Metastatic Small Bowel Adenocarcinoma Research Articles

S-1 as an alternative treatment after 5-fluorouracil-induced coronary vasospasm in a patient with small bowel adenocarcinoma: a case report.

5-Fluorouracil (5-FU) is a chemotherapeutic agent used worldwide to treat various solid tumors. It may cause adverse cardiotoxic events, the most common of which is coronary vasospasm. Recently, the 2022 European Society for Medical Oncology guidelines for metastatic colorectal cancer recommended S-1 as an alternative therapy after 5-FU-induced cardiotoxicity; however, only limited data on Asian patients are available. Here, we report a case of safe administration of S-1 to a 72-year-old Japanese female patient with metastatic small bowel adenocarcinoma who developed 5-FU-induced coronary vasospasm. While receiving modified FOLFOX6 (5-FU plus leucovorin and oxaliplatin) as palliative chemotherapy, she experienced chest pain with electrocardiographic ST elevation. Chemotherapy was temporarily suspended, but treatment was resumed by switching from modified FOLFOX6 to SOX (S-1 plus oxaliplatin) as the tumor began to worsen. Owing to the adverse event of enteritis, the patient's treatment was switched to S-1 monotherapy after cycle 3, and S-1 monotherapy was continued without any cardiotoxicity. S-1 may be a promising alternative therapy after 5-FU-induced cardiotoxicity.

Survival effects of primary and metastatic surgical treatment in metastatic small intestinal tumors: A propensity score-matching study.

ObjectiveTo analyze the effects of primary tumor resection and metastatic lesion resection on the survival of metastatic small intestinal tumors.MethodsThe research subjects were patients with metastatic small bowel tumors identified from 2004 to 2016 in the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching and Kaplan–Meier analyses were performed to analyze the effect of surgery on the prognosis.ResultsA total of 4,034 patients from the SEER database were analyzed. Both before and after the propensity score–matching analysis, the prognosis of patients who underwent primary tumor surgery and metastatic surgery was better than that of patients who did not undergo surgery; all were patients with metastatic small bowel adenocarcinoma (mSIA) or metastatic small intestinal neuroendocrine tumors (mSI-NETs) (all p < .005). Patients with mSIA and adequate lymph node dissection had a longer prognosis than mSIA patients with inadequate lymph node dissection, but this survival benefit was not present in mSI-NET patients. It made no difference in the prognosis of mSIA and mSI-NETs whether localized surgery or intestine-ectomy was performed. Patients with mSIA who underwent primary and metastatic excision plus chemotherapy had the best overall survival and cancer-specific survival rates, whereas mSI-NET patients who underwent primary and metastatic excision had the best overall survival and cancer-specific survival rates (all p < .001).ConclusionIn these carefully selected patients, primary tumor resection and/or metastatic lesion resection significantly improved the survival rates for patients with mSIA and mSI-NETs. The mSIA patients with resectable primary tumors seemed to require a sufficient number of lymph node dissections more than the patients with well-differentiated mSI-NETs.

Development and validation of prognostic nomograms for patients with metastatic small bowel adenocarcinoma: a retrospective cohort study

We aimed to explore factors associated with prognosis in patients with metastatic small bowel adenocarcinoma (SBA) as well as to develop and validate nomograms to predict overall survival (OS) and cancer-specific survival (CSS). Relevant information of patients diagnosed between 2004 and 2016 was extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Nomograms for predicting 1- and 3-year OS and CSS were established with potential risk factors screened from multivariate cox regression analysis. The discrimination and accuracy of the nomograms were assessed by concordance index (C-index), calibration plots, and the area under receiver operating characteristic curve (AUC). In total, 373 SBA patients with M1 category were enrolled. Multivariate analysis revealed that age, size and grade of primary tumor, primary tumor surgery, and chemotherapy were significant variables associated with OS and CSS. The C-index values of the nomogram for OS were 0.715 and 0.687 in the training and validation cohorts, respectively. For CSS, it was 0.711 and 0.690, respectively. Through AUC, decision curve analysis (DCA) and calibration plots, the nomograms displayed satisfactory prognostic predicted ability and clinical application both in the OS and CSS. Our models could be served as a reliable tool for prognostic evaluation of patients with metastatic SBA, which are favorable in facilitating individualized survival predictions and clinical decision-making.

