The long-term efficacy of imatinib with hepatic resection or other local treatment for gastrointestinal stromal tumours liver metastases: a retrospective cohort study.

BACKGROUND: The liver is the most common site of metastasis from gastrointestinal stromal tumors (GISTs). The authors aimed to evaluate imatinib (IM) combined with hepatic resection (HR) or other local treatments such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE), compared to IM monotherapy in long-term survival benefits in patients suffering from GIST liver metastases. METHODS: Our research encompassed 238 patients diagnosed with liver metastases of GISTs from January 2002 to April 2022 at the First Affiliated Hospital of Sun Yat-Sen University. The oncological outcomes of concern included overall survival (OS), progression-free survival (PFS), and liver-specific PFS. RESULTS: Of all 238 patients, 126 were treated with IM alone (IM group), 81 with IM combined with HR (IM+HR group), and 31 with IM combined with RFA/TACE (IM+RFA/TACE group). The median follow-up time was 44.83 months. The median OS in the IM group was 132.60 months and was not reached in either the IM+HR group or the IM+RFA/TACE group. The 10-year OS rate in the IM+HR group was significantly superior to the IM group and the IM+RFA/TACE group (91.9% vs. 61.1% vs. 55.2%, respectively, P =0.015), and the liver-specific PFS ( P =0.642) and PFS ( P =0.369) in the three groups showed a beneficial trend in the combined treatment group. Multivariate analyses showed that age less than or equal to 60 years (HR 0.280, P< 0.001) and IM+HR (HR 0.361, P =0.047) were independently associated with better OS. Achieving no evidence of disease through surgical intervention was independently correlated with enhanced OS (HR 0.099, P =0.034), liver-specific PFS (HR 0.388, P =0.014), and PFS (HR 0.402, P =0.004). CONCLUSIONS: In patients with GIST liver metastases, IM combined with HR might improve OS in selected patients compared with IM alone and IM combined with RFA/TACE. Achieving no evidence of disease status with surgical treatment of patients results in significant prolonging of OS, liver-specific PFS, and PFS.

A nomogram for predicting liver metastasis in patients with gastric gastrointestinal stromal tumor.

BACKGROUND: Liver metastasis (LIM) is an important factor in the diagnosis, treatment, follow-up, and prognosis of patients with gastric gastrointestinal stromal tumor (GIST). There is no simple tool to assess the risk of LIM in patients with gastric GIST. Our aim was to develop and validate a nomogram to identify patients with gastric GIST at high risk of LIM. METHODS: Patient data diagnosed as having gastric GIST between 2010 and 2019 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided into training cohort and internal validation cohort in a 7:3 ratio. For external validation, retrospective data collection was performed on patients diagnosed as having gastric GIST at Yunnan Cancer Center (YNCC) between January 2015 and May 2023. Univariate and multivariate logistic regression analyses were used to identify independent risk factors associated with LIM in patients with gastric GIST. An individualized LIM nomogram specific for gastric GIST was formulated based on the multivariate logistic model; its discriminative performance, calibration, and clinical utility were evaluated. RESULTS: In the SEER database, a cohort of 2341 patients with gastric GIST was analyzed, of which 173 cases (7.39%) were found to have LIM; 239 patients with gastric GIST from the YNCC database were included, of which 25 (10.46%) had LIM. Multivariate analysis showed tumor size, tumor site, and sex were independent risk factors for LIM (P < .05). The nomogram based on the basic clinical characteristics of tumor size, tumor site, sex, and age demonstrated significant discrimination, with an area under the curve of 0.753 (95% CI, 0.692-0.814) and 0.836 (95% CI, 0.743-0.930) in the internal and external validation cohort, respectively. The Hosmer-Lemeshow test showed that the nomogram was well calibrated, whereas the decision curve analysis and the clinical impact plot demonstrated its clinical utility. CONCLUSION: Tumor size, tumor subsite, and sex were significantly correlated with the risk of LIM in gastric GIST. The nomogram for patients with GIST can effectively predict the individualized risk of LIM and contribute to the planning and decision making related to metastasis management in clinical practice.

