Coming theses from other universities

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest and most treatment resistant types of cancer. Annually, 1500 persons are diagnosed with PDAC in Sweden and just as many succumb to the disease. In the last 15 years there has been a slow change for the better with new more effective treatment combinations for both the postoperative and palliative settings, as well as neoadjuvant approaches in borderline resectable cases and consequently five-year survival has slowly risen to almost 10% in Sweden.

The two main additions to the treatment toolbox, the combination chemotherapy regimens FOLFIRINOX and Gemcitabine/nab-paclitaxel (GnP), both came at the expense of increased toxicity. One of these, GnP, showed less than two months median survival benefit in the underlying randomized controlled trial, and as many PDAC patients are frail and old, the first aim of this thesis was to establish real-world evidence on this treatment and find potential prognostic markers associated with survival benefit in this treatment group.

Survival among the 75 first GnP treated patients in the Swedish South East health care region was almost a year (10.9 months) (Paper I) and the frequency of bone marrow toxicity was lower than expected. High pre-treatment S-Albumin and old age was associated with improved survival (Paper II) encouraging the use of this treatment in older patients.

The second half of this thesis focuses on PDAC in the postoperative setting. In the minority of PDAC patients with resectable disease more than 75% have relapses within two years despite curative intent surgery and adjuvant chemotherapy. Alternatives to Gemcitabine treatment have emerged in the adjuvant setting, mainly including FOLFIRINOX and GemCape. As there are no predictive markers available, prognostic information has become more important to guide the clinical decision making.

In a large retrospective cohort, representing a decade of pancreatic resections in the Swedish South East health care region, we show that the prognostic value of resection margin status can be sharpened by subdividing microscopically non-radical resections by margin distance as well as margin type. Furthermore, the relapse-free and overall survival in patients with extensive spread to lymph nodes, i.e. metastases in the para-aortal lymph nodes (PALN), were very poor. The benefit of surgery in this group of patients is questionable and should be subject for prospective trials (Paper III). To assess tissue based biomarkers a tissue microarray (TMA) based on this cohort as well as cohorts of PDAC resection specimens from the Swedish North and West health care regions was produced. The expression of dihydropyrimidine dehydrogenase (DPD), a key enzyme in the metabolism of antimetabolites, was assessed in the TMA with immunohistochemistry. DPD showed prognostic value in Gemcitabine treated patients, with poor survival in tumours with high DPD expression, but not in the untreated patient group (Paper IV).

In conclusion, outcomes in PDAC are slowly improving but are still among the worst in class. Continued efforts in all aspect of PDAC disease are essential, especially in early detection, development of better drugs, and biomarkers to guide in treatment decisions.