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FOLFIRINOX as First-Line Treatment for Unresectable Acinar Cell Carcinoma of the Pancreas: A Case Report FOLFIRINOX als Erstlinientherapie beim inoperablen Azinuszellkarzinom des Pankreas: Ein Fallbericht Authors

U. Schempf1, B. Sipos2, C. König3, N. P. Malek1, M. Bitzer1, R. R. Plentz1

Affiliations

1

3

Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany Institute of Pathology, University of Tuebingen, Tuebingen, Germany Department for Diagnostic and Interventional Radiology, University of Tuebingen, Tuebingen, Germany

Schlüsselwörter

Zusammenfassung

Abstract

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Azinuszellkarzinome (ACC) des Pankreas sind seltene Varianten des duktalen Adenokarzinoms des Pankreas. Die Chirurgie ist die einzige kurative Therapieoption und Protokolle für palliative Chemotherapien sind in diesem Zusammenhang noch nicht standardisiert. Wir berichten über einen 63-jährigen, weißen Patienten, der sich mit schmerzlosen Ikterus, Gewichtsverlust, erhöhtem Bilirubin sowie einem Pankreaskopftumor und Lebermetastase vorstellte. Die bioptische Sicherung der Pankreasläsion ergab den Nachweis eines ACC. Eine Therapie mit FOLFIRINOX führte zu einer signifikanten Verkleinerung des Primärtumors und einer Rückläufigkeit der Lebermetastase. Unser Fallbericht zeigt, dass FOLFIRINOX eine gut verträgliche Therapiemöglichkeit des inoperablen ACC darstellt und möglicherweise überlegen zu anderen chemotherapeutischen Substanzen ist .

Pancreatic acinar cell carcinoma (ACC) is a rare, aggressive variant of pancreatic ductal adenocarcinoma. Surgery is the only curative treatment option and protocols for palliative chemotherapies in this context are not standardized yet. We reported a 63-year-old white male patient who had painless jaundice, weight loss, elevated bilirubin, and a mass of the pancreatic head as well as liver metastasis. Core biopsy revealed the diagnosis of ACC. Therapy with FOLFIRINOX resulted in a significant decrease of the primary tumor and regressiveness of a liver metastasis after chemotherapy. Our report suggests that pancreatic ACC treated by FOLFIRINOX is well tolerated and might be superior to other single chemotherapies in this rare tumor disease.

Introduction

Case Report

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Acinar cell carcinoma (ACC) is a rare malignancy of the exocrine pancreas, accounting for up to 1 % of all pancreatic tumors [1 – 7]. Similar to other pancreatic cancer diseases, ACC is characterized by early metastasis at the time of diagnosis, this makes it often unsuitable for curative surgery. However, there are only single reports about the significant value of systemic chemotherapy [7 – 12]. Due to low patient numbers, the best treatment approach for unresectable ACC remains still unclear. Here, we present a case of unresectable pancreatic ACC treated successfully with FOLFIRINOX [13] in analogy to the standard therapy treatment of pancreatic ductal adenocarcinomas.

A 63-year-old white man was referred to our department with painless jaundice, existing for one week, in March 2012. He reported about a weight loss of 12 kg in the last three months. He denied fever, night sweat, chills, nausea or vomiting. He had a medical history of atrial fibrillation, chronic obstructive bronchitis and diabetes mellitus type 2. His physical performance status was excellent. Blood tests showed signs of cholestasis (bilirubin 15.6 mg/dL [normal up to 1.1 mg/dL], AP 315 U/L [normal 40 – 130 U/L], gGT 397 U/L [normal up to 60 U/L]). Lipase serum level and tumor markers (CEA, CA 19 – 9) were unchanged. An ultrasound scan confirmed an intra- and extrahepatic cholestasis syndrome. An additionally performed CT scan revealed a locally advanced and lymphogenic metastasized tumor of the pancreatic

● Azinuszellkarzinom (ACC) ● FOLFIRINOX ● Pankreas " "

Key words

● acinar cell carcinoma (ACC) ● FOLFIRINOX ● pancreas " " "

received accepted

8.6.2013 19.12.2013

Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1356439 Z Gastroenterol 2014; 52: 200–203 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0044-2771

