Pancreatic Cancer

Written by Fabio Casciani

Introduction

Pancreatic cancer is among the deadliest solid neoplasms, with an overall 5-year survival rate of approximately 10%.¹ It is commonly referred to as the ‘silent killer’, since diagnosis is mostly achieved at advanced stages. Surgical resection in combination with systemic chemotherapy offers the only chance of cure. Unfortunately, the bulk of patients present with distant metastases at the time of diagnosis and are only eligible for palliative interventions or best supportive care. Despite being a rare disease, pancreatic cancer it is responsible for approximately 5-15% of all cancer-related deaths^2,3. In contrast to other gastro-intestinal malignancies, it is expected that both its incidence and mortality will keep increasing over the next decades.² Therefore, scientific societies and healthcare organizations are currently addressing this condition as a global healthcare emergency.⁴

Multimodal treatment approaches including multi-agent cytotoxic drugs have provided minimal improvement in overall survival during the last decade. Therefore, cohesive, international collaborations are needed to gain knowledge on (molecular) drivers of tumour development, metastasis and chemotherapy-resistance.

Epidemiology and risk factors

Pancreatic cancer is on the rise among both sexes and all age classes. In Europe, with an estimated population of 750 million people, more than 80,000 new diagnoses are registered every year. On a global scale, some 440,000-530,000 annual incident cases are expected according to various reports^3,5 – doubling the number registered two decades ago. Therefore, pancreatic cancer is projected to become the second leading cause of cancer-related deaths worldwide by the end of this decade.⁶

An older age, as well as overweight and obesity, diabetes mellitus, smoking and alcohol consumption are recognized as the main risk factors for pancreatic cancer development. Furthermore, despite pancreatic cancer being universally considered a disease of the elderly, the global obesity epidemic observed among children and adolescents in the last few decades, along with an increase in alcohol consumption, may explain the increase of cases observed before the age of 50 (so called early-onset pancreatic cancer). While being a global phenomenon, it has been estimated that Eastern Europe is the region with the steepest increase in early-onset pancreatic cancer incidence.⁷

RISK FACTORS FOR THE DEVELOPMENT OF PANCREATIC CANCER

Finally, 10% pancreatic cancer cases are associated with a recognised genetic predisposition.⁸ Several genetic syndromes are well known to confer a higher lifetime risk of pancreatic cancer, including CDKN2A, hereditary breast/ovarian cancer syndrome, Lynch syndrome and hereditary pancreatitis.⁹ Nevertheless, genetic background prompting pancreatic carcinogenesis¹⁰ and molecular pathways of cellular derangement, tissue invasion capacity and metastasis are not well understood yet.

Clinical Presentation

Given the location of the pancreas deep in the retroperitoneal space, symptoms present late in the disease stage. Common symptoms include obstructive jaundice, gastric outlet obstruction, abdominal pain irradiating to the back, asthenia and unintentional weight loss. Additionally, complications such as pancreatitis, pancreatic insufficiency, new-onset or treatment-refractory diabetes mellitus, ascites and upper gastrointestinal bleeding might occur. It is essential for both the general population and primary care physicians to be aware of these symptoms, to avoid a delay in the diagnosis. To this respect, it is important to consider an abdominal ultrasound to rule out a pancreatic mass in every patient with new-onset diabetes or poor glycaemic control, in combination with (vague) abdominal pain, sudden weight loss, in the absence of a metabolic syndrome.

Symptoms of pancreatic cancer

Diagnosis and staging

The standard workup for pancreatic cancer diagnosis and staging comprises a thorough physical examination and thoracoabdominal, triphasic computer tomography (CT) scan, along with tissue acquisition – generally by performing fine needle biopsy (FNB) during endoscopic ultrasound (EUS) – and the measurement of serum CA 19-9. One may choose for a Magnetic Resonance Imaging (with hepato-specific contrast) or an additional positron emission tomography (PET)-CT to rule out metastases in the case of undetermined liver or peritoneal lesions. A staging laparoscopy can be considered in selective scenarios – for instance, a localized pancreatic lesion amenable for curative-intent surgical resection should extra-pancreatic lesions be excluded. Accurate staging is pivotal to deliver appropriate treatment. The most frequent sites of metastasis of pancreatic cancer include the liver, peritoneum and lung.

In the case of localized disease, a radiology-based classification has been traditionally employed according to the extension and degree of peri-pancreatic vessels involvement. While inaccurate from a biological standpoint, the distinction of anatomically resectable, borderline resectable and locally advanced (in the past referred to as ‘unresectable’ tumour) pancreatic cancer still drives treatment approaches and surgical indications.

Resectability of pancreatic cancer

Given the overall low prevalence of the disease and the lack of diagnostic modalities that allow early diagnosis of pancreatic cancer, there are no screening programs available for the general population. Instead, multiple dedicated surveillance programs have been built worldwide to target high-risk individuals who harbour a significant increased likelihood of developing pancreatic malignancies over the lifetime. Such efforts have varying results in early diagnosis of pancreatic cancer and improving survival.

