Patterns of Failure in Patients With Borderline Resectable/Locally Advanced Pancreatic Cancer After Preoperative Chemotherapy and Stereotactic Body Radiation Therapy.

Purpose: The role of preoperative stereotactic body radiation therapy (SBRT) in pancreatic cancer is controversial, and questions regarding the optimal dose and radiation treatment field remain. To better inform future investigations of SBRT dose and radiation fields, we evaluated the patterns of failure in patients with borderline resectable/locally advanced pancreatic cancer (BR/LAPC) after preoperative chemotherapy and SBRT in patients who underwent surgical resection. Methods and Materials: We performed a single-institution retrospective review of consecutive patients treated from September 2017 to January 2022 with BR/LAPC. Patients who underwent preoperative chemotherapy and SBRT followed by surgical resection were reviewed. SBRT was delivered to a dose of 33 Gy in 5 fractions. Kaplan-Meier overall survival and progression-free survival estimates were calculated. Results: In total, 18 patients (12 BRPC, 6 LAPC) were included. Median age was 69 years (range 41-84 years). Median follow-up was 30 months (range 13-59 months). Seventeen patients (94%) had a R0 resection and 13 (72%) underwent vascular reconstruction. Median overall survival and progression-free survival was 42 months (range 13-59 months) and 23 months (range 1-45 months), respectively. In total, 61% (11/18) patients experienced progression at any point during follow-up. Of the patients who experienced recurrence, 27% (3/11) experienced local progression as component of their first recurrence, whereas 100% (11/11) experienced distant progression as a component of their first recurrence. When examining all recurrences that occurred at any point in follow-up, 28% (5/18) of patients experienced local or locoregional recurrence and 61% (11/18) experienced distant progression. Conclusions: Local control and margin negative resection rates were excellent with preoperative chemotherapy and nondose-escalated SBRT in surgically resected patients with BR/LAPC. Distant recurrence was the predominant site of failure with lower incidences of isolated locoregional recurrences. Additional research is needed to determine the ideal treatment volume and patients who may benefit from dose escalation.

Role of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in the Management of Colorectal Peritoneal Metastases.

Peritoneal metastases from colon cancer are a particularly challenging disease process given the limited response to systemic chemotherapy. In patients with isolated peritoneal metastases, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy offers a potential treatment option to these patients with limited peritoneal metastases as long as a complete cytoreduction is achieved. Decision about a patient's candidacy for this treatment modality should be undertaken by a multidisciplinary group at expert centers.

Hepatic prohibitin 1 and methionine adenosyltransferase α1 defend against primary and secondary liver cancer metastasis.