Hope as a Lifeline: Imatinib Discontinuation in Patients With Oligometastatic Gastrointestinal Stromal Tumours.

BACKGROUND/AIM: This study explored how highly selected oligometastatic gastrointestinal stromal tumour (GIST) patients subjectively experienced the discontinuation of imatinib (IM) treatment. PATIENTS AND METHODS: Being an exploratory qualitative study, we applied a phenomenological and hermeneutical approach. We conducted in-depth semi-structured interviews with nine oligometastatic GIST patients who were in long-term clinical remission. The gathered data were interpreted using a thematic analysis. RESULTS: The analysis of the interview data revealed four main themes; getting one's life back, fear of recurrence, hope as a lifeline and the pros/cons of participating in this clinical trial. The participants disclosed that hope of being cancer free and without the side-effects of IM was essential for both participating in this study and enduring the uncertainty of drug discontinuation. CONCLUSION: Use of a qualitative approach in clinical trials can result in a better understanding of patients' perspectives and therefore lead to improved clinical practice.

Immune Infiltration, Cancer Stemness, and Targeted Therapy in Gastrointestinal Stromal Tumor.

Objective: To investigate the characteristics of the tumor immune microenvironment in patients with gastrointestinal stromal tumor (GIST) and identify cancer stem-like properties of GIST to screen potential druggable molecular targets. Methods: The gene expression data of 60 patients with GIST was retrieved from the Array Express database. CIBERSORT was applied to calculate the level of immune infiltration. ssGSEA and ESTIMATE were used to calculate the cancer stemness index and tissue purity. The Connectivity Map (CMAP) database was implemented to screen targeted drugs based on cancer stem-like properties of GIST. Result: There was a difference in the level of immune infiltration between the metastasis and non-metastasis GIST groups. The low level of T-cell infiltration was correlated with high tumor purity and tumor stemness index, and the correlation coefficients were -0.87 and -0.61 (p < 0.001), respectively. Furthermore, there was a positive correlation between cancer stemness index and cell purity (p < 0.001). The cancer stemness index in the metastasis group was higher than that in the non-metastasis group (p = 0.0017). After adjusting for tumor purity, there was no significant correlation between T-cell infiltration and cancer stemness index (p = 0.086). Through the pharmacological mechanism of topoisomerase inhibitors, six molecular complexes may be the targets of GIST treatment. Conclusion: Immune infiltration in GIST patients is related to cancer stem-like properties, and the correlation relies on tumor purity. Cancer stemness index can be used as a new predictive biomarker of tumor metastasis and targets of drug therapy for GIST patients.

Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study.

PURPOSE: Primary or secondary mutations in KIT or platelet-derived growth factor receptor alpha (PDGFRA) underlie tyrosine kinase inhibitor resistance in most GI stromal tumors (GISTs). Avapritinib selectively and potently inhibits KIT- and PDGFRA-mutant kinases. In the phase I NAVIGATOR study (NCT02508532), avapritinib showed clinical activity against PDGFRA D842V-mutant and later-line KIT-mutant GIST. VOYAGER (NCT03465722), a phase III study, evaluated efficacy and safety of avapritinib versus regorafenib as third-line or later treatment in patients with unresectable or metastatic GIST. PATIENTS AND METHODS: VOYAGER randomly assigned patients 1:1 to avapritinib 300 mg once daily (4 weeks continuously) or regorafenib 160 mg once daily (3 weeks on and 1 week off). Primary end point was progression-free survival (PFS) by central radiology per RECIST version 1.1 modified for GIST. Secondary end points included objective response rate, overall survival, safety, disease control rate, and duration of response. Regorafenib to avapritinib crossover was permitted upon centrally confirmed disease progression. RESULTS: Four hundred seventy-six patients were randomly assigned (avapritinib, n = 240; regorafenib, n = 236). Median PFS was not statistically different between avapritinib and regorafenib (hazard ratio, 1.25; 95% CI, 0.99 to 1.57; 4.2 v 5.6 months; P = .055). Overall survival data were immature at cutoff. Objective response rates were 17.1% and 7.2%, with durations of responses of 7.6 and 9.4 months for avapritinib and regorafenib; disease control rates were 41.7% (95% CI, 35.4 to 48.2) and 46.2% (95% CI, 39.7 to 52.8). Treatment-related adverse events (any grade, grade ≥ 3) were similar for avapritinib (92.5% and 55.2%) and regorafenib (96.2% and 57.7%). CONCLUSION: Primary end point was not met. There was no significant difference in median PFS between avapritinib and regorafenib in patients with molecularly unselected, late-line GIST.

