E-Newsletter - February 2018


The Argument for Simplicity in Clinical Trials During an Era of Precision Medicine

By John P. Leonard, MD 
Weill Cornell Medicine and New York Presbyterian Hospital
Chair, Alliance Lymphoma Committee

“Simplicity is the ultimate sophistication.”
– Leonardo da Vinci

In whatever area of oncology you practice, think for a minute about the patient you have seen recently who was the sickest due to their cancer – whether newly diagnosed or relapsed.  My bet would be that he or she did not end up participating in a clinical trial.  Yet the sickest of our patients – whether due to stage of cancer or “tumor burden,” comorbid illness, age, or other factors – are the ones who might ultimately most need the opportunity to receive novel treatment approaches and represent those who we need to learn about to understand the complexities of cancer. Unfortunately, various issues seem to converge in limiting the enrollment of these patients to prospective studies.

The Alliance Lymphoma Committee conducted CALGB 50303, a prospective randomized trial of the R-CHOP vs R-EPOCH treatment regimens in previously untreated diffuse large B cell lymphoma (DLBCL), the most common lymphoma subtype and one that is curable in approximately two-thirds of patients.  The trial mandated prospective tissue collection (including fresh tumor biopsies) as well as carefully performed PET imaging to make correlations with outcome.  As reported by Dr. Nancy Bartlett preliminarily at the 2016 American Society of Hematology annual meeting, there was no significant difference in efficacy overall between the two treatment arms, though subgroup analyses are ongoing.   However, nearly two-thirds of the patient population fell into low- or low-intermediate prognostic risk groups, and the outcome with the “control” R-CHOP treated group (two-year event-free survival) was about 75 percent, better than generally expected.   Similar observations have been recently noted in other trials in DLBCL requiring prospective tissue procurement and/or analysis prior to study entry.  Undoubtedly a contributing factor to this more favorable “patient selection” issue is the time and effort added to the enrollment process.  This may, depending on study specifics, delay the time to treatment causing anxiety and clinical concerns which could cause higher risk patients to be diverted away from study participation.

Any experienced clinical research nurse, coordinator or physician is familiar with the myriad of eligibility requirements and required testing prior to enrollment and treatment in cancer trials that cause “screen failures.”  We may exclude patients with recent prior cancers even if they are unlikely to recur.  If some “real world” patients have impaired performance status, could we try to enroll them in studies as feasible and appropriate?   Can we liberalize requirements around hematologic parameters, as well as kidney and liver function?  The answer to this is no in some cases, but undoubtedly yes in others.  The number and nature of pretesting and follow-up steps clearly cause some patients and families to decide against trial participation.  Why do some trials require both dedicated CT and PET-CT scans?  In follicular lymphoma (the second most common subtype), trials almost always require a baseline bone marrow biopsy as well as repeat biopsies in some cases to confirm complete response. These tests are painful, take time, and are expensive.   I have had numerous patients over the years either decline to participate in a study due to bone marrow requirements or refuse to allow repeat biopsies later in the study.  My colleague Sarah Rutherford recently reported that bone marrow assessments are almost entirely unnecessary to accurately assess response in this population as results very rarely change a response classification – we are now confirming these data in a larger series of patients from Alliance trials.  I shudder to think about the hours and money I have spent and pain I have inflicted performing what now may prove to be unnecessary bone marrow biopsies on patients who volunteered for clinical trials that required them.

As those involved in designing and analyzing clinical trials and trying to advance cancer care, I think that now is an important time for us to more critically analyze the requirements for testing that we incorporate into our studies.  In precision medicine strategies, we are tempted to include (and sometimes need to rely on) sophisticated tumor sampling and patient assessment and monitoring tools that will define our patient populations for more targeted therapy.  This should lead to improved outcomes for many of those suffering from cancer.  However, in this “sophistication,” we need to be sure that we do not inadvertently exclude categories of patients that need to also benefit from our efforts and contribute to our knowledge – and sometimes try to keep things “simple.”


For other articles in this issue of the Alliance E-News newsletter, see below.