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25 Therapy forAdvanced Gastrointestinal Stromal Tumors
covered by a strong echo. The operation was performed
smoothly.
25.1.3.3 Postoperative Pathology andGenetic
Testing
Pathological Diagnosis Liver tumor biopsy showed a small
amount of GIST in the liver tissue.
Immunohistochemistry CD117(+), DOG-1(+), CD34(−),
Vim (+), S-100(−), SMA (−), Ki-67 (Li: 3%).
Genetic Testing The amount of tissue collected was insuf-
cient and genetic testing could not be performed.
167
25.1.4 Prognosis
The patient continued to take oral imatinib 400 mg/d after
RFA and was regularly followed up with liver-enhanced MRI
in the outpatient clinic. By July 2020, the liver metastases
were assessed as SD (Fig. 25.4). In November 2020, an
enhanced MRI of the upper abdomen suggested partial progression of the patient’s liver metastases, and RFA was performed again. After that, the drug treatment was changed to
sunitinib 37.5 mg/d. Upon review 4 months later, the liver
metastasis was still progressing, and both RFA and TACE
were performed. The MRI was still suggestive of progression
on review after 2months, after which the patient switched to
regorafenib 120mg/d and a review after 40days suggested
Fig. 25.4 Enhanced MRI of the upper abdomen demonstrated SD 6
years after RFA
Fig. 25.5 Enhanced MRI of the upper abdomen in November 2020
continued progression (Fig. 25.5). The patient declined
fourth-line ripretinib treatment due to nancial factors, and a
hepatic segment resection with cholecystectomy and intraoperative RFA was subsequently performed on September 15,
2021. Intraoperatively, dense adhesions in the upper abdomen
were seen, and the liver was soft after the decomposition of
the adhesions. There was no visible cirrhosis or ascites, and
the spleen was normal. The tumor was located in the right
anterior S5 segmental septum, exhibited dense adhesion with
the right abdominal wall, was approximately 8×6cm in size,
and exhibited no envelope, invasion of blood vessels, cancerous thrombus in the bile duct, or portal thrombus. Multiple
sub-foci in the right and left liver were treated with intraoperative RFA.At the site of the original RFA treatment in the
right lobe of the liver, a huge purulent lesion, approximately
5 cm in size, was found attached to the abdominal wall.
Approximately 200mL of pus was visible after the incision
of this lesion. Postoperative pathology showed that the rst
specimen from the liver with hemorrhagic degeneration
necrosis and cystic degeneration was consistent with recurrent GIST. Several nodules were identied, with a maximal
diameter of approximately 1–1.5 cm, likely representing the
effects of therapy. The second specimen from the liver showed
brous tissue with hemorrhage, extensive degeneration, and
inammatory cell inltration, consistent with recurrent
GIST. Immunohistochemistry showed CD117(+), CD34(−),
DOG-1(+), S-100(−), Ki-67 (Li: 10%). Genetic testing
revealed an exon 11 deletion mutation in KIT without secondary mutations. The patient completed baseline upper abdominal enhancement MRI and resumed imatinib 400 mg/d
therapy after 2months with no new metastatic lesions in the
liver at follow-up until March 2022 (Fig.25.6).
168
Fig. 25.6 Postoperative baseline in October 2021 and 6-month postoperative enhanced MRI of the upper abdomen
X. Ma et al.
25.1.5 Experience inDiagnosis andTherapy
25.1.5.1 The Role ofImaging inDiagnosing
GIST Liver Metastasis
Common imaging modalities for GIST include conventional
methods (CT) and alternative methods (MRI, PET-CT). CT
is commonly used and widely available, and plays a key role
in the localization of the tumor, estimation of tumor burden
and metastasis, evaluation of invasive lesions, and responses
to medical management. MRI and PET-CT are used as alternatives when CT-enhanced scanning is contraindicated or
when previous diagnostic studies are inconclusive. For suspected liver metastases, MRI has certain advantages over
CT. Diffusion-weighted MRI (DWI) can help detect small
metastatic lesions and evaluate the efcacy of targeted therapy. It can also be used to evaluate the efcacy of targeted
therapy early in the treatment course. It is difcult to assess
whether liver nodules, especially those in the left lateral
hepatic lobe, are benign or malignant using CT scans during
routine follow-ups. Based on the lesions found in enhanced
MRI combined with the slow progression and history of
GIST, the diagnosis of GIST with liver metastasis was made
for this patient. Interestingly, the patient did undergo PET-CT
imaging previously, but no increased FDG uptake of the
lesion was noted. This may be related to the inhibition of
tumor activity during targeted drug treatment.
