Adenocarcinoma of the pancreas* takes the lives of 2500 Australians annually and because of the devastating effects of its diagnosis, has long been the poor cousin to other cancers. People with pancreatic cancer rarely survive to be champions of this disease. It has been noted to have the highest mortality to incidence ratio of any cancer and by 2020, will likely have the highest mortality of any cancer. Accordingly it is imperative that we drive awareness, research and treatment of this disease. Australia is privileged to have some of the best researchers in the world in the field of pancreatic cancer. This issue of Cancer Forum aims to take you through carcinogenesis, genomics and biology, and then into the clinical realms of epidemiology, diagnostics, treatment and palliation of pancreatic cancer. In each chapter we have asked Australian researchers and clinicians to review current knowledge, and then to inform us of their own practice.
*Approximately 90% of pancreatic cancer is pancreatic ductal adenocarcinoma. Accordingly, unless otherwise stated, the term ‘pancreatic cancer’ used in this Forum refers predominantly and typically to this tumour type.
Each year, over 2500 patients in Australia are diagnosed with pancreatic cancer. Pancreatic cancer is one of the most lethal tumour types with a five year survival of just 5%, thus there is a need to find alternative approaches to treatment. In recent years, the application of next generation sequencing has revealed the complex genomic landscape of pancreatic cancer, uncovering the mutation processes that occur during tumour development and has begun to identify new or repurposed therapeutic opportunities for pancreatic cancer patients. The identification of targets for therapy is a crucial goal of the large next generation sequencing studies as we move into an era of targeted or personalised medicine, where drugs will be selected based on the characteristics of a patient’s tumour. Due to the large degree of heterogeneity in pancreatic cancer, a personalised approach to treatment seems particularly warranted. This review will summarise some of the key findings from genome sequencing of pancreatic cancer, describing the major driver genes and perturbed pathways, and highlighting some of the new potential and promising therapeutic opportunities that have been uncovered.
Chronic pancreatitis, an inflammatory disease of the exocrine pancreas, has been reported to be a major risk factor for the development of pancreatic ductal adenocarcinoma. Evidence from pre-clinical mouse models has shown that both diseases share a common origin in the digestive enzyme-producing acinar cells, through acinar to ductal metaplasia. Moreover, both diseases are characterised by the presence of an abundant stroma, the components of which include activated pancreatic stellate cells and immune cell infiltrates, which signal to epithelial cells through the production of cytokines and chemokines. In this review we explore the links between chronic pancreatitis and pancreatic ductal adenocarcinoma, with particular reference to the role of the microenvironment in both diseases. A better understanding of the nature of the epithelial and stromal changes, as well as their interactions, has led to trialling novel therapeutic strategies for the prevention and/or treatment of pancreatic cancer.
Pancreatic cancer is a devastating disease with a five-year survival rate of 6%. A key driver of disease progression is the tumour microenvironment, which is characterised by fibrosis. A dynamic interplay between tumour cells, pro-fibrogenic pancreatic stellate cells and a dense extracellular matrix impedes effective drug delivery and promotes chemoresistance and metastases. In addition, mutations in pancreatic cancer are highly heterogeneous, making it difficult to effectively treat all patients with one approach. Thus, any effective pancreatic cancer treatment should consider targeting both pancreatic cancer cells and the stromal compartment. While basic research has provided promising new leads on therapeutic targets for this disease, many of them remain ‘undruggable’ by conventional approaches. Advances in nanoparticle technology and intravital preclinical imaging of live tumours is providing new insight into the behaviour of the disease in vivo and guiding how best to target this disease with higher specificity and lower off-target toxicity. Here, we describe in brief, key advancements in both rapidly emerging fields and highlight their current and future application in the treatment of pancreatic cancer.
