Summary Background Until now, only imatinib and sunitinib have proven clinical benefit in patients with gastrointestinal stromal tumours (GIST), but almost all metastatic GIST eventually develop ...resistance to these agents, resulting in fatal disease progression. We aimed to assess efficacy and safety of regorafenib in patients with metastatic or unresectable GIST progressing after failure of at least imatinib and sunitinib. Methods We did this phase 3 trial at 57 hospitals in 17 countries. Patients with histologically confirmed, metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib were randomised in a 2:1 ratio (by computer-generated randomisation list and interactive voice response system; preallocated block design (block size 12); stratified by treatment line and geographical region) to receive either oral regorafenib 160 mg daily or placebo, plus best supportive care in both groups, for the first 3 weeks of each 4 week cycle. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was progression-free survival (PFS). At disease progression, patients assigned placebo could crossover to open-label regorafenib. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01271712. Results From Jan 4, to Aug 18, 2011, 240 patients were screened and 199 were randomised to receive regorafenib (n=133) or matching placebo (n=66). Data cutoff was Jan 26, 2012. Median PFS per independent blinded central review was 4·8 months (IQR 1·4–9·2) for regorafenib and 0·9 months (0·9–1·8) for placebo (hazard ratio HR 0·27, 95% CI 0·19–0·39; p<0·0001). After progression, 56 patients (85%) assigned placebo crossed over to regorafenib. Drug-related adverse events were reported in 130 (98%) patients assigned regorafenib and 45 (68%) patients assigned placebo. The most common regorafenib-related adverse events of grade 3 or higher were hypertension (31 of 132, 23%), hand-foot skin reaction (26 of 132, 20%), and diarrhoea (seven of 132, 5%). Interpretation The results of this study show that oral regorafenib can provide a significant improvement in progression-free survival compared with placebo in patients with metastatic GIST after progression on standard treatments. As far as we are aware, this is the first clinical trial to show benefit from a kinase inhibitor in this highly refractory population of patients. Funding Bayer HealthCare Pharmaceuticals.
Summary Background The risk of recurrence of gastrointestinal stromal tumour (GIST) after surgery needs to be estimated when considering adjuvant systemic therapy. We assessed prognostic factors of ...patients with operable GIST, to compare widely used risk-stratification schemes and to develop a new method for risk estimation. Methods Population-based cohorts of patients diagnosed with operable GIST, who were not given adjuvant therapy, were identified from the literature. Data from ten series and 2560 patients were pooled. Risk of tumour recurrence was stratified using the National Institute of Health (NIH) consensus criteria, the modified consensus criteria, and the Armed Forces Institute of Pathology (AFIP) criteria. Prognostic factors were examined using proportional hazards and non-linear models. The results were validated in an independent centre-based cohort consisting of 920 patients with GIST. Findings Estimated 15-year recurrence-free survival (RFS) after surgery was 59·9% (95% CI 56·2–63·6); few recurrences occurred after the first 10 years of follow-up. Large tumour size, high mitosis count, non-gastric location, presence of rupture, and male sex were independent adverse prognostic factors. In receiver operating characteristics curve analysis of 10-year RFS, the NIH consensus criteria, modified consensus criteria, and AFIP criteria resulted in an area under the curve (AUC) of 0·79 (95% CI 0·76–0·81), 0·78 (0·75–0·80), and 0·82 (0·80–0·85), respectively. The modified consensus criteria identified a single high-risk group. Since tumour size and mitosis count had a non-linear association with the risk of GIST recurrence, novel prognostic contour maps were generated using non-linear modelling of tumour size and mitosis count, and taking into account tumour site and rupture. The non-linear model accurately predicted the risk of recurrence (AUC 0·88, 0·86–0·90). Interpretation The risk-stratification schemes assessed identify patients who are likely to be cured by surgery alone. Although the modified NIH classification is the best criteria to identify a single high-risk group for consideration of adjuvant therapy, the prognostic contour maps resulting from non-linear modelling are appropriate for estimation of individualised outcomes. Funding Academy of Finland, Cancer Society of Finland, Sigrid Juselius Foundation and Helsinki University Research Funds.