Metastatic small bowel adenocarcinoma: role of metastasectomy and systemic chemotherapy

BackgroundMetastatic small bowel adenocarcinoma (SBA) has a poor prognosis. Due to its rarity, high-quality data are lacking to guide treatment. This retrospective analysis was conducted to help characterize the treatment options for patients with metastatic SBA while providing clinically meaningful prognostic information.Patients and methodsIn total, 437 patients who initially presented with or developed metastatic SBA between September 1977 and September 2019 were identified from the MD Anderson Tumor Registry. Clinical data were collected from review of the medical record. Overall response rates (ORR), time to progression (TTP), and overall survival (OS) were assessed across various treatments and treatment lines.ResultsThe median OS from diagnosis of metastatic disease was 15.9 months [95% confidence interval (CI): 14.3-17.9]. Seventy-five patients (17.1%) underwent metastasectomy, which was associated with a median OS of 34.5 versus 17.1 months among patients who received chemotherapy alone (P < 0.001). Fluoropyrimidine plus platinum (n = 164) was the most common first-line chemotherapy, associated with an ORR of 59% and TTP of 8.1 months. Irinotecan with 5-FU (n = 101) was the most common second-line therapy associated with an ORR of 31% and TTP of 4.0 months. Twenty-two patients received immunotherapy; 5 of 6 patients with deficient mismatch repair (dMMR) responded, while 0 of 16 with proficient mismatch repair (pMMR) responded. Taxane-based chemotherapy was given to 34 patients with an ORR of 21% and a median TTP of 2.4 months. Among 11 patients who received anti-epidermal-growth-factor-receptor (EGFR) monotherapy, the best response was stable disease (SD) in 1 patient.ConclusionsIn well-selected patients with SBA, metastasectomy appears to be associated with improved OS. This improvement was seen across metastasectomy sites, including liver, lung and peritoneal. Anti-programmed cell death protein 1 (PD-1) based immunotherapy was active for dMMR SBA but not pMMR SBA. While taxane-based chemotherapy demonstrates therapeutic activity, the activity of anti-EGFR therapy was limited.

ZEBRA: An IRCI/ACCRU (RU021502I) Multicenter Phase II Study of Pembrolizumab in Patients With Advanced Small Bowel Adenocarcinoma (SBA)

Background: Small bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic SBA beyond first-line FOLFOX/CAPOX. Later-line therapy has been extrapolated from colorectal cancer (CRC) studies, though SBA is biologically distinct with higher rates microsatellite instability (MSI-H) and intratumoral T-lymphocyte infiltration. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response. Methods: Previously treated advanced SBA patients received pembrolizumab 200 mg IV q3 weeks until disease progression (PD), toxicity, or to 35 dose maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary survival and safety endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level. Findings: 40 patients were treated for median duration of 4 cycles (range 1-35). MSI status was available for 36 patients (90%). All 40 patients are off study treatment due to: PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AE, 5%). Three confirmed partial responses (PR) (8%; 95% CI: 2-20) did not meet pre-defined success criteria. Median overall survival (OS) 7 . 1 mo (95% CI: 5 . 1-17 . 1) and median progression free survival (PFS) 2 . 8 mo (95% CI: 2 . 7-4 . 2) were similar across primary tumor sites. One confirmed PR was seen in 32 MSS/MSI-low patients (3%). MSS response correlated with high tumor mutation burden (TMB). Two of four MSI-H patients had a confirmed PR (50%) and remain alive without progression. 25 patients (63%) had grade ≥ 3 AEs, 11 pts (28%) had grade 4/5 AEs. Interpretation: In the largest study of SBA to date, and the first using immunotherapy, pembrolizumab did not achieve the hypothesized response rate; however, we did identify responses in certain biomarker-selected cohorts. Trial Registration: RU021502I (ACCRU), MISP #52192 (Merck), NCT02949219 (clinicaltrials.gov). Funding Statement: Primary study funding and investigational product was provided by the Merck Investigator Studies Program (MISP), and additional site-specific funding provided by the Kavanagh Family Foundation (MDACC) and Kevin T. Doner Memorial Fund (MDACC). Declaration of Interests: None to declare Ethics Approval Statement: Ethics board review and human research protections monitoring were performed at each institution. The trial was conducted according to ICH GCP.