Pancreatic cancer is uncommon, but is projected to become the second leading cause of cancer-related death by 2030. The dismal five year survival of 5% reflects the advanced stage of the disease at presentation, at which time surgery is not possible. The establishment of clinical and pathological diagnosis currently relies on dedicated ‘pancreatic protocol’ CT, MRI/cholangiopancreatography, endoscopic ultrasound and guided fine needle aspiration. Given surgical resection of early stage cancer is curative at least in some cases, the concept of screening high-risk individuals to detect the cancer at its earliest stage has been evaluated over the last 10 years. Although the advances in imaging modalities, particularly those without radiation exposure, such as endoscopic ultrasound and MRI have made screening programs safe and feasible, studies demonstrating the impact of these programs on survival outcomes are lacking. Thus, screening of high-risk individuals is not ready for widespread clinical practice and should be conducted by clinicians who have expertise in endoscopic ultrasound for screening of high-risk individuals in a research setting with prospective data collection.
Up to 10% of pancreatic cancer cases have a heritable component. Some of these are clearly defined tumour predisposition syndromes known as hereditary pancreatic cancers, but most are familial cases, defined by family history and where the underlying genetic causes remain unknown. Genetic counselling is important in suspected inherited pancreatic cancer cases, to enable risk assessment and relevant genetic testing. Screening trials are available for at-risk individuals (i.e. >5% lifetime risk), although more long-term data is required to determine the risks, benefits and optimal approaches to pancreatic cancer surveillance.
Pancreatic neuroendocrine tumours are rare tumours that can either present with syndromes from excess hormonal production or from mass effect – from the primary or metastases. They vary widely in clinical course, with the main determinants of outcome being TNM staging and pathological grade. The available treatment options depend largely on the grade of the tumour – somatostatin analogues, targeted agents, chemotherapy and PRRT for lG1 and G2 PNETs, and chemotherapy as the mainstay of treatment for high grade NET/NECs. The paucity of randomised evidence in the treatment of this disease argues for ongoing research to understand the molecular genetics underlying PNETs, to develop possible future treatment options, as well as optimising use of existing ones.
Despite advances in multimodal therapy, surgery remains central to the management of patients with resectable pancreatic adenocarcinoma. Complete surgical clearance of disease offers the only real, albeit slim, chance of cure. For the greater proportion of patients with resectable macroscopic but occult microscopic disease, who ultimately recur early, short-term outcomes are still better compared to other currently available treatment modalities. Morbidity rates following pancreatic resection are worse than cancer surgery data for other intra-abdominal sites however, and involved margins are an unsurprising predictor of poor oncological outcome. Patient selection is therefore key. Refinements in surgical technique and treatment algorithms, such as the evolving use of neoadjuvant therapy, have improved appropriate selection for surgery, resectability rates and early postoperative outcomes. Review of contemporary Australian observational follow-up data highlights favourable local morbidity and mortality results, but persistently disappointing long-term survival outcomes reflective of the international picture. The surgeon’s current role remains to achieve complete local resection with minimal morbidity. Such an achievement maximises the successful utilisation of multimodal therapies targeting microscopic disease, and preserves the remaining quality of life for those patients with ultimately incurable disease suffering from aggressive tumour biology.
The role of radiotherapy in pancreatic cancer is controversial. Its utility in treatment has been investigated in a number of clinical settings, including before and after surgery for operable cancers and in the treatment of locally advanced, inoperable disease. Adjuvant treatment has had mixed results in trials and there is now interest in better selecting patients who may benefit from neoadjuvant treatment. The benefit of radiotherapy continues to be poorly defined, due in part to the large number of differing treatment regimens that have been investigated. This article reviews the current evidence for radiotherapy in pancreatic cancer, with a focus on identifying those patients who are most likely to benefit from radiotherapy treatment. It will also discuss some of the planning considerations.
While radiotherapy was considered an important treatment modality in locally advanced pancreatic cancer for several decades, the presentation of the LAP 07 trial results have impressed a concept that radiotherapy provides no benefit in this patient group. Further analysis however, revealed that the use of radiotherapy in the LAP 07 trial was associated with better local control and a greater chemotherapy-free interval, both meaningful palliation benefits. Further, the initiation of radiation was delayed by a four month period of induction treatment that employed a drug with only an 8% response rate, and progression free survival control of 3.1 months. A detailed review of the literature to date demonstrates that modern radiotherapy in locally advanced pancreatic cancer has a significant local effect, is well tolerated and associated with improved quality of life through providing durable local control, and in a subset population, resulting in long-term survival. Perhaps the most important conclusion of the LAP 07 study, which was very well conducted, is that delaying a local therapy for four months is not an effective sequencing strategy when the induction treatment is of borderline efficacy in a cancer with a rapid progression characteristic. While newer agents are improving survival, the outlook remains dismal. Optimising the integration of radiation needs to be a priority to define how this modality can assist the modest gains that have come about from a very large number of chemotherapy sequencing studies.
