Chemotherapy of advanced small-bowel adenocarcinoma: a multicenter AGEO study

Zaanan, Aziz; Laurent, Alexis; Gauthier, Mélanie; Malka, David; Locher, Christophe; Mitry, Emmanuel; Tougeron, David; Lecomte, Thierry; Gornet, Jean–Marc; Sobhani, Iradj; Moulin, Valérie; Afchain, Pauline; Taı̈eb, Julien; Bonnetain, Franck; Aparicio, Thomas

doi:10.1093/annonc/mdq038

Cited by 138 publications

(170 citation statements)

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“…9 The combination of 5-FU and a platinum-based agent has been considered more effective than other regimens such as oxaliplatinbased chemotherapy. 25,26 The main challenge for the near future is to identify molecular markers involved in small bowel carcinogenesis that predict chemosensitivity, and thus to improve survival. 5 Overman et al 27 observed that a high proportion of small intestinal adenocarcinomas express both EGFR and vascular endothelial growth factor (VEGF), suggesting that these patients may benefit from therapeutic strategies targeting EGFR and VEGF.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma

Jun

Kim

et al. 2016

Modern Pathology

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Activating KRAS and/or BRAF mutations have been identified as predictors of resistance to anti-epidermal growth factor receptor (EGFR) chemotherapy in colorectal cancer. But the status of KRAS and BRAF mutations and their clinicopathologic and prognostic significance has not been extensively evaluated in small intestinal adenocarcinomas. In this work, the KRAS and BRAF genes in 190 surgically resected small intestinal adenocarcinoma cases were sequenced and their association with various clinicopathologic variables, including survival of the patients, was analyzed. KRAS or BRAF mutations were observed in 63 (33%) cases. Sixty-one cases had KRAS mutations and 2 had BRAF mutations and the two types of mutation were mutually exclusive. The majority of KRAS mutations were G4A transition (43/61 cases, 71%) or p.G12D (31/61 cases, 51%). The patients with mutant KRAS tended to have higher pT classifications (P = 0.034) and more frequent pancreatic invasion (P = 0.020) than those with wild-type KRAS. Multivariate logistic regression analysis showed that certain mutated KRAS subtypes (G4A transitions and G12D mutations) were significantly correlated with higher pT classification (P = 0.015 and 0.004, respectively) than wild-type KRAS and other KRAS mutations. The patients with KRAS or BRAF mutation had a tendency to shorter overall survival than those with wild-type KRAS and BRAF (P = 0.148), but subgroup analysis demonstrated the patients with KRAS mutations showed worse survival (median, 46.0 months; P = 0.046) than those with wild-type KRAS (85.4 months) in lower pT classification (pT1-pT3) group. In summary, KRAS and, infrequently, BRAF mutations are observed in a subset of small intestinal adenocarcinomas, and are associated with higher pT classification and more frequent pancreatic invasion. KRAS mutation is a poor prognostic predictor in patients with lower pT classification tumors. Anti-EGFR targeted therapy could be applied to about two-thirds of small intestinal adenocarcinoma patients, namely those with wildtype KRAS and BRAF if they have metastatic disease, similar to colorectal cancer patients.

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Section: Discussionmentioning

confidence: 99%

Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma

Jun

Kim

et al. 2016

Modern Pathology

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“…Fluoropyrimidines are generally considered to be the key drugs for SBA and other gastrointestinal cancers. Most regimens used in previously reported studies of chemotherapy for unresectable SBA included fluoropyrimidines; to date, there has been no active regimen without these drugs [11][12][13][14][15][16][17][18][19][20][21][22][23]. However, no prospective or retrospective study has clearly showed advantages of a combination regimen compared with fluoropyrimidine monotherapy for unresectable SBA with regard to PFS or OS times.…”

Section: Discussionmentioning

confidence: 99%

“…A retrospective study conducted by AGEO compared oxaliplatin-and cisplatin-based chemotherapy. Although cisplatin (one of the key drugs for gastric cancer) was shown to be ineffective for colorectal cancer [24 -27], FOLFOX therapy (which includes oxaliplatin) was associated with significantly longer PFS and OS times in comparison with the combination of cisplatin and 5-FU for advanced SBA (4.8 vs. 6.9 months, p ϭ .02 for PFS; 17.8 vs. 9.3 months, p ϭ .04 for OS) [22].…”

Section: Discussionmentioning

confidence: 99%

“…Among the various types of combinations of 5-FU and platinum, oxaliplatin-containing regimens showed favorable efficacy in several studies. A retrospective study carried out by the Association des Gastroentérologues Oncologues (AGEO) showed a median progression-free survival (PFS) times of 6.9 months and a median overall survival (OS) times of 17.8 months with leucovorin ϩ 5-FU ϩ oxaliplatin (FOLFOX) therapy, which exceeded the results achieved with cisplatin ϩ 5-FU combination therapy [22]. A prospective phase II study of capecitabineoxaliplatin therapy showed a response rate of 50% and median OS time of 15.5 months [23].…”

