Part 2. Imatinib for Gastrointestinal Stromal Tumors
(GISTs)
Introduction
Policy Context of the Current Technology Assessment
Section 641 of the Medicare Prescription Drug, Improvement,
and Modernization Act (MMA) calls for a demonstration that would pay for drugs
and biologicals that are prescribed as replacements for drugs currently covered
under Medicare Part B. The demonstration
project will be national in scope and will be limited to 50,000 beneficiaries
or $500,000,000 in funding, whichever comes first. Forty percent of the funding for this
demonstration will be reserved for oral anti-neoplastic drugs.
CMS has requested an assessment of the efficacy of selected
oral cancer therapies included in the demonstration relative to drugs currently
covered under Medicare Part B. This
assessment will provide information that will be used to evaluate the likely
effects of the demonstration on patient outcomes and may also provide
underlying information to be used for cost-effectiveness analyses that will be
completed by CMS.
The scope of the assessment will be limited to the following
demonstration drugs and conditions:
- Imatinib
for treatment of chronic myeloid leukemia.
- Imatinib
for treatment of gastrointestinal stromal cancer.
- Gefitinib
for treatment of non-small cell lung cancer.
- Thalidomide
for treatment of multiple myeloma.
This report is
responsive to the second item: an
assessment of imatinib for the treatment of gastrointestinal stromal tumors
(GISTs).
Clinical
Context of the Current Technology Assessment
Although
relatively rare, GISTs represent the largest subset of mesenchymal tumors of
the gastrointestinal (GI) tract and about 5 percent of all sarcomas.1,2 They originate in the stroma, the
connective tissue that supports the organs involved in digestion. GISTs are now known to be derived from
muscle-like nerve cells called the Interstitial Cells of Cajal, which coordinate
the automatic movements of the GI tract.
During the last three decades there has been considerable debate about
GIST's cells of origin, nomenclature, diagnosis, and prognosis. Many cases have not shown up in cancer
registries, have been misclassified as other cancers, or defined as benign.1,3 For this reason, the exact incidence of
GIST is unknown, but is approximated at 5,000 to 10,000 cases in the U.S.
annually.4 Two recent studies from Scandinavia measure the incidence somewhat lower at 1.1
to 1.4 per 100,000.26,94 Nilsson 2004)
GISTs occur predominantly in middle and older aged
individuals; the median age at diagnosis is about 60 years.2 They affect men and women equally.2 The majority (70 percent) of tumors
occur in the stomach, with 20-30 percent in the small bowel and < 10 percent
elsewhere in the GI tract.1 GISTs vary greatly in size with tumor
sizes ranging from 1 to over 20 centimeters (cm).1
Surgical resection is the primary therapy of choice for all
localized gastrointestinal stromal cell lesions at
the time of initial presentation.3,5 The goal is to
completely remove the tumor. GISTs
are now classified based on a spectrum of risk, from very low-risk disease
(unlikely to recur or metastasize) to high risk disease which would commonly
recur and metastasize with life-threatening consequences; the rapidity and
timing of tumor progression and metastasis is highly variable.6 Five-year
survival rates after complete resection for all patients overall with primary
GIST and without accounting for risk stratification are 48-65 percent.5 The ability to resect the tumor is an
important prognostic determinant (Table 1). In a multivariate analysis of 200 cases
of GIST referred to a major cancer center, important negative predictors of
survival included male gender (relative risk (RR) 1.6, confidence interval (CI)
1.0-2.6), size > 5 cm (5-10 cm (RR 2.8, CI 1.3-6.2), > 10 cm (RR 4.4, CI
2.0-9.8)), and incomplete resection of the tumor (RR 3.9, CI 2.4-6.2).2 In this series, over 80 percent were
> 5 cm at the time of diagnosis.
Other single institution studies report similar findings.7
When complete resection was possible, local recurrence
occurred within 2 years in approximately 10 percent of individuals whose
primary tumor has been completely resected, metastatic recurrence in
approximately 15 percent, and synchronous local and metastatic in 5 percent.2 Complete resection is not possible in up
to 40 percent of cases.2,7,8
Pathology is important for differentiating GISTs from other
tumors and prognosis (Table 1).
