Pancreatic adenosquamous carcinoma has a poor prognosis, with limited prospective trial data to guide optimal treatment. The potential impact of drug metabolism on the treatment response of patients with pancreatic adenosquamous carcinoma is largely unknown.
We describe the case of a 51 year old woman with pancreatic adenosquamous carcinoma who, following surgical resection, experienced early disease relapse during adjuvant gemcitabine therapy. Paradoxically, this was followed by an exceptional response to capecitabine therapy lasting 34.6 months. Strong expression of cytidine deaminase was detected within the tumour.
This case study demonstrates that early relapse during adjuvant chemotherapy for pancreatic adenosquamous carcinoma may be compatible with a subsequent exceptional response to second line chemotherapy, an important observation given the poor overall prognosis of patients with adenosquamous carcinoma. Cytidine deaminase is predicted to inactivate gemcitabine and, conversely, catalyze capecitabine activation. We discuss strong intra-tumoural expression of cytidine deaminase as a potential mechanism to explain this patient’s disparate responses to gemcitabine and capecitabine therapy, and highlight the benefit that may be gained from considering similar determinants of response to chemotherapy in clinical practice.
Pancreatic adenosquamous carcinoma is estimated to account for fewer than 10% of all pancreatic exocrine malignancies (reviewed in [
A previously well 51 year old white Caucasian woman presented with sudden onset right upper quadrant abdominal pain. She took no regular medication and had no medical, surgical or family history of note. Unenhanced computerised tomography (CT) imaging, used due to a pre-existing iodine allergy, identified a 4 cm mass in the head of the pancreas associated with marked pancreatic and mild bile duct dilatation (Fig. Head of pancreas carcinoma with adenosquamous and undifferentiated components; (
At this point the Eastern Cooperative Oncology Group Performance Status (ECOG PS) of the patient was 0. A pancreaticoduodenectomy with SMV resection was performed. Histology confirmed a biphasic carcinoma with adenosquamous and undifferentiated components (Fig.
Post-operatively, adjuvant gemcitabine (1000 mg m− 2 on days 1, 8 and 15 of a 28-day cycle) chemotherapy was administered as part of the European Study Group for Pancreatic Cancer (ESPAC) 4 Trial (UKCRN ID 4307; ISRCTN96397434). However, after the second cycle of gemcitabine, the patient reported further right upper quadrant pain. ECOG PS dropped to 1 and unenhanced CT confirmed multiple hypodense liver lesions of new onset in keeping with liver metastases (Fig. Radiological progression of liver metastases, by unenhanced CT.
After 19 weeks of capecitabine therapy ECOG PS returned to 0, and the patient returned to work full time. Haematological indices improved. No further PRBC transfusions were required after 24 weeks and tranexamic acid was stopped. Palmar-plantar erythrodysesthesia, 14.6 months into capecitabine therapy, prompted a switch to a 2 week on, 2 week off treatment schedule which was well tolerated. Restaging CTs after 13.8 and 32.3 months of capecitabine therapy confirmed stable, measurable disease, but with marked calcification of liver metastases, indicative of disease response (Fig.
Capecitabine was discontinued and FOLFIRINOX chemotherapy (5-FU 400 mg m− 2 bolus followed by 2400 mg m− 2 infusion over 46 h; irinotecan 180 mg m− 2; oxaliplatin 85 mg m− 2) started, with granulocyte-colony stimulating factor (GCSF) support. Due to peripheral neurotoxicity, the oxaliplatin dose was reduced by 20% for cycle 7 and discontinued from cycle 8. The patient completed 12 cycles of the reduced intensity chemotherapy. An end of treatment CT demonstrated stable partially calcified liver metastases, and this was followed by a treatment break. Surveillance CT 13.3 months after initiating FOLFIRINOX and 4 years 5.3 months after initial presentation, confirmed stable disease (Fig.
To better understand the treatment responses observed and to explore future treatment options, tumor targeted DNA sequencing, tumour CDA expression, and whole blood CDA activity were analyzed. Genetic analysis identified a G12D mutation in CDA protein expression within adenosquamous and undifferentiated tumour components. Formalin-fixed paraffin-embedded sections of adenosquamous (
The poor prognosis of patients with pancreatic adenosquamous carcinoma may impact on the decision to consider second line chemotherapy. In the case described, despite early relapse during adjuvant gemcitabine therapy, the patient proceeded to have a 34.6 month remission on second line capecitabine. This is an exceptional response. To our knowledge, this is the first documented case of a patient with adenosquamous cancer having an exceptional response to second line treatment, in the context of early disease relapse.
CDA mediates the inactivation of gemcitabine [
The choice of adjuvant chemotherapy for pancreatic adenosquamous cancer has, to date, been largely guided by trials conducted almost exclusively in patients with pancreatic adenocarcinoma [
We are grateful to the Pharmacokinetics and Bioanalytics Core Facility at the CRUK Cambridge Institute for whole blood CDA analysis.
All authors (CMC, RB, HW, SU, IB, JR, PC, TJ, DIJ) contributed to this manuscript. SU conducted the radiographic analysis. RB conducted the histological analysis. HW conducted the CDA immunohistochemistry. CMC, RB, HW, SU, IB, JR, PC, TJ, DIJ interpreted the data. CMC wrote the original manuscript; CMC, RB, HW, SU, IB, JR, PC, TJ, DIJ reviewed and edited the manuscript. All authors read and approved the final manuscript.
Not applicable.
This work was supported by Cancer Research UK (funding the lab of DJ) and the Cambridge Experimental Medicine Initiative (funding CMC). These funders did not have a role in the design, collection, analysis and interpretation of the data or the writing of the manuscript.
The data generated and / or analyzed during this study are included in this published article.
Verbal informed consent was provided from the patient described in this case report, and written consent was provided from their next of kin.
The patient died prior to publication. Written informed consent was obtained from the patient’s next of kin, which is available for review by the Editor.
The authors declare that they have no competing interests.
Cytidine deaminase
Computerised tomography
Eastern Cooperative Oncology Group Performance Status
Fluorouracil, irinotecan, oxaliplatin
Granulocyte-colony stimulating factor
Magnetic resonance
Packed red blood cells
Superior mesenteric vein
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.