Quarterly Medical ReviewPancreatic cancer – What's next?
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.
Section snippets
Ongoing research for adjuvant treatments
Three clinical trials have demonstrated so far an improved survival with the administration of adjuvant chemotherapy (namely, CONKO-001, ESPAC-3 and ESPAC-4) [16], [17], [18]. All patients undergone surgery are candidate to receive subsequent adjuvant treatment, irrespective of the pTNM stage. Chemotherapy should be started within two or three months after index operation, as soon as patients have adequately recovered after surgery. Due to the high morbidity rate of pancreatic resections,
Ongoing research for neaoadjuvant and induction treatment
The actual standard of care for borderline resectable and locally advanced unresectable pancreatic cancer is induction chemotherapy with or without radiation therapy. In the setting of locally advanced cancer the goal is to obtain a down-staging of disease in order to make surgical resection achievable. For the borderline resectable disease, to select patients who will not show early systemic progression and, finally, can benefit from surgery. Combination regimens as FOLFIRINOX and
Local ablative techniques
The large amount of patients diagnosed with localized pancreatic cancer shows a locally advanced unresectable disease and even after induction therapy only a few of them get a radical resection. For those who still remain not operable several palliative procedures have been identified to achieve local tumor control and relief of symptoms. Those techniques are currently available in tertiary centers, although shared indications and guidelines are lacking. The choice to make use of such
Immunotherapy
In the era of precision medicine pancreatic cancer is still a challenge. Despite significant advances in understanding tumor biology and developing novel therapies, survival remains discouraging. Immunotherapy represents one of the newest option. Its function is to kill cancer cells augmenting the immune system through antibodies and T cell, that are able to differentiate between cancer and normal cells [39]. It has demonstrated clinical benefits in a number of malignancies [40], but not in
Molecular profiling of pancreatic cancer and implication for therapy
Pancreatic cancer is a genetic disease: its complexity and unpredictability show how it is a completely different disease in every single patient. New knowledge are emerging from genome sequencing and they could identify different subgroups of pancreatic cancers based not on histology, but on somatic and germline mutations.
A variety of different mutations and mutational signatures have been identified; the driver mutation in around 93% of pancreatic cancer cases is KRAS, with other recorded
Conclusions
This chapter focused on the most promising treatment options for pancreatic cancer in the field of chemo- and radio-therapy, local ablative therapies and targeted therapy. Some aspects of tumor biology and precision medicine were detailed too. While some of the therapeutic strategies reported are nowadays available for use in dedicated centers, some others are still under preclinical investigation. Both of them deserve attention by general practitioners and specialists other than
Disclosure of interest
the authors declare that they have no competing interest.
References (86)
- et al.
Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS)
Surgery
(2014) - et al.
Extended pancreatectomy in pancreatic ductal adenocarcinoma: definition and consensus of the International Study Group for Pancreatic Surgery (ISGPS)
Surgery
(2014) - et al.
Extended pancreatoduodenectomy as defined by the International Study Group for Pancreatic Surgery is associated with worse survival but not with increased morbidity
Surgery
(2015) - et al.
Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial
Lancet
(2017) - et al.
Nonoperative ablations of pancreatic neoplasms
Surg Clin N Am
(2018) - et al.
Precision immuno-oncology: prospects of individualized immunotheraphy for pancreatic cancer
Cancer
(2018) - et al.
Oncology meets immunology: the cancerimmunity cycle
Immunity
(2013) - et al.
Quantitative multiplex immunohistochemistry reveals myeloid-inflamed tumor-immune complexity associated with poor prognosis
Cell Rep
(2017) - et al.
CD40 stimulation obviates innate sensors and drives T cell immunity in cancer
Cell Rep
(2016) - et al.
Adenoviruses induce autophagy to promote virus raplication and oncolysis
Virologi
(2011)
Recent progress in developmant of siRNA delivery vehicles for cancer therapy
Adv Drug Deliv Rev
Cancer statistics, 2018
CA Cancer J Clin
Recent advantages in pancreatic cancer surgery
Curr Treat Options Gastroenterol
Meta-analysis of benefits of portal-superior mesenteric vein resection in pancreatic resection for ductal adenocarcinoma
Br J Surg
Pancreatectomy combined with superior mesenteric vein-portal vein resection for pancreatic cancer: a meta analysis
World J Surg
The impact of vascular resection on early postoperative outcomes after pancreaticoduodenectomy: an analysis of the American College of Surgeons National Surgical Quality Improvement Program Database
Ann Surg Oncol
Arterial resection during pancreatectomy for pancreatic cancer: a systematic review and meta-analysis
Ann Surg
Minimally invasive pancreaticoduodenectomy for periampullary disease: a comprehensive review of literature and meta-analysis of outcomes compared with open surgery
BMC Gastroenterol
Minimally invasive versus open pancreatoduodenectomy-systematic review and meta-analysis
Langenbecks Arch Surg
Comparing short-term and oncologic outcomes of minimally invasive versus open pancreaticoduodenectomy across low and high volume centers
Ann Surg
Minimally invasive versus open pancreaticoduodenectomy for cancer: practice patterns and short-term outcomes among 7061 patients
Ann Surg
Minimally invasive versus open distal pancreatectomy for ductal adenocarcinoma (DIPLOMA): a Pan-European Propensity Score Matched Study
Ann Surg
Pancreatic cancer: French clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, AFC)
Dig Liver Dis
Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial
JAMA
Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial
JAMA
CONKO-005: adjuvant chemotherapy with gemcitabine plus erlotinib versus gemcitabine alone in patients after R0 resection of pancreatic cancer: a multicenter randomized phase III trial
J Clin Oncol
Pancreatic adenocarcinoma, version 2.2017, NCCN Clinical Practice Guidelines in Oncology
J Natl Compr Canc Netw
Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline Update
J Clin Oncol
Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Ann Oncol
Implications of the pattern of disease recurrence on survival following pancreatectomy for pancreatic ductal adenocarcinoma
Ann Surg Oncol
FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer
N Engl J Med
Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine
N Engl J Med
The benefits of modified FOLFIRINOX for advanced pancreatic cancer and its induced adverse events: a systematic review and meta-analysis
Sci Rep
Unicancer GI PRODIGE 24/CCTG PA.6 trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas
J Clin Oncol
A randomized clinical trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer
N Engl J Med
Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group
Ann Surg
Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial
JAMA
Results of the randomized phase II portion of NRG Oncology/RTOG 0848 evaluating the addition of erlotinib to adjuvant gemcitabine for patients with resected pancreatic head adenocarcinoma
J Clin Oncol
Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1): a randomized, controlled, multicenter phase III trial
J Clin Oncol
Phase II LAPACT trial of nab-paclitaxel (nab-P) plus gemcitabine (G) for patients with locally advanced pancreatic cancer (LAPC)
J Clin Oncol
Systematic review of novel ablative methods in locally advanced pancreatic cancer
World J Gastroenterol
Local ablative strategies for ductal pancreatic cancer (radiofrequency ablation, irreversible electroporation): a review
Gastroenterol Res Pract
EUS-guided Radiofrequency Ablation (EUS-RFA) of solid pancreatic neoplasm using an 18-gauge needle electrode: feasibility, safety, and technical success
J Gastrointestin Liver Dis
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