25.1.5.2 Choosing theProper Treatment
Strategy forGIST withLiver
Metastases
The current domestic [1, 2] and international guidelines [3]
have pointed out that for some patients with liver metastases
from GIST who cannot undergo surgery, arterial embolization and RFA can also be considered palliative treatments.
Patients with locally progressive lesions who are not candidates for localized treatment are advised to use sunitinib or
high-dose imatinib. In this case, there was the progression of
a liver lesion during targeted therapy, which indicated that
drug resistance may have occurred. If the original targeted
therapy is maintained, the disease is expected to progress
further. However, unlike extensive progression, the patient
did not have metastases in the abdominal or pelvic cavities.
If isolated drug-resistant lesions can be appropriately treated,
second-line targeted drugs may not be needed. Treatment of
isolated liver metastasis includes surgical resection and RFA
[4]. Considering the size and location of the metastases, the
patient in this case nally received RFA treatment, and they
recovered after surgery, reecting the advantages of minimally invasive surgery.
The patient had been diagnosed with high-risk colonic
GIST and had surgery 10years ago, followed by radiofrequency ablation 6 years ago. No doubt targeted drugs
greatly contributed to prolonging the survival of this
patient, although the RFA treatment of liver metastases also
played an important role in avoiding the possible complications of open surgery. The treatment with RFA also avoids
prematurely switching to second-line drugs, which are
costly and associated with side effects. When both TKItargeted therapy and interventional therapy fail to benet
patients, accurate assessment of status and timely and
effective surgical intervention can provide longer survival
benets.
25.1.5.3 Proper Use ofNeedle Biopsy
In this case, a needle biopsy was performed on the liver
metastases, although molecular pathological examinations
could not be completed because an insufcient volume of
tissue was collected. Molecular pathology detection of drug-
25 Therapy forAdvanced Gastrointestinal Stromal Tumors
169
resistant lesions is very important, and the detection of new
drug-resistant mutations can guide the selection of targeted
molecular therapy. The GIST pathology community tends to
collect the smallest volume of specimens to complete the
tests that are sufcient to diagnose GIST (for example,
immunohistochemistry tests may only be performed for
CD117 and DOG-1) so that only enough specimens are collected for specic molecular testing.
25.1.5.4 The Therapeutic Value ofRFA During
GIST Drug Therapy forAdvanced Liver
Metastases
The value of local therapy for patients with advanced GIST
was proven as early as 2006 by Raut et al. [5] from Harvard
Medical School. A study published in the Journal of Clinical
Oncology showed that patients with advanced GIST who can
achieve stable or local progression under drug treatment may
benet from surgical resection, whereas patients with extensive progression are more suitable for local treatment using
RFA.Under the overall control of drug therapy for advanced
GIST where certain liver lesions are poorly controlled, local
treatments can be actively applied, including treatments, such
as RFA [6], interventional embolization, and absolute alcohol
injection. In this case, even when the patient showed partial
progression of liver tumor and poor efcacy of TKI drugs, the
growth of liver metastases was slowed by RFA and TACE,
which helped delay progressive metastasis of the disease.
25.2 Expert Comments
KuntangShen
A 2006 JCO study [5] showed that patients with stable or
locally progressive advanced GIST can benet from surgical
resection, while the survival of patients with extensive progression cannot be prolonged with surgical management.
However, the current domestic and international guidelines
have pointed out that for some patients with liver metastases
from GIST for whom surgery is not appropriate, arterial
embolization and RFA can also be considered for palliative
treatment. Patients with local progression where local treatment is not appropriate should switch to Sunitinib or highdose imatinib.
In conclusion, surgeons need to consider the patient’s
condition, compliance, economic status, previous surgical
procedures, and their own experience and surgical capabilities (especially the ability to respond to intraoperative emergencies), and carefully plan treatment for patients with
advanced GIST.We should not rashly perform improper surgery which increases medical risks and patient suffering, nor
should we ignore patients’ needs.
