Clinical Drug Experience Knowledgebase

Gastrointestinal Neuroendocrine Tumours (NETs) are gaining increasing international recognition as a highly prevalent disease, responsive to a number of therapies, some of which are proven, but many of which still require high quality clinical trial evidence to confirm their effectiveness and guide their use in practice. This study is the first prospective trial to evaluate modern combination chemotherapy. Given the paucity of randomized studies in neuroendocrine carcinomas (NECs), there are no clear evidence based guidelines. Patients are treated according to guidelines established for small cell lung cancer. Although these tumors are initially highly chemosensitive, the natural history of this disease is such that relapses occur early, which ultimately leads to a very poor prognosis. Prospective clinical trials in this group of patients needs to be conducted to establish an evidence based standard of care and to improve prognosis. NETs are a heterogeneous group of malignancies originating from cells of the neural. They have a variable and often long natural history. They commonly arise from the gastrointestinal tract (58%), pancreas or lung (27%), and low grade NETs can be associated with symptoms resulting from the secretion of hormones or vasoactive peptides. NETs used to be thought of as rare but recently have been shown to be more common with rising incidence rates (3.3/100,000 in Australia 2000-2006). Prevalence (35/100, 000) is much higher than incidence resulting from five year survivorship of ~ 60% resulting in NETs being more prevalent than either gastric, pancreatic, oesophageal or hepatobiliary adenocarcinomas, or any 2 of these cancers combined. They can present multiple complex clinical challenges, thereby significantly contributing to cancer related morbidity and health costs in the Australian population. More recently, international interest groups such as the European Neuroendocrine Tumor Society have identified the need to establish a framework promoting opportunities for research and ensuring that the available evidence is incorporated into clinical practice guidelines.

Almost all clinical trials investigating cytotoxic chemotherapy in NECs are small single arm studies with guidelines derived from expert opinion and from extrapolating results from small cell lung cancer studies. Most guidelines recommend the combination of a platinum compound with etoposide. This combination is an established standard of care for small cell lung cancer, another tumour with neuroendocrine differentiation. However, the data are less clear for non-pulmonary neuroendocrine neoplasms (NENs) and NECs.

It is striking that almost all published NEC chemotherapy studies are non randomized and include relatively small numbers of patients often with heterogeneous pathology. Although there are no prospective studies with carboplatin and etoposide for NECs, it is remarkable that it is widely accepted as the standard chemotherapy for this disease.

A Phase 2 multi-center trial evaluating the efficacy of chemotherapy with paclitaxel, carboplatin and etoposide in advanced poorly differentiated NECs showed after 4 cycles of this combination treatment, patients who achieved an objective response or stable disease went on to have 24 weeks of weekly paclitaxel as maintenance treatment. Of the 78 patients treated, 15% had a complete response and the overall response rate was 53%. Five patients remained disease free from 18 to 66 months after therapy. The median survival was 14.5 months. However, the authors concluded that the 3 drug combination was moderately toxic and had no obvious efficacy advantage over the standard platinum/etoposide regimens.

This year (2013 ASCO) in an abstract a single European centre reported relative responses up to 50% in a retrospective series of NECs using 3 weekly paclitaxel, carboplatin and etoposide.

NAB paclitaxel is suggested to achieve a higher intracellular tumour paclitaxel concentration via the albumin mediated transendothelial transport system.

Participants will receive albumin-bound paclitaxel (ABRAXANE®) 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Carboplatin will be given at an Area Under the Curve (AUC) = 5 mg/min/mL on Day 1 only of each 21-day cycle administered over 30 mins, beginning immediately after the completion of albumin-bound paclitaxel administration. Participants can continue treatment at the investigator's discretion until disease progression, development of an unacceptable toxicity, or withdrawal of consent.