Clinicopathological features and treatment outcome of oesophageal gastrointestinal stromal tumour (GIST): A large, retrospective multicenter European study.

BACKGROUND: Oesophageal gastrointestinal stromal tumours (GISTs) account for ≤1% of all GISTs. Consequently, evidence to guide clinical decision-making is limited. METHODS: Clinicopathological features and outcomes in patients with primary oesophageal GIST from seven European countries were collected retrospectively. RESULTS: Eighty-three patients were identified, and median follow up was 55.0 months. At diagnosis, 59.0% had localized disease, 25.3% locally advanced and 13.3% synchronous metastasis. A biopsy (Fine Needle aspiration n = 29, histological biopsy n = 31) was performed in 60 (72.3%) patients. The mitotic count was low (<5 mitoses/50 High Power Fields (HPF)) in 24 patients and high (≥5 mitoses/50 HPF) in 27 patients. Fifty-one (61.4%) patients underwent surgical or endoscopic resection. The most common reasons to not perform an immediate resection (n = 31) were; unresectable or metastasized GIST, performance status/comorbidity, patient refusal or ongoing neo-adjuvant therapy. The type of resections were enucleation (n = 11), segmental resection (n = 6) and oesophagectomy with gastric conduit reconstruction (n = 33), with median tumour size of 3.3 cm, 4.5 cm and 7.7 cm, respectively. In patients treated with enucleation 18.2% developed recurrent disease. The recurrence rate in patients treated with segmental resection was 16.7% and in patients undergoing oesophagectomy with gastric conduit reconstruction 36.4%. Larger tumours (≥4.0 cm) and high (>5/5hpf) mitotic count were associated with worse disease free survival. CONCLUSION: Based on the current study, enucleation can be recommended for oesophageal GIST smaller than 4 cm, while oesophagectomy should be preserved for larger tumours. Patients with larger tumours (>4 cm) and/or high mitotic count should be treated with adjuvant therapy.

Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial.

BACKGROUND: PDGFRA D842V mutations occur in 5-10% of gastrointestinal stromal tumours (GISTs), and previously approved tyrosine kinase inhibitors (TKIs) are inactive against this mutation. Consequently, patients have a poor prognosis. We present an updated analysis of avapritinib efficacy and long-term safety in this patient population. METHODS: NAVIGATOR (NCT02508532), a two-part, open-label, dose-escalation/dose-expansion phase I study, enrolled adult patients with unresectable GISTs. Patients with PDGFRA D842V-mutant GIST were a prespecified subgroup within the overall safety population, which included patients who received ≥1 avapritinib dose. Primary end-points were overall response rate (ORR) and avapritinib safety profile. Secondary end-points were clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS). Overall survival (OS) was an exploratory end-point. RESULTS: Between 7 October 2015 and 9 March 2020, 250 patients enrolled in the safety population; 56 patients were included in the PDGFRA D842V population, 11 were TKI-naïve. At data cut-off, median follow-up was 27.5 months. Safety profile was comparable between the overall safety and PDGFRA D842V populations. In the PDGFRA D842V population, the most frequent adverse events were nausea (38 [68%] patients) and diarrhoea (37 [66%]), and cognitive effects occurred in 32 (57%) patients. The ORR was 91% (51/56 patients). The CBR was 98% (55/56 patients). The median DOR was 27.6 months (95% confidence interval [CI]: 17.6-not reached [NR]); median PFS was 34.0 months (95% CI: 22.9-NR). Median OS was not reached. CONCLUSION: Targeting PDGFRA D842V-mutant GIST with avapritinib resulted in an unprecedented, durable clinical benefit, with a manageable safety profile. Avapritinib should be considered as first-line therapy for these patients.

