Feasibility and Timing of Cytoreduction Surgery in Advanced (Metastatic or Recurrent) Gastrointestinal Stromal Tumors During the Era of Imatinib.
ABSTRACT: The prognosis of advanced gastrointestinal stromal tumors (GISTs) was dramatically improved in the era of imatinib. Cytoreduction surgery was advocated as an additional treatment for advanced GISTs, especially when patients having poor response to imatinib or developing resistance to it. However, the efficacy and benefit of cytoreduction were still controversial. Likewise, the sequence between cytoreduction surgery and imatinib still need evaluation. In this study, we tried to assess the feasibility and efficiency of cytoreduction in advanced GISTs. Furthermore, we analyzed the impact of timing of the cytoreduction surgery on the prognosis of advanced GISTs. We conducted a prospective collecting retrospective review of patients with advanced GISTs (metastatic, unresectable, and recurrent GISTs) treated in Chang Gung memorial hospital (CGMH) since 2001 to 2013. We analyzed the impact of cytoreduction surgery to response to imatinib, progression-free survival (PFS), and overall survival (OS) in patients with advanced GISTs. Moreover, by the timing of cytoreduction to imatinib, we divided the surgical patients who had surgery before imatinib use into early group and those who had surgery after imatinib into late. We compared the clinical response to imatinib, PFS and OS between early and late cytoreduction surgical groups. Totally, 182 patients were enrolled into this study. Seventy-six patients underwent cytoreduction surgery. The demographic characteristics and tumor presentation were similar between surgical and non-surgical groups. The surgical group showed better complete response rate (P < .001) and partial response rate (P = 0.008) than non-surgical group. The 1-year, 3-year, and 5-year PFS were significantly superior in surgical group (P = 0.003). The 1-year, 3-year, and 5-year OS were superior in surgical group, but without statistical significance (P = 0.088). Dividing by cytoreduction surgical timing, the demographic characteristics and tumor presentation were comparable in early and late groups. The late cytoreduction group presented higher R0 resection rate (59.1% vs 31.5%, P = 0.025). However, the PFS and OS were comparable in both groups.Combining imatinib with cytoreduction increased the response rate to imatinib and prolonged PFS in patients with advanced GISTs. Moreover, early and late cytoreduction surgery was comparable in prognosis, although late cytoreduction revealed higher complete resection rate.
Project description:Gastrointestinal stromal tumors (GISTs) of the colon and rectum are the most common mesenchymal tumors of the gastrointestinal tract. GISTs of the colon and rectum constitute ~5% of all cases. Although colorectal GISTs can be small and found incidentally, the majority appear to be high risk and carry a significant likelihood of recurrent and metastatic disease. Surgery remains the mainstay of treatment for primary disease. There is now considerable interest in GISTs because they can be treated effectively with targeted molecular therapies, specifically tyrosine kinase inhibitors (TKIs), such as imatinib mesylate and sunitinib malate. GISTs are best treated by a multidisciplinary team comprised of the surgeon, medical oncologist, pathologist, and radiologist in the initial evaluation, management, and in continued follow-up. Increasing the number of resectable cases through pharmacologic debulking, optimizing the timing of surgery and organ preservation, reducing recurrence and surgical morbidity, prolonging survival, and possibly enhancing response to imatinib through surgical cytoreduction are all potential benefits of multidisciplinary management.
Project description:Background The benefit of surgical resection for advanced gastrointestinal stromal tumors (GISTs) following tyrosine kinase inhibitors (TKIs) treatment was still under debate. The present meta-analysis was designed to assess the value of surgical resection for the prognosis of patients with metastatic, recurrence and unresectable GISTs. Methods A systematic search of PubMed Central, PubMed, EMBASE and the Cochrane Library database was performed. Relevant studies of the role of surgery in advanced GISTs published before 1 May 2019 were identified. The quality of studies was assessed by the Newcastle-Ottawa Quality Assessment Scale. The progression-free survival (PFS) and overall survival (OS) were assessed through software Stata 15.0. Results A total of 6 retrospective studies including 655 patients were analyzed. The pooled result revealed that surgical resection group was associated with better PFS (HR = 2.08; 95% CI: 1.58 to 2.76; P<0.001) and better OS (HR = 2.13; 95% CI: 1.59 to 2.85; P<0.001) compared with TKIs treatment alone group. Conclusions Surgical resection following TKIs treatment could significantly improve the prognosis of patients with advanced GISTs.