25.3 Case 34 A47-Year-Old Woman
withAdvanced GIST Treated
withRipretinib asSecond-Line After
Progression withFirst-Line Imatinib
Therapy
XinliMa and XinhuaZhang
25.3.1 Introduction
Although imatinib is effective for many patients with GISTs,
tumor resistance to imatinib is common. Ripretinib is a type
II switch-controlled TKI, which aims to control broadspectrum mutations in KIT and PDGFRA.It has a favorable
response in patients with refractory advanced GIST and has
become an innovative treatment for heterogeneity of drug
resistance mechanisms.
25.3.2 Case Background
A 47-year-old woman was diagnosed with GIST with liver
metastases in June 2015 following a 1-year history of repeated
abdominal pain and distension. At the time of diagnosis, CT
revealed a tumor, approximately 12.4 cm ×12.9cm in size,
located between the greater curvature of the gastric fundus and
spleen with metastases in liver S5/6, and a core-needle biopsy
conrmed a diagnosis of GIST. Immunohistochemistry suggested tumor cells were positive for CD117, CD34, PDGFRA,
and Ki-67. Based on the management guideline for GIST, the
patient began to take imatinib 400mg/d as rst-line therapy.
Regular reviews over 8months of imatinib therapy showed the
tumor had signicantly reduced in size. The imatinib therapy
was considered to have proved a PR.Subsequently, the patient
underwent resection of the gastric fundus tumor and wedge
gastrectomy in February 2016in a tertiary teaching hospital,
but liver metastases were not resected (R2 resection).
Following this, she received postoperative imatinib maintenance treatment and regular surveillance showed disease control for 2.5years. However, ceased imatinib treatment in July
2018 because she experienced side effects of alopecia, nausea,
and fatigue.
In May 2019, 10months after discontinuation of imatinib
treatment, a CT scan indicated enlargement and new liver
metastases and abdominal metastases. From that time on,
imatinib 300mg/d was resumed regularly, with acceptable
plasma imatinib concentration. The patient regained PR
from the therapy. However, CT and PET-CT scans on May
18, 2021, indicated a new metastasis, approximately
4.3cm×4.4cm in size, in the hepatorenal recess, and multiple small lesions in the abdominal cavity. The size of the
170
X. Ma et al.
initial liver metastases was still stable. A biopsy of the lesion
in the hepatorenal recess conrmed GIST, with Ki-67 50%
positive. Mutational analysis demonstrated that the mutation
abundance of KIT exon 11 K558_E562del and exon 17
D816del were 4.0% and 2.6%, respectively, in peripheral
blood (ctDNA), while those in tissues sample were 49.7%
and 26.1%, respectively. In addition, a nonsense mutation in
PDGFRA exon 3 tested positive on ctDNA testing.
25.3.2.1 Past History andFamily History
The patient had a more than 20-year history of hypertension,
which was well controlled by drugs. The patient reported no
drug allergies. The patient’s parents were deceased and there
was no similar medical history in the family.
25.3.2.2 Physical Examination
The patient’s vital signs were stable, the patient showed no
signs of anemia, and the skin and mucous membranes were
free of yellow staining. The abdomen was at and soft, with
no rebound tenderness, abdominal masses or muscle guarding. The bowel sounds were normal.
25.3.2.3 Preliminary Diagnosis
Gastric GIST with liver metastasis.
25.3.3 Therapy
25.3.3.1 Case Analysis
This was a patient who had extensive progression of gastric
GIST with liver metastases after rst-line imatinib treatment. The preferred treatment would be second-line systematic targeted therapy. However, there were few progressive
lesions and a relatively low tumor burden, including the
original lesions and new lesions which were potentially
resectable. If there was an opportunity for effective systemic
treatment, another satisfactory cytoreductive surgery (CRS)
might increase the patient’s benet and prolong survival.
However, tumors with KIT exon 17 mutation are not sensitive to sunitinib, which is the standard second-line therapy
for GISTs. Limited evidence suggested that the usual thirdand fourth- line therapies regorafenib and ripretinib, respectively, may both be effective for GISTs with this mutation,
and that the ORR for ripretinib may be better and that the
safety was certainly superior to that of regorafenib. The
MDT discussion recommended ripretinib or regorafenib for
treatment choice, with ripretinib more favorably
recommended.
25.3.3.2 Treatment
After MDT discussion and sufcient explanation, the patient
gave informed consent and commenced ripretinib 150mg/d
from June 1, 2021. In order to obtain an earlier assessment of
ripretinib therapy, a plasma ctDNA test was conducted after
2 weeks of treatment, and this showed that the mutation
abundance of KIT exons 11 and 17 had decreased to zero.
