REVIEW

Cancerul pancreatic

 Pancreatic cancer

Alexandru C. Grigorescu

First published: 04 aprilie 2017

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/OnHe.38.1.2017.551

Abstract

Pancreatic cancer has the 12th incidence rate in the world. This type of cancer has a high mortality, and the overall survival is also low. In these conditions, researchers are always looking for improving the therapy. In this presentation, we mention the histological types of pancreatic cancer, the importance of systemic therapy for operable cases (pre- and post-surgery), and of chemotherapy for advanced and metastatic cancer. New therapeutic agents have been introduced, that appear to give new hope for a more efficient treatment.
 

Keywords
pancreatic cancer, chemotherapy, biotherapy

Rezumat

Cancerul pancreatic este pe locul al doisprezecelea ca incidenţă în lume. Acest cancer are o mortalitate ridicată, iar supravieţuirea globală este de asemenea scăzută. În aceste condiţii, se caută mereu îmbunătăţirea terapiei. În acest articol prezentăm tipurile histologice de cancer al pancreasului, alături de importanţa terapiei sistemice pentru cazurile operabile (pre- şi post-chirurgical) şi a chimioterapiei pentru boala metastatică. Sunt prezentaţi, de asemenea, noi agenţi terapeutici care par a da speranţe pentru un tratament mai eficient. 
 

Pancreatic cancer is the twelfth most common cancer in the world (sharing the same position with kidney cancer), with 338,000 new cases diagnosed in 2012. According to Pancreatic Cancer Action Network, there was an alarming increase of pancreatic cancer deaths in the United States of America in 2012.

The highest incidence of pancreatic cancer is registered in western countries (Northern America and Europe), and the lowest incidence - in Africa and Asia. In Romania, the age-standardised rate per 100,000 people was 7.9 in 2012.

Risk factors

For exocrine pancreatic cancer

Smoking is one of the most important risk factors for pancreatic cancer, overweight and obesity. Exposure to certain chemicals at work used in dry cleaning and metal working industries may raise a person’s risk of pancreatic cancer.

Other risk factors are: age (almost all patients with pancreatic cancer are older than 45 and about two-thirds are at least 65-years-old), gender (men are slightly more likely to develop pancreatic cancer than women), race (African Americans are slightly more likely to develop pancreatic cancer than whites), and family history (pancreatic cancer seems to run in some families). Inherited gene changes (mutations) can be passed from parent to child. These gene changes may cause as many as 10% of pancreatic cancers. There are some genetic syndromes that can cause pancreatic cancer:

  • Hereditary breast and ovarian cancer syndrome, caused by mutations in the BRCA1 or BRCA2 genes.
  • Familial atypical multiple mole melanoma (FAMMM) syndrome, caused by mutations in the p16/CDKN2A gene.
  • Familial pancreatitis, usually caused by mutations in the PRSS1 gene.
  • Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), most often caused by a defect in the MLH1 or MSH2 genes.
  • Peutz-Jeghers syndrome, caused by defects in the STK11 gene. This syndrome is also linked with polyps in the digestive tract and several other cancers.
  • Von Hippel-Lindau syndrome, caused by muta­tions in the VHL gene. It can lead to an increased risk of pancreatic cancer and carcinoma of the ampulla of Vater.

Pancreatic neuroendocrine tumors and cancers can also be caused by genetic syndromes, such as:

  • Neurofibromatosis, type 1, which is caused by mutations in the NF1 gene. This syndrome leads to an increased risk for many tumors, including somatostatinomas.
  • Multiple endocrine neoplasia, type I (MEN1), caused by mutations in the MEN1 gene. This syndrome leads to an increased risk of tumors of the parathyroid gland, the pituitary gland, and the islet cells of the pancreas.

Other conditions incriminated in the occurrence of pancreatic cancer are: diabetes, chronic pancreatitis, liver cirrhosis, ulcer-causing bacterium Helicobacter pylori.

Some factors are unclear and induced controversy: diets (high in red and processed meats), lack of physical activity, coffee, alcohol(4).

Types of pancreatic cancer

Exocrine pancreatic cancers

Pancreatic adenocarcinoma (about 95% of cancers of the exocrine pancreas).

Less common types of pancreatic exocrine carcinoma are: adenosquamous carcinomas, squamous cell carcinomas, signet ring cell carcinomas, undifferentiated carcinomas, and undifferentiated carcinomas with giant cells.

Ampullary cancer (carcinoma of the ampulla of Vater) - this type cancer isn’t technically pancreatic, but is included here because is treated much the same.

Neuroendocrine tumors of the pancreas (functioning NET): gastrinomas, insulinomas, somatostatinomas, VIPomas, PPomas (from cells that make pancreatic polypeptide).

Nonfunctioning NET (these tumors don’t make enough excess hormones to cause symptoms; they are more likely to be cancer than are functioning tumors): carcinoid tumors.

Benign and precancerous lesions in the pancreas:

  • serous cystic neoplasms: are almost always benign;
  • mucinous cystadenomas: almost always occur in women and some of them can progress to cancer;
  • intraductal papillary mucinous neoplasms: are benign tumors, they sometimes become cancer if not treated;
  • solid pseudopapillary neoplasms - are benign tumors but need surgical treatment(5).
TNM classification, 7th edition


Treatment

Surgical resection offers the only chance of cure for exocrine pancreatic cancer, but only 15 to 20 percent of cases are potentially resectable at presentation. Local unresectability is usually (but not always) due to vascular invasion(6). We will refer in this presentation mainly to the systemic therapy.

For borderline resectable disease, neoadjuvant chemotherapy is indicated(7). FOLFIRINOX has shown a 31% response rate in phase III trials, while gemcitabine-nab-paclitaxel has shown in phase III response rates of 23-29%(8).

