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Enhancing treatment strategies for small bowel cancer: a clinical review of targeted therapy and immunotherapy approaches

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Abstract

Small bowel cancer (SBC) is a rare and aggressive disease with a poor prognosis, necessitating the exploration of novel treatment approaches. This narrative review examines the current evidence on targeted therapy and immunotherapy for SBC, focusing on the two most common subtypes: adenocarcinoma and neuroendocrine tumor. A comprehensive search of PubMed, Scopus, and Google Scholar databases was conducted to identify relevant clinical trials and case reports published in English up to September 2023. The review includes 17 clinical trials and 10 case reports, indicating that targeted therapy and immunotherapy can have the potential to improve survival rates in patients with SBC. Notably, promising targeted medicines include bevacizumab, cetuximab, and trastuzumab, while pembrolizumab and nivolumab show potential as immunotherapies. However, it should be noted that the magnitude of the increase in survival rates with these interventions was small. Further research is needed to determine the optimal combination of targeted therapy and immunotherapy for individual patients with SBC.

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Abbreviations

CAPOX:

Capecitabin + oxaliplatin

CR:

Complete response

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

EGFR:

Epidermal growth factor receptor inhibitor

FDA:

Food and Drug Administration

FOLFIRI:

Folinic acid + fluorouracil + irinotecan

FOLFOX:

Folinic acid + fluorouracil + oxaliplatin

GI:

Gastrointestinal

HER2:

Human epidermal growth factor receptor 2

mFOLFOX:

Modified folinic acid + fluorouracil + oxaliplatin

MRI:

Magnetic resonance imaging

NET:

Neuroendocrine tumor

NTRK:

Neurotrophic receptor tyrosine kinase

OS:

Overall survival

PD:

Progression disease

PD-1:

Programmed death protein 1

PD-L1:

Programmed cell death ligand 1

PET-CT:

Positron emission tomography and computed tomography

PFS:

Progression-free survival

RR:

Response rate

SBA:

Small bowel adenocarcinoma

SBC:

Small bowel cancer

SD:

Stable disease

TRK:

Tyrosine receptor kinase

VEGF:

Vascular endothelial growth factor

References

  • Ali WAS, Liu W, Xiao Y, Fang J, Xu Q (2019) A case report of small bowel adenocarcinoma with liver metastases: genetic profiling and clinical management. Transl Cancer Res. 8(4):1624–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alifieris CE, Griniatsos J, Delis SG, Nikolaou M, Avgoustou C, Panagiotidis MI et al (2020) Capecitabine, oxaliplatin, irinotecan, and bevacizumab combination followed by pazopanib plus capecitabine maintenance for high-grade gastrointestinal neuroendocrine carcinomas. Am J Clin Oncol. 43(5):305–10

    Article  CAS  PubMed  Google Scholar 

  • Al-Toubah T, Halfdanarson T, Gile J, Morse B, Sommerer K, Strosberg J (2022) Efficacy of ipilimumab and nivolumab in patients with high-grade neuroendocrine neoplasms. ESMO Open. 7(1):100364

    Article  CAS  PubMed  Google Scholar 

  • Amano T, Iijima H, Shinzaki S, Tashiro T, Iwatani S, Tani M et al (2021) Vascular endothelial growth factor-A is an immunohistochemical biomarker for the efficacy of bevacizumab-containing chemotherapy for duodenal and jejunal adenocarcinoma. BMC Cancer. 21(1):978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aparicio T, Svrcek M, Zaanan A, Beohou E, Laforest A, Afchain P et al (2013) Small bowel adenocarcinoma phenotyping, a clinicobiological prognostic study. Br J Cancer 109(12):3057–66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aparicio T, Pachev A, Laurent-Puig P, Svrcek M (2022) Epidemiology, risk factors and diagnosis of small bowel adenocarcinoma. Cancers (Basel) 14(9):2268

  • Arai H, Battaglin F, Wang J, Lo JH, Soni S, Zhang W et al (2019) Molecular insight of regorafenib treatment for colorectal cancer. Cancer Treat Rev. 81:101912

    Article  PubMed  PubMed Central  Google Scholar 

  • Available from: https://seer.cancer.gov/statfacts/html/smint.html. Accessed 3 June 2023

  • Aydin D, Sendur MA, Kefeli U, Ustaalioglu BB, Aydin O, Yildirim E et al (2017) Evaluation of bevacizumab in advanced small bowel adenocarcinoma. Clin Colorectal Cancer. 16(1):78–83

    Article  PubMed  Google Scholar 

  • Baxevanis CN, Perez SA, Papamichail M (2009) Cancer immunotherapy. Crit Rev Clin Lab Sci 46(4):167–89

    Article  CAS  PubMed  Google Scholar 

  • Bou-Assaly W, Mukherji S (2010) Cetuximab (erbitux). AJNR Am J Neuroradiol. 31(4):626–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan DL, Rodriguez-Freixinos V, Doherty M, Wasson K, Iscoe N, Raskin W et al (2022) Avelumab in unresectable/metastatic, progressive, grade 2–3 neuroendocrine neoplasms (NENs): combined results from NET-001 and NET-002 trials. Eur J Cancer. 169:74–81

    Article  CAS  PubMed  Google Scholar 

  • Chan OTM, Chen Z-ME, Chung F, Kawachi K, Phan DC, Himmelfarb E et al (2010) Lack of HER2 overexpression and amplification in small intestinal adenocarcinoma. Am J Clin Pathol 134(6):880-5.

