A rationale for expanding the endpoints for clinical trials in advanced pancreatic carcinoma

Abstract

BACKGROUND. Using classical endpoints, such as response rate and survival, as the sole measures of benefit, little progress has been made in the treatment of advanced pancreatic carcinoma in the past 30 years. We challenge the assumption that response rate and survival are the only appropriate endpoints for clinical trials in this disease setting. METHOD.A review of the literature and roundtable discussion were undertaken. RESULTS. Using current imaging techniques, it is inherently difficult to distinguish pancreatic tumor from normal pancreas, inflammatory tissue, local fibrosis, and unopacified bowel. As a result, objective tumor measurements are often imprecise, unreliable, and irreproducible. This difficulty may explain the wide variation in response rates reported in clinical trials even when the same therapies are used. Tumor-related symptoms, such as anorexia, weight loss, severe pain (requiring opioid analgesia), and impaired functional status, are prevalent and debilitating characteristics of this disease. Tools that can assess these symptoms in a consistent fashion over time have been developed and have been integrated into clinical trials to evaluate new drugs in this setting. CONCLUSIONS. Systematic assessment of the impact of a new therapy on tumorrelated symptoms may provide a sensitive and accurate way to identi@ useful new treatments for patients with advanced pancreatic carcinoma. Such analyses can be a useful complement to the classical endpoints of response rate and survival.

Clinical relevance of circulating KRAS mutated DNA in plasma from patients with advanced pancreatic cancer

“…Furthermore, Diehl and colleagues described a 99.9% decrease in ctDNA levels during treatment of colorectal patients, whereas the tumor volume (composed of live and dead neoplastic cells in addition to stromal cells) decreased only slightly (Diehl et al., 2008). In pancreatic cancer patients, measurement of treatment efficacy by imaging is particularly challenging, as the tumor is often surrounded by a dense fibrotic tissue, making radiological (CT and PET scan) detection difficult (Rothenberg et al., 1996; Duffy et al., 2010). Thus, therapy decisions in this patient group are based not only on imaging, but also on evaluation of the CA19‐9 level, which is currently the most common and extensively used blood biomarker in pancreatic cancer management despite having several limitations (Duffy et al., 2010; Ballehaninna and Chamberlain, 2012).…”

An investigational new drug treatment program for patients with gemcitabine

“…Historically, single‐agent 5‐fluorouracil (5‐FU) has been a frequently used treatment that has produced tumor response rates in the range of 0–19% (since 1985 when computed tomography [CT] assessment of tumor response became standard) and a median survival of 4.2–5.5 months 1. A review of the literature on investigational new drugs (28 Phase II trials involving 25 agents) showed that, to date, there has been no improvement in patient outcome, with a median objective response rate of 0% (range, 0–14%) and a median survival of 3 months (range, 2–8.3 months) 2…”

What's new in pancreatic cancer treatment?

“…This observation led to the use of the clinical benefit response (CBR) as an alternative outcome measurement to evaluate the efficacy of gemcitabine in pancreatic cancer. CBR is a measure of clinical improvement in terms of pain intensity, analgesic consumption, performance status, and weight change 33,34. A patient will be considered a responder if rated “positive” for either of the primary measures of pain or performance status without a negative rating in the other parameters.…”