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Dr Zee Ying Kiat is a specialist in Medical Oncology at Parkway Cancer Centre. Before moving to his current practice, he was a Consultant Medical Oncologist at the National University Cancer Institute, Singapore (NCIS).

Dr Zee received his medical degree with dual distinction from University College London. After being accepted as a Member of the Royal College of Physicians (United Kingdom), Dr Zee worked at the Royal Marsden Hospital in London before completing specialist training in Medical Oncology at the National University Hospital, Singapore. He subsequently underwent fellowship training at The Christie Hospital and Paterson Institute for Cancer Research in Manchester, where his focus was on anti-cancer drug development.

At NCIS, Dr Zee conducted clinical and translational research as principal or co-investigator in local and international trials involving novel targeted therapies for colorectal, gastric, liver and pancreatic cancers. He has published his work as first author in high impact factor journals that include the British Journal of Cancer, Journal of Clinical Oncology, Lancet Oncology and Nature Reviews. In addition to general medical oncology, Dr Zee has a special interest in gastro-oesophageal, hepatobiliary, pancreatic and colorectal cancers.

Worldwide, pancreatic cancer is the 13th most common adult malignancy but eighth in terms of cancer death.1 In Singapore, the incidence of pancreatic cancer has increased over the past 40

years, with approximately 1,000 cases diagnosed between 2003 and 2007.2 Although pancreatic cancer did not feature among the 10 most common cancers in Singapore, it represented the sixth and seventh most common cause of cancer death in Singaporean males and females, respectively.2 This is largely due to warning symptoms usually appearing only once the disease has progressed to involve other structures. As a consequence, only 10% to 20% of patients have resectable pancreatic cancer at presentation.3

The term pancreatic cancer encompasses both endocrine and exocrine tumours, of which over 80% are adenocarcinomas. This article aims to provide an update on the diagnostic tools and treatment modalities in the management of patients with pancreatic adenocarcinomas.

Diagnostic ToolsDiagnostic workup for a patient with suspected pancreatic cancer is aimed at confirming a malignant process, delineating the extent of disease spread and identifying patients who are eligible for resection with curative intent. A biopsy specimen is not an absolute requirement prior to surgical resection when suspicion of cancer is high. Generally, the resection will provide therapeutic benefit, and substantially delaying surgery to confirm diagnosis could delay commencement of effective treatment.4

Computed TomographyTri-phasic pancreatic-protocol computed tomography (CT) is an important initial diagnostic test in patients with suspected pancreatic cancer. It aids in disease staging, and optimum CT scans provide up to 90% accuracy for the prediction of resectability.5 Imaging technology continues to improve, and the ability of high quality pancreatic-protocol CT scans to detect locally advanced and metastatic disease reliably has greatly reduced

Pancreatic AdenocarcinomasUpdate on diagnostic tools and treatment modalities

by Dr Zee Ying Kiat

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the number of unnecessary laparotomies and need for staging laparoscopies.6

Magnetic Resonance ImagingMagnetic resonance imaging (MRI) may be used for staging in patients who cannot tolerate intravenous contrast for CT.4 Its use in detecting small lesions and determining resectability is, however, increasing as new and faster MRI techniques enable imaging of the pancreas with higher resolution.

Positron Emission TomographyPositron emission tomography (PET) scanning uses 18F-fluorodeoxyglucose (FDG) to image the primary tumour and establish the presence of metabolically active metastatic disease. When combined with simultaneous CT scanning (PET-CT), it may be more sensitive than conventional imaging for the detection of pancreatic cancer and distant metastases.7

Endoscopic UltrasoundEndoscopic ultrasound (EUS) is becoming an increasingly important diagnostic modality. A meta-analysis by Iglesias Garcia and colleagues showed that EUS had a sensitivity of 96% for diagnosing pancreatic cancer.8 Sampling for diagnostic cytology can also be undertaken at the time of EUS. Endoscopic retrograde cholangiopancreatography (ERCP) with brush cytology or forceps biopsy is an effective way (90% to 95% sensitivity) to confirm the diagnosis of pancreatic cancer.7 However, ERCP is an invasive procedure that carries a 5% to 10% risk of significant complications, and is therefore usually reserved as a therapeutic procedure for biliary obstruction or for the diagnosis of unusual pancreatic neoplasms.7

Serum Tumour MarkersBlood tests may help guide further management. Carbohydrate 19-9 (CA19-9) was first identified in patients with cancer in 1981 and is now a widely used serum tumour marker.9 CA19-9 has a sensitivity of 80% and specificity of 73% for pancreatic cancer.10 Pre-operative levels of CA19-9 or more than 100 to 200 U/ml may predict unresectability and poorer survival.11 CA19-9 also has a role in assessing response to treatment and as a surveillance tool following treatment. With the advancement of high throughput techniques (DNA arrays and proteomics), a number of other potential molecular markers for pancreatic cancer have been identified, although to date these have not been found to be any more discriminating than CA19-9.7

Table 1. TNM staging system for exocrine and endocrine tumours of the pancreas.