A large, multicenter, retrospective analysis published online in February 13th in the Journal of the American College of Surgeons indicates that the addition of adjuvant chemotherapy, but not radiation, reduces the risk for distant recurrences and increases overall survival(9).

The role of systemic therapy was investigated in the ESPAC-1 trial, which showed improvement in median overall survival (OS) of 20.1 months with 5-fluorouracil (5-FU) compared with 15.1 months in the observation-only arm(9). Subsequently, the landmark study CONKO-001 showed improvement in median OS (22.1 vs. 20.2 months) and median disease-free survival (DFS; 13.4 vs. 6.9 months) with gemcitabine versus observation alone. After this study, 6 months of gemcitabine became the standard of care in the adjuvant setting of resected pancreatic adenocarcinoma. Because of the positive outcome observed with the use of 5-FU or gemcitabine, the ESPAC-3 trial set out to investigate whether one of these agents was superior to the other. There were no differences in the median OS of approximately 23 months, but 5-FU was associated with a higher rate of grades 3 to 4 toxicity, including mucositis, diarrhea, and myelosuppression(10).

Metastatic disease

In ESMO Clinical Practice Guidelines 2012, the monotherapy with gemcitabine (GEM) was considered the best option. Patients receiving GEM have a median survival of 6.2 months and a 1-year survival rate of 20%. The combinations of GEM and 5-FU or capecitabine, irinotecan, cis- or oxaliplatin do not confer a major advantage in survival even in large randomized phase III trials, and should not be used as standard first line treatment of locally advanced or metastatic pancreatic cancer. Meta-analysis of randomized trials with a combination of GEM and platinum analogues or of GEM and capecitabine suggested a survival benefit for these combinations for patients with a good PS. In contrast, an Italian phase III trial examining GEM/cisplatin did not confirm a survival benefit for the combination GEM/cisplatin(11).

New drugs

Liposomal irinotecan - “Nanoliposomal irinotecan combined with fluorouracil/leucovorin improved overall survival in metastatic pancreatic cancer patients who have already been treated with gemcitabine, according to updated results of the NAPOLI-1 phase III clinical trial presented at the 2016 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, held in January 21-23 in San Francisco (abstract 417)”(12).

Another tested treatment in phase II trial was IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365), an immunomodulator with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. This study concluded that was a suggestion of a beneficial effect on survival in patients with metastatic disease.

Immune checkpoint therapy

In an analysis made in 2016, the results were not yet conclusive. Most clinical studies on immune checkpoint inhibitors for pancreatic cancer are not yet completed and are still recruiting patients. Among the completed trials, we have data of a preliminary nature such as delayed disease progression and enhanced overall survival after treatment with immune checkpoint inhibitors in mono- or combination therapy. However, due to small sample sizes, major results are not yet identifiable(14).

Bibliografie

1. http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/pancreatic-cancer-statistics
2. www.pancan.org/wp-content/uploads/2013/01/incidence_report_2012_executive_summary.pdf [Last accessed April].
3. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN 2012 v1.1, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer, 2014.
4. The American Cancer Society medical and editorial content team, Revised: May 31, 2016, https://www.cancer.org/cancer/pancreatic-cancer/causes-risks-prevention/risk-factors.html
5. https://www.cancer.org/cancer/pancreatic-cancer/about/what-is-pancreatic-cancer.html#references 
6. http://www.uptodate.com/contents/treatment-for-potentially-resectable-exocrine-pancreatic-cancer 
7. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
8. Is It Times for Neoadjuvant Therapy in Pancreatic Cancer?, Carlson, Robert H. Oncology Times: 10 August 2016, Volume 38, Issue 15, p 26-27, http://journals.lww.com/oncology-times/Fulltext/2016/08100/Is_It_Times_for_Neoadjuvant_Therapy_in_Pancreatic.11.aspx 
9. Alexander M. Castellino, Pancreatic Cancer: Adjuvant Chemotherapy, but Not Radiation, PhD, February 24, 2016, http://www.medscape.com/viewarticle/859320 
10. http://am.asco.org/daily-news/adjuvant-therapy-pancreatic-cancer-have-we-raised-bar 
11. T. Seufferlein, J.B. Bachet, E. Van Cutsem, P. Rougier, Pancreatic Adenocarcinoma: ESMO Clinical Practice Guidelines, Published in 2012, Ann Oncol 2012; 23 (Suppl 7): vii33-vii40.

12. http://www.cancernetwork.com/pancreatic-cancer/liposomal-irinotecan-improves-survival-metastatic-pancreatic-cancer?GUID=9CE6938C-1D5E-42BA-BDE8-EE6C89DC52FC&XGUID=&rememberme=1&ts=29012016#sthash.FUli6Qih.dpuf
13. Angus G Dalgleish, Justin Stebbing, Douglas JA Adamson, Seema Safia Arif, Paolo Bidoli, David Chang, Sue Cheeseman, Robert Diaz-Beveridge, Carlos Fernandez-Martos, Rob Glynne-Jones, Cristina Granetto, Bartomeu Massuti, Karen McAdam, Raymond McDermott, Andrés J Muñoz Martín, Demetris Papamichael, Roberto Pazo-Cid, Jose M Vieitez, Alberto Zaniboni, Kevin J Carroll, Shama Wagle, Andrew Gaya and Satvinder S Mudan, Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer, World J Gastroenterol. 2016 Nov 21; 22(43): 9457–9476. 
14. Henrik Johansson, Roland Andersson, Monika Bauden, Sarah Hammes, Stefan Holdenrieder, and Daniel Ansari, Immune checkpoint therapy for pancreatic cancer, Cancer Research Frontiers, 2016 May; 2(2): 252-276.

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