Clinical review: Management of pancreatic cancer

A clinical review of the diagnosis and management of pancreatic cancer, including red flag symptoms.

Coloured axial CT scan showing cancer (green dots) in the pancreas and liver (Photograph: SPL)
Coloured axial CT scan showing cancer (green dots) in the pancreas and liver (Photograph: SPL)

Section 1: Epidemiology and aetiology

Pancreatic cancer is the 10th most common cancer in Europe with approximately 8,085 new cases diagnosed annually in the UK alone.1 With >95% mortality within one year, it can be a devastating diagnosis to make and treat.2

The age-standardised rate of pancreatic cancer is 10.5/100,000 in men compared with 8.2/100,000 in women, with the approximate lifetime risk of developing pancreatic cancer being one in 77 for men and one in 79 for women.1

The rate of incidence increases with age and the majority of cases (75%) occur in patients over the age of 65.1

The highest incidences of pancreatic cancer are within Europe and North America, with the lowest in Asia and Africa. Within the EU, the male populations of Hungary and the Czech Republic have the highest rates of disease.3 The most frequent histological type of pancreatic cancer is infiltrating ductal adenocarcinoma, originating from the exocrine tissue of the organ and accounting for 90% of all diagnoses.2

Risk factors
The most common risk factor is smoking, associated with 20-25% of all tumours.4

There are dietary factors thought to be protective and harmful in the development of pancreatic cancer, and although alcohol is not directly associated, its link to chronic pancreatitis does pose a cumulative risk of up to 4%.5 Many studies have examined the links between diabetes and pancreatic cancer, and it is clear that long-standing diabetes increases the risk of pancreatic cancer and can be an early manifestation of pancreatic tumours.4

There are several genetic conditions associated with the development of pancreatic carcinoma, including hereditary pancreatitis syndrome, hereditary non-polyposis colorectal carcinoma, BRCA2 related breast and ovarian cancer, Peutz-Jeghers syndrome and hereditary atypical multiple mole melanoma syndrome.

Section 2: Making the diagnosis

Pancreatic cancer rarely presents in the early stages. It has a high mortality, mainly due to metastatic disease at presentation, and it is inherently resistant to most treatment options. There is currently no screening programme for the detection of pancreatic cancer. The lack of reliable diagnostic tools and biomarkers is all too evident and defines the great need for clinical improvements for this disease.

Red flag symptoms
Clinical features of pancreatic cancer are notoriously vague and early diagnosis remains a major problem. The symptoms outlined in the box (below) should emphasise the importance of early referral for further investigations. The presence of clinical signs on examination frequently represents advanced and potentially unresectable disease.

Particular red flag symptoms of painless jaundice, pain, weight loss and new onset diabetes should alert early investigation, especially in patients with relevant risk factors. Painless jaundice is commonly associated with head of pancreas tumours and jaundice in association with body or tail tumours usually represents advanced disease.

Diabetes mellitus is a presenting feature in up to 10% of cases, thus one should be clinically suspicious when treating elderly patients with new-onset diabetes.4

Clinical features of pancreatic cancer
History/symptoms
  • Pain.
  • Unexplained weight loss.
  • Painless jaundice.
  • Late presenting diabetes mellitus.
Examination - Abdominal mass.
  • Icterus.
  • Hepatomegaly.
  • Ascites.
  • Trousseau's sign (migratory thrombophlebitis).
  • Courvoisier's sign (palpable gall bladder).
  • Virchow's node (palpable supraclavicular node).
  • Sister Mary Joseph's node (periumbilical nodules).

Investigations
Patients presenting with suspicious symptoms would undergo routine blood tests (FBC, clotting, renal function and LFTs) followed by imaging. Ca19-9 is not used in the diagnosis.

Ultrasonography can offer an initial non-invasive evaluation of tumours; however, it is by no means accurate and can be incorrect in a third of cases.6 Should there be a strong suspicion of cancer despite ultrasound, a fast-track two-week referral should be made.

CT of the chest, abdomen and pelvis is the standard imaging modality and also assists in staging of the disease. CT provides more accurate tumour definition than ultrasound, but can miss small liver and periportal lesions. Although magnetic resonance cholangiopancreatography offers better imaging of the biliary tree, pancreatic ducts and vascular invasion compared with CT, it is not used as standard and is generally reserved for those with severe liver or renal failure.

In patients presenting with jaundice, endoscopic retrograde cholangiopancreatography (ERCP) enables pathological sampling and offers palliative biliary stenting for patients with unresectable tumour or who are not fit for surgery.

