Transcatheter arterial chemoembolization with tyrosine kinase inhibitor in the 12-year treatment of hepatic metastases from gastrointestinal stromal tumor: a case report

Introduction

Gastrointestinal stromal tumor (GIST) is a rare tumor that originates from the mesenchymal cells of the gastrointestinal tract. The incidence of GIST is approximately 10–20 in every 100,000 people and the disease comprises less than 1% of all gastrointestinal tumors (1). The clinical features and treatment strategies of GIST have long been significant areas of research in oncology. GIST can occur anywhere from the esophagus to the rectum, but is most common in the stomach (about 60–70%) and small intestine (about 20–30%). The liver is the most common site for GIST metastasis, and about 20–60% of GIST patients eventually develop liver metastases (LM) (2).

Surgical resection has been a cornerstone in the treatment of GISTs, especially for localized tumors (3-5). However, surgery often fails to achieve a radical cure for advanced or recurrent GISTs, and the rate of recurrence after surgery is high (6-8). The approval of imatinib for the treatment of recurrent, metastatic, or unresectable advanced GISTs in 2002 revolutionized the treatment landscape by providing a tyrosine kinase inhibitor (TKI) that could significantly improve the survival and prognosis of GIST patients (9-11). TKIs effectively control tumor growth and spread by inhibiting KIT/PDGFRA and other tyrosine kinase receptors. However, drug resistance to TKIs has emerged as a significant challenge in the long-term management of GISTs. Currently, a variety of TKIs have been approved for use in patients with advanced GISTs that have become resistant to imatinib, including sunitinib, regorafenib, ripretinib, and avapritinib, which have varying sensitivities to different gene mutation types or loci (12).

Treatment of GIST with LM (GIST-LM) is particularly complex because the liver is the most common site of metastasis, and LM responds poorly to traditional chemoradiotherapy. In addition, the emergence of TKI resistance has further narrowed treatment options. Therefore, comprehensive approaches should be determined via multi-disciplinary teams (MDT), including a combination of interventional, local, and systemic treatments. Transcatheter arterial chemoembolization (TACE) is the standard treatment method for intermediate-stage liver cancer. A previous study performed by Cao et al. founded that TACE was both effective and well-tolerated in GIST patients experiencing LM following TKI failure and could prolong the survival outcomes (median overall time: 68.5 months). Another research showed that the median overall survival of GIST patients with LM could be extended to 74 weeks after receiving Embosphere^®-TAE treatment (13-15).

In this case report, the GIST patient with LM successively experienced post-surgical recurrence and resistance to TKI treatment, and by undergoing TACE treatment, the progression of intrahepatic tumors was ultimately controlled, achieving a survival period of 12 years. TACE plays an important role in the treatment of liver tumors and emergency bleeding. However, there were few reports on its use in the treatment of hepatic metastatic GIST. Here, we report the application of TACE combined with TKI in a GIST-LM patient. Facing sequential resistance to targeted drugs, waiting for new drugs due to economic factors, and experiencing two instances of liver tumor rupture with massive bleeding, the treatment has bought time and turned a critical situation into a safer one. By reviewing the 12-year treatment course of the patient, we tried to provide new perspectives and strategies for GIST treatment. We present this article in accordance with the CARE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-403/rc).

Case presentation

A male patient, born in February 1966, presented due to sudden abdominal pain at the end of February 2012. Computed tomography (CT) revealed a mass of 14 cm × 10 cm × 5 cm in the right middle abdomen. The middle segment of his small intestine was resected to remove the stromal tumor. The diagnosis of stromal tumor was confirmed by pathology, in which the frequency of nuclear fissures observed was 5/50 high power field (HPF). Immunohistochemistry and genetic testing were not performed at that time. In October 2015, positron emission tomography/computed tomography (PET-CT) identified a metastatic tumor of 15 cm × 10 cm in the left liver, and the lesions in the left liver and middle liver were removed. In June 2016, multiple liver masses were found by contrast-enhanced magnetic resonance imaging (MRI), with the largest one sized about 9 cm × 8 cm. The first session of middle hepatic artery TACE was performed. The patient started oral imatinib 200 mg once a day in July 2016. After 2019, imatinib 400 mg was given once daily. The disease was effectively controlled in the following 5 years, with a lesion size of 6 cm × 5 cm. The main side effect of imatinib was mild facial edema; the patient was a truck driver and could work normally.

In April 2021, the patient experienced vague pain in the upper right abdomen, and the disease progressed. CT revealed multiple LM, the largest of which was sized 12 cm × 9 cm. We considered that the patient developed tolerance to imatinib. Subsequently, the patient underwent 2 TACE sessions in May and July 2021, which effectively controlled the lesions and relieved abdominal distension and pain. Treatment with oral imatinib 400 mg once daily was continued. The patient was capable of performing light physical labor.