Beyond bevacizumab: a review of targeted agents in metastatic small bowel adenocarcinoma.

Small bowel cancers are rare tumors with an incidence 50-100-fold less than colorectal cancer. These tumors carry a poor prognosis. Owing to its rarity, treatment of this disease, particularly in its advanced stages, has not been optimized and is derived mainly from treatment regimens for colorectal cancer. Based on recent studies bevacizumab, an antibody directed against vascular endothelial growth factor and used in the management of metastatic CRC, has been added to treatment guidelines for metastatic small bowel adenocarcinoma. We investigate in this review the evidence behind other targeted treatments that may be beneficial in the treatment of metastatic small bowel adenocarcinoma. These are agents against EGFR, VEGFR-2, HER2, and NTRK as well as immune checkpoint inhibitors. The last class of drugs appears to hold the greatest promise based on the preponderance of evidence supporting its use. However, overall data remains sparse. Results of studies currently underway will be valuable in shedding more light on the management of this aggressive cancer.

Abstract 4467: Bim and CX3CR1/granzyme B in circulating CD8+ T cells are predictive biomarkers for PD-1 blockade therapy

Abstract Immunotherapy targeting immune checkpoints has become a common approach for many types of cancer but currently there are no reliable biomarkers to predict and monitor treatment response. Immunohistochemical staining of PD-L1, which was initially developed as a companion diagnostic, is problematic due to tumor heterogeneity, variations in specimen preparation and multiple scoring schemes. There is, therefore, a critical need for a better biomarker to guide the use of immunotherapy to improve clinical outcomes. We previously reported that higher levels of Bim and CX3CR1/granzyme B in CD8+ T cells were associated with increased response to PD-1 blockade therapy in patients with melanoma; high levels of Bim were also prognostic of poor survival in melanoma patients. In this study, we investigated the roles of Bim and CX3CR1/granzyme B in patients receiving PD-1 blockade therapy (i.e. pembrolizumab) for small bowel adenocarcinoma as part of planned correlative analysis of the ACCRU clinical trial, NCT02949219. Patients with unresectable or metastatic biopsy-proven small bowel adenocarcinoma (excluding ampulla of Vater and appendix) who had at least one prior line of systemic chemotherapy were eligible for the trial. Pembrolizumab (200 mg) was administered over 30 minutes intravenously every 3 weeks until unacceptable toxicity, disease progression, or patient refusal. All patients underwent peripheral blood collection at baseline prior to initiation of treatment and then after 3 cycles of treatment. Levels of Bim and CX3CR1/granzyme B in circulating T cells were quantified by flow cytometry using patients' peripheral blood mononuclear cells. Data was analyzed via Cox proportional hazards model, Wilcoxon Rank-Sum test, and Kaplan Meier curves using SAS 9.4. A total of 35 eligible patients were included in the analysis. Three patients had confirmed response (all partial responses) and 10 had stable disease as their best overall response. Seven patients had disease progression around the second blood draw. The median time from baseline to the second blood draw was 9 weeks. Lower levels of Bim in CD8+CD11ahi T cells at baseline on the percentage scale were associated with treatment response (median 54.5% vs. 79.5%; p=0.0087) and disease control (partial response plus stable disease; median 71.2% vs. 81.3%; p=0.0104) but higher levels led to worse progression-free survival (hazard ratio=1.05, 95% confidence interval 1.01-1.08; p=0.0051). In addition, positive changes in CX3CR1/granzyme B in CD8+CD11ahi T cells from baseline were associated with better overall survival (median 20.2 months vs. 3.7 months, p=0.0086). The levels of PD-1 and Ki-67 in CD8+CD11ahi T cells were not associated with treatment response or survival. In conclusion, Bim and CX3CR1/granzyme B are biomarkers that associate with response and survival benefits respectively of PD-1 blockade therapy. This preliminary data calls for a larger-scale, prospective study to validate their predictive and prognostic utilities. Citation Format: Mojun Zhu, Henan Zhang, Nathan R. Foster, Haidong Dong, Tanios S. Bekaii-Saab, Brandy L. Jaszewski, Patrick M. Boland, Michael J. Overman, Katrina Pedersen, Robert R. McWilliams, Academic and Community Cancer Research United (AACRU). Bim and CX3CR1/granzyme B in circulating CD8+ T cells are predictive biomarkers for PD-1 blockade therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4467.