MRI indicated SD after 4weeks of treatment. A repeat MRI
and CT scan after 80days of ripretinib treatment showed that
the lesion in the hepatorenal recess had shrunk about 17% in
diameter, which met treatment expectations (Fig.25.7). After
a subsequent MDT discussion, the patient underwent laparotomy in our hospital.
The main imatinib-resistant lesion was located in the
hepatorenal recess, which showed effective changes after
treatment. The texture was soft, and it was surrounded by a
thickened peritoneal capsule and fascia. Most of the other
Fig. 25.7 MRI and CT
results after ripretinib
treatment for 80+ days on
August 20, 2021, compared
with the baseline on May 17,
2021
25 Therapy forAdvanced Gastrointestinal Stromal Tumors
scattered peritoneal implant metastases were located in the
right-sided greater omentum, and a few were located in the
right diaphragmatic peritoneum. Liver metastases in S1,
S5, and S6 appeared to demonstrate effective changes
under targeted therapy. All visible lesions were removed,
and a R0/1 resection was accomplished (Fig.25.8).
25.3.3.3 Postoperative Pathology andGenetic
Testing
Postoperative pathology conrmed GIST. Plasma ctDNA
before surgery indicated that the mutation abundance of both
KIT exon 11 and 17 deletion remained at zero, while
PDGFRA exon 3 increased slightly from 0.9% to 1.0%
(Fig.25.9). Analysis of all resected tissues did not nd any
new mutation in KIT (Fig.25.10).
25.3.4 Prognosis
Considering that there was a secondary KIT exon 17 mutation
in multiple peritoneal metastases, suggesting that drugresistant lesions were widely distributed, it was recommended
that ripretinib treatment be resumed. The patient recovered
well and was discharged on the 8th POD.During ripretinib
treatment, mild adverse reactions, such as alopecia, palmarplantar erythrodysesthesia syndrome, and mild anemia (Hb:
106–113g/L), were present. The patient tolerated the therapy
well and there were no interruptions in treatment. The patient
stopped ripretinib for 5days before operation, and resumed
ripretinib at 150mg/d on the 7th day postoperatively.
171
Fig. 25.8 a Metastatic tumors of liver S5 and S6; b Hepatorenal recess
metastasis; c Omentum and small metastatic lesions; d Diaphragmatic
tubercle (1); e Ligamentum teres hepatis; f Metastatic tumor of liver S1;
g Diaphragmatic peritoneal tubercle; h Diaphragmatic tubercle (2); i
Adrenal tumor (myelolipoma)
Fig. 25.10 Mutation types and their abundance in all resected tissues
Fig. 25.9 ctDNA level before taking ripretinib (May 19, 2021),
2 weeks after ripretinib therapy (June 14, 2021) and 80 days after
ripretinib therapy (August 28, 2021)
172
X. Ma et al.
25.3.5 Experience ofDiagnosis andTherapy
Activating genomic alterations in KIT or PDGFRA drive cellular growth in most GISTs. Targeted therapy with TKIs has
revolutionized the treatment of GIST.Initially, imatinib was
approved for patients with KIT positive unresectable and/or
metastatic malignant GISTs. Although more than 80% of
patients with GIST receive clinical benet from imatinib
monotherapy, development of imatinib resistance is common, with more than half of patients developing progressive
disease in approximately 2 years, mostly attributed to
acquisition of secondary KIT mutations. These resistance
mutations could be heterogeneous, with multiple secondary
mutations from different lesions, or different mutations in a
single lesion from one patient. Given this heterogeneity, an
unmet need existed for a drug that inhibited a broad spectrum
of KIT and PDGFRA mutants, thus, blocking the various
resistance mutations and limiting the impact of further resistance mutations. In May 2020, oral ripretinib rst received
FDA approval for patients with advanced GIST who had
received prior treatment with ≥3 TKIs. Ripretinib is the rst
switch-controlled TKI which can control broad-spectrum
mutations in KIT and PDGFRA by inhibiting the switch
pocket and activation ring switch, as proven theoretically and
using preclinical cellular proliferation tests [7, 8].
For advanced GISTs which are resistant or intolerant to
imatinib, sunitinib is the standard second-line treatment for
progressive GISTs [9]. However, sunitinib is likely to be
ineffective for this patient due to secondary mutations in KIT
exon 17. After the failure of sunitinib treatment, the median
PFS for regorafenib has been shown as 4.8months, with an
ORR of 4.5% [10]. Studies have shown that some GISTs
with KIT exon 17 mutations are also resistant to regorafenib,
and the drug-related adverse reactions (including hand and
foot skin reactions, hypertension, and diarrhea) are experienced relatively more frequently in Asian patients [11].