In September 2022, the patient experienced abdominal pain and distension, and CT scan showed that some of the liver lesions had ruptured and bled, and then the fourth TACE session was performed at the right hepatic artery that fed the liver tumor area. The main discomfort after TACE was manifested as post-embolization syndrome: mild to moderate pain in the liver area and nausea within 1–2 days, fever of 38–39 ℃ from 2 to 5 days post-TACE, which gradually disappeared at 6–7 days.The oral imatinib dosage was adjusted to 400–600 mg once daily. In November 2022, the patient experienced rupture and bleeding of hepatic stromal tumors again, with a hemoglobin level of 65 g/L. He received the fifth TACE session at the right hepatic artery and phrenic artery. Drainage of hemoperitoneum (2,000 mL) was performed under the guidance of ultrasound guidance. Core needle biopsy of hepatic stromal tumor indicated the presence of spindle cell tumor, which were CD34 and CD117 positive, and the diagnosis of GIST was confirmed.

Genetic testing showed the presence of KIT exon 11 deletions involving in codons 557–558 (p.T574_H580del; c.1721_1741delCACAACTTCC TTATGATCACA), the mutation of arginine (the amino acid encoded by codon 946 of KIT exon 21) into stop codon KIT p.R946× (c.2836C>T), and the mutation of cysteine (encoded by codon 809 of KIT exon 17) into glycine KIT p.C809G (c.2425T>G).

Oral sunitinib 25 mg once daily was initiated in December 2022. Due to abdominal distention, the patient switched to regorafenib 80 mg once-daily treatment in March 2023. However, the symptom persisted, and he switched back to sunitinib in May 2023. Contrast-enhanced MRI in June 2023 showed multiple metastatic tumors in the liver and hepatogastric gap, with a maximum lesion of about 13 cm × 12 cm × 10 cm. Based on genetic testing, second-line and third-line drugs were used, but the therapeutic effects of sunitinib and regorafenib were relatively minor or intolerable. Therefore, the sixth TACE session (phrenic artery, right hepatic artery, and left gastric artery) was performed. Ten months after the rupture and bleeding of the liver lesion, the patient spent most of the time being treated in the hospital. Subsequently, the abdominal distension gradually disappeared and returned to a normal life.

In July 2023, oral ripretinib 150 mg once daily was initiated. By February 2024, CT and MRI showed that the lesions continued to shrink, with the largest lesion in the hepatogastric gap sized only 4 cm × 3 cm. The patient is currently on maintenance therapy with ripretinib, with stable disease. The patient was capable of performing housework and satisfactory drug tolerance (Figures 1,2).

Figure 1 The patient’s treatment summary from 2012 to 2024. TACE, transarterial chemoembolization; GIST-LM, gastrointestinal stromal tumor-liver metastases; CT, computed tomography; MRI, magnetic resonance imaging.

Figure 2 Changes in small intestinal stromal tumor and its liver metastases at different time points during the 12-year period. The intrahepatic tumors are large and multiple, and some of them become cystic after targeted therapy. (A) On 26 February 2012, CT revealed a large mass of 14 cm × 10 cm × 5 cm in the right mid-abdomen, showing uneven density, central hypodensity, and gas shadow. Small intestine stromal tumor resection was performed. (B) On 30 September 2015, PET-CT revealed multiple liver masses, with the largest one sized 15 cm × 10 cm in the left lobe of the liver. Bleeding was noted. Lobectomy of the left lateral liver + resection of the middle liver tumor was performed. (C) On 4 June 2016, contrast-enhanced MRI revealed multiple liver masses (maximum size: 9 cm × 8 cm), with abundant blood supply in the arterial phase. The first TACE session was performed. (D) In July 2021, CT performed after the 3rd TACE session revealed 2 tumor foci in the right hepatic artery (sized about 8 cm × 7 cm), with the deposition of iodized oil. (E) On 22 November 2022, liver tumor rupture occurred for the second time. Deposition of iodized oil was observed after TACE. (F) On 8 June 2023, contrast-enhanced MRI revealed multiple metastases in the liver and hepatogastric gap (maximum size: 13 cm × 12 cm × 10 cm, yellow arrows), and cystic changes are seen in some lesions. (G,H) On 28 February 2024, after 8 months of oral administration of ripretinib, CT and MRI show that the intrahepatic lesions are well controlled, and the largest mass in the hepatogastric gap is sized 4 cm × 3 cm (yellow arrows). CT, computed tomography; PET, positron emission tomography; MRI, magnetic resonance imaging; TACE, transarterial chemoembolization.