P-163 Systemic chemotherapy for previously treated metastatic small bowel adenocarcinoma

Metastatic small bowel adenocarcinoma (mSBA) is a rare condition with a poor prognosis. Enough data are not available on second-line chemotherapy (SLC) for mSBA. The aim of this study was to explore the efficacy and safety of SLC for mSBA patients.

Chemotherapy for patients with unresectable or metastatic small bowel adenocarcinoma: a systematic review.

There is no standard chemotherapy available for unresectable or metastatic small bowel adenocarcinoma (SBA) because of its rarity. This systematic review aims to assess the efficacy and safety of chemotherapy for patients with unresectable or metastatic SBA. In accordance with the PRISMA statements, literature search was conducted using PubMed, Scopus, and the Cochrane Central Register of Controlled Trials. The included studies were prospective randomized, nonrandomized, or observational studies. Risk of bias was assessed the ROBINS-I tool. Seven prospective single-arm Phase II studies were included in this review. Six of them were assessed as having a moderate risk of bias and one as having a serious risk of bias. A meta-analysis was not performed, because the studies were single-arm. Systemic chemotherapy based on fluoropyrimidine regimens achieved favorable outcomes with acceptable adverse effects as a first therapy; however, the regimens differed in each study. The object response rate was 18-50%, and the disease control rate was 29-87%. With 5-fluorouracil, adriamycin, and mitomycin-C regimen, one treatment-related death occurred. A second line of therapy including chemotherapy with nab-paclitaxel also showed favorable efficacy. The object response rate was 20%, and the disease control rate was 50%. Systemic chemotherapy based on fluoropyrimidine regimens was mainly used for unresectable or metastatic SBA. While it may achieve favorable outcomes with acceptable adverse effects, further evidence is needed.

Anti-EGFR Therapy in Metastatic Small Bowel Adenocarcinoma: Myth or Reality?

Background:Due to the relative rarity of small bowel adenocarcinoma (SBA), prospective trials, helping to guide therapeutic decisions, are lacking and the optimal therapy for advanced SBA is unknown. The role of targeted agents, such as anti–epidermal growth factor receptor (EGFR) and anti–vascular endothelial growth factor (VEGF), is unknown.Patients and Methods:This is a retrospective multicenter observational study that included patients with metastatic SBA treated with anti-EGFR antibodies (cetuximab or panitumumab) ± chemotherapy in the first (I) or second (II) line.Results:Thirteen patients with metastatic SBA, recruited from 5 Italian referral institutions, were included in the present retrospective analysis. All patients received anti-EGFR inhibitors as a single agent or in association with chemotherapy. More common G2 treatment–related side effects were skin reaction (8 patients, 53.8%), hypomagnesemia (6 patients, 46.2%), and diarrhea (8 patients, 61.5%). Grade 3 diarrhea was observed in only 1 patient. Conjunctivitis was not reported in any patients. Grade 4 toxicity was not reported. In the overall population, median progression-free survival was 5.526 months (95% confidence interval [CI]: 3.684-12.467). Median overall survival was 15.86 months (95% CI: 14.43-24.30). Complete response was observed in 15% of patients, partial response in 39% of patients, stable disease in 23% of patients, and progression disease in 15% of patients.Conclusions:In this retrospective analysis, anti-EGFR inhibitors showed to be a suitable addendum to chemotherapy in the I and II line, with an excellent tolerance and safety profile both in I and II line.

