Pancreatic Cancer : Alarm for Survival

Pancreatic cancer is one of the deadliest and a highly aggressive cancer. Its incidence and mortality are highest in developed countries. However, in Asia-Pacific region, the incidence and mortality rate of pancreatic cancer are also on increasing trend nowadays. Pancreatic cancer incidence rates increase with older age, the highest in the 7th and 8th decades. Clinical presentation of pancreatic cancer are usually non-specific, largely dependent on tumour size and location, with most patients experience symptoms already late in the disease. Computed tomography is considered the method of choice for diagnosis and staging of pancreatic cancer. Management for pancreatic cancer include surgical resection, radiotherapy, chemotherapy. Only surgical resection considered the potentially curative treatment for pancreatic cancer. Unfortunately, a lot of patients present with disease that is not surgically resectable. Prognosis for pancreatic cancer is very poor, despite surgery in resectable patients. The overall five-year survival rate is about less than 5%


Kata kunci: pancreatic cancer, diagnosis, management
Pancreatic Cancer: Alarm for Survival

INTRODUCTION
According to GLOBOCAN 2012, pancreatic cancer causing more than 331,000 deaths per year, which ranked as seventh leading cause of cancer death in both sexes together.Pancreatic cancer also ranked the 12th most common cancer in the world with 338,000 new cases.The highest incidence and mortality rates of pancreatic cancer are found in developed countries.In Asia Pacific region, the mortality rate of pancreatic cancer are on increasing trend nowadays. 2he incidence rates of pancreatic cancer for both sexes increase with age, the highest in the 7 th and 8 th decades of life.There are many condition that considered as risk factors for pancreatic cancer.The risk factors are divided into modifiable and non-modifiable.Modifiable risk factors include smoking, obesity, alcohol and dietary factors, while non-modifiable risk factors include increasing age, familial cancer syndromes, race, hereditary, diabetes mellitus, and chronic pancreatitis. 3he survival rate of pancreatic cancer is very poor; the overall 5-year survival is about less than 5%.Surgical resection is the only potentially curative treatment of choice for pancreatic cancer.The majority of patients are diagnosed at an advanced stage where surgical resection is not an option for treatment, hence the low survival rate.Despite improvements in imaging, surgical techniques and chemotherapy, overall survival has not improved in the past few decades. 1

Clinical Presentation
The clinical presentation of patients with pancreatic cancer are usually non-specific, it largely depends on the size and location of the tumor.Pancreatic cancer location approximately 60-70% in the head of pancreas, 20-25% in the body and tail of pancreas, dan the remaining 10-20% diffusely involve the pancreas.Symptoms of pancreatic cancer include jaundice, abdominal pain, weight loss, steatorrhoea, and new onset diabetes. 4

Diagnostics
Pancreas protocol CT is the gold standard for diagnosis and staging pancreatic cancer.The pancreatic protocol CT consists of dual-phase scanning using intravenous and oral contrast agents.It is the most widely used modality for diagno sis and staging of pancreatic cancer due to the fairly wide availability.CT can be used to assess po tential vascular involvement and meta stases. 5,6Although the widely used of CT for diagnosis of pancreatic cancer, MRI can also play an important role.MRI have more superior soft tissue contrast that can detect small, non-countour deforming tumors which may not be seen on CT.MRI and CT have similar performance for staging of pancreatic cancer.In some cases, MRI improves detection of hepatic metastases and characterization of CT-indeterminate liver lesions. 7nother modality used in the diagnosis of pancreatic cancer is endoscopic ultrasound (EUS).EUS with Fine Neddle Aspiration (FNA) can help secure tissue for cytologic diagnosis which made it essential for diagnosing pancreatic cancer.EUS can provide staging of suspected or proven pancreatic cancer, and cytological/histological proof of unresectable pancreatic cancer. 8Although EUS is a minimally invasive procedure, it is considered a safe procedure with low complication rates.Complications of EUS procedure include bleeding, pancreatitis, perforation, and rarely tumor seeding after EUS-FNA. 9