Interventional therapy

The Seldinger technique was used for cannulating the right femoral artery, and 5F-RH catheter was used for digital subtraction angiography (DSA) of the celiac artery, common hepatic artery, phrenic artery, and left gastric artery. Depending on the specific condition of the tumor, DSA was also performed for the superior mesenteric artery, intercostal artery, and right renal artery to identify all supplying arteries of the tumors. Subsequently, microcatheters (1.9–2.8 F) were superselectively inserted into each supplying artery. For stromal tumors with multiple metastases, the blood supply is more complex and may involve multiple different arteries. The diagnosis needs to be confirmed by the DANY-CT function in the DSA device. According to the size of the tumor, oxaliplatin 100 mg was diluted to 100 mL with glucose water for chemoperfusion. Epirubicin 30 mg + iodized oil 10–20 mL was used to make iodized oil emulsion to embolize the tumor area. In addition, microspheres with a diameter of 100–300 µm and/or 300–500 um (Merit Medical, South Jordan, UT, USA) were selected to embolize the supplying arteries in the tumor area. When the rupture and bleeding of liver tumor occurred, 710–1,000 µm gelatin sponge particles and 0.018 2/3 spring coils were used to strengthen the embolization (Figure 3). After the procedure, the patient received symptomatic treatment with liver preservation and rehydration for 4–7 days. The patient underwent a total of 6 TACE sessions and experienced mild hepatic discomfort and nausea after the procedure, which resolved within 24–48 hours. The patient began to take targeted drugs such as imatinib on the fourth day after TACE until the disease progressed or there were intolerable adverse reactions.

Figure 3 DSA shows the complexity of the supplying vessels of GIST-LM. The tumor vessels are small after targeted therapy, and TACE should be done with a special caution. (A) On 13 September 2022, abdominal distension lasted for 3 days, and CT revealed multiple intrahepatic tumors, rupture and bleeding of the tumor located at the right lower side of the liver (yellow arrow), and hemoperitoneum. (B-D) On 13 September 2022, DSA revealed that the right hepatic artery feeds the tumor area. (C) Hemorrhage from the right inferior hepatic artery is possible (yellow arrows). Iodized oil emulsion, microspheres, sponge granules were ultra-selectively injected via microcatheter for embolization (yellow arrows). (E) On 13 September 2022, DSA revealed that the superior mesenteric artery is not involved in blood supply. (F) On 10 November 2022, the patient experienced sudden abdominal pain for 3 hours. Contrast-enhanced CT revealed scattered mixed slightly hypo/hyperdense shadows after the interventional therapy. A slightly hypodense mass sized about 6 cm × 9 cm is seen in the hepatogastric gap, and bleeding is suspected (yellow arrow). A large volume of blood is observed within the abdominal cavity. (G) On 10 November 2022, DSA revealed that the left gastric artery (yellow arrows) and (H) phrenic artery branch supply the tumor in the hepatogastric gap (yellow arrows). The patient was then administered/applied with oxaliplatin 100 mg, epirubicin 30 mg + iodized oil emulsion 6 mL, 100–300 µm microspheres 3/5 vials, 560–710 µm gelatin sponge particles, 2 mm × 5 mm spring coils (for strengthening the embolization). (I,J) On 10 June 2023, DSA revealed that the right hepatic artery (yellow arrows) and left gastric artery feed the tumor area. Iodized oil emulsion, particulate balls, and spring coils were superselectively injected with microcatheter and microguidewire, respectively. DSA, digital subtraction angiography; GIST-LM, gastrointestinal stromal tumor-liver metastases; TACE, transarterial chemoembolization; CT, computed tomography.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

In our present case of a GIST-LM patient, the combination of TACE with TKI has been critical in controlling disease progression and maintaining quality of life. Although surgical resection is the treatment of choice for GIST, it often fails to achieve radical cure in patients with advanced or recurrent GIST, particularly in those with LM. Although TKI therapy has significantly improved outcomes in these patients, drug resistance remains a major challenge.

In our current case, the patient had undergone multiple surgical procedures and used multiple TKIs, including imatinib, sunitinib, and regorafenib. After imatinib resistance, genetic testing showed that the patient had mutations in exon 11, 21, and 17 of the KIT gene. The therapeutic benefits from sunitinib and regorafenib were relatively small due to the difference in TKI sensitivity among genes and the patient’s intolerance to sunitinib and regorafenib treatments. As a fourth-line drug for the all-patient population, ripretinib is a novel targeted drug that inhibits the activities of a broad spectrum of drug-resistant KIT/PDGFRA mutants (16). Evidence shows significant efficacy in patients who had failed or were intolerant to the previous 3 generations of TKIs, with sustained tumor shrinkage, good tolerability, and dramatically improved quality of life (17,18). Such a positive response underscores the potential of ripretinib in the treatment of TKI-resistant GISTs and the importance of selecting treatment protocols based on patient-specific genetic mutations and disease characteristics.

