Primary Resectable Gastrointestinal Stromal Tumors Research Articles

Advances in the research of the mechanism of secondary resistance to imatinib in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. At present, surgery is the first-line treatment for primary resectable GISTs; however, the recurrence rate is high. Imatinib mesylate (IM) is an effective first-line drug used for the treatment of unresectable or metastatic recurrent GISTs. More than 80% of patients with GISTs show significantly improved 5-year survival after treatment; however, approximately 50% of patients develop drug resistance after 2 years of IM treatment. Therefore, an in-depth research is urgently needed to reveal the mechanisms of secondary resistance to IM in patients with GISTs and to develop new therapeutic targets and regimens to improve their long-term prognoses. In this review, research on the mechanisms of secondary resistance to IM conducted in the last 5 years is discussed and summarized from the aspects of abnormal energy metabolism, gene mutations, non-coding RNA, and key proteins. Studies have shown that different drug-resistance mechanism networks are closely linked and interconnected. However, the influence of these drug-resistance mechanisms has not been compared. The combined inhibition of drug-resistance mechanisms with IM therapy and the combined inhibition of multiple drug-resistance mechanisms are expected to become new therapeutic options in the treatment of GISTs. In addition, implementing individualized therapies based on the identification of resistance mechanisms will provide new adjuvant treatment options for patients with IM-resistant GISTs, thereby delaying the progression of GISTs. Previous studies provide theoretical support for solving the problems of drug-resistance mechanisms. However, most studies on drug-resistance mechanisms are still in the research stage. Further clinical studies are needed to confirm the safety and efficacy of the inhibition of drug-resistance mechanisms as a potential therapeutic target.

Association between preoperative skeletal muscle mass depletion and poor relapse-free survival in patients with gastrointestinal stromal tumors after complete resection

ObjectivesThe aim of this study was to investigate the predictive effects of skeletal muscle mass (SMM) depletion on relapse risk in patients who had undergone complete surgical resection for primary resectable gastrointestinal stromal tumors (GISTs). MethodsThis retrospective study comprised 445 enrolled patients with primary resectable GISTs who had undergone surgical treatment between January 2013 and January 2021. The lumbar skeletal muscle index (SMI) was assessed using abdominal computed tomography images taken within 7 d preoperatively. Univariate and multivariate Cox regression analyses were performed to identify independent risk factors for nomogram construction. Predictive accuracy and discriminative ability were measured using the concordance index (C-index). ResultsThree- and 5-y relapse-free survival (RFS) rates for patients in the low SMI group were significantly worse than those in the high SMI group (81.3 and 75.4% versus 92.3 and 91.6%, respectively; P < 0.001). In stratification analysis using modified National Institutes of Health criteria, high-risk patients with low SMI showed significantly shorter RFS (P = 0.001). Multivariate analysis indicated that tumor size, tumor location, mitotic rates, the platelet-to-lymphocyte ratio, the prognostic nutritional index, and SMM depletion were independent prognostic factors for RFS (P < 0.05). These six variables were selected for nomogram construction, which showed superior discrimination with a C-index of 0.82. ConclusionsThere was a significant association between preoperative SMM depletion and a high risk for relapse in patients who had undergone complete resection for primary resectable GISTs, especially in patients with high-risk GIST. Our simple, practical, novel nomogram intuitively predicted RFS in these patients.