BACKGROUND & AIMS: The liver is a common site of cancer metastasis, most commonly from colorectal cancer, and primary liver cancers that have metastasized are associated with poor outcomes. The underlying mechanisms by which the liver defends against these processes are largely unknown. Prohibitin 1 (PHB1) and methionine adenosyltransferase 1A (MAT1A) are highly expressed in the liver. They positively regulate each other and their deletion results in primary liver cancer. Here we investigated their roles in primary and secondary liver cancer metastasis. METHODS: We identified common target genes of PHB1 and MAT1A using a metastasis array, and measured promoter activity and transcription factor binding using luciferase reporter assays and chromatin immunoprecipitation, respectively. We examined how PHB1 or MAT1A loss promotes liver cancer metastasis and whether their loss sensitizes to colorectal liver metastasis (CRLM). RESULTS: Matrix metalloproteinase-7 (MMP-7) is a common target of MAT1A and PHB1 and its induction is responsible for increased migration and invasion when MAT1A or PHB1 is silenced. Mechanistically, PHB1 and MAT1A negatively regulate MMP7 promoter activity via an AP-1 site by repressing the MAFG-FOSB complex. Loss of MAT1A or PHB1 also increased MMP-7 in extracellular vesicles, which were internalized by colon and pancreatic cancer cells to enhance their oncogenicity. Low hepatic MAT1A or PHB1 expression sensitized to CRLM, but not if endogenous hepatic MMP-7 was knocked down first, which lowered CD4+ T cells while increasing CD8+ T cells in the tumor microenvironment. Hepatocytes co-cultured with colorectal cancer cells express less MAT1A/PHB1 but more MMP-7. Consistently, CRLM raised distant hepatocytes' MMP-7 expression in mice and humans. CONCLUSION: We have identified a PHB1/MAT1A-MAFG/FOSB-MMP-7 axis that controls primary liver cancer metastasis and sensitization to CRLM. IMPACT AND IMPLICATIONS: Primary and secondary liver cancer metastasis is associated with poor outcomes but whether the liver has underlying defense mechanism(s) against metastasis is unknown. Here we examined the hypothesis that hepatic prohibitin 1 (PHB1) and methionine adenosyltransferase 1A (MAT1A) cooperate to defend the liver against metastasis. Our studies found PHB1 and MAT1A form a complex that suppresses matrix metalloproteinase-7 (MMP-7) at the transcriptional level and loss of either PHB1 or MAT1A sensitizes the liver to metastasis via MMP-7 induction. Strategies that target the PHB1/MAT1A-MMP-7 axis may be a promising approach for the treatment of primary and secondary liver cancer metastasis.

Socioeconomic disparities in patients with small bowel neuroendocrine tumors.

BACKGROUND AND OBJECTIVES: Demographic and socioeconomic disparities affect cancer specific outcomes in numerous malignancies, but the impact of these for patients with small bowel neuroendocrine tumors (SBNETs) is not well understood. The primary objective was to investigate the impact of demographic and socioeconomic factors on overall survival (OS) for patients with SBNETs. METHODS: We performed a retrospective cohort study utilizing the National Cancer Database to assess patients diagnosed with SBNET between 2004 and 2015. Patients were stratified by demographics, socioeconomic factors, insurance status, and place of living. RESULTS: The 5-year OS for the entire cohort was 78.5%. The 5-year survival was worse in patients with lower income (p < 0.0001), lower education (p < 0.0001), not in proximity to a metro area (p = 0.0004), and treatment at a community cancer center (p < 0.0001). Adjusting for age and sex, factors associated with worse OS were lower income (<$38 000) (hazard ratio [HR]: 1.16, 95% confidence interval [CI]: 1.04-1.28), lower education (>20% no HSD) (HR: 1.14, 95% CI: 1.02-1.26), no insurance (HR: 1.66, 95% CI: 1.33-2.06), and not living in proximity to a metro area (HR: 1.27, 95% CI: 1.10-1.47). CONCLUSIONS: Patient demographics and socioeconomic factors play an important role in survival of patients with SBNETs, specifically proximity to a metro area, median income, education level, and type of treatment center. Strategies to improve access to care must be considered in this at-risk population.

Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline.

PURPOSE: To develop recommendations for systemic therapy for well-differentiated grade 1 (G1) to grade 3 (G3) metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). METHODS: ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS: Eight randomized controlled trials met the inclusion criteria for the systematic review. RECOMMENDATIONS: Somatostatin analogs (SSAs) are recommended as first-line systemic therapy for most patients with G1-grade 2 (G2) metastatic well-differentiated GI-NETs. Observation is an option for patients with low-volume or slow-growing disease without symptoms. After progression on SSAs, peptide receptor radionuclide therapy (PRRT) is recommended as systematic therapy for patients with somatostatin receptor (SSTR)-positive tumors. Everolimus is an alternative second-line therapy, particularly in nonfunctioning NETs and patients with SSTR-negative tumors. SSAs are standard first-line therapy for SSTR-positive pancreatic (pan)NETs. Rarely, observation may be appropriate for asymptomatic patients until progression. Second-line systemic options for panNETs include PRRT (for SSTR-positive tumors), cytotoxic chemotherapy, everolimus, or sunitinib. For SSTR-negative tumors, first-line therapy options are chemotherapy, everolimus, or sunitinib. There are insufficient data to recommend particular sequencing of therapies. Patients with G1-G2 high-volume disease, relatively high Ki-67 index, and/or symptoms related to tumor growth may benefit from early cytotoxic chemotherapy. For G3 GEP-NETs, systemic options for G1-G2 may be considered, although cytotoxic chemotherapy is likely the most effective option for patients with tumor-related symptoms, and SSAs are relatively ineffective. Qualifying statements are provided to assist with treatment choice. Multidisciplinary team management is recommended, along with shared decision making with patients, incorporating their values and preferences, potential benefits and harms, and other characteristics and circumstances, such as comorbidities, performance status, geographic location, and access to care.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

