Gemcitabine, Cisplatin, and Durvalumab for Alpha-Fetoprotein-Producing Cancer of Unknown Primary Suspected from the Biliary Tract: A Case Report

Abstract

Introduction

Cancer of unknown primary (CUP) often presents with distant metastases, and chemotherapy remains the standard treatment. Chemotherapeutic regimens are selected based on tumor marker profiles and immunohistochemical staining of tumor cells, with the most suitable agents chosen according to the presumed primary site. Until recently, chemotherapy for biliary tract cancer has typically consisted of a combination of gemcitabine and cisplatin (CDDP). However, immune checkpoint inhibitors (ICIs) have also been introduced in recent years.

Case Presentation

We report the case of a 67-year-old man who was found to have elevated serum alpha-fetoprotein (AFP) levels and enlarged lymph nodes at the hepatic on abdominal-pelvic CT. EUS-FNA/B and laparotomy biopsy of the lymph nodes confirmed a diagnosis of AFP-producing adenocarcinoma. Immunohistochemical staining demonstrated positivity for CA19-9, CK19, and CK20, suggesting a biliary tract origin. After initial chemotherapy treatment, the regimen was switched to a combination of gemcitabine, combination of gemcitabine and cisplatin, and durvalumab (GCD), and treatment was continued. Six months after initiating GCD therapy, the patient achieved a partial response on CT imaging and was transitioned to durvalumab monotherapy for maintenance. Tumor shrinkage persisted, and maintenance therapy with durvalumab alone was successfully sustained for 24 months. Following subsequent disease progression, rechallenge with GCD therapy again proved effective, and a 3-year overall survival was achieved.

Conclusion

Although CUP generally carries a poor prognosis, GCD therapy may represent an effective option for CUP with suspected biliary tract origin.

Introduction

Cancer of unknown primary (CUP) is a malignancy characterized by distant metastases with no identifiable primary lesion. It accounts for approximately 3–5% of all malignancies. Although certain subtypes of CUP respond well to specific therapies, resulting in long-term survival in 15–20% of cases, the overall prognosis remains poor, and no standardized treatment strategy has been established [1–3].

For biliary tract cancer, combination chemotherapy with gemcitabine and cisplatin has long been the standard of care [4]. However, recent studies have demonstrated the efficacy of incorporating immune checkpoint inhibitors (ICIs), such as durvalumab or pembrolizumab, into gemcitabine and cisplatin regimens [5–7]. Consequently, ICIs have become increasingly integrated into clinical practice.

Here, we describe a case of CUP presumed to originate from the biliary tract, in which the patient achieved a favorable response to combination therapy with gemcitabine, cisplatin, and durvalumab (GCD).

The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000553541).

Case Report

A 67-year-old man presented with elevated alpha-fetoprotein (AFP) levels detected during follow-up after achieving sustained virologic response (SVR) for chronic hepatitis C. Abdominal and pelvic computed tomography (CT) revealed enlarged lymph nodes in the hepatic hilum (Fig. 1a). Endoscopic ultrasound-guided fine-needle aspiration/biopsy and laparotomy lymph node biopsy confirmed the diagnosis of AFP-producing adenocarcinoma (Fig. 2a, b). Immunohistochemical staining was positive for CA19-9, CK19, and CK20 (Fig. 2c–e), and negative for glypican-3, suggesting a biliary tract origin. Despite comprehensive imaging, including CT, contrast-enhanced magnetic resonance imaging, positron emission tomography-CT, as well as upper gastrointestinal endoscopy and colonoscopy, no primary tumor was identified (Fig. 1a–c).

Fig. 1.

a Contrast-enhanced abdominal and pelvic CT showing enlarged lymph nodes in the hepatogastric ligament (blue arrow). The primary site remains unclear. b EOB-MRI revealing a mass in the hepatogastric ligament with a maximum diameter of 7 cm. c PET-CT showing high uptake in the hepatogastric ligament and para-aortic region.

Fig. 2.

a Hematoxylin and eosin staining confirmed the diagnosis of adenocarcinoma. b AFP staining. c CA19-9 staining. d CK19 staining. e CK20 staining.

Following review by a multidisciplinary cancer board comprising medical oncologists, surgeons, pathologists, and radiologists, chemotherapy for CUP of presumed biliary tract origin was recommended. The patient initiated gemcitabine and cisplatin (GC) therapy, achieving a partial response (PR) on CT after 2 months. After 3 months, treatment was escalated to the GCD regimen.

After 6 months of GCD therapy (9 months from treatment initiation), PR was sustained according to RECIST criteria (Fig. 3), and maintenance therapy with durvalumab monotherapy was commenced. At 14 months, the patient maintained a PR on CT, with AFP levels decreasing from 1,637.0 ng/mL at baseline to 246.0 ng/mL and CA19-9 levels dropping from 166.1 U/mL to 19.0 U/mL (Fig. 4).

Fig. 3.

CT scans at baseline (a, e) and at 6 (b, f) and 12 (c, g) months after the start of treatment showed significant shrinkage of the lymph nodes in the hepatogastric ligament (blue arrow) and the para-aortic lymph nodes (yellow arrow). However, the para-aortic lymph nodes regrew at 24 months (d, h).