Based on the phase I study of ripretinib, the median PFS of
and ORR second-line treatment with ripretinib in patients
with advanced GIST after imatinib resistance are 10.7months
and 19.4%, respectively [8]. This shows potential applied
value in terms of efcacy and safety of the drug. As can be
seen from the whole process of treatment, this patient was
successfully treated with ripretinib. The administration of
ripretinib for systematic control and tumor shrinkage gave
the patient an opportunity to obtain a non-evidence disease
(NED) cytoreductive surgery. Although ripretinib was not
superior to sunitinib in terms of PFS in the phase III trial
(INTRIGUE, NCT03673501) [12], meaningful clinical
activity, fewer grade 3/4 treatment-emergent adverse events,
and improved tolerability were observed with ripretinib.
Before the second operation, the patient had a good
response to ripretinib, and the ctDNA tests became negative.
Imaging showed that the tumor focus was smaller than before
treatment, and most of the adverse reactions related to the
treatment of ripretinib were grade 1 and tolerable, suggesting
that the treatment was effective and safe. As a minimally invasive detection technique, peripheral blood ctDNA detection
has the advantages of being non-invasive, safe, exible and
convenient, overcomes tumor heterogeneity, and allows a
series of evaluations over time [13]. It is widely used in the
diagnosis of lung cancer and breast cancer, the exploration of
drug resistance mechanisms, postoperative minimal residual
disease (MRD) monitoring, prognosis, and so on. With regard
to this patient, ctDNA tests were negative in the early stage of
ripretinib treatment, which showed an effective treatment
response earlier than imaging re-examination, and for a drug
whose mechanism of drug resistance is not clear, early efcacy evaluation is crucial to doctors’ decision-making. The
therapeutic effect with dynamic monitoring of ctDNA in this
patient was highly consistent with that of imaging and demonstrated the effective therapeutic response earlier than imaging could. Although there are fewer ctDNA exfoliated in
GIST than in other tumors, continuous monitoring can reect
the dynamic changes of the tumor when ctDNA is positive
[14]. It is a feasible and promising method to guide the treatment and predict the prognosis of patients with advanced
GIST.It is expected to become a biomarker for non-invasive
dynamic detection of GIST.
The target treatment effect of ripretinib was met before the
operation. The genotyping of the resected specimens demonstrated that lesions which appeared after the patient developed
resistance to rst-line treatment (diaphragm, peritoneum, hepatorenal recess nodule) all carried a mutation in KIT exon 17,
which indicated that secondary drug- resistant tissues might be
widely distributed. If imatinib was resumed after operation, it
was likely to lead to further tumor recurrence or metastasis in
a short period of time, so continuation of ripretinib was recommended after comprehensive consideration. It should be
pointed out that there was also a certain risk in the decision to
continue postoperative ripretinib maintenance treatment as the
mechanism of ripretinib resistance is not yet clear. If the
patient develops ripretinib resistance in the future, the choice
of the subsequent treatments is still uncertain.
25.4 Case 35 A39-Year-Old Woman
withAdvanced GIST Who Underwent
Cytoreductive Surgery After FourthLine Ripretinib Therapy
BoNi and LinxiYang
25.4.1 Case Background
The patient, a 39-year-old woman, underwent partial small
bowel resection of a pelvic mass at her local hospital in
September 2016. Intraoperative exploration revealed that
the tumor had ruptured. The postoperative pathology
showed small intestinal GIST, with a maximal diameter of
25 Therapy forAdvanced Gastrointestinal Stromal Tumors
173
12 cm, and no clear mitoses were found. Genetic testing
revealed a heterozygous deletion mutation in KIT exon 11,
and codons 559–565 were deleted. The patient did not
receive adjuvant therapy after surgery and was followed up
regularly. On February 12, 2018, a CT scan in our hospital
revealed multiple pelvic masses, and the recurrence was
considered (Fig. 25.11). The patient then started imatinib
400 mg standard treatment, and the whole abdomen
enhanced CT was reviewed every 3months. On September
20, 2019, the abdominal enhanced CT showed that the multiple nodules in the pelvis were smaller than before, and the
enhancement degree was weakened (Fig. 25.12). After
23 months of imatinib treatment, the abdominal CT scan
showed disease progression (Fig. 25.13), and the patient
was switched to sunitinib 37.5mg/d. After 80days, the disease was assessed as PD on the abdominal CT scan
(Fig.25.14). After 83 days of 120 mg/d regorafenib treatment, an abdominal CT scan showed further progression of
the disease (Fig.25.15). The patient started daily treatment
with ripretinib 150mg in August 2020, with regular review.