Correspondence PD Dr. Ruben R. Plentz Internal Medicine I, Medical University Hospital Otfried-Mueller-Str. 10 72076 Tuebingen Germany Tel.: ++ 49/70 71/2 98 43 38 Fax: ++ 49/70 71/29 59 06 Ruben.Plentz@med. uni-tuebingen.de

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Kasuistik chromogranin-A, CD56, Muc-1, Muc-2, CEA-M, and CA 19 – 9 were not detected. Beta-catenin exhibited a regular membranebound staining. The proliferation rate determined by the MIB-1 " Fig. 2 d). In summary, histoloantibody was focally about 40 % (● gical findings were in line with ACC of the pancreas. The case of the patient was presented at our in-house cancer conference and palliative chemotherapy was recommended. Taking into account the excellent performance status and the nearly unchanged lab parameters with declined bilirubin level after implantation of a plastic endoprothesis into the biliary duct, we recommended FOLFIRINOX [biweekly chemotherapy regimen with 5-FU (400 + 2400 mg/m²), oxaliplatin (80 mg/m²) and irinotecan (180 mg/m²)] treatment. Two months after the start of chemotherapy we performed a new imaging study. The CT scan showed remarkable shrinkage of the pancreatic tumor mass, liver dissemination was stable. In addition chemotherapy was well tolerated, no severe complications were observed and the patient gained weight again. Five months

Fig. 1 Inhomogenous tissue in the pancreatic head (a arrow head), representing the ACC and suspected liver lesion (b arrow head) detected by CT scan before start of the chemotherapy. After two months of chemotherapy the liver tissue underwent fatty degeneration and the initial suspicion of the existence of a liver metastasis could be confirmed by CT scan (c arrow head).

Fig. 2 Histological images of the ACC. a Solid tumor cell sheets embedded in paucicellular fibrous stroma (H&E staining). b Fine granular pattern in the cytoplasm (PAS staining). c Strong immunolabelling for bcl-10 which is an acinar cell marker (DAB labelling). d Proliferation rate up to 40 % by Ki67 (MIB1 antibody). All pictures were taken at 400 × magnification.

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" Fig. 1a, b). However, the liver head and suspect liver formation (● lesion was initially not well detected due to low contrast. Confirmation of hepatic dissemination was initially achieved by contrast-enhanced ultrasound. After two months of chemotherapy, the patient developed a chemotherapy-induced fatty degeneration of the liver tissue and the initial suspicion on the existence of a hepatic metas" Fig. 1c). Due to obstructive tasis could be confirmed by CT scan (● jaundice by ACC, an endoscopic retrograde cholangiopancreatography (ERCP) with papillotomy and implantation of a plastic endoprothesis was performed. Next, a core biopsy of the pancreatic tumor was performed. Histological examination showed large solid tumor cell nests, which were composed of polygonal tumor cells showing eosinophilic " Fig. 2a). The round nuclei exhibited a moderate cytoplasm (● polymorphism with small nucleoli. Some areas contained broad hypocellular fibrous bands. PAS stain revealed focal granular po" Fig. 2a). Immunohistochemically, cytokeratin 7 and sitivity (● " Fig. 2c) showed a strong expression. Synaptophysin, bcl-10 (●

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after the start of FOLFIRINOX treatment, the patient asked for a chemotherapy break to visit family in his home country. In total, treatment was stopped for six weeks. After this break we decided to modify our therapy regime due to slight polyneuropathic disorders during the last chemotherapy cycles and to keep an option if progress would be detected in the future. Finally, we continued FOLFIRI (5-FU 400 + 2400 mg/m² and irinotecan 180 mg/m²) and stopped oxaliplatin exposition. After three more months of chemotherapy de-escalation the primary tumor mass was constant " Fig. 3a). After another four months of treatment, the liver me(● " Fig. 3a, b). tastasis could no longer be detected on the CT scan (● On request of the patient a further therapy break was taken for a period of 6 months. After the break, the pancreatic tumor mass was still stable and the chemotherapy was continued with FOLFIRI. Until now the tumor stage is unchanged and patient’s quality of life is acceptable.

