The doxorubicin-streptozotocin combination for the treatment of advanced well-differentiated pancreatic endocrine carcinoma

Abstract

Due to their rarity, only few trials have studied the role of the doxorubicin-streptozotocin (DS) combination in advanced well-differentiated pancreatic endocrine carcinomas (AWDPEC). However, the published results are inconsistent. We reviewed all AWDPEC (5-year period, 45 patients) treated in our institution with the DS combination for: objective response rate (ORR), progression-free survival, overall survival (OS) and toxicity. An ORR of 36% (95% Confidence Interval (CI) 22–49) was obtained, with 16 partial responses (PR). The mean duration of PR was of 19.7 months. Two and 3-year OS rates were 50.2 and 24.4%, respectively. Toxicities were mainly digestive (grade ⩾3 vomiting, 13%) and haematological (grade ⩾3 neutropenia, 24%). Previous systemic chemotherapy and malignant hepatomegaly were associated with a poorer ORR (P=0.033, P=0.016) and OS (P=0.008, P=0.045). Multivariate analysis demonstrated previous chemotherapy as the only independent predictive-factor for survival (P=0.013). In conclusion, our data confirm the sensitivity of AWDPEC to the DS combination, with an ORR of 36% and a remarkable median response duration of 19.7 months, and suggests that it could be considered as a valid option in first-line therapy.

Introduction

Pancreatic endocrine carcinomas (PECs) are rare malignancies, accounting for less than 2% of all gastrointestinal tract malignant tumours and less than 1% of endocrine tumours [1]. They can be classically divided in 2 groups, based on the potential presence of typical clinical symptoms at disease onset: “functional” and “non-functional” pancreatic tumours, respectively 2, 3, 4. Approximately half of PECs express at least one active hormone, such as insulin, gastrin, glucagon or somatostatin. These are responsible for intermittent and often typical, but non-specific, symptomatology. Non-functional tumours are usually diagnosed at a later stage, based upon symptoms related to the tumour burden itself [4].

Therapeutic management of PEC represents a challenge for the physician. Treatment choice is dictated by pathological differentiation and the stage at diagnosis, as well as by the presence of hormone-related symptoms. Well-differentiated PEC (WDPEC) are usually slow-growing tumours that sometimes allow for therapeutic abstention. However, they can display accelerated progression, requiring a much more aggressive attitude to treatment. In the case of localised WDPEC, surgery remains the only curative treatment. However, in the peculiar situation of multiple gastrinomas as part of the MEN1 syndrome, the debate is still open.

WDPEC are considered relatively chemosensitive neoplasms and in cases of a high tumour burden and/or rapidly progressive metastatic disease, chemotherapy is an appropriate therapeutic option 5, 6, 7, 8, 9. First data concerning chemotherapeutic effectiveness in WDPEC date back to 1968, when Murray-Lyon and colleagues reported a case of insulinoma responding to streptozotocin [9]. Since then, several chemotherapeutic agents, including doxorubicin and dacarbazine (DTIC), have been evaluated as single agent therapy. Both demonstrated interesting effects in advanced WDPEC (AWDPEC), with 20–30% response rates, and a tolerable toxicity profile 6, 8. Later, Moertel and colleagues demonstrated, in a prospective randomised trial comparing doxorubicin-streptozotocin (DS), streptozotocin/5-fluorouracil and chlortozotocin, an objective response rate (ORR) of 69% with a median survival of 26.5 months in the DS arm, results that were significantly superior to those of the other 2 regimens. This association became thereafter a standard therapy for progressive AWDPEC. However, a recent study failed to confirm the outstanding anti-tumour activity of the DS combination [10]. Such discrepant results prompted us to review our institution experience of DS in AWDPEC treatment, with three main aims: (1) ORR, (2) toxicity, (3) prognostic parameters of objective response and survival.