Project description:BACKGROUND:Preoperative imatinib mesylate therapy for gastrointestinal stromal tumors (GISTs) is controversial. This study aimed to explore the clinical efficacy and optimal duration of preoperative imatinib mesylate (IM) therapy in patients with locally advanced and recurrent/metastatic GISTs. METHODS:We retrospectively examined patients who received preoperative imatinib mesylate therapy from January 2013 to December 2018 at Xiangya Hospital, Central South University and the Second Xiangya Hospital of Central South University, China. Clinical data, including the results of tests for mutations in KIT and PDGFR, findings from regularly conducted re-examinations, abdominal-enhanced computed tomography/magnetic resonance imaging data, responses to imatinib, progression-free survival, and overall cancer-specific survival, were recorded. RESULTS:A total of 25 patients were enrolled in our study, including 18 with a locally advanced GIST and 7 with recurrent or metastatic GISTs. Their ages ranged from 22 to 70?years (M:F = 1.6:0.9), with a mean age of 50.48 ± 12.51?years. The tumor locations included the stomach (56.0%), rectum (16.0%), enterocoelic/retroperitoneal sites (12.0%), and the small intestine (12.0%). Based on testing for mutations in KIT and PDGFR, 22 patients received 400?mg/day KIT, and 3 patients received 600?mg/day PDGFR. The median duration of preoperative IM therapy was 8.96 ± 4.81?months, ranging from 3 to 26?months. According to the Choi criteria, 24 patients achieved a partial response (PR), and 1 patient had stable disease (SD). All patients underwent surgery after preoperative IM therapy, and no postoperative complications appeared. The 2-year PFS and 5-year PFS were 92% and 60%, respectively, and the total 5-year cancer-specific survival (CSS) was 92%. CONCLUSION:Preoperative imatinib therapy is feasible for locally advanced and recurrent/metastatic GISTs and can effectively shrink the tumor size, allow organ sparing, and avoid extensive organ resection. Moreover, the optimal duration of preoperative IM therapy in patients with locally advanced and recurrent/metastatic GISTs was 8.96 ± 4.81?months, ranging from 3 to 26?months, and gastric GISTs had a better response to preoperative IM therapy than did non-gastric GISTs.
Project description:OBJECTIVES:To assess complete gross resection (CGR) rates and survival outcomes in patients with advanced ovarian cancer who underwent primary debulking surgery (PDS) during a 13-year period in which specific changes to surgical paradigm were implemented. METHODS:We identified all patients with stage IIIB-IV high-grade ovarian carcinoma who underwent PDS at our institution, with the intent of maximal cytoreduction, from 1/2001-12/2013. Patients were categorized by year of PDS based on the implementation of surgical changes to our approach to ovarian cancer debulking (Group 1, 2001-2005; Group 2, 2006-2009; Group 3, 2010-2013). RESULTS:Among 978 patients, 78% had stage IIIC disease and 89% had disease of serous histology. Carcinomatosis was found in 81%, and 60% had bulky upper abdominal disease (UAD). Compared to Group 1, those who underwent PDS during the latter 2 time periods had higher ASA scores (p?<?0.001), higher-stage disease (p?<?0.001), and more often had carcinomatosis (p?=?0.015) and bulky UAD (p?=?0.009). CGR rates for Groups 1-3 increased from 29% to 40% to 55%, respectively (p?<?0.001). Five-year progression-free survival (PFS) rates increased over time (15%, 16%, and 20%, respectively; p?=?0.199), as did 5-year overall survival (OS) rates (40%, 44%, and 56%, respectively; p?<?0.001). On multivariable analysis, CGR was independently associated with PFS (p?<?0.001) and OS (p?<?0.001). CONCLUSIONS:Despite higher-stage disease and greater tumor burden, CGR rates, PFS and OS for patients who underwent PDS increased over a 13-year period. Surgical paradigm shifts implemented specifically to achieve more complete surgical cytoreduction are likely the reason for these improvements.
Project description:The prognostic significance of pelvic and para-aortic lymphadenectomy during primary debulking surgery for advanced-stage ovarian cancer remains unclear. This study aimed to evaluate the survival impact of lymph node dissection (LND) in patients treated with optimal cytoreduction for advanced ovarian cancer. Data from 158 consecutive patients with stage IIIC-IV disease who underwent optimal cytoreduction (<1 cm) were obtained via retrospective chart review. Patients were classified into two groups: (1) lymph node sampling (LNS), node count <20; and (2) LND, node count ?20. Progression-free (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Among the included patients, 96 and 62 patients underwent LND and LNS as primary debulking surgery, respectively. There were no differences in the extent of debulking surgical procedures, including extensive upper abdominal surgery, between the groups. Patients who underwent LND had a marginally significantly improved PFS (P = 0.059) and significantly improved OS (P < 0.001) compared with those who underwent LNS. In a subgroup with negative lymphadenopathy on preoperative computed tomography scans, revealed LND correlated with a better PFS and OS (P = 0.042, 0.001, respectively). Follow-ups of subsequent recurrences observed a significantly lower nodal recurrence rate among patients who underwent LND. A multivariate analysis identified LND as an independent prognostic factor for PFS (hazard ratio [HR], 0.629; 95% confidence interval [CI], 0.400-0.989) and OS (HR, 0.250; 95% CI, 0.137-0.456). In conclusion, systematic LND might have therapeutic value and improve prognosis for patients with optimally cytoreduced advanced ovarian cancer.