Under the light microscope GISTs are composed of spindle-shaped or
epithelioid appearing cells; the cells are usually more numerous with less
eosinophilic cytoplasm than leiomyomas.9,10 The immunohistochemical staining pattern
is critical for diagnosis.
Immunohistochemistry is the use of antibodies or antisera to detect a
specific marker within a pathological specimen; when a tumor reacts with an
immunohistochemical stain, then it is termed "positive" for that
antigen and the tumor is recognized as producing the specific marker of
interest. Approximately 70 percent
of GISTs are positive for CD34, 20-30 percent are positive for smooth muscle
actin (SMA), 10 percent are positive for S100 protein, and 5 percent are
positive for desmin.10 CD117, the antigen that corresponds with
the c-kit proto-oncogene product, is positive in over 90 percent of GISTs.1,11-15 Other tumors are CD117 positive but most
of these do not occur in the GI tract and are not part of the differential for
GIST.1 The WHO classification of
gastrointestinal tumors indicates that the term GIST should be reserved for
CD117 positive tumors, but the current literature accepts the concept that
there are some CD117 negative GISTs.16
In
GIST a specific change or mutation in DNA at the point of the c-kit
proto-oncogene causes a cellular enzyme known as KIT to be switched
"on" all the time.
These activating mutations are most commonly localized on exon 11 (57-71
percent), exon 9, or exon 13 of the KIT gene.1 KIT is a tyrosine
kinase enzyme responsible for sending growth and survival signals inside the
cell. If it is "on",
the cell stays alive and grows or proliferates. The overactive, uncontrolled
mutant KIT enzyme triggers the malignant growth of GIST tumor cells. GISTs with mutant KIT are more likely to
be aggressive tumors characterized by more frequent recurrence and a higher
associated mortality rate. For
example, in a Japanese study of 124 patients with GIST, 89 percent were KIT
positive, 57 percent of c-kit mutations
were missense mutations on exon 11, and the patients with mutation-positive
GISTs showed more frequent recurrences (p < 0.001) and higher mortality (p
< 0.001) than did those with mutation-negative GISTs.12 Other groups have observed similar
findings, but this was not consistent across all studies.17-19 Exon 9 mutations have also been
associated with more aggressive tumor characteristics, including larger tumor
size and extra-gastric locations.20,21 CD117 negative GISTs may have a mutation
in the platelet-derived growth factor receptor (PDGFR) gene that produces a
similar tyrosine kinase; this does not appear to be prognostically significant.15,22,23
Pathological
characteristics such as sites of origin outside of the stomach, large size,
nuclear atypia, high mitotic rate, and mucosal invasion are also associated
with the ability of a cancer to spread.1,15,24 For example, in one series of 1,074
cases of GIST, mitotic activity predicted survival such that only 3 percent of
patients with low mitotic activity (≤ 5/50 HPFs) died, as opposed to 46
percent with high mitotic activity (> 5/50 HPFs, p < 0.0001).15 Larger tumor size and location (e.g.,
stomach fundus and gastroesophogeal junction) undermine tumor respectability
and hence are negative predictors of prognosis.5,15 Taken together, tumors with high mitotic
activity and larger size are most aggressive, such that 16 percent of patients
with small mitotically active tumors (2-5 cm, > 5/50 HPFs) died, as opposed
to 49 percent with mitotically active 5-10 cm tumors, and 86 percent with
mitotically active > 10 cm tumors.15 These two factors (mitotic
count and tumor size) were used by and NIH-convened workshop to define the risk
of aggressive behavior in GISTs;25 the validity of this scheme
was demonstrated in a subsequent population-based study.26
Recent
reviews suggest that scientifically advanced genetic markers, including
DNA-copy number changes, telomerase activity, KIT mutation status, and KIT
mutation type (point vs. deletion) may be useful in more accurately identifying
tumors with malignant potential,13,15,24 however,
the most important utility of KIT and PDGFR genotyping may be in prediction of
drug effects using kinase inhibitors such as imatinib.27
Table 1: Summary of Major Tumor Characteristics Reported
To Predict Poor Survival
Most
consistently reported characteristics
- Size > 5 cm.
- Inability to completely resect the tumor.
- Exon 11 and 9 KIT mutations.
