Abstract
Background/Aim: The efficacy of systemic therapy for unresectable small bowel adenocarcinoma that is refractory to fluoropyrimidines and oxaliplatin has not yet been established because of the rarity of this cancer. Although immunotherapy with anti-PD-1 antibodies has shown robust efficacy in the treatment of esophagogastric adenocarcinoma, its effectiveness in small bowel adenocarcinoma remains unclear. Case Report: In the first case, a 75-year-old man was diagnosed with metastatic moderately differentiated adenocarcinoma of the jejunum with stable microsatellite instability. After receiving multiple lines of therapy, including fluoropyrimidines plus oxaliplatin, irinotecan, and paclitaxel, the patient was treated with nivolumab and achieved a partial response that lasted for 12 months. In the second case, a 65-year-old man was diagnosed with an unresectable locally advanced duodenal adenocarcinoma. High microsatellite instability was confirmed by polymerase chain reaction-based testing. After showing resistance to 5-fluorouracil and oxaliplatin, the patient received nivolumab and ipilimumab therapy. Although therapy was discontinued because of immune-related colitis and skin rash, a partial response was achieved. Conclusion: Treatment with immune checkpoint inhibitors is effective for refractory small bowel adenocarcinoma, irrespective of the microsatellite status.
Small bowel adenocarcinoma (SBA) is a rare form of cancer, and systemic therapy has been established for advanced SBA, particularly after the progression of first-line therapy with fluorouracil plus oxaliplatin-based regimens (1-3). To date, several cytotoxic-agent-based therapies, including regimens containing irinotecan or taxane, have been reported; however, their efficacy is limited (4). Given the current situation, there is an urgent and unmet medical need for additional treatment options for refractory SBA.
Historically, treatment strategies for refractory SBA have been based on clinical practices employed for colorectal cancer. Nevertheless, recent advancements in genomic and epigenetic studies have suggested that SBA possesses unique characteristics that differentiate it from both gastric and colorectal cancer (5). Notably, nivolumab (NIV), an anti-programmed death-1 (PD-1) inhibitor, has demonstrated efficacy as a later-line treatment for gastric adenocarcinoma with an overall response rate of 10% (6). However, the effectiveness of immunotherapy in refractory SBA remains unclear. Given the high expression of programmed death ligand-1 (PD-L1) in SBA (7), immunotherapy with PD-1 inhibitors is likely to be a viable treatment option for this rare cancer. In this report, we present two cases of SBA, one with microsatellite-stable (MSS) status and the other with high microsatellite instability (MSI-H), both of which were treated with immune checkpoint inhibitors (ICIs). Written informed consent was obtained from both patients.
Cases Report
Case 1. A 70-year-old male presented with unilateral inguinal lymph node swelling. Contrast-enhanced computed tomography (CT) revealed a jejunal mass, and biopsy conducted via esophagogastroduodenoscopy (EGD) confirmed the presence of a moderately differentiated SBA (Figure 1A). A comprehensive biological evaluation of the tumor was performed as follows. First, a multi-gene panel test (FoundationOne®) identified the following variants: CCND1 amplification, CDK4 amplification, MDM2 amplification, and PIK3CA mutation (N1044S). Additionally, the microsatellite status was stable, and the tumor mutational burden (TMB) was six mutations per megabase. Both RAS and BRAF were wild-type [determined through polymerase chain reaction (PCR)-based testing, RASKET-B]. Immunohistochemistry (IHC) of human epidermal growth factor-2 (HER2) and PD-L1 expression [combined proportion score (CPS) by 28-8 clone] was rated as 1+ and <5 (≥1, <5) judging from the criteria employed in gastric cancer. To prevent bowel obstruction, surgical resection of the primary site and subsequent duodenojejunostomy were performed before initiating systemic therapy. Following resection, enlargement of the para-aortic and inguinal lymph nodes was observed, leading to the initiation of capecitabine plus oxaliplatin therapy as the first-line treatment. Subsequently, the patient received irinotecan plus S-1 and weekly paclitaxel therapy. Following these treatment regimens, immunotherapy with NIV (200 mg/kg, administered every 2 weeks) was introduced. After completing four cycles of NIV, a partial response lasting over 12 months was achieved, accompanied by low-grade dermatitis (Figure 1B).
Computed tomography performed before (A) and after (B) nivolumab therapy in Case 1. Para-aortic lymph node metastasis after nivolumab therapy.
Case 2. A 56-year-old male presented with epigastric pain, and CT revealed swelling of the transverse part of the duodenum. EGD revealed a duodenal obstruction, and the lesion was impassable during the procedure. Subsequent endoscopic biopsy confirmed the presence of moderately differentiated adenocarcinoma. Microsatellite status evaluation, conducted using the PCR-based FALCO® test, indicated MSI-H. The RAS and BRAF genes were wild-type, as determined using the PCR-based RASKET-B method. IHC of HER2 and PD-L1 expression (CPS by 28-8 clone) was rated as 1+ and <5 (≥1, <5) judging from the criteria employed in gastric cancer. The institutional tumor board review concluded that the tumor was unresectable (Figure 2A). Therefore, systemic therapy was recommended following the clinical stage of T4N0M0 according to the 8th edition of the Union for International Cancer Control. In addition, the patient was evaluated as a potential candidate for conversion surgery, indicating the possibility of future resection. The 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) regimen was initiated as first-line therapy. After experiencing disease progression with FOLFOX therapy, the patient was treated with NIV (3 mg/kg, every 3 weeks) and ipilimumab (IPI, 1 mg/kg, every 3 weeks) based on data from colorectal cancer treatment. A partial response accompanied by low-grade dermatitis was confirmed on CT (Figure 2B). Further assessment using fluorodeoxyglucose positron emission tomography-CT demonstrated a complete metabolic response (Figure 3). Following the completion of NIV and IPI therapy, the patient underwent maintenance NIV (3 mg/kg, every 2 weeks), accompanied by dermatitis and adrenal insufficiency. A summary of these two cases is shown in Table I.