Palliative chemotherapy for patients with synchronous metastases of small-bowel adenocarcinoma: A reflection of daily practice.

As small-bowel adenocarcinoma (SBA) is scarce, no standard systemic regimen in metastatic disease has been defined. To obtain insights into the use and effects of palliative chemotherapy in patients with metastatic SBA in a population-based setting. Data from the Netherlands Cancer Registry of patients with metastatic SBA between 2007 and 2016 were used (n = 522). For patients treated with palliative chemotherapy, differences in treatment regimens and survival were evaluated. Palliative chemotherapy was received by 38% of patients (n = 199). First-line combination chemotherapy was administered to 80% of patients, mainly CAPOX/FOLFOX. Single-agent chemotherapy mostly consisted of capecitabine. Second-line treatment, mostly irinotecan-based (58%), was prescribed to 27% of patients. Age 70 years or older was an adverse predictive factor for receiving first-line combination chemotherapy (odds ratio (OR) 0.2, 95% confidence interval (CI) 0.08-0.62) and second-line therapy (OR 0.3, 95% CI 0.10-0.72). Median overall survival with palliative chemotherapy was 9.3 months, compared with 3.0 months without. In subanalyses, patients who received only first-line treatment had a median overall survival of 5.6 and 7.0 months after single-agent and combination chemotherapy, respectively. A minority of patients were treated with palliative chemotherapy. First-line treatment consisted predominantly of oxaliplatin-based combination chemotherapy, whereas second-line treatment was mainly irinotecan-based. Population-based median overall survival for selected patients treated with chemotherapy amounted to nine months.

Addition of Bevacizumab to First-Line Palliative Chemotherapy in Patients with Metastatic Small Bowel Adenocarcinoma: A Population-Based Study.

Data about the use and effectiveness of targeted therapy in metastatic small bowel adenocarcinoma (SBA) are scarce. The aim of this population-based study was to obtain insights into the use and effectiveness of targeted therapy in patients with synchronous metastases of SBA. Data were retrieved from the Netherlands Cancer Registry. Patients treated with palliative chemotherapy and/or targeted therapy for synchronous metastatic SBA between 2007 and 2016 were included (n = 187). Differences in treatment and the subsequent effects on overall survival (OS) were evaluated. In first-line treatment, 25 patients (13%) received additional targeted therapy, exclusively bevacizumab, and mostly in combination with CAPOX/FOLFOX (n = 24). A primary ileal tumour was predictive for receiving bevacizumab in first-line treatment (odds ratio 3.2, 95% confidence interval (CI) 1.06-9.93). Median OS for patients in whom bevacizumab was added to first-line chemotherapy was 9.3months, compared to 9.1months with chemotherapy only (p = 0.85). Median OS for patients receiving first-line treatment only was 8.5months with and 6.4months without the addition of bevacizumab, respectively (p = 0.54). In multivariable survival analyses, the addition of bevacizumab was no prognostic factor (hazard ratio 1.01, 95% CI 0.65-1.59). Bevacizumab was the only prescribed targeted therapy in first-line treatment. Considering the limited number of patients receiving first-line bevacizumab and the unknown reasons to prescribe additional targeted therapy, the corresponding survival rates of patients treated with and without additional bevacizumab in first-line treatment might suggest a limited clinical effect of bevacizumab in addition to first-line palliative chemotherapy on OS. Future research should focus on identifying the subgroup of patients who might benefit from anti-VEGF therapy in metastatic SBA.