- High mitotic rate.
Less
consistently reported characteristics
- Site of origin.
- Nuclear atypia.
- Mucosal invasion.
- DNA copy number changes.
- Telomerase activity.
- KIT point vs. deletion mutations.
|
In the pre-imatinib era, the usual
course after complete resection has been vigilant watchful waiting.3,5 Adjuvant chemotherapy
after surgery designed to reduce the chance of GIST recurrence has been moderately
successful.28,29 In a 1997 meta-analysis of randomized
trials of doxorubicin-containing chemotherapy, adjuvant chemotherapy improved
recurrence-free survival (hazard ratio (HR) 0.75, CI
0.64-0.87, p 0.0001) but not overall survival (HR 0.89, CI 0.76-1.03, p 0.12).28 Recurrent disease may be treated with
repeat surgery when possible.2 The prognosis for unresectable or
metastatic GIST has historically been poor, with 5-year survival rates
estimated to be lower than 5 percent.1,5 Historically unresectable or metastatic
disease was treated with radiotherapy, single-agent doxorubicin, single-agent
ifosfamide, and combination chemotherapy including these agents although none
of these have clinically meaningful anti-tumor activity.1 Management of advanced tumor and
improvements in survival with these interventions has been poor.16 Hence, the usual plan of care in the pre-imatinib
era was resection whenever possible with or without adjuvant
therapy, surveillance for recurrence and metastatic disease, followed by
chemotherapy for advanced disease generally with doxorubicin- and/or
ifosfamide-based regimens and possibly radiotherapy for selected cases.
The UK National Institute for Clinical Excellence (NICE) conducted a
systematic review of non-imatinib treatments for advanced GIST.16 The interventions reviewed were
heterogeneous including novel chemotherapeutics and/or standard sarcoma
chemotherapy regimens. The studies
included patients with GISTs, non-specific soft tissue sarcomas, GI sarcomas,
and leiomyosarcomas. Overall
survival 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. A total of 13 of 258 patients (5
percent) achieved a partial response, while 64 (24 percent) had stable
disease. NICE
concluded that the heterogeneity of treatments, small numbers of patients
involved, diagnostic difficulties, and uncontrolled study designs made it
difficult to interpret these studies as a true historical baseline for
imatinib.
The
National Cancer Institute (NCI) health professionals guidelines at www.cancer.gov are a frequent resource for U.S.
oncologists.30 Expert reviewers of this systematic
summary of the literature highlight that this NCI guideline is very outdated in
terms of recommendations for the management of GIST. In recommending chemotherapeutics, this
site does not specifically differentiate recurrent or metastatic advanced GIST
from other advanced soft-tissue sarcomas.
According to this summary, which is related to soft-tissue sarcomas
overall and is not focused on GIST, only doxorubicin and ifosfamide show
response rates > 20 percent for advanced disease when used as single agents.
- Doxorubicin:
Single-agent doxorubicin response rates vary from 15-34 percent
with median 26 percent; the majority of these responses are partial
responses only.31 In 1999, Bramwell, et al. of Program
in Evidence-based Care of Cancer Care Ontario conducted a systematic
review of randomized trials and developed an evidence-based guideline on doxorubicin
for advanced soft-tissue sarcomas (available at http://www.guidelines.gov). In this guideline, single-agent
doxorubicin response rates ranged from 16-30 percent; meta-analysis did
not show a significant response benefit for single-agent doxorubicin nor
combination chemotherapy containing doxorubicin.32 Toxicity data were also reviewed in
this document. This summary is
related to soft-tissue sarcomas overall and is not focused on GIST.
- Ifosfamide: In a
widely-cited review of chemotherapy for advanced soft tissue sarcomas,
single-agent ifosfamide response rates vary from 7-38 percent with median
26 percent in patients with previously treated sarcomas.31 Similar estimates were cited by
other reviewers.33 Approximately 24 percent of
patients who have progressed after doxorubicin can respond to ifosfamide.34 There is a clear dose-response
relationship with single agent ifosfamide.35,36 In sequential studies, one group
reported response rates of 10 percent at 6 g/m2, 14 percent at
8 g/m2 , 21 percent at 10 g/m2, and 29 percent at 14
g/m2.36 Again, this summary is related to
soft-tissue sarcomas overall and is not focused on GIST.