Classification

In the last decade, the development of high throughput sequencing technologies has led to the characterisation of molecular-based subtypes of pancreatic cancer that not only present distinct genomic alterations, but also correlate with unique treatment response rates and survival estimates.¹¹ Given the rapid accumulation of genomic information and the linkage of molecular and clinical data, it is expected that the definition of molecular subtyping will soon be integrated into diagnostic and therapeutical algorithms,¹² realising a fully mature ‘precision oncology’ paradigm for pancreatic cancer treatment

Treatment

Regardless of disease stage, it is mandatory that the treating physician rapidly involves a core multidisciplinary team to plan, deliver and monitor the best treatment approach throughout the entire patient’s journey. This multidisciplinary team should include professionals with specific competence in radiology, interventional endoscopy, medical oncology, radiation oncology, surgery, pathology, geriatric medicine and oncological genetics. Furthermore, palliative medicine, nutrition, physical medicine and psycho-oncology experts should be available for consultation.

Given the high specialisation and professionalism required to treat pancreatic cancer patients, physicians should refer their patients to certified, high-volume pancreatic cancer care institutions with top-quality facilities. Furthermore, patients should be enrolled in clinical trials whenever possible.

Treatment of Metastatic Disease

Patients with metastatic disease are candidates to receive primary chemotherapy with the intent to relieve symptoms, improve quality of life and prolong survival. Effective multi-agent chemotherapy regimens available today include (modified) FOLFIRINOX (a combination of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin, administered once every two weeks)¹³ and the combination of Gemcitabine and nanoparticle albumin-bound Paclitaxel (administered weekly for three weeks in a 28 day-long cycle).¹⁴

As of today, neither local ablative treatments nor surgery have a role in the management of metastatic pancreatic cancer, although several reports have showed prolonged survival with the implementation of metastasis-directed treatments in selected patients sensitive to primary chemotherapy¹⁵. Similarly, single molecule targeting drugs and immunotherapy combinations are not recommended as first-line, standard-of-care approaches, and are mainly administered in the context of experimental protocols.

It is of utmost importance that consultation within multidisciplinary teams should occur as early as possible in the patient journey. Such an approach aims to define treatment goals, tailor therapeutical opportunities (sparing scarcely tolerable, potentially futile treatments) and provide full multi-level support to the patient and their caregivers. Best supportive care must be offered to every patient.

Treatment of Locally Advanced, Unresectable Disease

Pancreatic cancer with extensive venous or arterial infiltration assessed at imaging – without distant metastases – is commonly defined as locally advanced. In this scenario, the likelihood of achieving a complete resection is nihil. Therefore, primary chemotherapy is necessary to improve quality of life and reach sustained disease control. Best supportive care, with or without palliative radiation therapy, must be delivered to patients with declining performance status. In 10-20% of patients with initial locally advanced disease who show sustained radiological response to chemo(radiation) therapy and improving performance status, curative intent resection can be considered¹⁶ after referral to high-volume institutions with expertise in complex pancreatic surgery. It needs to be emphasised that extended pancreatectomies with concomitant vascular and multi-visceral resections are associated with extremely high postoperative morbidity and mortality rates even at tertiary-level institutions¹⁷. Consequently, the indication to commit to surgery in the case of locally advanced pancreatic cancer remains controversial and should be made on a case-to-case level only after consultation of a multidisciplinary team and accurate patient counselling.

Treatment of Localised, Anatomically Resectable and Borderline Resectable Disease

The treatment goal for patients with localised pancreatic cancer with no – or limited – vascular involvement is to achieve complete tumour clearance and subsequent, sustained disease-free survival. In this scenario, tumour resection followed by six months of adjuvant chemotherapy represents the only chance of cure. A paradigm shift has been recently witnessed following the publication of a multi-institutional randomised controlled trial¹⁸ showing unprecedented survival gain obtained through the combination of surgery and administration of six months of adjuvant (modified) FOLFIRINOX, which currently represents standard of care.

The administration of preoperative chemo(radiation) treatment (so called neoadjuvant approach) has gained momentum in the last decade, and currently represents a valid option supported by some international guidelines. In fact, long-term analysis of recently published randomized controlled trials demonstrated a limited, yet significant survival gains for patients receiving neoadjuvant chemotherapy versus upfront surgery for (borderline) resectable pancreatic cancer.¹⁹ Putative benefits of such an approach include the opportunity to obtain tumour shrinking, or downsizing, to increase the likelihood of achieving surgical clearance (namely, improving complete resection rates) as well as to treat micro-metastatic disease. However, optimal treatment sequence, chemotherapy regimen, the role of radiation therapy, as well as the optimal interval between chemo(radiation) and surgery remain uncertain.²⁰

It is likely that future randomized studies encompassing biological markers of tumour chemo-sensitivity for patient stratification and treatment allocation will provide high-quality data to assess the optimal therapeutical algorithm for localized pancreatic cancer. As of today, the choice between upfront versus post-treatment surgery in the case of anatomically resectable disease without distant metastases should be based on a case-by-case level following accurate patient counselling.

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