Clinical outcome of salvage chemotherapy after oxaliplatin based chemotherapy for metastatic small bowel adenocarcinoma

Abstract Background Although palliative chemotherapy (CTx) for metastatic small bowel adenocarcinoma (mSBA) has not been established, fluoropyrimidine plus oxaliplatin (FOx) is globally accepted as a standard CTx based on several studies. While CTx for colorectal cancer has been recommended in NCCN guidelines, limited efficacy of irinotecan (IRI) and panitumumab for mSBA had also been shown in western countries. Thus, there has been no salvage line chemotherapy (SLC) which can be recommended for mSBA after failure to FOx. The aim of this study was to provide the information of clinical outcomes of SLC for mSBA after failure of FOx. Methods mSBA patients (pts) who received SLC after failure of FOx from 2010 to 2019 in our institute were retrospectively analyzed. Pts who received 1st line CTx other than FOx, ongoing FOx, or with insufficient follow-up were excluded. Results Of 59 mSBA pts, eligible 33 were extracted from our database. Age (median): 58 year-old, PS (0/1/>=2): 3/21/9, primary site (duodenum/jejunum and ileum): 13/20, stage (IV/recurrence): 23/10. Metastatic sites were peritoneum in 25 (75.8%) pts, and liver in 12 (36.4%). Twenty-two (66.7%) pts received SLC, pts with good PS (0-1) tended to receive SLC. As 2nd line CTx, 16 of 22 pts (72.7%) received IRI-based CTx and gemcitabine (GEM) in 3. Eight of 22 pts received 3rd line CTx; nab-paclitaxel (off-label use for APC-wild type) in 4, and GEM in 2. MST in all pts was 4.5 months, which was longer in pts treated with SLC than those with best supportive care (5.7 vs 1.7 months, p Conclusion Limited efficacy of SLC for mSBA was shown also in Japanese population. This is very important baseline data to lead to the future drug development.

A case report of small bowel adenocarcinoma with liver metastases: genetic profiling and clinical management

Small bowel adenocarcinoma (SBA) is a rare cancer. Optimal treatment regimens have not been established for SBA. This is due in part to the low disease incidence and subsequently, the lack of large, properly designed, randomized clinical trials. In this study, we present a case of an advanced small bowel adenocarcinoma patient with a prolonged progression-free survival of more than 3 years. Genetic profiling of this patient was used to predict prognosis and guide clinical management of the disease. The patient was treated with bevacizumab in combination with XELOX based on her genetic background and our experience in treating colorectal cancer. This treatment strategy, which was tolerable and effective, may be considered as a viable therapeutic strategy for the treatment of metastatic SBA.

A case report of small bowel adenocarcinoma with liver metastases: genetic profiling and clinical management

Small bowel adenocarcinoma (SBA) is a rare cancer. Optimal treatment regimens have not been established for SBA. This is due in part to the low disease incidence and subsequently, the lack of large, properly designed, randomized clinical trials. In this study, we present a case of an advanced small bowel adenocarcinoma patient with a prolonged progression-free survival of more than 3 years. Genetic profiling of this patient was used to predict prognosis and guide clinical management of the disease. The patient was treated with bevacizumab in combination with XELOX based on her genetic background and our experience in treating colorectal cancer. This treatment strategy, which was tolerable and effective, may be considered as a viable therapeutic strategy for the treatment of metastatic SBA.

Small bowel adenocarcinoma: A single center experience.

