From one-size-fits-all to customized treatment of gastric cancer: subgroup analyses of the CRITICS
Marcel Verheij,
The Netherlands
PD-0891
Abstract
From one-size-fits-all to customized treatment of gastric cancer: subgroup analyses of the CRITICS
Authors: Marcel Verheij1, Astrid Slagter2, Irene Caspers3, Karolina Sikorska4, Cornelis van de Velde5, Elma Meershoek-Klein Kranenbarg5, Johanna van Sandick6, Edwin Jansen2, Hanneke van Laarhoven7, Nicole van Grieken8, Annemiek Cats3
1Radboud University Medical Center, Radiation Oncology, Nijmegen, The Netherlands; 2Netherlands Cancer Institute, Radiation Oncology, Amsterdam, The Netherlands; 3Netherlands Cancer Institute, Gastrointestinal Oncology, Amsterdam, The Netherlands; 4Netherlands Cancer Institute, Biometrics, Amsterdam, The Netherlands; 5Leiden University Medical Center, Surgical Oncology, Leiden, The Netherlands; 6Netherlands Cancer Institute, Surgery, Amsterdam, The Netherlands; 7Amsterdam University Medical Center, Medical Oncology, Amsterdam, The Netherlands; 8Amsterdam University Medical Center, Pathology, Amsterdam, The Netherlands
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Purpose or Objective
Current treatment strategies do not fully acknowledge biological and molecular differences at the patient and tumor level that impact on outcome. The identification of specific subgroups that respond differently to treatment may guide future trial design. Post-hoc analyses of the CRITICS gastric cancer (GC) trial were performed to reveal such subgroups.
Material and Methods
The CRITICS trial randomized 788 pts to preop chemotherapy (CT) and surgery followed by either CT or chemoradiotherapy. Intention-to-treat analysis showed no difference in survival. Post-hoc analyses focused on (1) age (≥70 vs <70 yrs), (2) gender stratified by histological subtype (intestinal vs diffuse), (3) molecular subgroups (EBV+, MSI-high, EBV−/MSS).
Results
(1) Age: 172 (22%) were older pts. During preop CT, 77% older vs 62% younger pts developed severe toxicity (p<0.001). Similar proportions of older vs younger pts underwent curative surgery (81%) with comparable postop complications and mortality. Postop therapy started in 64% older vs 78% younger pts (p<0.001). Survival was not different.
(2) Gender: Female sex was associated with distal tumor localization in both histological subtypes and younger age in diffuse type GC. (Near-)complete histopathological response was achieved in 142 (24%) males vs 17 (29%) females (p=0.464) with intestinal type and in 11 (8%) males vs 15 (16%) females (p=0.077) with diffuse type. Tumor-positive resection margins were more common in females (22%) vs males (12%) with diffuse type (p=0.032). During preop CT, severe toxicity occurred in 327 (63%) males and 184 (71%) females (p=0.015). Survival was significantly longer in pts with intestinal vs diffuse type (p<0.001), but not different between sexes.
(3) Molecular subgroups: 5-yr cancer-specific survival was 69.8% in 25 pts with EBV+, 51.7% in 27 pts with MSI-high and 38.6% in 402 pts with EBV-/MSS tumors. Remarkably, the favorable outcome of MSI-high tumors was entirely attributable to women. All 3 MSI-high tumors with moderate/complete histopathological response (3/27, 11.1%) had substantial mucinous differentiation. No EBV+ tumors had a mucinous phenotype. 115/402 (28.6%) of EBV-/MSS tumors had moderate/complete response, of which 23/115 (20.0%) had a mucinous phenotype.
Conclusion
(1) Postoperative treatment compliance was poorer in older vs younger pts. As comparable proportions of pts underwent curative surgery, future studies should focus on neoadjuvant treatment. The ongoing CRITICS-II trial addresses this strategy. (2) Tumor-positive resection margins were higher in females vs males with diffuse type GC. CT-related toxicity was more often seen in females. Stratified for histological subtype, gender did not affect survival. Future studies should be powered and stratified for gender and histological subtype. (3) Women with MSI-high tumors had favorable outcome compared to EBV-/MSS. Major response was limited to mucinous MSI-high tumors. The mucinous phenotype might be a relevant parameter in future trials for MSI-high pts.