Abstract Background Laparoscopic gastrectomy (LG) is reported to be associated with faster recovery than open gastrectomy (OG); however, the influence of the surgical approach on initiation timing of ...adjuvant chemotherapy (AC) remains unclear. Methods This was a single-institutional retrospective observational study. Patients with pathological stage II/III gastric cancer undergoing LG with D2 lymphadenectomy (LG group: n=74) were matched 1:1 with patients selected from 214 similar patients undergoing OG (OG group: n=74), identically matching gender, age, pathological stage, and type of gastrectomy, and comparing AC initiation timing between the two groups. Factors associated with delayed initiation of AC were investigated in a multivariable analysis. Results AC was performed in 86.5% (LG) and 83.8% (OG) of patients ( p= 0.64). The median time interval before AC was significantly shorter in the LG vs. OG group (5.7 vs. 6.6 weeks, respectively, p <0.001), and significantly more patients received AC within 6 weeks (60.8% vs. 27.0%, p <0.001). Independent factors associated with delayed initiation of AC (>6 weeks) were: morbidity (≥grade 3a; odds ratio (OR): 16.1, 95% confidence interval (CI): 1.86–143), open surgery (OR: 5.17, 95% CI: 2.50–13.1), and postoperative weight loss ≥ 8% (OR: 2.47, 95% CI: 1.07–5.71). Conclusions LG may be associated with shorter intervals before AC. Postoperative morbidity should be reduced as much as possible.
Background Peritoneal dissemination is frequently found during laparotomy in patients with serosa-invading gastric cancer. Detection of exfoliated cancer cells in abdominal lavage cytology is ...indicative of stage IV because of its strong association with peritoneal dissemination. Herein we have described peritoneal lavage cytology using a bedside procedure under local anesthesia. Methods A prospective study of 113 patients with serosa-invading gastric cancer but without peritoneal metastases was performed. A drainage tube was inserted into the abdominal cavity for peritoneal lavage. Patients with negative cytology (CY0) were scheduled for curative gastrectomy. Results The bedside procedure was performed safely without any complications. Lavage cytology identified CY1 in 35 (31.0%) patients and CY0 in 78 (69.0%) patients. Patients with CY0 underwent laparotomy and peritoneal lavage cytology, and 9 were found to have peritoneal disease (3 with operative CY1, 4 with peritoneal dissemination, and 2 with both operative CY1 and peritoneal dissemination). Two other patients had small, distant metastases. Finally, curative gastrectomy was achieved in 67 (59.3%) patients, but not in 46 (40.7%) patients. Thus, our bedside, pre-operative peritoneal lavage detected 76.1% (35/46) of noncurative disease before operative with a false-negative rate for detecting peritoneal disease of 20.5% (9/44). Patients with pre-operative CY1 had a poorer prognosis than pre-operative CY0 (2-year cause-specific survival 26.6% vs 82.6%). Conclusion Pre-operative bedside peritoneal lavage under local anesthesia followed by cytology is a simple and safe method for the pre-operative diagnosis of peritoneal dissemination and may help to reduce unexpected, noncurative surgery.
Background Natural orifice transluminal endoscopic surgery (NOTES) requires fast and steady CO2 insufflation into the intraluminal and intra-abdominal spaces through a flexible endoscope. However, an ...optimal endoscopic insufflation system has yet to be determined. Objective To verify the performances of 2 currently available CO2 insufflators in an experimental NOTES setting: (1) an automatic pressure-regulated surgical insufflator (UHI-3) and (2) a manual endoscopic insufflator (UCR). Design An inanimate bench study followed by an acute animal experiment. Setting Osaka University and Olympus Research and Development Department. Main Outcome Measurements The UHI-3 or UCR was connected to an endoscope of differing length and diameter via an insufflating line of differing length and diameter. The flow rates at the tip of the endoscope (bench test), the time to establish pneumoperitoneum, and the time to re-establish pneumoperitoneum after forceful suction (porcine model) were obtained. Results The UHI-3 failed to feed CO2 through an insufflating channel but fed CO2 via a working channel but required a large channel (>3 mm) and a wide insufflating line (>7 mm) to accomplish an acceptable flow rate. UCR fed CO2 through the insufflating channel; however, the time taken to establish pneumoperitoneum and the time taken to re-establish pneumoperitoneum after forceful suction were longer compared with the time taken for UHI-3 insufflation via the working channel or laparoscopic cannula. Limitations Bench/animal study with small sample numbers; no human trial. Conclusions The currently available CO2 insufflators are not optimal for NOTES. Modification of an endoscopic insufflation system and/or development of a dedicated overtube with an insufflating function are therefore essential.
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