Cancer of the pancreas is the ninth most commonly diagnosed cancer in Ireland. There were equal numbers of male and female patients diagnosed with pancreatic cancer per year between 1994 and 2010, although the incidence rates are higher in men. 

Almost 75% of cases were diagnosed in patients over 65 years, while 5% were diagnosed in those under 50 years of age. The major risk factors for pancreatic cancer include smoking, hereditary predisposition to pancreatic cancer or other malignancies, chronic pancreatitis and diabetes. 

Presentation

Typical presenting symptoms include weight loss, abdominal pain, jaundice or pruritus. Weight loss can be dramatic and associated with anorexia, early satiety, diarrhoea or steatorrhoea. Pain is present in 80-85% of patients with locally advanced or advanced disease. Painless jaundice is present in 50% of patients with potentially resectable or curable disease, while painful jaundice is present in 50% with unresectable disease. Occasionally pancreatitis or newly diagnosed diabetes can be the first sign of pancreatic cancer. 

Unfortunately, the majority of cases (67%) are diagnosed at an advanced stage due to the relatively asymptomatic nature of the disease. 

Objective findings may include palpable masses, jaundice, hepatomegaly, ascites, Virchow’s node or Sr Mary Joseph node. Many patients with pancreatic cancer are in a hypercoagulable state. Therefore, there is a high incidence of thromboembolic events in this cohort of patients. 

Diagnosis and staging

A diagnosis of pancreatic cancer is usually made radiologically by finding a mass in the pancreas often obstructing the pancreatic duct or biliary tree. The TNM staging classification is used to stage pancreatic cancer. However, in clinical practice, pancreatic cancer is typically divided into resectable, locally advanced/unresectable and metastatic stages. 

CT scans can delineate the extent of disease, identify potential sites for tissue biopsy and identify potentially resectable patients. Endoscopic ultrasound (EUS) visualises the pancreas and allows fine needle aspiration. Over 70% of cases diagnosed are adenocarcinomas, while only 4% are neuroendocrine tumours. If EUS and ERCP are performed together, therapeutic CBD stenting can be performed at the same time. 

Magnetic resonance imaging (MRI) and MRCP are also useful in diagnostic work-up. 

Laparoscopy performed prior to surgical resection may demonstrate intraperitoneal metastases and therefore rule out a surgical option. Up to one-third of apparently resectable tumours have intraperitoneal metastases at laparoscopy.²

Serum CA19-9 should not be used as a diagnostic tool although it has reported sensitivity and specificity of 80-90%. However, these values are closely related to tumour size and may be elevated in other cancers and other benign pancreaticobiliary disorders. 

Treatment

Localised disease

Surgical resection is the only modality clearly proven to cure pancreatic adenocarcinoma. However, less than 15% of patients in Ireland present with resectable disease. Of these, only 20% are actually cured with surgery, with a five-year survival rate of 25-30% in node-negative disease and 10% in node-positive disease. On occasion, surgery may be used as a palliative procedure for locally advanced disease. 

There is no consensus regarding optimal management of resected pancreatic cancer. The use of adjuvant treatment is the strongest predictor for survival. The three-year survival rate is significantly higher in those receiving adjuvant treatment compared to those who do not.

No randomised trials have compared neoadjuvant to adjuvant therapy. Neoadjuvant chemoradiotherapy has been used in patients with resectable tumours or in patients with marginally resectable tumours who may be downstaged and become resectable after treatment. Neoadjuvant treatment may also avoid unsuccessful surgery in those with rapidly progressing disease. Either gemcitabine or 5-fluorouracil (5-FU) based chemoradiation may be used in the neoadjuvant setting. 

Chemoradiotherapy, radiotherapy or chemotherapy alone can all be used as adjuvant treatments. The use of chemotherapy alone in the adjuvant setting varies between the EU and the US. Most Europeans recommend chemotherapy alone, while our US counterparts often use a combination of chemoradiotherapy. 

The GITSG study initially showed an improved survival in patients receiving radiation concurrently with bolus 5-FU compared to radiation alone.³ Gemcitabine has also been used successfully as a radiosensitiser. For example, the GERCOR trial showed lower local recurrence rates, local and distant progression in patients receiving gemcitabine-based chemoradiotherapy versus chemotherapy alone.⁴

There have not been any comparative trials assessing gemcitabine versus 5-FU as radiation sensitiser. Despite the above evidence, there have been several subsequent studies which have not shown any improved survival rates for adjuvant chemoradiation. 