Pancreatic cancer is a highly lethal disease due to its late presentation and its innate resistance to treatment. Although much research has been conducted in order to discover and develop new therapeutic targets to combat this disease, the survival gains for patients have been modest. This review aims to synopsize the current literature which has framed the approach to first and second line therapy of advanced disease. We look at the evolution of targeted therapies and briefly discuss current trials evaluating the role of immunotherapy. Finally, we cover the future of pancreatic cancer, in particular the essential role that predictive and prognostic biomarkers need to take in order to change the way we approach clinical trial design and management of patients.
People diagnosed with pancreatic cancer suffer the worst five-year survival of any cancer. Resection of the primary tumour currently provides the only potential for cure. Increasing the proportion of patients who undergo surgical resection and ensuring that this occurs in a high-volume setting may lead to population-level survival gains. Access to chemotherapy in both adjuvant and palliative settings may lead to further improvements. Worse survival has been reported for patients from lower socio-economic and rural areas than those who are wealthier and living in major cities. Management in higher-volume hospitals tends to be associated with higher survival. Differences in patient factors such as age, performance status and the presence of co-morbidities may partly explain the survival discrepancies. However, international and limited Australian data suggest that not all patients receive optimal treatment, and that variability in care may be related to socio-demographic factors. There is considerable investment in identifying new strategies for diagnosis and treatment. However, immediate improvements could be made by implementing policies and procedures that enable all patients to be managed by high-performing multidisciplinary teams, ensuring receipt of optimal curative and supportive treatment modalities. This will also enable full realisation of benefits expected to accrue from the development of new treatments over the coming decades.
The management of patients with advanced pancreatic cancer often requires a multi-disciplinary approach with individualised therapy. Addressing the underlying causes of several of the troublesome symptoms that are relatively unique to the pathophysiology of pancreatic cancer is crucial in order to optimise the function and comfort of people diagnosed with this poor prognosis cancer. Early recognition and response is likely to improve outcomes later in the course of the disease, but more work needs to be done to compare expectant and reactive approaches to the most troublesome symptoms in advanced pancreatic cancer. Given such a poor outlook, referral to a palliative care service that has an active, team-based approach that includes dietetics, gastroenterology, interventional pain expertise and liaison psychiatry is likely to deliver the best possible outcomes. Such programs need to be in centres with sufficient caseload to ensure that meaningful outcomes can be measured prospectively and these teams are also best placed to incorporate new knowledge and approaches as the evidence base continues to evolve.
Pancreatic cancer is acknowledged as one of the most challenging diseases in the 21st century. Despite the recent focus on research and novel therapies, by 2030 pancreatic cancer is projected to be the second leading cause of cancer death after lung cancer. With incidence and mortality rising against the trend in other cancers, the importance of a whole team approach to achieve best quality of life and care is critical. Recent Australian research has reported significant unmet needs for psychosocial and supportive care for people affected by pancreatic cancer. Nihilism has been identified as a problem in pancreatic cancer that affects clinicians, patients, carers and families. This can lead to loss of hope and people becoming disengaged from care, resulting in increased distress, poor quality of life and signs of demoralisation. Meaning-centred therapies can help with reducing demoralisation, improving existential wellbeing, increasing dignity and legacy building. Effective interventions can ease the existential distress that is often experienced at end of life and help family members during the grieving process. Essential in providing optimal care for patients and caregivers is timely and appropriate discussions about the importance of palliative care in managing symptoms and improving quality of life. Early integration of psychosocial and supportive care is recommended to achieve best quality of life and relieve suffering.