449 Background: Small bowel adenocarcinoma (SBA) represents only 2% of GI malignancies. There is limited data to guide clinical decisions, largely extrapolated from colorectal cancers (CRC). We evaluated treatment strategies and outcomes in patients (pts) with early and advanced SBA. Methods: We identified 56 pts with SBA diagnosed between 1/2005 - 1/2018 and treated at our institution. Demographics, pathological features, treatments, and molecular data were abstracted via medical record review. Data was analyzed with SAS statistical software. Results: Median age was 61, 54% male, site: duodenum (D 37.5%), duodenal ampula (A 17.9%), jejunum (J 19.6%), ileum (I 12.5 %), unknown (12.5%). Predisposing conditions were: IBD (6), Lynch (2), and Peutz-Jeghers syndromes (1). Stage (stg) at diagnosis was I (5%), II (20%), III (34%) and IV (41%). Primary tumor resection occurred in 33 pts: 21 received adjuvant chemotherapy, mostly FOLFOX; 17 developed metastatic disease. Treatment for metastatic SBA (n = 40) included 5FU-based chemotherapy without or with anti-VEGF (n = 18), or anti-EGFR therapies (n = 9). Median lines of therapy was 2 (range 1-7). For pts with stg I-III SBA, median DFS/OS was 21/38 mos. For stg IV pts, OS was 19.8 mos; 18/35/8/14 mos for D, A, J and I, respectively. Molecular biomarkers with targeted (28) or next generation sequencing (10) were available for 28 metastatic SBA pts: KRAS MUT (8), TP53 MUT (5), ERBB2 MUT (2), MSI-H (2), ERBB2, CCNE1 amplification (1 each), and NRAS, BRAF, CDKN2A, ERBB3, ATM, PIK3CA MUT (1 each). OS was 20 vs 19 mos for pts with KRAS WT vs MUT stg IV SBA, respectively. Among 16 pts with KRAS WT SBA, OS for those treated (9) or not (7) with anti-EGFR antibodies was 25 mos vs 21 mos. One pt with KRAS WT, ERBB2 amplification/ERBB2 V777L activating mutation is alive 5yrs+ from stg IV diagnosis on anti-EGFR plus chemotherapy (best response was 4 mos SD with trastuzumab/pertuzumab). Conclusions: This retrospective study demonstrates heterogeneity among SBA, overall inferior outcomes compared to CRC pts, and emphasizes genomic alterations which could be exploited therapeutically. Randomized studies for KRAS WT SBA pts should test the benefit from anti-EGFR targeted therapies in this rare tumor type.

Bevacizumab in metastatic small-bowel adenocarcinoma: A systematic review and meta-analysis.

Cancers of the small bowel could account for less than 5% of all gastrointestinal malignancies. Of these tumors, adenocarcinomas were the major histologic subtype and generally carried a poor prognosis. High expression of vascular epithelial growth factor (VEGF) could be seen in small bowel adenocarcinomas. A systematic review was conducted here to determine if bevacizumab, a recombinant humanized antibody against VEGF, could offer clinical benefit among patients with metastatic small bowel adenocarcinoma when combined with chemotherapy. A search for relevant published and unpublished studies was performed using PubMed, ScienceDirect, Google Scholar, the American Society of Clinical Oncology meetings library, ClinicalTrials.gov, and ISRCTN registry. Information on study design, methods, intervention, and outcomes were extracted from selected eligible studies. Methodological quality was then assessed using the Newcastle-Ottawa Scale. There was a significant improvement in mean overall survival with the addition of bevacizumab with chemotherapy versus chemotherapy alone. The use of bevacizumab with chemotherapy, likewise improved progression-free survival and objective response rate compared to chemotherapy alone. Continued use of bevacizumab beyond first progression also appeared to show benefit. The conduct of prospective controlled studies by consortia to offset the rarity of small bowel adenocarcinomas could further elucidate the efficacy of bevacizumab in the treatment of this disease.

Resection of small bowel adenocarcinoma metastases: Results of the ARCAD-NADEGE cohort study

IntroductionData are lacking with regard to curative resection of metastasis from small bowel adenocarcinoma (SBA). This study evaluated outcomes and prognostic factors in patients with curatively resected metastatic SBA. MethodsA series of 34 patients undergoing resection of metastatic SBA from January 2009 to November 2014 at French centers were included into this cohort study. The primary endpoint was overall survival (OS). Secondary endpoints were recurrence-free survival (RFS) and prognostic factors. Univariate analyses were performed to determine prognostic risk factors. ResultsThe sites of SBA metastases were peritoneal (29.4%), liver (26.5%), lymph nodes (11.8%), lung (2.9%), multiple (14.7%), and other (14.7%). Thirty (88.2%) patients received adjuvant or perioperative chemotherapy, mainly was oxaliplatin-based (76.5%). The median OS was 28.6 months and RFS was 18.7 months. Fourteen (41.2%) patients survived for more than 36 months. In univariate analysis, poor differentiation (P = 0.006), invaded margins (P = 0.003), and lymphatic invasion in the primary tumor (P = 0.039) were associated with decreased OS. ConclusionOverall survival of patients after resection of metastatic SBA remains poor, but long-term survivors are observed. Resection of metastatic SBA should be consider if patients are expected to be operated on with curative intent and have moderately or well-differentiated tumors.

