Stage I duodenal adenocarcinoma cured by a short treatment cycle of pembrolizumab: a case report

Introduction

According to the National Cancer Database (NCDB), the duodenum is the most common site of small bowel adenocarcinoma (SBA), although overall it is still a rare kind of malignant tumor. Traditionally, the primary therapeutic intervention for localized cases is endoscopic resection, a method bounded by restricted applicability and ambiguous long-term efficacy. Conversely, advanced cases predominantly undergo open surgery paired with chemotherapy, a strategy notwithstanding its potential for significant bodily harm but a propensity for postoperative complications. Moreover, the substantiality of chemotherapy in overall survival remains questionable [1]. Nowadays, immunotherapy has been widely applied in cancer treatment and has promising efficacy [2]. Immune checkpoint inhibitor (ICI) therapy has emerged as a novel alternative in oncological treatment, distinguishing itself by targeting specific biomarkers — deficiency in DNA mismatch repair (dMMR) and high microsatellite instability (MSI-H) — regardless of the organ site or histology involved [3]. At present, the guidelines strongly recommend that pembrolizumab be used alone for previously treated duodenal cancers that are unresectable or recurrent, and that have been indicated by immunohistochemistry or genetic testing as MSI-H or dMMR. However, can this indication be modified or broadened? In this article, we analyze the possibility with a case of pembrolizumab in the treatment of early-stage duodenal adenocarcinoma, which may provide some enlightenment for broadening the treatment indications of ICI.

Case presentation

A female in her 70s underwent a routine gastrointestinal screening because of a history of blood in her stool. A flattened bulge about 1.2 × 1.5 cm in size was incidentally revealed by gastroscopy on the anal side of the duodenal papilla without papilla involvement, with a depression in the middle, which was slightly stiff and shown a reddening on indigo carmine staining. Further refinement of the ultrasound endoscopy showed thickened mucosa and partial incompleteness of the submucosal layer at the lesion (Figure 1).

Figure 1:

Endoscopic and pathologic comparisons of the duodenal leison before and after ICI therapy. (A) A flat bulge found on the anal side of the duodenal papilla, with a depression in the middle; (B) amplified feature of the lesion under white light; (C) the depressed part of the lesion is reddened by Indigo rouge staining; (D) ultrasound endoscopy shows thickened mucosa and partial invasion of the submucosal layer; (E) only rough mucosa can be seen at the original lesion site 31 months after ICI treatment; (F) the mucosa is not obviously reddened by Indigo rouge staining; (G) pathological image of biopsy specimen before ICI treatment with adenocarcinoma cells; (H) pathological image of biopsy specimen after ICI treatment. Chronic inflammation of mucosal tissue with partial surface erosion and atrophy of villi is observed, without obvious tumor cells. ICI, immune checkpoint inhibitor.

Biopsy pathology suggested high-grade heterogeneous hyperplasia (WHO criteria)/moderately differentiated tubular adenocarcinoma > highly differentiated tubular adenocarcinoma (Japan criteria), immunohistochemistry (IHC) showed MLH1 (−), PMS2 (−), MSH2 (+), MSH6 (+). After endoscopy, the patient underwent positron emission tomography (PET)/CT, which showed a slightly elevated FDG metabolism in the local wall of the descending duodenum, with no distant metastases. Pancreaticoduodenectomy (Whipple) and chemotherapy were considered in a multi-disciplinary treatment. However, the patient may be intolerant to both of options due to advanced age and cardiovascular and cerebrovascular diseases. Considering a loss of function in the DNA mismatch repair protein MLH1, PD-1 inhibitor, pembrolizumab monotherapy was finally selected, with the regimen of pembrolizumab 200 mg (d1) in a 21-day treatment cycle [3]. The patient was then treated regularly for 2 cycles, with dizziness, mouth ulcers and rash occurring during the medication, all of which improved by symptomatic treatment. The patient didn’t return for further cycles for personal reasons, and she didn’t get any other treatment as well. 5 months after the second cycle, the repeat gastroscopy showed no significant change. However, in the repeat gastroscopy after 31 months of the second cycle, we were surprised to find that the original lesion was only visible as a rough mucosa with peristalsis, and no significant reddening on indigo carmine staining. Biopsy showed chronic inflammation, suggesting almost complete remission.

