Half of the eight deadliest cancers are of the upper gastrointestinal tract origin, including the pancreas, liver, oesophagus, and stomach. Pancreatic cancer is top of the list with the lowest five-year survival rate of 9%.
However, cancers originating from the lungs, colon, breast, and prostate have only historically been considered to be the major cancer types in the US due to their high incidence and mortality rates. Aside from lung cancer, which has a five-year survival rate below 50%, the other three major cancer types have five-year survival rates ranging between 66% and 99%, indicating that scientific advances in medical practice have translated into a high survival rate in these cancers.
Although the overall incidence and death rates for cancer in the US are declining, pancreatic cancer is following the opposite trend. In 2016, deaths from pancreatic cancer surpassed breast cancer and are expected to exceed deaths from colorectal cancer in the early 2020s. This will position pancreatic cancer as the second leading cause of cancer-related deaths in the US.
The trajectory of pancreatic cancer deaths could be attributed to the scarcity of clinical advances, which is mainly driven by inadequate clinical research. Although National Comprehensive Cancer Network (NCCN) guidelines indicate that clinical trials are the preferred treatment option for all stages of pancreatic adenocarcinoma (PAC), low clinical trial enrolment and suboptimal design are the major reasons underlining the slow progress in understanding the disease and the persistent poor outcomes for patients.
In 2011, 4.57% of US patients with pancreatic cancer were enrolled to a clinical trial in the US. Although this compares favourably to the overall estimate of a less than 3% clinical trial enrolment rate among adult patients with cancer in the US, it was far below the rate required to complete the total enrolment for pancreatic cancer trials, where 15% of the target enrolment rate was achieved in 2011 in the US.
When pancreatic cancer trials are grouped according to disease stage, 83% and 26% of the total patient population with resectable and metastatic PAC, respectively, would have had to register in clinical trials to fulfil the entire trial portfolio in 2011. This means that the number of patients to fully complete the total clinical trial portfolio for pancreatic cancer significantly exceeds the supply of patients provided by an average clinical trial enrolment rate of 4.57% in 2011, even if all eligible patients were recruited to clinical trials.
Slow accrual rate is a major cause of delay in the initiation of clinical trials, alongside extensions in trial duration and trial termination due to insufficient number of patients enrolled. Time is of utmost importance and more effective strategies for clinical advancement are necessary to accelerate progress.
Following the 1996 US Food and Drug Administration (FDA) approval of gemcitabine, only four other treatment options were added to the treatment algorithm of PAC in the last two decades: Tarceva (erlotinib) in combination with gemcitabine in 2005; FOLFIRINOX in 2011; Abraxane (albumin-bound paclitaxel) in combination with gemcitabine in 2013; and Onivyde (liposomal irinotecan) in combination with fluorouracil (5-FU) and leucovorin in 2015.
A total of 35 different agents or combination regimens were evaluated in 39 Phase III clinical trials in advanced PAC between 1997 and 2015, resulting in a success rate of 11%. In 85% of these Phase III trials, the study was conducted despite their preceding Phase II trials not having met its primary endpoint.
Follow-up Phase III trials were initiated based on encouraging secondary endpoints, subset analysis results, or a promising second Phase II trial conducted elsewhere. This translates into a large amount of patients, time, and capital wasted on a large proportion of negative-result trials that could have been predicted based on the Phase II readout. Directing these resources to early stage clinical trials could more effectively identify new therapeutic approaches and result in a higher chance of major advancement in PAC survival rates.
More effective approaches need to be implemented to design and conduct clinical trials in pancreatic cancer. The Pancreatic Cancer Action Network (PANCAN) maintains an up-to-date database of clinical trials that match patients’ stage of disease to trials that are open in a reasonable distance. The efforts of PANCAN resulted in a steady increase in the number of PAC-specific clinical trials open in the US between 2011 and 2015.
Similarly, there has been a dramatic increase in the number of clinical trials enrolling previously treated patients during the same period. This follows the observation that in 2011, two-thirds of the patients who contacted PANCAN were ineligible for 90% of the clinical trials that were open because they had already received prior treatment. The increase in clinical trials for patients with relapsed / refractory disease provides these patients with more options and a multistep treatment plan that has higher chances of improving survival.
In addition, the range of treatment types evaluated in clinical trials has expanded significantly between 2011 and 2015. In 2011, clinical trials evaluating targeted therapies composed 29% of the PAC landscape. In 2015, 40% of PAC trials focused on therapies targeting specific molecular pathways. The increased investigation of targeted therapies is expected to result in more frequent use of molecular profiling in PAC clinical trials, which could significantly improve clinical trial design by identifying subsets of patients who have the highest chance of responding to a specific treatment and enrolling them in the clinical trial.
PANCAN’s clinical trial database reported in 2016 that 12% of the clinical trials required an assessment of a biomarker for enrolment. It is anticipated that this percentage will increase over time as more targeted treatments are evaluated in PAC clinical trials. PANCAN’s 'Know Your Tumor' initiative is driving this effort as patients with pancreatic cancer across the US are provided access to multi-omic molecular profiling of their tumours and can be assigned personalised treatment approaches accordingly.
In pancreatic cancer trials, more is not necessarily better. Past trials enrolled large numbers of unselected patients with pancreatic cancer and delivered modest improvements in survival. Following this approach of treating all patients with chemotherapeutic agents is unlikely to transform the current treatment paradigm and is likely to squander the already limited resource of patients willing to participate in clinical trials.
It is imperative to closely match the supply of clinical trials to the demand of the patients with pancreatic cancer by thoroughly profiling the molecular characteristics of the patients’ tumours, disseminating the practice of tumour profiling across the US and other regions, and applying this information to the clinical trial design and execution.
Only an integrated approach involving the National Cancer Institute (NCI), the pharmaceutical industry, and patient advocacy groups such as PANCAN could achieve this and set the stage for vast improvements in the current treatment paradigm and rapid advances toward improving survival in pancreatic cancer.