Discussion !

Pancreatic ACC is a rare subgroup of pancreatic tumors, accounting for 1 % of all pancreatic neoplasms [1 – 7]. Many ACCs are diagnosed already with metastases and have to be classified as unresectable tumors. Thus, it is of high interest to improve palliative treatment models to improve survival rates. Currently, there are

only few case reports and review articles about chemotherapy in patients with pancreatic ACC available. However, studies about locally advanced ACC reported about the benefit of chemoradiation with 5-FU, gemcitabine or capecitabine as chemosensitizing agents [1, 9, 10, 14]. Butturini et al. reported about postoperative gemcitabine-based chemotherapy [15]. For metastasized ACC a few reports favour 5-FU therapy [1, 16, 17]. Simon et al. reported that a patient with pancreatic ACC was treated with FOLFOX 4 after progression under gemcitabine chemotherapy [10]. FOLFOX 4 treatment resulted in a radiological and clinical improvement. Yamamoto and Seki et al. found an advantage of S1 monotherapy in ACC [8, 12]. In contrast gemcitabine application was not satisfactory [12]. Recently, Morales et al. showed the advantage of panitumumab as a third-line chemo" Table 1 summarizes the therapy in two patients with ACC [11]. ● current state of literature [7, 8, 10 – 12, 17 – 20]. Remarkable is that most of the data are from case reports and show a wide range of different chemotherapy substances without a final recommendation for a standard therapeutic approach. In conclusion, our report on a patient with pancreatic ACC treated by FOLFIRINOX showed a good initial response with decreased primary tumor and liver metastasis. Further studies are necessary to confirm FOLFIRINOX treatment for patients with unresectable pancreatic ACC as a first-line therapy compared to other chemotherapeutic drugs.

Fig. 3 After eight months of chemotherapy a long-segment atrophy of the pancreas (a arrow head) was detected by CT scan. After twelve months of de-escalated chemotherapy the liver showed no signs of cholestasis and no liver metastasis (b arrow head).

Table 1

Overview about current literature on chemotherapeutic treatment options of primary unresectable ACC.

publication

year

chemotherapy

survival

number of

Sorscher et al. [17]

2008

cisplatin/etoposid, paclitaxel, gemcitabine/5-FU/leucovorin

progression free after > 41 weeks

1

Seki et al. [12]

2009

gemcitabine, S-1

patient 1: BSC after 21 months patient 2: BSC after 2 months patient 3: BSC after 56 weeks patient 4: BSC after 6 months

4

Distler et al.[18]

2009

“neoadjuvant” 5-FU for 12 months

no recurrence for > 18 months after 1 resection

Antoine et al. [19]

2009

gemcitabine/irinotecan, gemcitabine/oxaliplatin, docetaxel/capecitabine, gemcitabine/erlotinib, phase I study of cisplatin/protein kinase C inhibitor sunitinib/sirolimus

3 years

Armstrong et al. [20]

2011

paclitaxel/thalidomide, capecitabine, imatinib, etoposid, liposomal 70 months doxorubicin, sorafenib/temozolomid, albumin bound paclitaxel/ bevacizumab

patients

1

1

Simon et al. [10]

2011

gemcitabine, FOLFOX 4

progression free after 2 years

1

Yamamoto et al. [8]

2011

S-1

resection after 5 cycles, recurrence free for 2 years after resection

1

Lowery et al. [7]

2011

gemcitabine/oxaliplatin, gemcitabine/docetaxel/capecitabine, cisplatin/irinotecan, cisplatin/gemcitabine, gemcitabine/erlotinib

median overall survival 19.6 months

18 (unresectable at first diagnosis)

Morales et al. [11]

2012

capecitabine/oxaliplatin, irinotecan/capecitabine, FOLFIRI/bevacizumab, panitumumab

12 and 15 months

2

BSC = best supportive care

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Kasuistik

FOLFIRINOX as first-line treatment for unresectable acinar cell carcinoma of the pancreas: a case report.

Pancreatic acinar cell carcinoma (ACC) is a rare, aggressive variant of pancreatic ductal adenocarcinoma. Surgery is the only curative treatment optio...
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