Fig. 4.

Trends in AFP and CA19-9 levels.

The patient received durvalumab monotherapy for 24 months, until CT imaging demonstrated progression in the lymph nodes (Fig. 3), at which point a new therapeutic strategy was initiated. The patient was subsequently treated with S-1 monotherapy; however, AFP levels rose and CT imaging revealed enlargement of the lymph nodes, indicating a lack of response. At 36 months, rechallenge with GCD therapy was performed, resulting in a renewed decline in AFP levels, and the patient ultimately achieved a 3-year overall survival.

Discussion

This case illustrates the potential of GCD therapy to achieve durable disease control in AFP-producing CUP of presumed biliary tract origin. Although CUP generally carries a poor prognosis, our findings suggest that applying site-specific treatment strategies based on presumed origin can improve outcomes, even in rare subtypes such as AFP-producing adenocarcinoma.

GCD therapy, adapted from the standard regimen for biliary tract cancer, provided significant clinical benefit [5, 7]. The patient achieved PR after 6 months and maintained this response with durvalumab for an additional 24 months. These results highlight the possibility of achieving prolonged survival by tailoring biliary tract cancer treatment approaches to CUP cases, with strongly suspected biliary origins. Notably, the TOPAZ-1 trial demonstrated improved 2-year survival with durvalumab plus gemcitabine-cisplatin (23.6%; 95% CI: 18.7–28.9) compared to chemotherapy alone (11.5%; 95% CI: 7.6–16.2), reinforcing the value of ICIs in biliary tract malignancies [8–11]. Although durvalumab has not yet been established as standard therapy for CUP, this case supports its potential utility in selected patients. In the present case, rechallenge with GCD therapy after disease progression also proved effective, yielding a renewed decline in AFP levels and contributing to the achievement of 3-year overall survival. Although robust evidence for the rechallenge of ICIs remains limited, several systematic reviews have reported that ICI rechallenge can be effective in selected patients [12, 13], and our case similarly demonstrated a favorable response, supporting the potential value of this strategy.

AFP-producing extrahepatic cholangiocarcinoma is exceedingly rare, with limited cases reported in the literature (Table 1) [14–16]. Although AFP is most commonly associated with hepatocellular carcinoma, elevated AFP levels have been reported in gastric and ovarian malignancies and in intrahepatic cholangiocarcinoma [17–20]. There is no standard chemotherapy for AFP-producing tumors; thus treatment should be guided by the tumor’s origin. In this case, immunohistochemical findings supported a biliary tract origin, and GCD therapy – modeled after standard biliary tract cancer regimens – proved effective. This suggests that GCD may offer a viable approach even for rare AFP-producing subtypes [21].

Table 1.

Reported cases of alpha-fetoprotein-producing extrahepatic cholangiocarcinoma

Reference	Age, years	Gender	Primary site	Treatment	Outcome
12	79	Female	Distal	Surgery	No recurrence
13	49	Female	Distal	Surgery	No recurrence
14	65	Male	Distal	FOLFOX	48-month survival
Our case	67	Male	CUP	GCD	36-month survival

Our case is the first reported case of unknown primary suspected from the biliary tract.

CUP, cancer of unknown primary; GCD, gemcitabine, cisplatin, and durvalumab; FOLFOX, leucovorin, 5-fluorouracil, and oxaliplatin.

Serum AFP levels were instrumental in monitoring treatment response and disease progression. The baseline AFP level of 1,637.0 ng/mL declined to 246.0 ng/mL during therapy, correlating with imaging findings and underscoring AFP’s utility as a biomarker in this context. CA19-9 levels mirrored this trend, providing complementary evidence of therapeutic efficacy.

Finally, although ICIs are associated with immune-related adverse events (irAEs), the patient tolerated durvalumab monotherapy well, with no significant irAEs reported over 24 months of treatment. This favorable safety profile highlights the feasibility of incorporating ICIs into treatment strategies for AFP-producing biliary tract CUP in appropriately selected patients [22].

In conclusion, this case underscores the potential efficacy of GCD therapy in achieving long-term disease control in AFP-producing CUP presumed biliary tract origin. Serum AFP levels served as valuable biomarkers throughout treatment, and durvalumab maintenance therapy was effective and well tolerated. Further studies are warranted to validate those findings and to optimize treatment strategies for this rare and challenging disease subset.

Statement of Ethics

This study was conducted in accordance with the Ethical Principles for Medical Research Involving Human Subjects as outlined in The Declaration of Helsinki. Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

H.K. received honoraria from Gadelius Medical. All remaining authors declare that they have no conflict of interest.

Funding Sources

No funding was received for this study.

Author Contributions

K.S.: conceptualization, data curation, writing – original draft, and writing – review and editing. S.N., M.F., M.K., Y.O., N.K., R.M., and N.M.: writing – review and editing. S.M.: pathological diagnosis and writing – review, and editing. H.K.: supervision, writing – review and editing, and final approval of the manuscript.

Funding Statement

No funding was received for this study.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.