A Young Man with an Abnormal Chest X-ray

Gastrointestinal stromal tumors(GIST) are an uncommon neoplasms of the GI tract. We present a rare case of esophageal GIST in a previously healthy young male. A 30 year old male presented to the ED after waking up ith cough, eigastric pain, nausea and vomiting. A chest x- ray showed upper mediastinal widening. Contrast enhanced CT scan incshowed a posterior mediastinal mass. Transbronchial needle aspiration and biopsy of a subcarinal mass was performed which revealed necrotic tissuecand was not diagnostic. Repeat biopsy with right video assisted thoracic surgery was performed. Immunohistochemistry was positive for CD117. A repeat chest x-ray 3 months later revealed resolution of previously described mass. He remained well until 10 months after initial presentation when he presented with chest pain, back pain and dry cough. A chest CT revealed a recurrent 5 cm subcarinal density. Right thoracotomy and resection of the mass was performed. Pathology results showed GIST with high mitotic rate. Patient was started on Imatinib. Endoscopic ultrasound two months later showed a residual mass. Fine needle aspiration and biopsy was positive for GIST. He underwent esophagectomy. Histologic evaluation revealed high grade epithelioid GIST. Patient has been asymptomatic without recurrence since.Figure 1Figure 2Figure 3GISTs affect mainly older individuals. It occurs mainly in stomach and express KIT or cell surface marker cd117 in 85-90% of cases, which is a tyrosine kinase receptor. Initial patient evaluation is usually with CT scan. Radical surgery is the treatment of choice in primary resectable GISTs. Almost all are associated with a risk of recurrence with rate of 40-50%. Imatinib Mesylate, inhibitor of KIT Tyrosine Kinase is used as an adjuvant therapy to decrease the risk of post operative recurrence. High risk tumors have a risk of 66% recurrence, making it obvious that surgery alone is not sufficient to provide long term survival. It is also used as neoadjuvant in cases that complete surgical resection is impossible and also for reducing tumor size. Since patients with high risk GIST relapse within 2 years, the follow up should be adopted to tumor criteria. CTS in the technique of choice for follow up. Our patient is particularly unique because of the age of presentation and location of tumor. Immunohistochemistry for CD117 has a high value of specificity for GIST. Treatment is complete resection. Recurrence is mainly dependent on mitotic activity. Imatinib is a useful adjuvant.

Non-Exposed Endoscopic Wall-Inversion Surgery for Gastrointestinal Stromal Tumor of the Stomach: First Case Report in Korea.

Laparoscopic wedge resection of the stomach is a widely accepted treatment for primary resectable gastrointestinal stromal tumors (GISTs). However, it is difficult to determine the appropriate incision line from outside of the stomach, and many attempts have been made to avoid unnecessary resection of unaffected gastric tissues. Recently a technique called non-exposed endoscopic wall-inversion surgery (NEWS) was introduced to avoid exposure of GIST to the peritoneum. Here, we describe the first published case of NEWS for GIST of the stomach practiced in Korea.

The economic burden of gastrointestinal stromal tumor (GIST) recurrence in patients who have received adjuvant imatinib therapy

Objective:To estimate the economic burden of gastrointestinal stromal tumor (GIST) recurrence in patients who received imatinib adjuvant therapy.Methods:Data from the MarketScan and PharmMetrics databases between January 2000 and March 2013 were extracted. Patients who had received at least one diagnosis of GIST, had undergone a primary surgery for GIST, and had received at least one prescription for imatinib were included in the analysis. An algorithm was applied to identify those who had a subsequent GIST recurrence. Patients who experienced a recurrence and those who did not have a recurrence were compared for differences in healthcare utilization measures and healthcare costs within 6 months after the recurrence, while adjusting for potential confounding factors.Results:A total of 540 patients with primary resectable GIST who received imatinib adjuvant therapy were identified, including 444 (82.2%) patients who did not experience GIST recurrence and 96 (17.8%) patients who did experience recurrence. Patients who experienced GIST recurrence utilized significantly more healthcare resources in all categories than patients who did not have a recurrence, including the number of hospitalizations, days of hospitalization, emergency room visits, outpatient visits, and other medical services (all p-values <0.01). The total healthcare cost was significantly higher for patients with GIST recurrence, with a difference of $4464 per patient per month (p < 0.01). Both the medical and pharmacy costs were significantly higher with adjusted differences of $3488 and $1423 per patient per month, respectively (both p-values <0.01).Conclusions:Patients who had GIST recurrence after surgical resection incurred significantly more healthcare resource utilization and greater healthcare costs within 6 months after the recurrence than patients who did not have recurrence. These findings suggest that GIST recurrence is associated with a substantial economic burden.