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Endoscopic ultrasound has been shown to be more sensitive and specific compared with CT in diagnosis, particularly for tumours <3cm in="" diameter="" sup="">7 Lack of equipment, finances and trained staff has meant it is not widely used in the UK.

It is important prior to treatment that a biopsy is taken to confirm the histological diagnosis of the pancreatic cancer.

Section 3: Managing the condition

The TNM staging classification offers a formal way to stage pancreatic cancer (see box, below).

Patients can also be staged clinically, based on how resectable the disease is:

  • Resectable disease: absence of extrapancreatic disease without evidence of direct invasion of the superior mesenteric vein (SMV) or the coeliac axis.
  • Borderline resectable disease: absence of extrapancreatic disease with some superior mesenteric artery encasement, and coeliac encasement and short segment SMV occlusion.
  • Locally advanced/unresectable disease: absence of extrapancreatic disease, unreconstructable SMV/portal vein occlusion with coeliac encasement and lymph node involvement beyond the field of resection.
  • Metastatic disease: any disease involving distant metastasis.

By staging pancreatic tumours, clinicians can decide on the best management plan for the patient. In the preoperative setting, CT is the standard modality for staging, but should imaging be inconclusive, laparoscopy or laparotomy combined with intraoperative ultrasonography can be performed.

All patients should be discussed at a hepatobiliary multi-disciplinary team meeting to ensure all modalities of therapy are considered, especially in managing symptoms.

Operable cancer
Treatment of operable pancreatic cancer is by radical resection in the form of a modified Whipple's procedure (removal of the duodenum, part of the stomach and the head of the pancreas) for tumours of the head of the pancreas, and a distal pancreatectomy with splenectomy for tumours of the pancreatic body and tail.

This is followed by adjuvant chemotherapy, normally in the form of single agent gemcitabine.9 Combined therapies are still under investigation and there is currently a phase III clinical trial comparing adjuvant gemcitabine versus gemcitabine and capecitabine.10

In some centres, postoperative chemoradiotherapy may be an option for patients with large tumour diameter (>3cm) and in patients with R1 resection (for example, resected margins which are microscopically positive for tumour).11

It is important to note that only 15-20% of patients are deemed operable and the median survival after surgery is in the range of 12-18 months.12

Borderline resectable disease represents patients who initially may not be operable (due to close margins or proximity to blood vessels), but have good performance status and are thus considered for cytoreductive treatment in the form of either chemotherapy or chemoradiotherapy before surgery to render their cancer resectable.

Inoperable cancer
In patients with unresectable disease, and where the cancer is confined to the pancreas, chemotherapy in the form of gemcitabine +/capecitabine would be considered. The benefit of chemoradiation in the treatment of locally advanced disease is much debated and some retrospective studies have shown benefit in survival.13

There are continuing trials, such as the French Intergroup Study (LAP-07), which aim to draw conclusions on the benefit of additional chemoradiation.

Newer treatments, such as Cyberknife (R) therapy, are also showing promise as a mode of palliation in locally advanced disease, but long-term follow-up is still pending.14,15

Metastatic cancer
The aim of management in patients with metastatic disease is to ensure an adequate quality of life. This is achieved through aggressive symptom control with assistance from the palliative care team and by chemotherapy.

Stage IV disease is treated with single agent gemcitabine or combination therapies.16


In Whipple surgery the jejunum is attached to the remains of the pancreas and stomach to bypass the removed organs (Photograph: SPL)

Section 4: Future therapies and follow-up

The ACCORD study has shown promising results using the new combination of 5FU, oxaliplatin and irinotecan (FOLFIRINOX), compared with gemcitabine alone.17

Other therapeutic options include combination of erlotinib and gemcitabine, which has recently been approved by the US Food and Drug Administration and the European Medicines Agency on the basis of a randomised trial from the National Cancer Institute of Canada.

However, the modest overall survival gain (6.24 versus 5.91 months, HR 0.82) and the high economic costs have raised debate as to the rationale of this treatment in a metastatic setting.18

Pancreatic cancer is now acknowledged as an individualised disease, and new therapies and treatment modalities are being explored for the disease itself rather than from other tumour types.

Therefore the inclusion of as many patients as possible into clinical trials is vitally important to redefine the therapeutic landscape for this cancer.

Follow-up
Patients are routinely followed up with each cycle of chemotherapy to evaluate response and toxicity.

Monitoring of symptoms and imaging are useful to monitor disease response and progression. Pancreatic cancer has a poor prognosis, with overall survival of 0.4-4%, the lowest of all solid cancers.19

Section 5: Case study

A 71-year-old woman presented with obstructive jaundice. She was found to have a mass in the head of the pancreas on CT scan with no evidence of metastatic disease.

