SIEGE
Pancreatic cancer is caused by abnormal cells growing in an uncontrolled way in the pancreas. The most common type of pancreatic cancer is pancreatic adenocarcinoma (PDAC). Because symptoms of PDAC are hardly noticed, most patients are diagnosed at the later stage. A current standard treatment for PDAC patients with cancer spreading to other parts of the body (metastatic PDAC) is a combination chemotherapy regimen using two drugs - nab-paclitaxel (nabP) and gemcitabine (Gem). They are routinely given on days 1, 8 and 15 of a 28 day cycle intravenously, one after the other on the same day.
SIEGE (Scheduling nab-paclItaxEl with GEmcitabine) was a UK multi-centre, randomised phase II trial. It was designed to test in patients an observation in mice experiments that suggested the mice lived longer if nabP was given at least 24 hours before Gem. 146 patients with metastatic pancreatic cancer took part in the trial. They received either standard same-day dosing, or next-day dosing, where Gem was given 24-h after nabP. The primary goal of the study was to measure how long it took for tumours to grow in the 2 groups of patients treated using the different dosing schedules.
The trial results were published in 2020 (ref). The results showed that more patients responded to treatment using next-day dosing schedule, where Gem was given 24-h after nabP and the period of time before tumours grew again (progress-free survival, PFS) increased slightly compared with the standard same-day dosing of the 2 drugs. Yet there was no difference found on how long people lived overall after the treatment (overall survival, OS) between two groups. The benefits of next-day dosing were therefore not sufficient to justify changing how the treatment is usually given.
The team looked to see whether there were any patient characteristics or blood tests that might identify those patients who might benefit more from treatment (ref). The strongest predicters were patient fitness (also referred to as ‘performance status’) and the presence of liver metastases at the start of treatment. In terms of blood tests, a fall in albumin level during the 8-week period after starting treatment appeared to correlate with poorer survival, whilst other inflammatory markers were not useful predicters of survival. Cancers shed pieces of their genetic material, called DNA, into the bloodstream and this can be measured as circulating tumour DNA, or ctDNA. Looking for specific ctDNA involving a gene called KRAS, which is characteristic of PDACs, patients with detectable KRASmutant ctDNA prior to starting treatment had worse survival compared with those in whom it was undetectable. More research is needed to find out how useful ctDNA measurement might be in the future.