Prescribing decision drivers in patients with recurrent gastrointestinal stromal tumor (GIST) previously treated with adjuvant imatinib: A retrospective chart extract-based approach.

e21515 Background: Adjuvant imatinib (IM) is the standard of care for primary resectable GIST. However, little is known about prescribing habits following disease recurrence. This study identifies main prescribing decision drivers in recurrent GIST pts following completion of adjuvant IM treatment. Methods: Using an online data collection system, clinical information was retrieved on 410 pts treated with adjuvant IM for ≥6 months for primary resectable KIT+GIST, who discontinued IM treatment, had a recurrence (while off IM), and subsequently restarted IM or initiated sunitinib. Pt-level data were collected at primary diagnosis and at first recurrence. Prescribing decision drivers were identified using logistic regression models. Physicians were also surveyed to identify factors that influence their prescribing decisions. Results: Following initial disease recurrence, 77% of pts restarted IM and 23% initiated sunitinib. IM duration at primary diagnosis was the main prescribing decision driver; pts treated with IM for a shorter period of time (≤18 months) were 7.0 times more likely to restart IM than pts with longer IM duration (p&lt;.01). Pts who took longer (≥12 months) to develop recurrence after IM discontinuation (Odds ratio [OR]=3.4; p=&lt;.01 ), had a low mitotic rate at recurrence (OR=2.8; p=&lt;.01), or had a recurrence inside the gastrointestinal system (OR=2.7; p=&lt;.01) were also more likely to be prescribed IM following recurrence. These findings were consistent with the top survey responses on factors influential to prescribing decisions after recurrence: time to develop recurrence (55%), pt risk profile (53%), and IM duration prior to recurrence (51%). Conclusions: Based on information of pts who restarted IM or initiated sunitinib, IM treatment duration at primary diagnosis, time to develop recurrence after IM discontinuation, tumor location and mitotic rate at recurrence seem to be the main prescribing decision drivers. These findings were consistent with physicians’ main factors reported to influence their prescribing decisions following recurrence.

Comparison of the Long-Term Risk of Recurrence and Other Clinical Outcomes in GIST Patients Receiving Imatinib as Adjuvant Therapy—A Retrospective Chart Extract-Based Approach

PurposeTo compare characteristics of patients, the risk of recurrence, and mortality among adult patients with primary resectable gastrointestinal stromal tumor (GIST) receiving short-term (6–12 months) versus long-term (≥ 24 months) imatinib therapy.MethodsDetailed information on primary resectable KIT-positive GIST patients initiated on imatinib adjuvant therapy was retrospectively collected for short- and long-term imatinib patients from 318 US oncologists using an online data collection form. Patient characteristics were compared using Wilcoxon and Chi-square tests. Disease recurrence and mortality rates were compared using multivariate Cox proportional hazard models.ResultsAmong the 406 short-term and 406 long-term imatinib patients, the median follow-up was 916 and 970 days, respectively. While patients generally had similar demographic characteristics, the short-term group had a higher prevalence of cardiovascular and ischemic heart diseases and patients in the long-term group had a higher pre-surgery risk profile. This finding was consistent with the main reason reported by oncologists for prescribing adjuvant imatinib over longer duration, i.e., patient risk profile. Disease recurrence [5.9 versus 1.2 %, (p < .001)] and mortality rates [7.1 % versus 2.0 %, (p < .001)] were higher in short- versus long-term patients. The adjusted risk of recurrence was 5.30 times (p < .001) higher, and mortality risk was 4.02 times (p < .001) higher in short- versus long-term patients.ConclusionsPatient risk profile is an important factor in oncologists’ decisions to prescribe adjuvant imatinib. Despite the higher risk profile observed in long-term patients, the long-term use of imatinib was associated with a reduction in long-term risk of disease recurrence and mortality.

Phase II Trial of Neoadjuvant/adjuvant Imatinib Mesylate for Advanced Primary and Metastatic/recurrent Operable Gastrointestinal Stromal Tumors: Long-term Follow-up Results of Radiation Therapy Oncology Group 0132

Imatinib inhibits the KIT and PDGFR tyrosine kinases, resulting in its notable antitumor activity in gastrointestinal stromal tumor (GIST). We previously reported the early results of a multi-institutional prospective trial (RTOG 0132) using neoadjuvant/adjuvant imatinib either in primary resectable GIST or as a planned preoperative cytoreduction agent for metastatic/recurrent GIST. METHODS.: Patients with primary GIST (≥5 cm, group A) or resectable metastatic/recurrent GIST (≥2 cm, group B) received neoadjuvant imatinib (600 mg/day) for approximately 2 months and maintenance postoperative imatinib for 2 years. We have now updated the clinical outcomes including progression-free survival, disease-specific survival, and overall survival at a median follow-up of 5.1 years, and we correlate these end points with duration of imatinib therapy. Sixty-three patients were originally entered (53 analyzable: 31 in group A and 22 in group B). Estimated 5-year progression-free survival and overall survival were 57% in group A, 30% in group B; and 77% in group A, 68% in group B, respectively. Median time to progression has not been reached for group A and was 4.4 years for group B. In group A, in 7 of 11 patients, disease progressed >2 years from registration; 6 of 7 patients with progression had stopped imatinib before progression. In group B, disease progressed in 10 of 13 patients>2 years from registration; 6 of 10 patients with progressing disease had stopped imatinib before progression. There was no significant increase in toxicity compared with our previous short-term analysis. This long-term analysis suggests a high percentage of patients experienced disease progression after discontinuation of 2-year maintenance imatinib therapy after surgery. Consideration should be given to studying longer treatment durations in intermediate- to high-risk GIST patients.