What Is the Role of Lymph Node Resections in Small Islet Tumors?

Well-differentiated nonfunctional pancreatic neuroendocrine tumors are often indolent neoplasms without lymph node (LN) metastasis at diagnosis. Patients with PNETs that are functional or >2 cm should have surgical resection as per the standard of care. However, in appropriately selected patients with NF PNETs <2 cm who are at low risk of LN metastasis, the extent of surgery and lymphadenectomy could be limited.

Contemporary Cancer Program Practice Profile Report Compliance Rates for Gastric Cancer: A National Cancer Database Analysis.

BACKGROUND: The Commission on Cancer (CoC) established quality measures to be reported in National Cancer Database (NCDB) Quality Reporting Tools. Compliance is provided to accredited cancer programs as Cancer Program Practice Profile Reports (CP3R). At the time of this study, the quality metric for gastric cancer (GC) was removal and pathologic examination of 15 regional lymph nodes for resected GC (G15RLN). OBJECTIVE: This study evaluates national trends in quality metric compliance for GC based on CoC CP3R. METHODS: The National Cancer Database (NCDB) was queried from 2004-2017 to identify patients with stage I-III GC who met criteria for inclusion. National trends in compliance were compared. Overall survival (OS) was compared stage for stage. RESULTS: Overall, 42 997 patients with GC qualified. In 2017, 64.5% of patients met compliance with G15RLN compared to 31.4% in 2004. When comparing academic and non-academic institutions, compliance was met 67.0% vs 60.0% of the time in 2017 (P < .01) and 36% vs 30.6% of the time in 2004 (P < .01). On multivariate logistic regression, patients receiving care at academic institutions (OR 1.5, 95% CI 1.4-1.5) and who underwent surgery at institutions in the >75th percentile for case volume (OR 1.5, 95% CI 1.4-1.6) had higher odds of compliance. When stratified by stage, median OS was better across all stages when compliance was met. CONCLUSION: Compliance rates with GC quality measures have improved over time. Compliance with the G15RLN metric is associated with improved OS, stage for stage. Continued efforts to improve compliance rates across all institutions are critical.

Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment.

Liver metastasis is a major cause of death in patients with colorectal cancer (CRC). Fatty liver promotes liver metastasis, but the underlying mechanism remains unclear. We demonstrated that hepatocyte-derived extracellular vesicles (EVs) in fatty liver enhanced the progression of CRC liver metastasis by promoting oncogenic Yes-associated protein (YAP) signaling and an immunosuppressive microenvironment. Fatty liver upregulated Rab27a expression, which facilitated EV production from hepatocytes. In the liver, these EVs transferred YAP signaling-regulating microRNAs to cancer cells to augment YAP activity by suppressing LATS2. Increased YAP activity in CRC liver metastasis with fatty liver promoted cancer cell growth and an immunosuppressive microenvironment by M2 macrophage infiltration through CYR61 production. Patients with CRC liver metastasis and fatty liver had elevated nuclear YAP expression, CYR61 expression, and M2 macrophage infiltration. Our data indicate that fatty liver-induced EV-microRNAs, YAP signaling, and an immunosuppressive microenvironment promote the growth of CRC liver metastasis.