Randomized phase III study of observation versus adjuvant capecitabine and oxaliplatin in curatively resected small bowel adenocarcinoma: A Japan Clinical Oncology Group study (JCOG1502C).

TPS539 Background: Small bowel adenocarcinoma (SBA) is extremely rare tumor. Surgery is broadly applied as a standard treatment for localized SBA. However, the patients with localized SBA have poor prognosis even after curative resection (5-year survival: 40-65%), and most of them experience relapse. To prevent relapse, postoperative therapies are considered as most promising. However, there is no prospective study of postoperative therapies for curatively resected SBA patients and which regimens improve prognoses is unknown. For metastatic SBA, fluoropyrimidine and oxaliplatin is now regarded as global standard chemotherapy. Therefore, Japan Clinical Oncology Group (JCOG) planned a multicenter randomized phase III trial to confirm the superiority of postoperative capecitabine and oxaliplatin (CAPOX) to observation for curatively resected SBA under the Advanced Medical Care System of the Ministry of Health, Labour and Welfare, Japan. This study is a counterpart trial of BALLAD trial conducted in International Rare Cancer Initiative (IRCI) (clinical trials gov; NCT02502370), and the integrated analysis of BALLAD trial and JCOG1502C is planned. Methods: Eligibility criteria include histologically proven adenocarcinoma located in the duodenum (except Ampulla of Vater) / jejunum / ileum, curatively resected with regional lymph nodes dissection, pathological stage I (T1b-2N0M0) / stage II / stage III. Eligible patients are randomized into observation arm or CAPOX arm. CAPOX (130 mg/m2 of oxaliplatin on day 1, and 1000 mg/m2 of capecitabine twice a day for 14 days) is repeated every 3 weeks for 6 months (total 8 courses). The primary endpoint is RFS. The 3-year RFS of observation arm is assumed to be 70% and expected a 10% increase in CAPOX arm. The sample size was calculated as 150 (75 per arm) with a one-sided alpha level of 10%, a statistical power of 70%, an accrual period of 6.5 years. This study has been registered in the UMIN Clinical Trials Registry (UMIN000027280). This trial was activated in 9 May 2017, and no patients was enrolled as of Sep 2017. We will increase the number of participating sites up to 20 throughout Japan. Clinical trial information: UMIN000027280.

Trial in progress: A multicenter phase II study of pembrolizumab in patients with advanced small bowel adenocarcinomas.

TPS535 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy, possibly because of the high rate of immunosurveillance in baseline small bowel function, and is frequently diagnosed in late stages. Due to these factors, there is no consistent standard of care for metastatic disease beyond first-line where several prospective studies have confirmed activity of FOLFOX/CAPOX. Historically, second-line treatment of SBA has been extrapolated from colon/gastric cancer. Recent studies suggest that SBA has a distinct genomic profile, including higher incidence of microsatellite instability, compared to gastric and colon cancers. Additionally, the tumor microenvironment reflects a greater degree of PD-L1 expression and infiltration by lymphocytes. Immune checkpoint inhibitors have not previously been tested in SBA unselected for MSI status. Methods: The study is a phase 2, multicenter, single-arm clinical trial of pembrolizumab (200 mg IV every 3 weeks) for patients with unresectable or metastatic SBA refractory to first-line chemotherapy. Forty patients with any tumor mismatch repair status will be enrolled at 8 US sites as part of the ACCRU network and International Rare Cancer Initiative (IRCI) with a primary objective to assess the confirmed response rate (H0 p &lt; 10%, HA: p &gt; 30%) to pembrolizumab. Secondary endpoints include PFS, OS, and adverse events. Correlative aims include assessing blood and tissue biomarkers (i.e. PD-L1, MSI-H/MSS status, cfDNA, mutation burden, etc.) for association with clinical benefit. An interim analysis will be performed to assess efficacy after 18 patients become evaluable. The study is open with 16 patients enrolled at time of submission. Clinical trial information: NCT02949219.