Primary tumor (T)

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

Tis Carcinoma in situ*

T1 Tumor limited to the pancreas, 2cm or less in greatest dimension

T2 Tumor limited to the pancreas, more than 2cm in greatest dimension

T3 Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery

T4 Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)

Regional lymph nodes (N)

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Regional lymph node metastasis

Distant metastasis (M)

M0 No distant metastasis

M1 Distant metastasis

Anatomic stage/prognostic groups

Stage 0 Tis N0 M0

Stage IA T1 N0 M0

Stage IB T2 N0 M0

Stage IIA T3 N0 M0

Stage IIB

T1 N1 M0

T2 N1 M0

T3 N1 M0

Stage III T4 Any N M0

Stage IV Any T Any N M1

Note: cTNM is the clinical classification, pTNM is the pathologic classification.*This includes lesions classified as PanIinIII classification.Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer New York, Inc.

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Treatment ModalitiesPatients with pancreatic cancer are best managed by a multidisciplinary team that includes medical oncologists, surgeons, radiologists, gastroenterologists, radiation oncologists, pathologists and when appropriate, pain management and palliative care experts. An important consideration in defining treatment is tumour stage, and the preferred staging system for pancreatic cancer is the tumor-node-metastasis (TNM) system of the combined American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) [Table 1].12

SurgerySurgery remains the only curative treatment for patients with pancreatic adenocarcinoma. When performed with curative intent, surgery achieves a five-year survival of 10% to 15% and median survival of 11 to 18 months.7 Most pancreatic adenocarcinomas (78%) arise from the head, neck or uncinate process of the pancreas, and require a pancreatoduodenectomy.13 Distal pancreatectomy is performed for tumours of the body or tail of the pancreas.14 Absolute contraindications to pancreatic resection include liver, peritoneal, or distant lymph node metastases, or where the patient is deemed medically unfit for major surgery. Patient age, tumour size, local lymph node metastases and continuous invasion of the stomach or duodenum are not contraindications to resection. Advances in surgical techniques and perioperative care mean that tumour involvement of the major vessels around the pancreas is no longer an absolute contraindication to curative resection, although encasement of the hepatic artery, superior mesenteric artery, and coeliac axis means surgery is unlikely to confer any survival benefit.7,15

Pancreatoduodenectomy with resection of the portal and/or superior mesenteric vein is safe and feasible, with a similar mortality and morbidity to pancreatoduodenectomy without vascular resection.16 It should, however, only be performed if a disease-free (R0) resection margin can be achieved. If an R0 resection can be obtained, median survival is significantly improved compared to resections with tumour positive margins (13 versus six months; p=0.0002).17

Adjuvant TherapyAdjuvant treatment is recommended for patients who have undergone pancreatic resection with curative intent.18 The benefit of adjuvant therapy has been established from findings of randomised controlled trials. In the GITSG trial, fluorouracil-based chemoradiation was superior to observation alone.19 The CONKO-001 trial concluded that adjuvant gemcitabine was superior to observation alone, with median overall survival of 22.1 versus 20.2 months.20 Investigators on the ESPAC-3 trial compared adjuvant gemcitabine with fluorouracil and found no difference in survival.21 Whether the addition of radiation to adjuvant chemotherapy alone improves survival remains unproven and controversial.

The ESPAC-1 trial compared chemotherapy with chemoradiotherapy and noted that chemoradiotherapy failed to increase survival and was possibly harmful, although the trial had limitations with regard to its design and variability in radiation delivery.22 The RTOG-9704 trial compared gemcitabine with fluorouracil before and after fluorouracil-based chemoradiotherapy and found no significant difference in survival between both treatment arms.23 In many centres, particularly in Europe, patients receive adjuvant chemotherapy without radiotherapy. Some

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centres, particularly in the USA, still use adjuvant chemoradiotherapy, suspecting that radiotherapy can be helpful in some patients, and clinical trials to date have not convincingly ruled out such a benefit.4 Other adjuvant regimens are under investigation. Adjuvant trials underway include those testing the role of erlotinib, the combination of gemcitabine, docetaxel, and capecitabine (NCT00882310), and the granulocyte-macrophage colony-stimulating factor secreting vaccine for pancreatic cancer, with or without cyclophosphamide as a T regulatory-depleting agent (NCT00727441). The ESPAC-4 trial is currently in phase 3, and compares gemcitabine alone against combination therapy of gemcitabine plus capecitabine in patients within one year of a potentially curative resection (ISRCTN96397434).

