect GIST response,
that the effect of KIT exon 11 mutations on outcomes with imatinib is unclear,
that we have a lot to learn about the CD34 phenotype, and that p53 may
portend poorer prognosis in GIST.
Only one abstract focused on side effects of imatinib for GIST. Mean
corpuscular volume (MCV) was monitored for 33 advanced GIST patients treated
with 400 mg daily.93 A total of 42 percent developed
an elevated MCV over the upper limit of normal, without coincident anemia
or explanation. This side effect was asymptomatic.
Overall, preliminary review of this forthcoming evidence suggests that new
data will soon be available to inform ideal dosing, ideal dosing schedules,
timing with surgery, and likelihood of response. In addition
to ongoing phase II and III studies, future clinical studies will likely
focus on refining the molecular predictors of response and developing related
tests for routine clinical use. The other active area of GIST
clinical research is to develop radiological tests that are less invasive
and are more predictive of response to imatinib and outcome. Given
the growing number of recent articles about neoadjuvant and adjuvant imatinib,
further prospective and coordinated studies of the use of imatinib in this
clinical context need to be undertaken. Further, many patients
with GIST still have progressive or recurrent disease despite imatinib. Imatinib
resistance is a main topic in CML research. Research on imatinib
resistance in GIST is likely to be forthcoming, including an understanding
of the molecular basis of this resistance and new methods to overcome it. And,
like in CML, combinations of imatinib and other chemotherapies will likely
be studied in the future.
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