Adjuvant imatinib therapy for gastrointestinal stromal tumors

Surgery is the standard of care for primary resectable gastrointestinal stromal tumors (GISTs), but half of surgically treated patients relapse. Imatinib (IM) has been shown to prolong recurrence-free survival after complete surgery and is now approved as adjuvant therapy (400 mg/day) for high-risk GIST patients. IM is well tolerated, with mild to moderate side effects observed. Whether adjuvant IM prolongs overall survival is under evaluation in two ongoing clinical trials.

Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): Long-term follow-up results of RTOG 0132.

10057 Background: Imatinib mesylate (IM), which inhibits the KIT and PDGFR tyrosine kinases, has known activity against GIST. We previously reported early results of the first reported multi-institutional prospective trial (RTOG 0132) using neoadjuvant imatinib mesylate (IM) either in primary resectable GIST or as a planned preoperative cytoreduction agent for metastatic GIST (Eisenberg et al., JSO 2009). Methods: Patients with primary GIST (≥5cm, Group A) or operable metastatic/recurrent GIST (≥2 cm, Group B) received neoadjuvant IM (600 mg/day) for approximately two months and maintenance IM after surgery for 2 years. We have now updated the clinical outcomes including progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS) at a median follow-up of 5.1 years and correlate these endpoints with duration of IM therapy. Results: Sixty-three patients were originally entered (53 analyzable), 31 patients in Group A and 22 in Group B. Estimated 5-year PFS and DSS were 57% A, 30% B; and 77% A, 77% B, respectively. Estimated 5-year OS was 77% for A, and 68% for B. Median time to progression has not been yet reached for Group A and is 4.4 years for Group B. In Cohort A, 7/11 patients progressed > 2 years from registration; 6/7 progressing patients had stopped IM prior to progression. In Cohort B, 10/13 patients progressed> 2 years from registration; 6/10 progressing patients had stopped IM prior to progression. The rate of treatment-related grade 4/5 toxicities was 23% (12/53). There was no increase in long term surgical complications using neoadjuvant and extended IM therapy. Conclusions: This long-term analysis of RTOG 0132 suggests a high percentage of patients progressed after discontinuation of 2-year maintenance IM therapy following surgical resection. Consideration should be given to studying longer treatment durations in high-risk GIST patients.

Gastrointestinal Stromal Tumors: Disease and Treatment Update

Gastrointestinal Stromal Tumors: Disease and Treatment Update

Gastrointestinal stromal tumors: from a surgical to a molecular approach.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. These tumors span a wide clinical spectrum from benign to malignant and have long been recognized for their nearly absolute resistance to chemotherapy and radiation treatment. We reviewed the worldwide experience on GIST diagnosis, prognosis and treatment and describe our own series. PubMed was searched for references using the terms gastrointestinal stromal tumor, GIST and gastrointestinal sarcoma. Recent reports were given emphasis because GIST is a novel clinical entity and older published work on gastrointestinal sarcomas might be contaminated with other histologic tumor types. At present, surgery is the standard treatment for primary resectable GIST. To increase the activity of conventional chemotherapeutic agents, locoregional therapies are being implemented in the clinical setting. A major breakthrough is the development of a new class of anticancer agents targeting tumor-specific molecular abnormalities. Preliminary results on administration of imatinib mesylate, a signal transduction inhibitor, are particularly encouraging, showing potent activity of this drug against metastatic GIST. Molecular targeting of the critical pathogenetic mechanism underlying GIST might not only revolutionize the strategy to treat locally advanced and metastatic GIST but also improve disease control after macroscopically radical surgery.