Neoadjuvant TherapyThe rationale for neoadjuvant therapy is to increase the incidence of R0 resections, downstage borderline resectable disease to allow resection, and reduce loco-regional recurrence.7 However, there are no large multicentre randomised controlled trials of neoadjuvant therapy for pancreatic cancer. Meta-analysis of the available data shows that one-third of patients with locally advanced disease without distant metastases can achieve a significant tumour response to neoadjuvant treatment, increasing the chances of achieving a R0 resection, thereby reducing local recurrence and potentially improving disease-free survival.24 Since no advantage has been recorded of neoadjuvant treatment over adjuvant therapy for patients with clearly resectable disease, and strong evidence exists that adjuvant therapy increases survival, most centres use adjuvant treatment, reserving neoadjuvant therapy for patients with borderline resectable disease.4 The optimum neoadjuvant regimen remains undefined, although combination chemotherapy is usually given.

RadiotherapyApproximately 30% to 40% of patients have locally advanced unresectable pancreatic cancer at presentation. Typically, these patients have tumour adherence or invasion into adjacent structures, particularly the coeliac and superior mesenteric vessels. Treatment options include radiotherapy alone, chemoradiotherapy, and chemotherapy alone. In most settings, radiotherapy alone does not provide optimal tumour control, and local failure rates are high.25 Nevertheless, radiation as a single modality may be considered in the setting of palliating pain for a patient who, due to medical comorbidities, is not considered a candidate for combined chemoradiotherapy, and whose pain is not adequately controlled with opiate analgesia. Chemotherapy alone may be used for patients too frail to tolerate chemoradiation. Trials have been conducted to ascertain if chemotherapy alone is preferable to chemoradiotherapy in patients with locally advanced unresectable disease, although these have been inconclusive.

Systemic ChemotherapySystemic chemotherapy provides benefit to patients with metastatic pancreatic cancer, improving disease-related symptoms and survival when compared to best supportive care alone. Fluorouracil and gemcitabine are both approved by the US Food and Drug Administration (FDA) for use in patients with advanced pancreatic cancer, although gemcitabine is superior to fluorouracil in terms of improving disease-related symptoms and overall survival.26 Gemcitabine-based combination treatments have since been evaluated. In particular, the combination of gemcitabine and capecitabine (an orally administered prodrug of fluorouracil) has been evaluated for individuals with advanced pancreatic tumours in phase 2 and phase 3 clinical trials.27

Findings of a phase 3 trial showed that, compared with gemcitabine alone, the combination of gemcitabine and capecitabine yielded a better response and longer progression-free survival, with a trend towards improved overall survival.28 In another study, a significant overall survival benefit for this combination was reported in the subgroup of patients with good performance status, and data from a meta-analysis indicated a

Systemic chemotherapy provides benefit to patients with metastatic pancreatic cancer, improving disease-related symptoms and survival when compared to best supportive care alone.

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28CunninghamD,ChauI,StockenDD,ValleJW,SmithD,StewardW,HarperPG,DunnJ,Tudur-SmithC,WestJ,FalkS,CrellinA,AdabF,ThompsonJ,LeonardP,OstrowskiJ,EatockM,ScheithauerW,HerrmannR,NeoptolemosJP.PhaseIIIrandomizedcomparisonofgemcitabineversusgemcitabinepluscapecitabineinpatientswithadvancedpancreaticcancer.JClinOncol.2009Nov20;27(33):5513-8

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significant overall survival benefit for this combination.28,29 Conroy et al noted in a phase 3 trial that for patients with good performance status, the combination of fluorouracil, irinotecan, and oxaliplatin achieved a median survival of 11 months (versus 6.8 months for gemcitabine alone).30 In phase 3 clinical trials, the combination of gemcitabine and the epidermal growth factor receptor (EGFR) inhibitor, erlotinib, was modestly superior to gemcitabine alone.31 Erlotinib is approved by the US FDA for use in pancreatic cancer.

ConclusionPancreatic adenocarcinoma is an aggressive malignancy, and most patients present with relatively advanced disease. It is associated with an extremely poor prognosis, with a five-year survival probability of less than 5% for all stages. Tri-phasic pancreatic-protocol CT is an important diagnostic tool, although simultaneous PET scanning may be more sensitive in the detection of distant metastases. EUS is also becoming an increasingly important diagnostic modality. The only chance for cure or longer survival is surgical resection. However, only 10% to 20% of patients have resectable disease. While surgical techniques have improved, most patients who undergo complete resection experience a recurrence. Adjuvant chemotherapy reduces the recurrence rate and improves outcomes. There is a potential role for radiation therapy as part of treatment for locally advanced disease, although its use in both the adjuvant and neoadjuvant settings remains controversial. Palliative systemic therapy improves disease-related symptoms and survival in patients with metastatic disease.