Project description:OBJECTIVE:To refine treatment recommendations for patients with metastatic gastrointestinal stromal tumors (GISTs) treated with tyrosine kinase inhibitors (TKIs) and surgery. BACKGROUND:Early reports suggested that patients with metastatic GIST responding to TKIs treated with surgery may have favorable outcomes. However, identification of prognostic factors was limited by small cohorts. METHODS:Progression-free survival (PFS) and overall survival (OS) from time of surgery and from start of initial TKI was determined. Multivariate analysis was conducted on all patients undergoing GIST metastasectomy between 2001 and 2014 at 2 institutions. RESULTS:We performed 400 operations on 323 patients with metastatic GIST on TKIs. Radiographic response at time of surgery was classified as responsive disease (RD, n = 64, 16%), stable disease (SD, n = 100, 25%), unifocal progressive disease (UPD, n = 132, 33%), and multifocal progressive disease (MPD, n = 104, 26%). For patients on imatinib before surgery, radiographic response was predictive of PFS from time of surgery (RD 36 months, SD 30 months, UPD 11 months, MPD 6 months; P < 0.001) and from imatinib initiation (RD 71 months, SD 51 months, UPD 47 months, MPD 33 months; P < 0.001). Radiographic response was predictive of OS from time of surgery (RD not reached, SD 110 months, UPD 59 months, MPD 24 months; P < 0.001), and from imatinib initiation (RD not reached, SD 144 months, UPD 105 months, MPD 66 months; P = 0.005). Radiographic response was not predictive of PFS/OS for patients on sunitinib. Metastatic mitotic index ?5/50 HPF, MPD, and R2 resection were prognostic of worse PFS/OS; primary mutation was not. CONCLUSIONS:Surgery in metastatic GIST patients in the absence of MPD on imatinib is associated with outcomes at least comparable with second-line sunitinib and may be considered in select patients.
Project description:Although imatinib mesylate (IM) has revolutionized the management of gastrointestinal stromal tumors (GISTs), drug resistance remains a challenge. Previous studies have shown that the expression of aurora kinase A (AURKA) predicts recurrence in patients with primary, surgically resected GISTs. The current study aimed to evaluate the significance of AURKA expression as an unfavorable prognostic marker for advanced GISTs, and provide evidence that AURKA could be a potential therapeutic target in GISTs. The prognostic significance of the expression of AURKA, along with other clinicopathological factors, was analyzed in a cohort of 99 IM-treated patients with advanced GISTs. The potential use of an inhibitor of AURKA as a therapeutic agent against GISTs was also tested in GIST cell lines. Among 99 enrolled patients, poor performance status, large tumor size, drug response, and AURKA overexpression were independent prognostic factors for poor progression-free survival (PFS). For overall survival (OS), only large tumor size and AURKA overexpression were identified as independent unfavorable factors. In an in vitro study, MLN8237, an AURKA inhibitor, inhibited growth of both IM-sensitive and IM-resistant GIST cells in a concentration-dependent manner, and exhibited synergistic cytotoxicity with IM in GIST cells. The inhibitory effect of MLN8237 in GIST cells could be attributed to the induction of G2/M arrest, apoptosis, and senescence. Our study shows that AURKA expression independently predicted poor PFS and OS in patients with advanced GISTs who were treated with IM. An AURKA inhibitor may have potential as a therapeutic agent for both IM-sensitive and IM-resistant GISTs.