POLE-Mutant Colon Cancer Treated with PD-1 Blockade Showing Clearance of Circulating Tumor DNA and Prolonged Disease-Free Interval.

Colon cancer with high microsatellite instability is characterized by a high tumor mutational burden and responds well to immunotherapy. Mutations in polymerase ɛ, a DNA polymerase involved in DNA replication and repair, are also associated with an ultra-mutated phenotype. We describe a case where a patient with POLE-mutated and hypermutated recurrent colon cancer was treated with pembrolizumab. Treatment with immunotherapy in this patient also led to the clearance of circulating tumor DNA (ctDNA). ctDNA is beginning to emerge as a marker for minimal residual disease in many solid malignancies, including colon cancer. Its clearance with treatment suggests that the selection of pembrolizumab on the basis of identifying a POLE mutation on next-generation sequencing may increase disease-free survival in this patient.

The Evolving Landscape of Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) represent a heterogeneous group of tumors, with variable presentation based on the location of origin and degree of metastatic spread. There are no randomized control trials to guide surgical management; however, surgery remains the mainstay of treatment for most gastroenteropancreatic NETs based on retrospective studies. Metastatic disease is common at the time of presentation, particularly in the liver. There is a role for cytoreduction for improvement of both symptoms and survival. Robust prospective randomized data exists to support the use of medical therapies to improve progression-free and overall survival in patients with advanced, metastatic, and unresectable NETs.

Hyperthermic intraperitoneal chemotherapy for gastric cancer: a narrative review.

BACKGROUND AND OBJECTIVE: Gastric cancer (GC) is the 5th most common malignancy globally, and although there have been modest gains in improving survival rates, it remains a leading cause of death. A component contributing to the poor survival rates includes advanced disease stage at presentation. Approximately 30-40% of GC patients present with metastases at diagnosis, with poorer outcomes when peritoneal metastases are present. However, recent studies have demonstrated potential utility of hyperthermic intraperitoneal chemotherapy (HIPEC) for GC with peritoneal carcinomatosis (GCPC) and for prevention of peritoneal carcinomatosis in high-risk patients. HIPEC for GC is highly debated. It is currently not recommended as part of standard of care for GC. The objective of this study is to discuss the various factors influencing the success of HIPEC, current intraperitoneal (IP) chemotherapy treatment regimens, timing of HIPEC administration, major randomized controlled trials (RCTs) and non-RCTs (NRCTs), and meta-analyses in GC patients. METHODS: A review of the Library of Congress, the Cochrane Review, Google Scholar, PubMed, and ClinicalTrials.gov was performed. All articles and trials with available data in English with full text were considered. Necessary keywords used to search included "gastric cancer" and/or "HIPEC". Included articles were independently reviewed by authors. KEY CONTENT AND FINDINGS: Optimal HIPEC administration timing is unclear, but many utilize it in a neoadjuvant or prophylactic setting. Signet ring pathology and epithelial mesenchymal transition (EMT) cell histologic subtypes may have more aggressive pathology, limiting HIPEC success rates. Patients who receive complete cytoreduction and have low peritoneal carcinomatosis index (PCI) burden have been shown to have improved median overall survival (OS) after HIPEC. The data suggests in GCPC, HIPEC can modestly improve recurrence-free and OS. The data regarding benefits of prophylactic HIPEC in advanced GC (AGC) remains mixed. CONCLUSIONS: HIPEC for GC is controversial. Much of the literature is exploratory in nature or difficult to compare, as many outcomes are novel/not cross validated against substantial preceding data, with highly variable patient populations and study designs. However, in certain clinical scenarios in high volume centers, some patients with non-metastatic or low burden disease who undergo prophylactic or intraoperative HIPEC may benefit with improved overall and recurrence free survival (RFS).