Thirteen months later, the abdominal CT scan again showed
tumor progression.
Fig. 25.11 The CT found tumor recurrence
Fig. 25.12 CT after 20months of imatinib treatment
Fig. 25.13 CT after 23 months of imatinib treatment (tumor
progression)
Fig. 25.14 CT after 80 days of sunitinib treatment (tumor
progression)
174
Fig. 25.15 CT after 83days of regorafenib treatment (tumor progression)
Fig. 25.16 Repeated CT after ripretinib treatment, tumor progression after the 13th cycle
X. Ma et al.
25.4.1.1 Past History andFamily History
The patient was previously healthy and reported no history
of drug allergies. The patient’s parents were alive, and there
was no similar medical history in the family.
25.4.1.2 Physical Examination
The patient’s vital signs were stable, and the skin and mucous
membranes were neither yellowish nor pale. The abdomen
was at, and no gastrointestinal or peristaltic waves were
seen. An old surgical scar was seen in the mid-abdomen. The
abdomen was soft, with no rebound tenderness or palpable
mass in the abdomen. The bowel sounds were normal.
25.4.1.3 Auxiliary Examination
Abdominal CT Multiple patchy nodular foci were observed
in the left lower abdominal wall and pelvic cavity, considered to represent GIST tumor spread and implantation. The
number of nodules in the pelvis had increased and some
were enlarged compared to the previous images (June 17,
2021) (Fig.25.16).
25.4.2 Therapy
25.4.2.1 Case Analysis
The patient is a young to middle-aged woman with advanced
GIST of focal disease progression under fourth-line drug
treatment. The pelvic tumor diameter decreased during
ripretinib treatment. After multidisciplinary consultation and
discussion, despite the tumor was closely related to the uter-
ine appendages and the rectosigmoid colon, it was deemed
that the pelvic progressive lesions were still resectable, and
surgical treatment was recommended for tumor cytoreduction
and resistance mutations.
25.4.2.2 Treatment
The patient underwent laparotomy with abdominal and pelvic tumor cytoreduction, partial rectal resection, and bilateral adnexectomy in our hospital on August 26, 2021. The
tumors were mostly located in the pelvis: scattered in the
uterine bladder depression, rectum uterine depression, pelvic
oor peritoneum, and invading the rectosigmoid junction
and bilateral appendages, with a maximum diameter of about
12cm. The tumor near the right appendix was approximately
7 cm, and a mass of approximately 1 cm in diameter was
found in the abdominal wall next to the original surgical incision on the left (Fig. 25.17). No obvious metastasis was
found in the liver, and the ascites was about 100mL.
25.4.2.3 Postoperative Pathology andGenetic
Testing
Pathological Diagnosis The pelvic mass, uterus-vesical
indentation nodule, abdominal wall nodule, pelvic oor nodule, left paraovarian nodule, sigmoid mesenteric nodule, and
right para-adnexal mass were all GIST metastases (after targeted drug therapy). Among them, the uterus-vesical nodule,
abdominal wall nodule, pelvic oor nodule, left paraovarian
nodule, and sigmoid mesenteric nodule had sparse tumor cell
density, interstitial brosis, and obvious changes after treatment. The tumor cells of the pelvic tumor and right adnexal
25 Therapy forAdvanced Gastrointestinal Stromal Tumors
abc
Fig. 25.17 The gross specimen. a Pelvic tumor; b Next to the left adnexa; c Next to the right adnexa
175
tumor had partially retreated, with interstitial brosis and
focal necrosis. High tumor cell density areas were still visible (20% of all tissues in the pelvic mass and 80% of all tissues in the right para-adnexal tumor). In the active area of
tumor cell proliferation, tumor cells were distributed in clusters around blood vessels, with a mitotic count >10/50 HPF,
which was in line with partial response to treatment.
Immunohistochemistry Ki-67 (Li: 40%), VIM (+), CD117
(+), CD34 (+), DOG-1 (+), SMA (−), S-100 (−), SDHB (+),
ALK-D5F3 (−), BRAF (−), Pan-TRK (−), C-MYC (−), P53
(+).