  • Chen EY, Vaccaro GM (2018) Small bowel adenocarcinoma. Clin Colon Rectal Surg 31(5):267–77

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen X, Zhou R, Li Y, Qu X, Qu YC, Li WZ et al (2022) Case report: a case of duodenal adenocarcinoma achieving significantly long survival treating with immune checkpoint inhibitors and chemotherapy without positive biomarkers. Front Immunol. 13:1046513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dang TO, Ogunniyi A, Barbee MS, Drilon A (2016) Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer. Expert Rev Anticancer Ther. 16(1):13–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Dosso S, Molinari F, Martin V, Frattini M, Saletti P (2010) Molecular characterisation and cetuximab-based treatment in a patient with refractory small bowel adenocarcinoma. Gut. 59(11):1587–8

    Article  PubMed  Google Scholar 

  • Dell’Aquila E, Zeppola T, Stellato M, Pantano F, Scartozzi M, Madaudo C et al (2020) Anti-EGFR therapy in metastatic small bowel adenocarcinoma: myth or reality? Clin Med Insights Oncol. 14:1179554920946693

    PubMed  PubMed Central  Google Scholar 

  • Desai J, Deva S, Lee JS, Lin CC, Yen CJ, Chao Y et al (2020) Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors. J Immunother Cancer 8(1)

  • Dogan I, Aydin E, Khanmammadov N, Paksoy N, Saip P, Aydiner A (2023) Termination of trastuzumab in HER2-positive metastatic breast cancer patients who received trastuzumab beyond progression. Sci Rep. 13(1):8779

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Drilon A, Oxnard GR, Tan DSW, Loong HHF, Johnson M, Gainor J et al (2020) Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer. N Engl J Med. 383(9):813–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duke ES, Bradford D, Marcovitz M, Amatya AK, Mishra-Kalyani PS, Nguyen E et al (2023) FDA approval summary: selpercatinib for the treatment of advanced RET fusion-positive solid tumors. Clin Cancer Res Of1-of6

  • Falcone R, Roberto M, Filetti M, Anselmi E, Marchetti P (2018) Anti epidermal growth factor receptor therapy in small bowel adenocarcinoma: case report and literature review. Medicine (Baltimore). 97(3):e9672

    Article  PubMed  PubMed Central  Google Scholar 

  • Gemmete JJ, Mukherji SK (2011) Panitumumab (vectibix). AJNR Am J Neuroradiol 32(6):1002–3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerber DE (2008) Targeted therapies: a new generation of cancer treatments. Am Fam Physician. 77(3):311–9

    PubMed  Google Scholar 

  • Gulhati P, Raghav K, Shroff RT, Varadhachary GR, Kopetz S, Javle M et al (2017) Bevacizumab combined with capecitabine and oxaliplatin in patients with advanced adenocarcinoma of the small bowel or ampulla of Vater: a single-center, open-label, phase 2 study. Cancer. 123(6):1011–7

    Article  CAS  PubMed  Google Scholar 

  • Gulhati P, Raghav K, Shroff R, Varadhachary G, Javle M, Qiao W et al (2018) Phase II study of panitumumab in ras wild-type metastatic adenocarcinoma of small bowel or ampulla of Vater. Oncologist. 23(3):277-e26

    Article  CAS  PubMed  Google Scholar 

  • Hamad A, Singhi AD, Bahary N, McGrath K, Amarin R, Zeh HJ et al (2017) Neoadjuvant treatment with trastuzumab and FOLFOX induces a complete pathologic response in a metastatic ERBB2 (HER2)-amplified duodenal cancer. J Natl Compr Canc Netw. 15(8):983–8

    Article  PubMed  Google Scholar 

  • Hirao M, Komori M, Nishida T, Iijima H, Yamaguchi S, Ishihara R et al (2017) Clinical use of molecular targeted agents for primary small bowel adenocarcinoma: a multicenter retrospective cohort study by the Osaka Gut Forum. Oncol Lett. 14(2):1628–36

    Article  PubMed  PubMed Central  Google Scholar 

  • Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–42

    Article  CAS  PubMed  Google Scholar 

  • Jiang Q, Li M, Li H, Chen L (2022) Entrectinib, a new multi-target inhibitor for cancer therapy. Biomed Pharmacother 150:112974