Claudin-18.

CONTEXT.­: Claudin-18 is expressed in some gastric cancers. Clinical trials are evaluating it as a therapeutic target. OBJECTIVES.­: To evaluate claudin-18 expression in intestinal metaplasia, dysplasia, and adenocarcinoma of the distal esophagus/gastroesophageal junction and stomach and to evaluate claudin-18 expression in gastric and nongastric neuroendocrine tumors as a marker of gastric origin. DESIGN.­: Samples included gastroesophageal junction with intestinal metaplasia (n = 40), dysplasia (n = 54), and adenocarcinoma (n = 20) and stomach with intestinal metaplasia (n = 79), dysplasia (n = 43), and adenocarcinoma (n = 25). Additionally, gastric (n = 40) and nongastric (n = 322) neuroendocrine tumors were included. Claudin-18 expression was evaluated for any staining as positive and by meeting clinical trial inclusion criteria (≥2+ intensity in ≥50% of tumor). RESULTS.­: Claudin-18 staining was not significantly different across dysplasia categories in the gastroesophageal junction (P = .11) or stomach (P = .12). The rate of positive staining was higher in gastroesophageal junction than stomach for intestinal metaplasia (37 of 40 [92.5%] versus 37 of 79 [46.8%]; P < .001) and high-grade dysplasia (33 of 38 [86.8%] versus 9 of 16 [56.3%]; P = .03). Intestinal metaplasia showed staining in 7 of 37 autoimmune gastritis samples (18.9%) compared with 30 of 42 samples without autoimmune gastritis (71.4%) (P < .001). Adenocarcinoma showed similar staining in gastroesophageal junction (15 of 20; 75.0%) and stomach (17 of 25; 68.0%) (P = .85). Eighty percent (32 of 40) of gastric neuroendocrine tumors were positive for claudin-18 expression, with 57.5% (23 of 40) meeting clinical trial inclusion criteria. Comparatively, 0.62% (2 of 322) of nongastric neuroendocrine tumors showed staining (P < .001). CONCLUSIONS.­: Claudin-18 staining was similar in intestinal metaplasia, dysplasia, and adenocarcinoma. Claudin-18 was negative in most cases of intestinal metaplasia in autoimmune gastritis, indicating that intestinal metaplasia in this setting may differ from other forms. Claudin-18 was sensitive and specific for gastric origin in neuroendocrine tumors.

Therapeutic Advances and Challenges in the Management of HER2-Positive Gastroesophageal Cancers.

Gastroesophageal cancer is one of the most common cancers in the world, with a high rate of mortality. While there has been significant progress over the past decade, particularly with the addition of anti-HER2 therapies to platinum-based chemotherapy agents in the advanced setting, the prognosis remains poor and the treatment options for this disease entity remain limited. In this review, we discuss the current therapeutic landscape for HER2-positive gastroesphageal cancer and the seminal clinical trials that have shaped our approach to this disease entity. In addition, we highlight some of the challenges to the understanding and management of this disease, specifically discussing the breadth of molecular diversity and intratumoral heterogeneity of HER2 expression that impact the clinical efficacy and prognosis. Furthermore, we discuss the potential role of next-generation sequencing (NGS) and circulating-tumor DNA (ctDNA) as complementary tools to immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH) to guiding clinical decision making. Finally, we highlight promising clinical trials of new treatment regimens that will likely reshape the therapeutic approach to this disease entity.

Circulating tumor DNA dynamics and response to immunotherapy in colorectal cancer.