Discussion

Cells of dMMR tumors frequently exhibit programmed death ligand 1 (PD-L1) on their membranes, accompanied by a rich presence of infiltrating lymphocytes demonstrating elevated levels of checkpoint proteins, including programmed death 1 (PD-1). PD-1 related genes also have predictive value in immunotherapy [4]. As an ICI treatment spearhead, pembrolizumab is a humanized immunoglobulin G4 monoclonal antibody that interacts with the PD-1 receptor expressed on lymphocytes, inhibiting the binding of its ligands PD-L1 and PD-L2, and consequently rejuvenating T cell mediated antitumor activity. The response tends to be durable [5]. The standard treatment of pembrolizumab is 200 mg once every 3 weeks. The average response time is more than 1 year, and the maximum treatment duration can be more than 2 years. Studies have also used a dose of 10 mg/kg body weight every 2 weeks [6]. Endoscopic treatment grapples with limited indications and a high likelihood of incomplete resection and postoperative recurrence, while surgical approaches, though potent, pose significant risks and potentially severe adverse repercussions. Compared with the above two invasive treatments, ICI therapy is a non-invasive treatment. It requires less patient tolerance, but its efficacy and prognosis have not been fully elucidated. Now ICI treatment is confined to previously treated unresectable, or recurrent cancer [7]. According to real-world data on microsatellite instability status in various unresectable or metastatic solid tumors, the incidence of dMMR/MSI-H in duodenal cancer was at a relatively high level of approximately 5.60 % compared to other solid tumors [8]. Thus, ICI therapy should not be ignored in duodenal cancer. However, patients usually require durable treatment, the curative effect is usually far from satisfactory, and good prognosis in early or local tumors seems to be unsustainable in metastatic diseases [9]. In a study that evaluated the efficacy of PD-1 blockade in patients with advanced dMMR cancers across 12 different tumor types (including SBA), complete remission was achieved only in 21 % of patients, and the overall survival was not significantly prolonged [6].

The remarkable case elucidated a favorable outcome following just two cycles of pembrolizumab treatment in early-stage duodenal adenocarcinoma, and a significant deviation from the established norms of ICI therapy application, steering us towards a contemplative juncture to reassess the current therapeutic guidelines. What is the reason for that ICI therapy had a so ideal efficacy in early-stage duodenal tumors? We made the following conjectures. Firstly, tumor mutational burden (TMB) was considered closer to pembrolizumab efficacy, with both dMMR/MSI-H and MSS tumors with TMB≥10 mt/Mb being responsive to pembrolizumab treatment [9]. TMB tends to be lighter in early-stage tumors than in advanced-stage ones. The patient didn’t have a TMB test and it remains unknown if it made the sense. Secondly, tumor microenvironment (TME) varies according to tumor types and tumor progression, and it may affect the efficacy of ICI therapy. TME in an early-stage duodenal tumor may be more receptive to pembrolizumab [10]. Thirdly, individual differences in patients also have an impact on the efficacy of ICI treatment. For example, the frequency of MSI-H is higher in female patients and patients under 40 or over 80 years old [8], which encourages to identify patients who may have pathological indications of MSI-H at an early stage and guide the selection of subsequent treatment approaches. The case encourages us to delve into potential conjectures of ICI therapy for tumors, proposing that ICI therapy may have untapped potential in early-stage tumors. However, the hypothesis warranted rigorous scrutiny through well-orchestrated clinical and foundational research endeavors by clinicians and researchers to lay a more solid theoretical foundation. Besides, more precise indicators should be found to predict the responsiveness, and thus obtain more desirable results in selected patients. It’s also of great clinical significance, especially for early-stage duodenal cancer patients who cannot tolerate resection surgery. What’s more, ICI has been proven to have high safety, which can avoid postoperative complications and improve patient prognosis physically and psychologically. Can the indication of ICI therapy be modified or broadened in duodenal cancer? The pursuit of this answer, although long, holds a promise steeped in profound clinical and patient relevance.

Conclusions

In conclusion, ICI may have unexpected effect on therapy of early-stage duodenal cancer. More specific indicators need to be discovered for a more accurate indication for this kind of therapy.