    Article  CAS  PubMed  Google Scholar 

  • Klein O, Kee D, Markman B, Michael M, Underhill C, Carlino MS et al (2020) Immunotherapy of ipilimumab and nivolumab in patients with advanced neuroendocrine tumors: a subgroup analysis of the CA209-538 clinical trial for rare cancers. Clin Cancer Res. 26(17):4454–9

    Article  CAS  PubMed  Google Scholar 

  • Klimstra DS, Beltran H, Lilenbaum R, Bergsland E (2015) The spectrum of neuroendocrine tumors: histologic classification, unique features and areas of overlap. Am Soc Clin Oncol Educ Book 35(1):92–103

  • Lacombe C, Perrier M, Hentic O, Brixi H, De Rycke O, Cros J et al (2023) FOLFOX-bevacizumab chemotherapy in patients with metastatic neuroendocrine tumors. J Neuroendocrinol. 35(1):e13227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Legué LM, van Erning FN, Bernards N, Lemmens V, de Hingh I, Creemers GJ (2019) Addition of bevacizumab to first-line palliative chemotherapy in patients with metastatic small bowel adenocarcinoma: a population-based study. Target Oncol 14(6):699–705

    Article  PubMed  Google Scholar 

  • Liu J, Chen Z, Li Y, Zhao W, Wu J, Zhang Z (2021) PD-1/PD-L1 checkpoint inhibitors in tumor immunotherapy. Front Pharmacol. 12:731798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lluch-Gómez J, Núñez-Álvarez V, de la Torre-Hita C, Bernal-Gómez M, Campini-Bermejo A, Perdomo-Zaldívar E et al (2023) Real world evidence of adjuvant trastuzumab in HER2 positive early breast cancer. Sci Rep. 13(1):7168

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  • Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L et al (2014) Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 371(17):1609–18

    Article  PubMed  Google Scholar 

  • Maio M, Ascierto PA, Manzyuk L, Motola-Kuba D, Penel N, Cassier PA et al (2022) Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study. Ann Oncol. 33(9):929–38

    Article  CAS  PubMed  Google Scholar 

  • Markham A (2020) Selpercatinib: first approval. Drugs. 80(11):1119–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martinelli E, De Palma R, Orditura M, De Vita F, Ciardiello F (2009) Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy. Clin Exp Immunol 158(1):1–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mehnert JM, Bergsland E, O’Neil BH, Santoro A, Schellens JHM, Cohen RB et al (2020) Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: results from the KEYNOTE-028 study. Cancer. 126(13):3021–30

    Article  CAS  PubMed  Google Scholar 

  • Nagaraj G, Zarbalian Y, Flora K, Tan BR Jr (2014) Complete response and prolonged disease-free survival in a patient with recurrent duodenal adenocarcinoma treated with bevacizumab plus FOLFOX6. J Gastrointest Oncol 5(1):E1-6

    PubMed  PubMed Central  Google Scholar 

  • Overman MJ, Varadhachary GR, Kopetz S, Adinin R, Lin E, Morris JS et al (2009) Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater. J Clin Oncol. 27(16):2598–603

    Article  CAS  PubMed  Google Scholar 

  • Overman MJ, Pozadzides J, Kopetz S, Wen S, Abbruzzese JL, Wolff RA et al (2010) Immunophenotype and molecular characterisation of adenocarcinoma of the small intestine. Br J Cancer 102(1):144–50

    Article  CAS  PubMed  Google Scholar 

  • Pan SY, Morrison H (2011) Epidemiology of cancer of the small intestine. World J Gastrointest Oncol 3(3):33–42

    Article  PubMed  PubMed Central  Google Scholar 

  • Patel SP, Othus M, Chae YK, Giles FJ, Hansel DE, Singh PP et al (2020) A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART SWOG 1609) in patients with nonpancreatic neuroendocrine tumors. Clin Cancer Res. 26(10):2290–6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santini D, Fratto ME, Spoto C, Russo A, Galluzzo S, Zoccoli A et al (2010) Cetuximab in small bowel adenocarcinoma: a new friend? Br J Cancer 103(8):1305; author reply 6.