Genetic Testing Right adnexal tumor and pelvic tumor:
Heterozygous mutation in exon 11 of KIT, 558–565 loss,
heterozygous mutation in exon 13 of KIT, 654GTG>GCG,
and a heterozygous mutation in exon 17 of KIT,
823TAT>GAT.
Uterus-vesical nodule, abdominal wall nodule, pelvic
oor nodule, left paraovarian nodule, and sigmoid mesenteric nodule: Heterozygous mutation in exon 11 of KIT,
558–565 loss. Exons 9, 13 and 17 of KIT, as well as exons 12
and 18 of PDGFRA, were all wild type.
25.4.3 Prognosis
The patient completed a baseline CT postoperatively and
was discharged 8days after surgery. Due to economic factors, the patient chose to continue regorafenib maintenance
therapy after surgery, and the CT scan showed no obvious
progression of the remaining multiple small nodules in the
pelvis 6months after surgery.
25.4.4 Experience ofDiagnosis andTherapy
25.4.4.1 A New Treatment Option forPatients
withAdvanced GIST-Ripretinib
The patient was initially diagnosed with small intestine GIST,
and the intraoperative exploration revealed that the tumor had
ruptured. For economic reasons, she did not receive adjuvant
imatinib therapy at that time, resulting in multiple abdominal
and pelvic metastases. After 23months of standard rst-line
treatment with imatinib, her disease showed signs of progression neither sunitinib nor regorafenib provided signicant
treatment benet, which may be related to secondary multidrug resistance mutations. Fortunately, the patient was treated
with the newer TKI drug, ripretinib. Ripretinib, as a broadspectrum KIT/PDGFRA inhibitor designed with a switch
pocket, has efcient inhibitory effects on GIST of different
gene mutation types. This treatment provided the patient with
a PFS of 13months, which was already much higher than the
median PFS reported as a result of the INVICTUS study
(6.3months), and the reliable efcacy of subsequent line therapy had been proven. Ripretinib is a new treatment option for
patients with advanced GIST, especially those with conrmed
multidrug-resistant mutations after progression [7, 8].
25.4.4.2 Selection andGrasp ofTiming
forSurgical Intervention
inAdvancedGIST
In the course of targeted drug therapy, the patient actually
had more than one opportunity for surgical intervention:
when recurrence and metastasis were found, when imatinib
resistance was identied after 23months of treatment, and
when ripretinib resistance was identied after 13months of
treatment. At all three time points, the tumor had not progressed extensively, and multi-organ resection was not
176
X. Ma et al.
required for surgery. However, when tumors became resistant to second and third-line drugs and the disseminated
lesions in the abdomen and pelvis had progressed extensively, surgery should not be the rst choice. Since the patient
was a woman of childbearing age, and the tumor happened to
involve the uterus and double adnexa, the changes in hormone levels caused by adnexectomy should also be considered in the preoperative evaluation. The success of surgical
treatment depends on the ability to effectively intervene
before the disease progresses widely in the patient’s body.
The purpose of surgical treatment is to completely remove
drug-resistant lesions, and to remove as many lesions that
respond to treatment as possible without increasing the risk,
so as to prolong and slow down the re-progression time of
tumor lesions as much as possible.
25.5 Expert Comments
HuiCao
Gastrointestinal stromal tumors are the most common mesenchymal tumors of the alimentary tract, which are more
common in the stomach (50–60%). The most common metastatic sites after radical resection are the liver and peritoneum, and 70–80% of activating mutations in KIT and
PDGFRA are considered the main oncogenic drivers of
GIST. Imatinib is the rst-line standard treatment for
GIST.Although imatinib is effective for many patients with
GISTs, tumor resistance to imatinib is common. Ripretinib is
a type II switch-controlled TKI, which aims to control broadspectrum mutations in KIT and PDGFRA. It has favorable
responses for patients with refractory advanced GIST and
has become an innovative treatment for heterogeneity of
drug resistance mechanisms.
Case 34 shows us the successful application of molecular
detection prediction, individualized second-line treatment
with ripretinib after rst-line imatinib progression, dynamic
monitoring of efcacy with ctDNA and, once again, cytoreductive surgery, which may provide reference for the selective application of ripretinib combined with surgery in later
line treatment for metastatic GISTs.
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