Circulating tumor DNA (ctDNA) is increasingly being investigated as a tool to detect minimal residual disease in resected, stage I-III colorectal cancer. Recent ctDNA studies have indicated that detection of ctDNA following surgery for resectable colorectal cancer confers a significantly higher risk of recurrence than those with negative ctDNA postoperatively. In those with postoperative ctDNA positivity, clearance of minimal residual disease with adjuvant chemotherapy is a positive prognostic indicator. Lastly, ctDNA has demonstrated superior sensitivity to the conventional blood tumor marker carcinoembryonic antigen (CEA) and can offer median lead times of up to 11 months for radiographic detection of recurrence during the surveillance of resected, stage I-III colorectal cancer. In metastatic colorectal cancer (mCRC), there is growing evidence to suggest that plasma ctDNA can be used to monitor tumor response to conventional chemotherapy as well. The present case series demonstrated that plasma ctDNA is a predictor of tumor response to immunotherapy in patients with mCRC that are microsatellite stable or microsatellite instability high. Plasma ctDNA could serve as a dynamic marker of immunotherapy response even in colorectal tumors that were CEA non-producers. Overall, these findings add to ongoing efforts to establish the role of plasma ctDNA in monitoring response to immunotherapy in CRC.

Chemotherapy predictors and a time-dependent chemotherapy effect in metastatic esophageal cancer.

BACKGROUND: Chemotherapy has long been shown to confer a survival benefit in patients with metastatic esophageal cancer. However, not all patients with metastatic disease receive chemotherapy. AIM: To evaluate a large cancer database of metastatic esophageal cancer cases to identify predictors of receipt to chemotherapy and survival. METHODS: We interrogated the National Cancer Database (NCDB) between 2004-2015 and included patients with M1 disease who had received or did not receive chemotherapy. A logistic regression model was used to examine the associations between chemotherapy and potential confounders and a Cox proportional hazards model was employed to examine the effect of chemotherapy on overall survival (OS). Propensity score analyses were further performed to balance measurable confounders between patients treated with and without chemotherapy. RESULTS: A total of 29182 patients met criteria for inclusion in this analysis, with 21911 (75%) receiving chemotherapy and 7271 (25%) not receiving chemotherapy. The median follow-up was 69.45 mo. The median OS for patients receiving chemotherapy was 9.53 mo (9.33-9.72) vs 2.43 mo (2.27-2.60) with no chemotherapy. Year of diagnosis 2010-2014 [odds ratio (OR): 1.29, 95% confidence interval (CI): 1.17-1.43, P value < 0.001], median income > $46000 (OR: 1.49, 95%CI: 1.27-1.75, P value < 0.001), and node-positivity (OR: 1.35, 95%CI: 1.20-1.52, P < 0.001) were independent predictors of receiving chemotherapy, while female gender (OR: 0.86, 95%CI: 0.76-0.98, P = 0.019), black race (OR: 0.76, 95%CI: 0.67-0.93, P = 0.005), uninsured status (OR: 0.41, 95%CI: 0.33-0.52, P < 0.001), and high Charlson Comorbidity Index (CCI) (OR for CCI ≥ 2: 0.61, 95%CI: 0.50-0.74, P < 0.001) predicted for lower odds of receiving chemotherapy. Modeling the effect of chemotherapy on OS using a time-dependent coefficient showed that chemotherapy was associated with improved OS up to 10 mo, after which there is no significant effect on OS. Moreover, uninsured status [hazard ratio (HR): 1.20, 95%CI: 1.09-1.31, P < 0.001], being from the geographic Midwest (HR: 1.07, 95%CI: 1.01-1.14, P = 0.032), high CCI (HR for CCI ≥ 2: 1.16, 95%CI: 1.07-1.26, P < 0.001), and higher tumor grade (HR for grade 3 vs grade 1: 1.28, 95%CI: 1.14-1.44, P < 0.001) and higher T stage (HR for T1 vs T4: 0.89, 95%CI: 0.84-0.95, P < 0.001) were independent predictors of worse OS on multivariable analyses. CONCLUSION: In this large, retrospective NCDB analysis, we identified several socioeconomic and clinicopathologic predictors for receiving chemotherapy and OS in patients with metastatic esophageal cancer. The benefit of chemotherapy on OS is time-dependent and favors early initiation. Focused outreach in lower income and underinsured patients is critical as receipt of chemotherapy is associated with improved OS.