However, in other GI cancers where local failure is a common problem, survival benefits have been shown using combinations of adjuvant chemotherapy and radiotherapy. As a result, despite any large randomised trials, chemoradiotherapy is a commonly used approach for adjuvant therapy for pancreatic adenocarcinoma.

At least three randomised controlled trials and two meta-analyses suggest significant survival benefits from chemotherapy alone without RT in the adjuvant setting. The ESPAC 1 trial showed a survival advantage in those who received adjuvant chemotherapy alone over no adjuvant treatment. The ESPAC 3 trial investigated bolus 5-FU versus gemcitabine. There were similar survival rates between the two groups but toxicities were higher in the 5-FU arm. Therefore, gemcitabine is the preferred drug if chemotherapy alone is the adjuvant treatment of choice. 

Locally advanced disease

Locally advanced disease is described as unresectable disease without distant metastases. Median survival is eight to 12 months for those with unresectable disease. Chemoradiotherapy has traditionally been the standard of care based on limited studies. External beam radiation with concurrent 5-FU chemotherapy shows improved overall survival when compared to external beam radiation alone.⁵ Several studies have shown that infusional 5-FU used in combination with radiation is superior to bolus 5-FU and radiation. Capecitabine may also be used as a radiation sensitiser as is practice in other GI malignancies. 

Radiation alone may be considered for palliation of pain in those not a candidate for chemoradiotherapy. Despite some evidence favouring chemoradiation over radiation alone, there have been mixed results in trials comparing combination chemoradiotherapy to chemotherapy alone. Two separate meta-analyses comparing chemoradiotherapy versus chemotherapy alone have not shown any survival benefit for chemoradiation.⁶ 

Chemotherapy alone is increasingly used for patients with locally advanced pancreatic cancer. Gemcitabine-based chemotherapy regimens have response rates and survival advantages similar to those achieved with chemoradiation. 

One phase II trial evaluated gemcitabine plus oxaliplatin in the neoadjuvant setting in patients with initially unresectable or borderline resectable tumours. Forty per cent had significant downstaging of disease rendering surgical resection possible.⁷ In another study, up to one-third of unresectable or borderline resectable tumours could be rendered resectable with neoadjuvant therapy. 

Metastatic disease

Survival rates remain poor despite systemic treatment. Median survival is only three to six months for those presenting with metastatic disease. American Society of Clinical Oncology (ASCO) guidelines recommend that CA 19-9 be measured at the start of treatment and then serially throughout treatment. Suspected disease progression based on rising tumour markers should be confirmed radiographically.⁸ Single-agent chemotherapy has been the mainstay of treatment for metastatic pancreatic cancer. However, with single agents, objective response rates are seldom above 10%. 

Some studies have shown an improvement in symptoms, eg. pain, weight loss and improved performance status without a corresponding objective response to treatment. Therefore, symptom control has now been accepted as a beneficial endpoint for evaluating treatments.

Gemcitabine has shown clinical benefit in metastatic pancreatic cancer without an objective response rate.⁹ Several studies have consistently shown significant improvements in clinical benefit and survival. Therefore, gemcitabine is currently first-line therapy of metastatic pancreatic cancer. 

The agent 5-FU has been used since the 1950s and objective response rates vary from 0-67%. There appears to be little difference between bolus and infusional schedules, with median survival rates ranging from 10-24 weeks.¹⁰ 

Gemcitabine has been directly compared to 5-FU chemotherapy and both the median survival and clinical benefit, although poor, favoured gemcitabine. Clinical benefit was defined as improvement in pain, use of analgesia, weight gain, or improving performance status. As a result gemcitabine has been established as standard of care in the metastatic setting. 

Capecitabine is absorbed through the GI tract. Capecitabine monotherapy was shown to have clinical benefit response rates of 24%, although only 7% had objective response rates.¹¹ 

Multiagent regimens containing gemcitabine are consistently associated with higher response rates, but no clear survival benefit. A combination of gemcitabine plus capecitabine has been reported as superior to gemcitabine alone.¹² A combination of oxaliplatin and gemcitabine has also been shown to be superior to gemcitabine alone in relation to response rates and progression-free survival.¹³ 

Most recently, a phase III trial (ACCORD 11) assessed the folfirinox regimen which consists of infusional 5-FU, leucovorin, oxaliplatin and irinotecan. This has shown superiority over gemcitabine monotherapy in previously untreated metastatic pancreatic cancer.¹⁴

Objective response rates were significantly higher with folfirinox (32% versus 9%) as was median overall survival (11.1 versus 6.8 months). Treatment-related toxicity was significantly worse in the folfirinox arm. However, this regimen delayed the time to degradation in quality of life. Based on these data, folfirinox is now the preferred regimen for a limited cohort of patients with metastatic pancreatic cancer who have a good performance status and normal bilirubin levels. 