  • Siegel RL, Miller KD, Wagle NS, Jemal A (2023) Cancer statistics, 2023. CA Cancer J Clin 73(1):17–48

    Article  PubMed  Google Scholar 

  • Sigal D, Tartar M, Xavier M, Bao F, Foley P, Luo D et al (2017) Activity of entrectinib in a patient with the first reported NTRK fusion in neuroendocrine cancer. J Natl Compr Canc Netw. 15(11):1317–22

    Article  PubMed  Google Scholar 

  • Strosberg J, Mizuno N, Doi T, Grande E, Delord JP, Shapira-Frommer R et al (2020) Efficacy and safety of pembrolizumab in previously treated advanced neuroendocrine tumors: results from the phase II KEYNOTE-158 study. Clin Cancer Res 26(9):2124-30

  • Syn NL, Teng MWL, Mok TSK, Soo RA (2017) De-novo and acquired resistance to immune checkpoint targeting. Lancet Oncol. 18(12):e731–e41

    Article  PubMed  Google Scholar 

  • Takayoshi K, Kusaba H, Uenomachi M, Mitsugi K, Makiyama C, Makiyama A et al (2017) Suggestion of added value by bevacizumab to chemotherapy in patients with unresectable or recurrent small bowel cancer. Cancer Chemother Pharmacol. 80(2):333–42

    Article  CAS  PubMed  Google Scholar 

  • Thomas AS, Schwartz M, Quigley E (2019) Gastrointestinal lymphoma: the new mimic. BMJ Open Gastroenterol 6(1):e000320

    Article  Google Scholar 

  • Tomasello G, Petrelli F, Ghidini M, Russo A, Passalacqua R, Barni S (2017) FOLFOXIRI plus bevacizumab as conversion therapy for patients with initially unresectable metastatic colorectal cancer: a systematic review and pooled analysis. JAMA Oncol 3(7):e170278

    Article  PubMed  PubMed Central  Google Scholar 

  • Tsang H, Yau T, Khong PL, Epstein RJ (2008) Bevacizumab-based therapy for advanced small bowel adenocarcinoma. Gut 57(11):1631–2

    Article  CAS  PubMed  Google Scholar 

  • Vergara JP, Sacdalan DBL, Amurao-Amante M, Sacdalan DL (2019) Bevacizumab in metastatic small-bowel adenocarcinoma: a systematic review and meta-analysis. Rare Tumors. 11:2036361318825413

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang Z, Li W, Wei Y, An L, Su S, Xi C et al (2021) A HER2-mutant patient with late-stage duodenal adenocarcinoma benefited from anti-HER2 therapy and PD-1 inhibition: a case report. J Gastrointest Oncol. 12(4):1939–43

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu T, Wang X, Xin Y, Wang Z, Gong J, Zhang X et al (2023) Trastuzumab combined with irinotecan in patients with HER2-positive metastatic colorectal cancer: a phase II single-arm study and exploratory biomarker analysis. Cancer Res Treat. 55(2):626–35

    Article  CAS  PubMed  Google Scholar 

  • Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE et al (2008) One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 26(18):3063–72

    Article  PubMed  Google Scholar 

  • Yao H, Sokas C, Welch HG (2022) Rising incidence of cancer of the small intestine: overdiagnosis and better diagnosis of low-lethality disease. Gastroenterology. 162(6):1749–51.e2

    Article  PubMed  Google Scholar 

  • Zhang G, Lin L, Dong D, Qiu H, Liu T, Lian L et al (2021) Nivolumab plus regorafenib in patients with small bowel adenocarcinoma: a case report. Medicine (Baltimore). 100(4):e24295

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang L, Geng Z, Hao B, Geng Q (2022) Tislelizumab: a modified anti-tumor programmed death receptor 1 antibody. Cancer Control. 29:10732748221111296

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhong L, Li Y, Xiong L, Wang W, Wu M, Yuan T et al (2021) Small molecules in targeted cancer therapy: advances, challenges, and future perspectives. Signal Transduct Target Ther 6(1):201

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

    Mehrshad Ebrahimpour & Hamidreza Hosseinzadeh

  2. Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

    Farshad Abedi & Omid Arasteh

  3. Department of Hematology and Oncology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Mohammad Moeini Nodeh & Abolghasem Allahyari

  4. Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Amirhossein Sahebkar

  5. Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Amirhossein Sahebkar

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  1. Mehrshad Ebrahimpour
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Contributions

M.E. made contributions to the initial draft of the manuscript and was responsible for the creation and formatting of the tables. H.H. contributed to the drafting of the manuscript and designing and refining the figures. F.A., M.MN., A.A., and A.S. contributed to the critical revision of the article. Lastly, O.A. made contributions by conceiving the initial idea for the study and participated in the revision process.

M.E. made contributions to the initial draft of the manuscript and was responsible for the creation and formatting of the tables. H.H. contributed to the drafting of the manuscript and designing and refining the figures. F.A., M.MN., A.A., and A.S. contributed to the critical revision of the article. Lastly, O.A. made contributions by conceiving the initial idea for the study and participating in the revision process. The authors confirm that no paper mill and artificial intelligence was used.

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Correspondence to Omid Arasteh.

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Ebrahimpour, M., Hosseinzadeh, H., Abedi, F. et al. Enhancing treatment strategies for small bowel cancer: a clinical review of targeted therapy and immunotherapy approaches. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-02992-1

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