Section: Introductionmentioning

confidence: 97%

“…Fluorouracil (5-FU) is the most commonly used agent for the treatment of unresectable or recurrent SBA, and various 5-FU based regimens have been used [11][12][13][14][15][16][17][18][19][20][21][22][23]. In a retrospective analysis, Overman et al reported that combination therapy with 5-FU and platinum compounds showed more favorable results than other regimens [21].…”

Section: Introductionmentioning

confidence: 99%

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Multicenter Retrospective Study of 132 Patients with Unresectable Small Bowel Adenocarcinoma Treated with Chemotherapy

Tsushima

Taguri

Honma³

et al. 2012

The Oncologist

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Background. No standard chemotherapy regimen has been established for unresectable or recurrent small bowel adenocarcinoma (SBA).Methods. Clinical courses of 132 patients with unresectable or recurrent SBA who received chemotherapy at 41 institutions in Japan were reviewed retrospectively. Patients were classified into five groups according to first-line chemotherapy regimens: fluoropyrimidine monotherapy (group A), fluoropyrimidine-cisplatin (group B), fluoropyrimidine-oxaliplatin (group C), fluoropyrimidine-irinotecan (group D), and other regimens (group E).Results. The number of patients in each group was as follows: groups A, 60 patients; group B, 17 patients; group C, 22 patients; group D, 11 patients; and group E, 22 patients. Median progression-free survival (PFS) times were as fol-

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Evaluation of Systemic Treatments of Small Intestinal Adenocarcinomas

et al. 2023

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ImportanceAlthough small intestinal adenocarcinomas (SIAs) are rare, they have a poor prognosis, and the optimal treatment strategies are largely unknown. Because of the lack of high-quality evidence, guidelines for colorectal cancer are often followed in the treatment of SIAs.ObjectiveTo review the current evidence regarding survival benefit of systemic therapies, including chemotherapy, targeted agents, and immunotherapy, for patients with SIAs.Data SourcesFollowing the Preferred Reporting Items for Systematic Reviews and Meta-analyses, MEDLINE and Embase were searched for articles published from January 1, 2005, until June 1, 2022.Study SelectionRetrospective cohort studies and prospective phase 2 or 3 trials describing survival after systemic therapies for patients with SIAs were eligible for inclusion. Assessment of study eligibility was blinded and performed by 3 reviewers.Data Extraction and SynthesisThe reviewers independently extracted data. Random effects, inverse variance, pairwise meta-analyses were performed.Main Outcomes and MeasuresPrimary outcomes were overall survival (OS) and progression-free survival (PFS) of patients with SIAs after systemic therapies. Measures of interest included hazard ratios for survival and median survival times.ResultsOverall, 57 retrospective cohort and phase 2 studies of 35 176 patients were included. Adjuvant chemotherapy, generally fluoropyrimidine-based, was associated with increased OS in stage I to III SIAs (hazard ratio [HR], 0.60; 95% CI, 0.53-0.68), especially in stage III tumors (HR, 0.55; 95% CI, 0.48-0.64), irrespective of tumor localization. Palliative chemotherapy was also associated with an OS benefit (HR, 0.48; 95% CI, 0.40-0.58). Fluoropyrimidine-oxaliplatin combinations were superior to other regimens (OS: HR, 0.54; 95% CI, 0.30-0.99; PFS: HR, 0.46; 95% CI, 0.30-0.71). Furthermore, bevacizumab added to chemotherapy compared with chemotherapy alone was associated with significantly prolonged PFS (HR, 0.62; 95% CI, 0.43-0.89). Immunotherapy showed a 50% overall response rate in previously treated defective mismatch repair tumors.Conclusions and RelevanceIn this systematic review and meta-analysis, adjuvant and palliative chemotherapy were both associated with improved survival of patients with SIAs, especially fluoropyrimidine-based regimens and fluoropyrimidine-oxaliplatin combinations. Adding bevacizumab to chemotherapy appears to prolong PFS and deserves further investigation. Immunotherapy seems beneficial and should be considered for patients with defective mismatch repair tumors. International collaborations should be undertaken to confirm and improve efficacy of systemic therapies for patients with SIAs.

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Chemotherapy of advanced small-bowel adenocarcinoma: a multicenter AGEO study

Abstract: This is the largest study of chemotherapy in advanced SBA. Baseline PS and CEA and CA 19-9 levels were the main prognostic factors. FOLFOX seems to be the most effective platinum-based chemotherapy regimen.

Cited by 138 publications

References 32 publications

Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma

Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma

Multicenter Retrospective Study of 132 Patients with Unresectable Small Bowel Adenocarcinoma Treated with Chemotherapy

Evaluation of Systemic Treatments of Small Intestinal Adenocarcinomas

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