Staging
The American Joint Committee on Cancer (AJCC) 8 th edition staging system for pancreatic cancer is shown Table 1.This new staging system different from the previous 7 th edition.The T category is revised from descriptive to size-based definitions.Another change, resectability is removed from the T4 category because the definition of resectability is not consistent among institutions and evolves with advances in surgical technique. 10

Resectable
Surgical resection is a potentially curative treatment for pancreatic cancer, but only 15-20% of patients present with a resectable disease. 11Patients who have localized disease with no metastases, good performance status and no significant comorbidities are a good candidate for surgical resection.The classic surgery for resection is a pancreaticoduodenectomy, also known as Whipple procedure. 12Pancreatic cancer patients who undergo surgical resection is recommended to be given adjuvant chemotherapy. 13ESPAC-4 trial showed that patients with resected pancreatic cancer who were given adjuvant combination of gemcitabine and capecitabine had improve overall survival compared with only gemcitabine (OS: 28 months vs. 25.5 months; HR for death 0.82; 95% CI 0.68-0.98). 14here is still no recommendation to giving neoadjuvant chemotherapy in resectable pancreatic cancer because no significant improvement in overall survival. 15

Borderline Resectable
Borderline resectable pancreatic cancer have a higher risk for positive margin after resection.Therefore, neoadjuvant therapy recommended to be given before surgical resection of borderline resectable pancreatic cancer.A study using FOLFIRINOX followed by capecitabine based chemoradiation for borderline resectable pancreatic cancer showed a successful pancreatectomy (68%) with negative margins resection rates (93%). 16

Locally Advanced
Patients with locally advanced pancreatic cancer who underwent surgical resection usually had a poor prognosis due to high rates of margin positivity after surgical resection.Systemic chemotherapy is the preferred treatment for locally advanced pancreatic cancer.A systematic review and meta analysis study using FOLFIRINOX as systematic chemotherapy showed a median overall survival longer (24.2 months) compared to gemcitabine (6-13 months).The study also showed about 28% patients were able to underwent surgical resection of tumour and 78% of them had negative margin resection. 17Chemotherapy in this situation is never curative, and its palliative benefit must be balanced against its potential toxic side effects.Despite treatment, the survival outcomes remain poor. 18

Endoscopic Ultrasound (EUS) Interventional Therapy
EUS interventional therapy in pancreatic cancer management is emerging.Many applications using EUS include fiducials placement, brachytherapy, fine needle injection (FNI) and radiofrequency ablation (RFA).Fiducial are inert radiopaque spheres, coils, or cy lindricals that are implanted inside or adjacent to the tumor in order to aid image-guided radiation therapy (IGRT).EUSguided fiducials placement first reported by Pishvaian et al in case series of 13 patients where technical success achieved in 94% patients. 19][22] EUS-brachytherapy apply the insertion of a radioactive seed (io dine-125, iridium-192, and palladium-103) directly into the pancreatic tumor.Brachytherapy still need more larger studies for evaluation.[25] EUS-FNI apply direct injection of therapeutic agents into pancreatic tumors.] EUS-RFA role in management of pancreatic cancer had been showed in recent studies.A study by Song et al demonstrated safety and feasibility of EUS-RFA in patients with unresectable pancreatic cancer.Technical success in this study was achieved 100% however overall survival can't be assessed. 28

CONCLUSION
Pancreatic cancer still considered one of the deadliest cancer types.Survival rate of this disease is very poor.There are many diagnostics modality for diagnosing pancreatic cancer but early diagnosis of pancreatic cancer is still difficult.One of the factor is because patients only experience symptoms of pancreatic cancer late in the course of the disease.Despite treatment, pancreatic cancer high aggressiveness and resistance to modern chemo-radiotherapy are associated with low rates of long-term survival.Studies using EUS as interventional therapy showed promising results.More larger studies are needed to establish the role of these procedures in the treatment of pancreatic cancer.There are no screening recommendations for pancreatic cancer, so primary prevention is of utmost importance.

Table 1 . American Joint Committee on Cancer (AJCC) 8 th edition staging system for pancreatic cancer
Reprinted from American Joint Committee on Cancer (AJCC) 8 th edition