Inguinal GIST: A Systematic Literature Review of Primary and Metastatic Cases.

BACKGROUND/AIM: Gastrointestinal stromal tumor (GIST) has a wide spectrum of clinical manifestations. Involvement of the groin region can cause interesting presentations but, as of 2020, has rarely been investigated. Our aim was to assess the clinicopathological and prognostic features of GIST appearing in this specific part of the body. MATERIALS AND METHODS: We investigated the world literature dealing with primary or metastatic GIST appearing in the inguinal region (IGIST). A case of metastatic IGIST from our clinical records was also included. RESULTS: We found only six cases of primary and nine of metastatic IGIST. All were of male gender, and most aged 60 years or more (10 cases). Inguinal hernia (11 cases) was the patient type most frequently affected. The association between metastatic IGIST and inguinal lymphadenopathy was statistically significant (p=0.049). CONCLUSION: IGIST is a rare entity with particular clinical manifestations. Inguinal hernia and inguinal lymphadenopathy should be carefully investigated in patients with a history of GIST.

Rapidly progressive stridor in a case of GIST.

We report the case of an 84-year-old male patient suffering from a gastrointestinal stromal tumour (GIST) of the rectum who was referred to our ENT (Ear-Nose-Throat) clinic for a rapidly progressive stridor, aphagia and dysphonia. The clinical examination revealed a mass arising from the posterior wall of the pharynx, which obstructed the laryngeal inlet and thus the airway. A metastasis of the GIST was suspected. After completing the investigation with radiological imaging, the patient underwent surgery, which consisted of a tracheostomy to secure the airway and a biopsy of the mass. The pathological examination confirmed the suspected diagnosis of a GIST vertebral metastasis.

Gastrointestinal Stromal Tumor Incidentally Detected on 18F-Fluciclovine PET/CT.

ABSTRACT: We present a case of metastatic gastrointestinal stromal tumor incidentally detected on 18F-fluciclovine PET/CT. A 68-year-old man with history of intermediate-risk prostate cancer (Gleason score 4 + 3 = 7; pT2cN0M0) previously treated with retropubic radical prostatectomy, adjuvant whole pelvis radiation, and androgen deprivation therapy (leuprolide) presented with slowly rising serum prostate-specific antigen over 3 years, concerning for recurrent prostate cancer. To identify potential sites of recurrent disease, an 18F-fluciclovine PET/CT was obtained. Multiple tracer-avid mesenteric masses and enlarged lymph nodes were found throughout the abdomen and pelvis, later biopsy-proven to reflect metastatic gastrointestinal stromal tumor.

Financial Implications of Avapritinib for Treatment of Unresectable Gastrointestinal Stromal Tumors in Patients With a PDGFRA Exon 18 Variant or After 3 Previous Therapies in a Hypothetical US Health Plan.