TACE plays a significant role in the treatment of intermediate and advanced liver cancer as well as hepatic hemangiomas. Moreover, TACE for colorectal cancer LM is also listed as an option in the Japanese colorectal cancer treatment guidelines. TACE and percutaneous ablation are mature and effective interventional radiology therapies for primary hepatocellular carcinoma, metastatic liver cancer and hepatic hemangioma. Since the blood supply of liver tumors mainly comes from the hepatic artery, the LM from GISTs generally have rich blood supply on DSA, which, however, is partially reduced after targeted therapy and/or cystic changes. Hepatic artery chemoembolization mechanically blocks the arterial blood supply to the tumor and increases intratumoral drug concentration. Most patients with ruptured liver tumors present with acute abdomen as the first symptom, with abdominal pain being the most common clinical manifestation. Hypotension and other hypotensive symptoms are common because 33–99% of patients will develop hemorrhagic shock. TACE can achieve immediate hemostasis in 86–99% of ruptured liver tumors. In the situation where the patient’s vital signs are unstable, how to both embolize the bleeding blood vessels and take into account the liver reserve function of the patient’s large liver tumor to avoid serious complications such as liver failure after hemostasis, is a test of the technical skills of the interventional radiologist.

TACE effectively controlled the growth of LM and relieved symptoms in our current case. By blocking the blood supply to the tumor and increasing local drug concentrations, TACE provides an important option for inoperable GIST patients. It not only stopped bleeding promptly but also effectively controlled tumor growth without causing severe complications, which further confirmed the good safety and effectiveness of TACE combined with TKI in treating patients with advanced GIST-LM.

Progression typically occurs after 6–7 months of ripretinib therapy in the whole-patient population. Although patients with KIT exon 17 mutations secondary to KIT exon 11 mutations may have a longer median progression-free survival with ripretinib therapy, resistance to ripretinib can still occur. Further treatment options should be considered. Previous clinical studies have suggested that the progression-free survival can be further prolonged when the patient is on dose-escalated ripretinib (19-21). Considering the favorable therapeutic efficacy and safety of the standard dose of ripretinib, ripretinib intrapatient dose escalation may be a treatment option after disease progression, as recommended by the National Comprehensive Cancer Network (NCCN) and Chinese Society of Clinical Oncology (CSCO) guidelines. Furthermore, in patients experiencing progressive disease (PD) after ripretinib dose escalation, the combinations with other TKIs have shown certain efficacy in treating advanced drug-resistant GISTs, which may provide new treatment options for GIST patients in late-line settings (22-24).

As a relatively rare and specific tumor, GIST has highly diverse biological behaviors and significant differences in disease conditions. Each treatment has its limitations. Domestic and foreign guidelines have clearly clarified the tiered structure of drug treatment for GIST: first-line imatinib, second-line sunitinib, third-line regorafenib, fourth-line ripretinib and avapritinib. However, with the gradual popularization of the clinical application of targeted drugs, the problem of drug resistance has gradually emerged and become the main reason restricting the efficacy of advanced GIST. In particular, after multiple lines of drug therapy have progressed, the choice of posterior line therapy remains limited and the efficacy is unsatisfactory. To sum up, our present case report highlights the importance of individualized, multimodal treatment strategies in patients with advanced GISTs. The patient experienced multiple targeted drug resistance over the course of 12 years. Liver tumors ruptured and hemorrhaged twice during his 6 interventional treatment sessions, during which complete hemostasis and lesion shrinkage were achieved, gaining a treatment opportunity for the patient. GIST-LM faces the challenges of successive drug resistance, economic factors, waiting for available new drugs, and massive hemorrhage from giant stromal tumor rupture. TACE has won valuable treatment time and turned to safety for patients. TACE can treat tumors that have already appeared, but for mesenchymal tumors that have not yet appeared, it is necessary to combine with TKIs.Future research should focus on exploring new treatment combinations and optimizing the sequence of treatments, ultimately improving patients with advanced GIST prognosis and quality of life.

Conclusions

TACE combined with TKI therapy is valuable for long-term cancer survival in patients with advanced GIST, and our findings provide a new perspective and treatment strategy for the treatment of LM from GIST.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-403/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-403/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-403/coif). Y.Z. reports that she is an employee of Medical Affairs Department, Zai Lab (Shanghai) Co., Ltd, Shanghai, China. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Jones)