Pancreatic cancer is the 7th most commonly diagnosed cancer in New Zealand, with increasing incidence over a 20 year period (1996-2017) (Te Aho O Te Kahu 2020) (1). Outcomes remain grim – the survival rate at 1 year is less than 50%, and 82% are diagnosed with locally-advanced or metastatic disease (SEER 2022) (2). For those diagnosed at early stage, current standard of treatment with surgery and chemotherapy offers only modest benefit (3, 4) - those receiving adjuvant modified FOLFIRINOX had a 3-year disease-free survival rate of 39.7%, and those receiving adjuvant gemcitabine, 21.4%. Adjuvant chemotherapy is also associated with significant morbidity – 75.9% of those who had adjuvant mFOLFIRINOX and 52.9% receiving gemcitabine had grade 3-4 adverse reactions (4).
There are no readily modifiable risk factors aside from smoking, obesity and H. pylori infection (5, 6). BMI of at least 30 kg/m2 was associated with a close to two-fold risk of developing pancreatic cancer (RR of 1.72)(5). Both smoking and H. pylori were associated with a summary relative risk ranging from 1.2 to 2.2 (6).
In NZ, disparities exist between Māori and non-Māori patients – Māori have a 50% increased risk of developing pancreatic cancer and were 12% more likely to die from pancreatic cancer compared to non-Māori, with higher rates of locally advanced/metastatic disease (7).
Although pancreatic cancer evolves in a stepwise fashion from precursor pancreatic intraepithelial neoplasia to invasive adenocarcinoma (8), in a similar manner to colorectal adenomas, there are no acceptable protocols for screening. A systematic review undertaken by the US Preventive Services Task Force Early found that there was low diagnostic yield for imaging-based screening, ranging from 0 to 75 cases per 1000 persons (9). Early detection and treatment of pancreatic precursor lesions, most commonly intraductal papillary mucinous neoplasms (IPMN), may be the best current strategy to prevent invasive pancreatic cancer with its associated morbidity and mortality (10).
The rates of IPMN progression to invasive cancer range from 7.77% at 10 years for low risk IPMNs to 25% at 10 years for high risk IPMN (11). Certain features are associated with higher risk of evolving into malignancy, namely cyst size of greater than 3 cm, cyst wall enhancement, solid components within the cyst, multicystic lesions, serum CEA > 5, serum CA 19-9 >37 IU/ml, neutrophil-to-lymphocyte ratio of > 2, and platelet-to-lymphocyte ratio of > 120 (12). Certain genomic features are also associated with high risk; DNA sequence variants in TP53, SMAD3, CDKN2A, PIK3CA, which were associated with high-grade dysplasia and/or carcinoma, whereas GNAS and KRAS were associated with low-grade dysplasia (13). A gene expression meta-analysis looking at 12 low-risk and 23 high-risk IPMNs identified 270 upregulated, and 161 downregulated genes in high risk IPMN (14).
High-risk lesions are usually recommended to have surgical intervention, although these operations are associated with significant morbidity and mortality - the 30 day mortality rates from pancreatoduodenectomy and total pancreatectomy were 2.9% and 5.4% respectively, and overall morbidity rates were 34.7% and 31.9% (15). As a result, a substantial proportion of patients are unable to have major surgery and adjuvant chemotherapy due to significant comorbidities.
IPMN are usually diagnosed incidentally on CT or MRI scans performed for another reason. In the Northern Region of NZ, 1450 IPMN were diagnosed in patients in 2019 and 2020 (personal communication, Dr Marius van Rijnsoever). Ethnicity information was available for 736 patients, of whom 98 (13%) were Māori and 52% were NZ European. Each year about 40-50 EUS-guided aspiration procedures have been performed to further assess IPMN considered to be at increased risk of transformation into invasive malignancy. Of 353 such cases in the last 10 years, 15% and 4% of cases were recorded in Māori and Pasifika, respectively.
Endoscopic Ultrasound-guided Pancreatic Cyst Ablation (EUS-PCA)
Over the last 15 years, endoscopic ultrasound-guided pancreatic cyst ablation (EUS-PCA) has been established as an effective minimally-invasive alternative to surgery (16). Initial studies have utilised single agent ethanol (17), with the subsequent addition of intralesional paclitaxel and replacement of ethanol with 0.9% sodium chloride, and most recently, the addition of gemcitabine to paclitaxel (18). A study by Dewitt et al compared injection of ethanol versus saline lavage – ethanol resulted in a mean reduction of 42.9% but this is associated with significant rates of pancreatitis (4-5%) (17). Adding paclitaxel to ethanol increased cyst ablation rates with minimal change in toxicity (16). Further small trials showed that injection of paclitaxel and gemcitabine was safe and effective (about 65% complete response rates at 12 months) and, in the CHARM trial by Moyer et al, was equally effective with fewer complications than the same chemotherapy drugs given with ethanol (18-20). Furthermore, longer follow-up of patients showed sustained benefit without relapse in >95% of patients with complete response, at a median of 6 years post-EUS-PCA (10). About 8% of patients in this trial underwent surgery for persistent cysts.
In the setting of later stage cancer, the MPACT trial established gemcitabine/nab-paclitaxel as a standard of care in metastatic pancreatic adenocarcinoma – patients who received combination treatment with gemcitabine/nab-paclitaxel had higher overall survival rates of 4% at 3 years versus 0% with gemcitabine alone (21). Adjuvant single agent gemcitabine has also been shown to result in significant improvement in 5-year disease-free survival (DFS) (16.0%) versus those undergoing observation alone (6.5%) (22).