Importance: With the approval of avapritinib for adults with unresectable or metastatic gastrointestinal stromal tumors (GISTs) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 variant, including PDGFRA D842V variants, and National Comprehensive Cancer Network guideline recommendations as an option for patients with GIST after third-line treatment, it is important to estimate the potential financial implications of avapritinib on a payer's budget. Objective: To estimate the budget impact associated with the introduction of avapritinib to a formulary for metastatic or unresectable GISTs in patients with a PDGFRA exon 18 variant or after 3 or more previous treatments from the perspective of a US health plan. Design, Setting, and Participants: For this economic evaluation, a 3-year budget impact model was developed in March 2020, incorporating costs for drug acquisition, testing, monitoring, adverse events, and postprogression treatment. The model assumed that avapritinib introduction would be associated with increased PDGFRA testing rates from the current 49% to 69%. The health plan population was assumed to be mixed 69% commercial, 22% Medicare, and 9% Medicaid. Base case assumptions included a GIST incidence rate of 9.6 diagnoses per million people, a metastatic PDGFRA exon 18 mutation rate of 1.9%, and progression rate from first-line to fourth-line treatment of 17%. Exposures: The model compared scenarios with and without avapritinib in a formulary. Main Outcomes and Measures: Annual, total, and per member per month (PMPM) budget impact. Results: In a hypothetical 1-million member plan, fewer than 0.1 new patients with a PDGFRA exon 18 variant per year and 1.2 patients receiving fourth-line therapy per year were eligible for treatment. With avapritinib available, the total increase in costs in year 3 for all eligible adult patients with a PDGFRA exon 18 variant was $46 875, or $0.004 PMPM. For patients undergoing fourth-line treatment, the total increase in costs in year 3 was $69 182, or $0.006 PMPM. The combined total budget impact in year 3 was $115 604, or $0.010 PMPM, including an offset of $3607 in postprogression costs avoided or delayed. The higher rates of molecular testing resulted in a minimal incremental testing cost of $453 in year 3. Conclusions and Relevance: These results suggest that adoption of avapritinib as a treatment option would have a minimal budget impact to a hypothetical US health plan. This would be primarily attributable to the small eligible patient population and cost offsets from reduced or delayed postprogression costs.

[Significance of surgical treatment for recurrent and metastatic gastrointestinal stromal tumors].

In patients with recurrent or metastatic gastrointestinal stromal tumor (GIST), imatinib is the mainstay treatment, which has significantly improved outcome. However, approximately half of patients who have initial respose to imatinib will develop secondary resistance within 2 years, leading to progressive disease. Available data suggest that cytoreductive surgery may be considered in patients with metastatic GIST who respond to imatinib and have relatively low tumor burden, particularly in whom a R0/R1 resection is anticipated. The evidence of benefit from surgery in patients with focal tumor progression on imatinib is limited, but after surgical resection of progressive lesions, shifting to second line therapy should be initiated. Patients with multifocal progression are not suitable for surgical intervention. In the meantime, surgery for patients treated with sunitinib is feasible, yet survival benefit remains controversial. Thus, surgery should be considered in patients with metastatic GIST whose disease responds to imatinib with a goal of performing R0/R1 resection. On a case-by-case basis, surgical intervention should be determined after careful multidisciplinary consultation to achieve safety, improvement of symptoms and long-term survival benefits.

[Past and present of risk stratification of gastrointestinal stromal tumors and its clinical value].

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma in the gastrointestinal tract. Biological behavior of GIST is varied. It is very important to accurately assess the risk of recurrence and metastasis after resection of primary tumor in order to guide adjuvant therapy and predict prognosis. With increasing understanding of the biological behavior of GIST, the risk stratification criterion has undergone continuous reform and improvement since its introduction. In the early stage, clinical parameters such as tumor size and mitotic rate were formulated as risk stages, and then tumor site, tumor rupture and other factors were included to form a more accurate AFIP standard and modified NIH risk stratification. Recently, more researches have used new statistical methods such as nomogram and contour maps, which more accurately predict risk of recurrence and better guide adjuvant treatment. Thus, individualized treatment of GIST becomes possible.

Surgically treated gastric melanoma of unknown primary: A case report from a 10-year survivor.

We describe an extremely rare case of simultaneous double melanoma of the stomach with no other obvious primary source. The patient has survived for more than 12 years post-complete gastrectomy. The patient was a woman in her seventies who was referred for anemia by another clinic. Esophagogastroscopy revealed an ulcerated gastric tumor that was diagnosed as a gastrointestinal stromal tumor (GIST) by endoscopic biopsy. She was admitted to our hospital for further examination and treatment. Gastroscopy at our institution revealed two submucosal tumors in the gastric wall. Since no metastatic lesions were detected after systemic exploration, multiple GIST of the stomach was diagnosed, and a total gastrectomy was performed. Malignant melanoma was diagnosed in both lesions by a histopathological study of the resected stomach. The patient's postoperative progress was good, and thorough examination of the skin did not result in the discovery of any systemic neoplastic lesions which could be regarded as the source for the primary tumor. No anticancer treatments were used. The patient has survived, with no recurrence for over ten years postsurgery. Strong evidence is presented in this case for the diagnosis and treatment of gastric malignant melanoma.