The Landmark Series: Appendiceal Primary Peritoneal Surface Malignancy.

Appendiceal primary peritoneal surface malignancies are rare and include a broad spectrum of pathologies ranging from indolent disease to aggressive disease. As such, the data that drive the management of appendiceal peritoneal surface malignancies is generally not based on prospective clinical trial data, but rather consists of level 1 data based on retrospective studies and high-volume institutional experiences. Complete surgical debulking typically offers the best chance for long-term survival. This review highlights the landmark articles on which management of primary appendiceal peritoneal surface malignancies are based.

A Comparison of Clinicopathologic Outcomes Across Neoadjuvant and Adjuvant Treatment Modalities in Resectable Gastric Cancer.

Importance: Treatment of resectable gastric cancer (RGC) uses a multimodal approach, including surgical treatment and chemotherapy with or without radiation therapy, and the optimal treatment strategy and timing of each of these modalities is unknown. Objective: To investigate the association of various neoadjuvant and adjuvant treatment modalities with pathologic complete response (pCR), surgical margin status (SMS), and overall survival (OS) in RGC. Design, Setting, and Participants: For this comparative effectiveness study, the National Cancer Database was interrogated to identify patients with RGC diagnosed from 2004 to 2015. Patients with gastric adenocarcinoma that was cT2-T4b, any N, and M0 and who underwent definitive surgical treatment were included. Main Outcomes and Measures: The association of 9 treatment groups (ie, neoadjuvant chemoradiation only [nCRT], neoadjuvant chemotherapy only, adjuvant chemotherapy only [aCT], adjuvant chemoradiation only [aCRT], neoadjuvant chemotherapy and adjuvant radiation, chemotherapy with timing unknown [CTTU], chemoradiation therapy with timing unknown, radiation therapy with timing unknown (RTTU), and no perioperative therapy [NT]) with 3 end points (ie, pCR, SMS, and OS) was analyzed. The analysis was done using logistic regression and Cox proportional hazards models with adjustment for baseline characteristics. Data were analyzed from September 2019 through February 2020. Results: Among 183 204 patients with RGC who were screened, 3064 patients were included in the analysis (median [IQR] age, 68 [57-77] years; 1764 [57.6%] men). There were 1584 tumors (51.7%) located in the antrum and 1539 stage 2 tumors (50.2%). On multivariable analyses among 1939 patients (owing to 137 patients with missing data for pCR and the exclusion of 988 patients with aCT and aCRT from pCR analysis), nCRT was associated with increased odds of pCR compared with NT, with the greatest odds ratio (OR) among all treatments (OR, 59.55; 95% CI, 10.63-333.56; P < .001). RTTU had the next highest OR (29.96; 95% CI, 2.92-307.53; P = .004). In multivariable analysis for OS among 3061 patients (owing to missing data for OS), CTTU was associated with decreased risk of death compared with NT (hazard ratio, [HR], 0.41; 95% CI, 0.35-0.48; P < .001), with the lowest HR, as was nCRT (HR, 0.48; 95% CI, 0.35-0.66; P < .001), with the next lowest HR. Median OS was greatest among patients treated with CTTU (53.9 months; 95% CI, 44.5-61.0 months), followed by nCRT (39.1 months; 95% CI, 26.9 months-not applicable) and aCT (36.1 months; 95% CI, 28.88-49.18 months), while 2-year OS rates were 65.6% (95% CI, 61.3%-69.5%) for CTTU, 63.6% (95% CI, 52.3%-73.0%) for nCRT, and 59.7% (95% CI, 54.2%-64.7%) for aCT. Conclusions and Relevance: This study found that nCRT was associated with the highest pCR rate, while CTTU (ie, neoadjuvant or adjuvant therapy) was associated with the greatest OS.