She underwent stenting at ERCP for a biliary stricture. It was felt on review of her scans that the pancreatic mass was potentially resectable.

The patient went on to have a pylorus-preserving pancreaticoduodenectomy (modified Whipple's procedure) and made a good recovery.

Histology showed a moderate to poorly differentiated adenocarcinoma that appeared to be arising from an intraductal papillary mucinous neoplasm. The maximum dimension was 31mm.

There was evidence of perineural and vascular invasion in the resected specimen and the tumour was less than a millimetre from the superior mesenteric vein. Seven out of 26 lymph nodes were involved. The tumour was thus staged at T3N1M0.

She was referred for adjuvant chemotherapy as part of the ESPAC-4 trial with consideration of chemoradiotherapy for her close surgical margins.

Section 6: Evidence base

Clinical trials

  • Neuhaus P, Riess H, Post S et al. CONKO-001: final results of the randomized phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer. J Clin Oncol 2008; 26(15S): (Abstr LBA4504).
  • Conroy T, Desseigne F, Ychou M et al. Phase III trial comparing FOLFIRINOX (F: 5FU/leucovorin, irinotecan and oxaliplatin) versus gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma. J Clin Oncol 2010; 28: 15s.
  • ESPAC-4: Gemcitabine and Capecitabine vs. Gemcitabine alone as adjuvant therapy following surgical resection (ongoing recruitment) www.lctu.org.uk/trial/trial_info

Guidelines

Key texts

  • Allegra CJ. Bethesda handbook of clinical oncology.
  • Greene FL. American Joint Committee on Cancer: Cancer Staging Manual, Exocrine and Endocrine Pancreas. New York, Springer, 2010.

Online

Reflect on this article and add notes to your CPD Organiser on MIMS Learning

    CPD IMPACT: EARN MORE CREDITS

    These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

    • Present a summary of this article to your colleagues in a clinical meeting.
    • Discuss the appropriate use of tumour markers.
    • Perform a case review of your patients with pancreatic cancer over the past five years and present the findings with any lessons learned.

    References
    1. Cancer Research UK. Cancer incidence - UK statistics. Accessed 12 February 2012.

    2. Cascinu S, Falconi M, Valentini V et al. Ann Oncol 2010; 21 Suppl 5: v55-8.

    3. Ferlay J, Shin HR, Bray F et al. http://globocan.iarc.fr/

    4. Raimondi S, Maisonneuve P, Lowenfels AB. Nat Rev Gastroenterol Hepatol 2009; 6(12): 699-708.

    5. Lowenfels AB, Maisonneuve P, Cavallini G et al. N Engl J Med 1993; 328(20): 1433-7.

    6. Takhar AS, Palaniappan P, Dhingsa R et al. BMJ 2004; 329(7467): 668-73.

    7. Mertz HR, Sechopoulos P, Delbeke D et al. Gastrointest Endosc 2000; 52: 367-71.

    8. Greene FL. American Joint Committee on Cancer: Cancer Staging Manual, Exocrine and Endocrine Pancreas. New York, Springer, 2010; 285-95.

    9. Neuhaus P, Riess H, Post S et al. J Clin Oncol 2008; 26(15S): (Abstr LBA4504).

    10. www.lctu.org.uk/trial/trial_info.asp?id=48&tgcode=4&menuid=30

    11. Regine WF, Winter KA, Abrams RA et al. JAMA 2008; 299(9): 1019-26.

    12. Zuckerman DS, Ryan DP. Cancer 2008; 112(2): 243-9.

    13. Huguet F, Andre T, Hammel P et al. J Clin Oncol 2007; 25(3): 326-31.

    14. Shen ZT, Wu XH, Li B et al. Chin J Cancer 2010; 29(9): 802-9.

    15. Li J, Ng J, Allendorf J at el. Highlights from the 2011 ASCO Annual Meeting. Chicago, IL, USA; JOP 2011; 12(4): 347-50.

    16. Tempero MA, Berlin J, Ducreux M. Ann Oncol 2011; 22(7): 1500-6.

    17. Conroy T, Desseigne F, Ychou M et al. J Clin Oncol 2010; 28: 15s.

    18. Moore MJ, Goldstein D, Hamm J et al. J Clin Oncol 2007; 25(15): 1960-6.

    19. Jemal A, Murray T, Samuels A et al. CA Cancer J Clin 2003; 53: 5-26.

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