Project description:BACKGROUND:Gastrointestinal stromal tumors (GISTs) are the most frequently diagnosed mesenchymal neoplasms of the gastrointestinal tract. Despite their biological and clinical heterogeneity, the majority of these tumors are positive for the receptor tyrosine kinase KIT and are driven by KIT- or platelet-derived growth factor receptor alpha (PDGFRA)-activating mutations. There are still uncertainties regarding their clinical and molecular characterization and the optimal treatment regimens, making it difficult to establish a universal treatment algorithm for these tumors. SUMMARY:From a clinical perspective, the main difference between GISTs and other gastrointestinal neoplasms is that the benign or malignant behavior of GISTs cannot be predicted from histopathology, but instead relies on empirically established scoring systems. Clinical data suggest that malignant potential may be an inherent quality of some GISTs rather than a feature acquired by the tumor during disease progression. Thus, some patients may require prolonged anti-tumor treatment even after complete surgical removal of the tumor. KEY MESSAGE:Although GISTs are the most frequently occurring mesenchymal neoplasms in the gastrointestinal tract, no universal treatment algorithms exist. This paper reviews the current evidence that guides the management of GISTs. PRACTICAL IMPLICATIONS:The management of localized GISTs involves the use of surgical resection, with the inclusion of preoperative tyrosine kinase inhibitor treatment for locally advanced, primarily unresectable tumors and for resectable cases requiring extensive surgery. Imatinib is also indicated as adjuvant therapy after complete surgical removal of GISTs with a high estimated risk of recurrence unless specific mutations conferring imatinib resistance are present. The optimal duration of adjuvant treatment is still controversial. For patients with metastatic imatinib-sensitive GISTs, imatinib constitutes the first-line standard treatment. Molecular characterization of the tumor (with respect to the PDGFRA and KIT genes) is mandatory prior to imatinib therapy. Sunitinib and regorafenib are established as alternative treatments for patients demonstrating generalized disease progression on imatinib. New tyrosine kinase inhibitors such as ponatinib and crenolanib as well as drugs targeting alternative pathways are currently under investigation. Surgery and locally ablative treatments may be indicated in some metastatic patients.
Project description:Gastrointestinal stromal tumors (GISTs) express the receptor tyrosine kinase KIT. Most GISTs have mutations in the KIT or PDGFRA gene, causing activation of tyrosine kinase. Imatinib, a tyrosine kinase inhibitor (TKI), is the first-line palliative treatment for advanced GISTs. Sunitinib was introduced for patients with mutations not responsive to imatinib. The aim was to compare the survival of patients with high-risk resected GISTs treated with TKI prior to surgery with historical controls and to determine if organ-preserving surgery was facilitated.Ten high-risk GIST-patients had downsizing/adjuvant TKI treatment: nine with imatinib and one with sunitinib. The patients were matched with historical controls (n = 89) treated with surgery alone, from our population-based series (n = 259). Mutational analysis of KIT and PDGFRA was performed in all cases. The progression-free survival was calculated.The primary tumors decreased in mean diameter from 20.4 cm to 10.5 cm on downsizing imatinib. Four patients with R0 resection and a period of adjuvant imatinib had no recurrences versus 67% in the historical control group. Four patients with residual liver metastases have stable disease on continuous imatinib treatment after surgery. One patient has undergone reoperation with liver resection. The downsizing treatment led to organ-preserving surgery in nine patients and improved preoperative nutritional status in one patient.Downsizing TKI is recommended for patients with bulky tumors with invasion of adjacent organs. Sunitinib can be used for patients in case of imatinib resistance (e.g., wild-type GISTs), underlining the importance of mutational analysis for optimal surgical planning.
Project description:Objective: to analyze the evolution of surgical techniques and strategies, and to determine their influence on the survival of patients with stage III or IV epithelial ovarian cancer (EOC). Methods: a retrospective data analysis was performed in two French tertiary cancer institutes. The analysis included clinical information, cytoreductive outcome (complete, optimal and suboptimal), definitive pathology, Overall Survival (OS), and Progression-Free Survival (PFS). Three surgical strategies were compared: Primary Cytoreductive Surgery (PCS), Interval Cytoreductive Surgery (ICS) after three cycles of Neo-Adjuvant Chemotherapy (NAC), and Final Cytoreductive Surgery (FCS) after at least six cycles of NAC. We analyzed four distinct time intervals: prior to 2000, between 2000 and 2004, between 2005 and 2009, and after 2009. Results: data from 1474 patients managed for International Federation of Gynecology and Obstetrics (FIGO) stages III (80%) or IV (20%) EOC were analyzed. Throughout the four time intervals, the rate of patients who were treated only medically increased significantly (10.1% vs. 22.6% p < 0.001). NAC treatment increased from 20.1% to 52.2% (p < 0.001). Complete resection rate increased from 37% to 66.2% (p < 0.001). Of our study population, 1260 patients (85.5%) underwent surgery. OS was longer in cases of complete cytoreduction (Hazard Ratio (HR) = 2.123 CI 95% [1.816-2.481] p < 0.001) but the surgical strategy itself did not affect median OS. OS was 44.9 months, 50.3 months, and 42 months for PCS, ICS, and FCS, respectively (p = 0.410). After adjusting for surgical strategies (PCS, ICS, and FCS), all patients with complete cytoreduction presented similar OS with no significant difference. However, PFS was three months shorter when FCS was compared to PCS (p < 0.001). Conclusion: In our 30 years' experience of EOC management, complete resection rate was the only independent factor that significantly improved OS and PFS, regardless of the surgical strategy.