Pancreatic cancer – What's next?

Summary

This chapter focuses on the most recent advantages in the medical treatment of localized pancreatic cancer.

Introduction

Pancreatic cancer is a dreadful disease, with the only curative chance being a radical surgical resection. Unfortunately, only 15–20% of patients is candidate for upfront surgery at the time of diagnosis. The large amount of patients are diagnosed with either locally advanced unresectable disease due to an extensive vascular infiltration, or metastatic disease. Prognosis has not been improved in the last decades, with almost 8% of patients alive 5 years after diagnosis [1].

In the last few years management of pancreatic cancer has shifted toward a multimodal approach with encouraging results [2]. Radical surgery with subsequent chemotherapy still remains the goal for patients with localized disease. Surgical principles and techniques have not substantially changed: complete tumor resection with free margins and a consistent number of peripancreatic lymph nodes harvested (15 at least) is still the minimum standard requested to pancreatic surgeons [3]. Vascular and multiorgan resections are currently performed to reach the purpose, although there is still no consensus on the real benefit this extended surgery could provide in terms of perioperative morbidity and prognosis [4], [5], [6], [7], [8], [9]. As well as for the treatment of other gastrointestinal malignancies, even for pancreatic cancer surgery a minimally invasive approach has been adopted worldwide to mitigate the surgical trauma with respect to the oncological principles of resection [10], [11]. Once again the level of evidence to justify a standard minimally invasive approach (either laparoscopic or robotic) is still low and randomized clinical trials are strongly needed [12], [13]. For example, the DIPLOMA randomized controlled trial comparing open vs. minimally invasive distal pancreatectomy was recently opened for enrollment in Europe and USA [14].

Technical aspects are of great interests for pancreatic surgeons and ignite academic debates, but they have not changed indications for surgery nor long-time prognosis so far. For those who are not deemed suitable for resection but still have a localized disease, a combination of chemo- and occasionally radio-therapy is now offered to make a subsequent resection achievable. As suggested by the brand new released French Guidelines, this should be named “induction therapy” rather than “neoadjuvant therapy”, since secondary exploration and resection rates are quite low (25%) [15]. No clinical trial demonstrated the superiority of a regimen over the others and the available evidence mostly relies on retrospective series. Thus results of ongoing randomized trials comparing different chemo-radio-therapy combinations are waited to define a new standard of care in the setting of localized borderline resectable/unresectable disease.

When disease remains unresectable after induction therapy but does not show distant spreading, local ablation has gained consensus to reinforce local control and stimulate patient's own immune response against cancer. Local ablation is actually an option in the armory of surgeons and clinical oncologists at dedicated high volume centers, although quite limited experiences are reported in literature. Ablation can be performed through different procedures. The promising results obtained in terms of safety and survival lead to consider such techniques a valid option after a multidisciplinary team evaluation.

Because of its complex pathogenesis and poor response to traditional treatments, pancreatic cancer forced researchers to develop and test new approaches. In recent years, great interest was raised by the introduction of immunotherapy for the treatment of gastrointestinal and non-gastrointestinal malignancies. Immunotherapy is focused on the suppression of the immune response, the mechanism by which cancer cells can survive and establish tumor. Unfortunately, this strategy has been quite disappointing in pancreatic ductal adenocarcinoma, first of all because of unique immunologic hallmarks.

Precision medicine, that is the opportunity to treat patients by striking the molecular basis of disease, needs implementations starting from genetic, that is the basis of cancer. For pancreatic cancer, as well as for different malignancies, a real step forward could be a new classification of disease based on the genetic features of mutated cells, rather than morphological features only. Great promises are awaited in this field to get a personalized-treatment suitable for use.