For the majority of patients who do not meet these criteria, a gemcitabine-containing regimen is the standard of care. Gemcitabine alone and in combination with capecitabine or oxaliplatin are all acceptable options for care. 

Over 60% of patients of all ages diagnosed with pancreatic cancer in Ireland do not receive systemic treatment for their disease (surgery, radiotherapy or chemotherapy). However, over 40% have a palliative intervention such as biliary stenting. 

Less than 10% have radiotherapy. Up to one-third of patients across all age groups are now being treated with chemotherapy. This figure rises to almost 60% in those aged under 65. 

Local practices

As outlined above, there are many chemotherapy regimens used in the treatment of pancreatic cancer. The local practice in the Mater Hospital is to consider folfirinox for those with locally advanced disease, good performance status and good liver function. 

In those with metastatic disease and a good performance status, or locally advanced disease but not suitable for folfirinox, a gemcitabine-based couplet is used, most often gemcitabine and oxaliplatin. Those with a poorer performance status and metastatic disease are often treated with single-agent gemcitabine. 

In keeping with international guidelines, our patients ideally should be enrolled in a clinical trial. We are currently recruiting patients with locally advanced pancreatic cancer into the Otsuka trial which is a phase II placebo controlled double blind trial assessing gemcitabine + dasatinib versus gemcitabine + placebo. 

Survival

Unfortunately, there has been little change in incidence or mortality rates for pancreatic cancer over the past 15 years in Ireland. The incidence rates and mortality rates are essentially equal, highlighting the poor prognosis from pancreatic cancer. 

The five-year survival rate is approximately 5-6%. Less than 2% diagnosed in Ireland live longer than three years and 87% die within 12 months of diagnosis. These grim statistics highlight the need for ongoing research in this area and stress the importance of enrolment in clinical trials where possible.

References

1. National Cancer Registry Ireland. www.ncri.ie
2. Thomson BN, Parks RW, Redhead DN, et al. Refining the role of laparoscopy and laparoscopic ultrasound in the staging of presumed pancreatic head and ampullary tumours. Br J Cancer 2006; 94: 213
3. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985; 120: 899
4. Van Laethem JL, Hammel P, Mornex F et al. Adjuvant gemcitabine alone versus gemcitabine-based chemoradiotherapy after curative resection for pancreatic cancer: a randomized EORTC-40013-22012/FFCD-9203/GERCOR phase II study. J Clin Oncol 2010; 28: 4450
5. A multi-institutional comparative trial of radiation therapy alone and in combination with 5-fluorouracil for locally unresectable pancreatic carcinoma. The Gastrointestinal Tumour Study Group. Ann Surg 1979; 189: 1705
6. Huguet F, Girard N, Guerche CS et al. Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: a qualitative systematic review. J Clin Oncol 2009; 27: 2269
7. Sahora K, Kuehrer I, Eisenhut A et al. NeoGemOx: Gemcitabine and oxaliplatin as neoadjuvant treatment for locally advanced, nonmetastasized pancreatic cancer. Surgery 2011; 149: 311
8. Locker GY, Hamilton S, Harris J et al. ASCO 2006 update and recommendations for the use of tumour markers in gastrointestinal cancer. J Clin Oncol 2006; 24: 5313
9. Rothenberg ML, Moore MJ, Cripps MC et al. A phase II trial of Gemcitabine in patients with 5-FU refractory pancreas cancer. Ann Oncol 1996; 7: 347
10. Van Rijswijk RE, Jeziorski K, Wagener DJ et al. Weekly high-dose 5-fluorouracil and folinic acid in metastatic pancreatic carcinoma: A phase II study of the EORTC Gastrointestinal Tract Cancer Cooperatve Group. Eur J Cancer 2004; 40: 2007
11. Cartwright TH, Cohn A, Varkey JA et al. Phase II study of oral Capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol 2002; 20: 160
12. Cunningham D, Chau I, Stocken DD, et al. Phase III randomized comparison of Gemcitabine versus Gemcitabine plus Capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 2009; 27: 5513
13. Louvet C, Andre T, Liedo G et al. Gemcitabine combined with Oxaliplatin in advanced pancreatic adenocarcinoma: final results of a GERCOR multicenter phase II study. J Clin Oncol 2002; 20: 1512
14. Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus Gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364: 1817