Combination
of these drugs may be more effective, especially for younger patients who can
tolerate this program; a randomized trial of 340 patients with advanced sarcoma
showed a higher response rate (32 percent vs. 17 percent, p < 0.002) and
longer time-to-progression (TTP, 6 vs. 4 months, p < 0.02) for doxorubicin,
dacarbazine, ifosfamide, and mesna (MAID) vs. doxorubicin and dacarbazine
alone.37 According to the NCI website,
sequential use of doxorubicin followed by ifosfamide or other drugs with each
subsequent recurrence is still frequently preferred for older patients.30 GIST is not specified within these
trials, and given the difficulty with diagnosis of GIST during the period
during which these trials were conducted any specific referrals to GIST
outcomes are suspect.
Across
this body of work representing the comparative efficacy for single and
multi-agent chemotherapy for GIST, there are repeated problems with reliability
of the information. Nearly all of
this work pre-dated the ability to distinguish GIST from other soft tissue
sarcomas. GIST is likely to be more
chemoresistant than other soft tissue sarcomas,38,39 and therefore the estimated
efficacy of doxorubicin- and/or ifosfamide-based chemotherapy for GIST is
likely to be less than the overall efficacy for soft tissue sarcomas reported
here. The inclusion of GIST in the
original studies about chemotherapy for soft tissue sarcomas may in fact reduce
the estimated efficacy of doxorubicin- and/or ifosfamide-based chemotherapy of
other non-GIST soft tissue sarcomas.
The Technology
Both the KIT tyrosine kinase and Platelet-Derived Growth Factor
Receptor Alpha (PDGFRA) targets of imatinib are receptor tyrosine kinase
proteins that are located within the plasma membrane on the surface of both
normal cells as well as the cells of GIST.40,41 In the normal
state, KIT is stimulated by stem cell factor (SCF) sending a signal inside the
cells that tells them to grow only as needed, while the PDGFRA is stimulated by
platelet derived growth factor (PDGF) dimers acting as a ligand for the
receptor. As described previously,
in the vast majority (95 percent) of GIST
lesions, the DNA of the c-kit proto-oncogene is mutated and the KIT and PDGFRA
proteins are continuously switched "on" in the absence of
regulating ligands. This continuous
"on" state is called constitutive KIT or PDGFRA protein kinase
activity. This constant signal
tells the cancerous cells to keep growing and is a critical contributing factor
to the development and maintenance of the malignancy.
Imatinib (STI-571, trade name Gleevec [USA] or Glivec [non-US])
is a derivative of 2-phenylaminopyrimidine.16 Imatinib is a
tyrosine kinase inhibitor that targets several different tumor proteins,
including the KIT and PDGFRA proteins that are the major etiologic factors of
GIST.40 It is a
competitive inhibitor of the tyrosine kinases associated with PDGFRA, the
Abelson (ABL) protein, and the KIT protein. Imatinib works by blocking, or turning off,
the message from these relevant target signaling proteins, so that the
cancerous cells stop growing.
Imatinib is available as an oral medication and is usually
taken once a day at a recommended dose of either 400 milligrams/day (mg/d) or
600 mg/d.42,43 Imatinib
should be administered with a meal and a large glass of water. Doses over 600 mg/d should be
administered in divided doses, e.g., 400 mg twice daily. Tablets are available in 100 mg and 400
mg forms. Treatment can be
continued as long as there is no unacceptable toxicity.
Imatinib
was first used in patients with chronic myelogenous leukemia (CML). It was Food and Drug Administration
(FDA) approved for the treatment of
patients with KIT (CD117) positive unresectable and/or metastatic malignant
GIST on February 1, 2001.42,43
Scope and Key Questions
The key questions for this review were developed with
experts in the field of oncology, health economics, and health policy. The key questions are as follows:
- 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?
- In
patients with GIST, what is the effect of imatinib compared to doxorubicin
(Adriamycin) and ifosfamide on adverse effects, tolerability, and compliance
with treatment?
- What
patient or tumor characteristics distinguish treatment responders from
non-responders and have potential to be used to target therapy?
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