Computed tomography performed before (A) and after (B) nivolumab plus ipilimumab therapy in Case 2. Shrinkage of primary lesion was confirmed after immunotherapy.
Fluorodeoxyglucose (FDG)-positron emission tomography/CT performed after completion of nivolumab plus ipilimumab therapy in Case 2. The figure shows FDG uptake in the primary lesion disappeared (metabolic complete response).
Clinicopathological features and clinical outcomes in immunotherapy.
Patient perspective. Our patient (case 1) was refractory to several lines of chemotherapy and understood the risk of adverse events and the limited evidence for immunotherapy. By providing informed consent, the patient insisted we proceed with the immunotherapy. The other patient (case 2) was refractory to first-line therapy. Based on molecular status (MSI-H) and clinical evidence of immunotherapy for MSI-H cancers, we decided to proceed with immunotherapy as a salvage treatment.
Discussion
Here, we present two cases of metastatic or unresectable SBA treated with ICIs. These cases demonstrate the efficacy of ICIs for refractory SBA, regardless of MSI status. Importantly, the treatment landscape of immunotherapy for gastrointestinal tract cancers differs. ICIs have become part of the standard of care for esophagogastric carcinoma (8); however, their application in colorectal cancer is limited to MSI-H cases. The KEYNOTE-158 study reported a response rate of 42.1% to pembrolizumab monotherapy in MSI-H SBA (9). Previous studies have shown that the proportion of MSI-H patients with SBA is 8.6% (10), suggesting that immunotherapy may be a potent strategy in a subset of patients with advanced SBA. Therefore, patients with advanced SBA should undergo comprehensive analysis, including assessment of microsatellite status, and if MSI-H is present, immunotherapy should be considered as a core treatment strategy. Although MSI-H is a strong positive predictive marker for checkpoint inhibitors in esophagogastric adenocarcinoma (8, 11) and colorectal adenocarcinoma (12), response rates have been observed in MSS cases of esophagogastric adenocarcinoma but not in colorectal adenocarcinoma. However, the role of immunotherapy in treating advanced SBA remains unclear. The ZEBRA study investigated the efficacy of pembrolizumab in advanced SBA, and among 40 patients, four achieved partial response or unconfirmed partial response (13). Two of these patients were classified as MSS and had a high TMB (13.3 mutations/megabase, 11.6 mutations/megabase). Approximately 10% of SBA cases have high TMB levels, indicating the importance of high TMB as a marker of SBA (5). However, the present case was classified as MSS and had a low TMB. Similarly, a case report by Chen et al. described a patient with SBA without MSI-H and high TMB, who achieved a response lasting for 17 months (14). The patient was treated with an ICI and irinotecan. Previous studies have suggested that some patients with SBA without positive biomarkers may still respond to anti-PD-1 therapy; however, the likelihood is limited. Overall, further research is warranted to identify predictive markers for immunotherapy in SBA beyond MSI and TMB. In the second case, NIV plus IPI therapy was administered as second-line treatment. Previous studies have demonstrated the efficacy of pembrolizumab monotherapy (15), NIV monotherapy (16), and NIV plus IPI (17) in previously treated MSI-H colorectal adenocarcinoma, with overall response rates of 33%, 31%, and 69%, respectively. Although these studies are not directly comparable, combination therapy appears to have a stronger antitumor effect in terms of tumor response. Based on our tumor board discussion, the patient was recognized as a candidate for conversion surgery; therefore, combination therapy was chosen as the second-line treatment. In conclusion, ICIs demonstrated efficacy and appeared to be an important treatment option for metastatic SBA, regardless of MSI status. Further investigation and exploratory studies are warranted.
Conclusion
Treatment with immune checkpoint inhibitors was effective in treating refractory small bowel adenocarcinoma, irrespective of the microsatellite status.
Acknowledgements
The Authors thank Dr. Yuhei Yamaguchi and Dr. Takumi Ito for meaningful advice, and Editage (www.editage.jp) for English language editing.
Footnotes
Authors’ Contributions
Keiji Sugiyama: Conceptualization, Data collection, Writing - original draft; Seira Owaki, Mariko Sato, Kazuhiro Shiraishi, and Kyoko Kato: Writing - review and editing; Chiyoe Kitagawa: Supervision.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
Funding
This study did not receive any specific grants from funding agencies in the public, commercial, or non-profit sectors.
- Received October 2, 2023.
- Revision received October 26, 2023.
- Accepted October 27, 2023.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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