[Case of Peritoneal Dissemination from Gastrointestinal Stromal Tumor of Jejunum Treated with Repeated Non-Curative Surgery].

A 71-year-old male presented with abdominal distension and fever to our hospital. Abdominal CT revealed a huge tumor in abdomen, and non-curative surgery was performed. Peritoneal dissemination was widespread and the tumor invaded the bladder and sigmoid-colon mesenterium. Two months after the initial surgery, CT showed liver metastasis, and oral administration of imatinib mesylate was started. The peritoneal dissemination and liver metastasis showed a decrease, and this was well controlled for 45 months without severe side effects. Abdominal CT revealed peritoneal dissemination in the ileocecum after 43 months since the administration of imatinib. Therefore, sunitinib treatment was initiated. After 3 months of sunitinib administration, the tumor perforated. Emergency operation was performed to resect the ileocecum, and sunitinib was continued for 1 year. In GIST with liver metastasis and peritoneal dissemination, repeated surgical resection combined with chemotherapy is important to improve the patient's survival.

Activity and safety of the multi-target tyrosine kinase inhibitor cabozantinib in patients with metastatic gastrointestinal stromal tumour after treatment with imatinib and sunitinib: European Organisation for Research and Treatment of Cancer phase II trial 1317 'CaboGIST'.

BACKGROUND: Gastrointestinal stromal tumour (GIST) is commonly treated with tyrosine kinase inhibitors (TKIs), but most patients ultimately develop secondary resistance. Cabozantinib, a multi-targeted TKI inhibitor, has activity in patient-derived GIST mouse xenograft models and can overcome compensatory MET signalling occurring on TKI treatment. European Organisation for Treatment of Cancer (EORTC) 1317 'CaboGIST' assessed the safety and activity of cabozantinib in patients with GIST who had progressed on imatinib and sunitinib. METHODS: In this multi-center, open label, single arm phase II study, eligible GIST patients received oral cabozantinib (60 mg) once daily. Primary end-point was the progression-free survival rate at 12 weeks assessed by the local investigator per Response Evaluation Criteria in Solid Tumours 1·1. If at least 21 of the first 41 eligible and evaluable patients were progression-free at week 12, the activity of cabozantinib was sufficient to warrant further exploration according to the A'Hern one-stage study design. FINDINGS: A total of 50 eligible patients started treatment between 02/2017 and 08/2018, including four (8%) still continuing cabozantinib at clinical cut-off (09/2019). The number of 3-weekly treatment cycles ranged from 1 to 30. Among the first 41 eligible and evaluable patients, 24 were progression-free at week 12 (58·5%, 95% confidence interval [CI] 42·0-74·0%). Among all 50 patients, 30 were progression-free at week 12 (60%, 95% CI 45-74%). Seven patients achieved a partial response (14%, 95% CI 6-27%), and 34 had stable disease (68%, 95% CI 53-80%) as best response. Progression was seen in eight patients (16%, 95% CI 7-29%), and one was not evaluable. Disease control was achieved in 41 patients (82%, 95% CI 69-91%). Median progression-free survival was 5·5 months (95% CI 3·6-6·9). The most common adverse events were diarrhoea (76%), palmar-plantar erythrodysesthesia syndrome (60%), fatigue (50%), hypertension (42%), weight loss (40%) and oral mucositis (30%), with 32 (64%) patients requiring dose reductions, 27 (54%) having treatment interruptions and no cabozantinib-related deaths observed. INTERPRETATION: EORTC 1317 met its primary end-point, with 24/41 patients being progression-free at week 12 of treatment. The objective response was 14% with an encouraging disease control rate of 82%. Results of this trial confirm preclinical findings and warrant further exploration of cabozantinib in GIST. CLINICAL TRIAL NUMBERS: EORTC 1317, NCT02216578, EudraCT 2014-000501-13.