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Although oncology researchers seek to describe the significance of clinical trial outcomes with scientific rigor, the terminology used to communicate those findings in the peer-reviewed literature sometimes falls short in conveying the impact that a given therapy may have on patients in a real-world scenario.
Maurie Markman, MD
Although oncology researchers seek to describe the significance of clinical trial outcomes with scientific rigor, the terminology used to communicate those findings in the peer-reviewed literature sometimes falls short in conveying the impact that a given therapy may have on patients in a real-world scenario. The quest for more precise language is an ongoing struggle, both for oncology specialists and for generalists seeking to translate clinical data into meaningful information.
Two recent letters to the editor in peer-reviewed oncology publications provide poignant examples of this dilemma. In the first letter,1 the authors question the use of the description “increasing survival in pancreatic cancer” for the title of an article2 about clinical trial findings, suggesting that the “title strikes us as inappropriately rosy, given the modest benefits and substantial toxic effects observed.”1 The second letter3 expresses concern about the description in an article abstract4 about a combination therapy program as being “well tolerated” considering the degree of objectively reported toxic events.
The intent of noting these specific letters to the editor is not to suggest anything of concern in the original peer-reviewed manuscripts. In fact, in both cases the authors of the primary report have provided rational justifications for their use of these descriptive terms.5,6 Rather, the focus of this commentary is to emphasize the difficulty of objectively describing clinical trial outcomes when specific words or terms realistically may have quite subjective meanings.
For example, consider the term, clinical benefit rate. This description, which is increasingly utilized in the clinical trial domain, commonly combines the experience of patients whose cancers have demonstrated objective biological activity, defined as a complete or partial response/remission usually using Response Evaluation Criteria in Solid Tumors (RECIST),7 plus those whose cancers have not progressed (again, usually employing RECIST) for a protocol-specified period of time that is often a duration of no more than several months.8
The fundamental problem here, of course, is that there is absolutely nothing inherent in the failure of a cancer to grow at a particular rate or to demonstrate a limited or even a major degree of shrinkage that indicates that a patient has actually attained any level of clinical benefit.
That is, does mere shrinkage of one or more cancerous masses indicate that a patient with cancer-related pain has experienced improvement in that pain, or that an individual with cancer-related bowel obstruction has experienced relief of that obstruction or an improvement in appetite, nutritional status, or quality of life? Further, what if the decrease in the size of tumor masses is associated with substantial chemotherapy-induced peripheral neuropathy or mucositis? In this setting, can such a response truly be classified as achieving clinical benefit?
Similarly, a decline in the size of one or more mass lesions can reasonably be considered to represent a biological effect of an antineoplastic strategy. However, such a conclusion would not necessarily be appropriate for the category of response known as stable disease. That a cancer has not progressed (by standard RECIST) in 2, or 3, or 4 months may only represent the inherent natural history of a given malignancy in a specific patient. With or without therapy, the cancer may exhibit the same or a similar time frame for one or more masses to demonstrate a measurable increase in size. Therefore, why assume that the simple absence of progression by RECIST for a limited period of time actually represents clinical benefit? And, as previously noted, the use of this terminology is even more problematic if the so-called clinical benefit is associated with serious symptomatic adverse events.
Even the more neutral term of objective response, as in, “The patient achieved a partial or a complete response of measurable disease,” requires further discussion. In the evaluation of the relative degree of biological activity of a specific antineoplastic program in a clinical trial, and in particular a direct comparison between “regimen A” versus “regimen B” in a well-designed phase III randomized study, the utility of defining an objective response is clear. Even if this definition may appear to be considerably more than a little arbitrary (eg, RECIST), the study investigators will at least be employing the same criteria to declare a response within the specific study, and researchers will be using similar vocabulary when discussing outcomes across different trials. Of course, this assumes the criteria are rigorously applied within a given study and by the community of clinical researchers.
However, is it truly rational to suggest that a partial response of a single, measurable 1.5-cm or 2-cm metastatic mass in the lung of a patient with “cancer C” has the same clinical impact as in an individual who achieves a partial response of multiple relatively large measurable masses in the lung, liver, skin, abdominal wall, etc, in the same malignancy? Yet we employ the identical terminology to define the degree of response in both clinical settings.
Further, while it would be technically correct to declare that both a patient with an existing single 2-cm mass in the lung that is found to increase to 2.5 cm (in maximum diameter) as the only evidence of progression, and a patient with numerous new lesions in the lung, liver, bone, and brain have experienced progressive disease, it is likely that the short-term clinical implications of these events will be quite different. At the clinical level, this difference will almost certainly be substantially magnified if the first patient (single growing mass) remains completely asymptomatic and the second individual (multiple new masses) experiences an increase in pain (requiring narcotic analgesia) as well as a decrease in appetite and the ability to conduct activities of daily living. Yet in our current clinical oncology lexicon, the simple term progressive disease might reasonably be employed in both settings.
Likewise, even the expression complete response often requires additional precision in its use in oncology. At its simplest level, a complete response includes the absence of any cancer-related symptoms, normalization of serum tumor markers, and no evidence of the malignancy by physical examination or imaging studies.
However, with the increasing sensitivity of radiographic technology, small, poorly defined abnormalities may be noted in the absence of other manifestations of the cancer. If observed in the absence of other manifestations of the malignancy, does this mean the cancer is not in a complete remission? Finally, what about the rapidly evolving arena of circulating tumor cells, or cancer-associated DNA?
It is possible or even likely that in the near future the term “complete response,” used today to describe the clinical status of patients with metastatic solid tumors, will have a very different meaning, similar to the substantial change in the definition currently used to describe the status of the malignancy in patients with chronic myelogenous leukemia, where the concept of measuring deep molecular response is gaining ground.9Why should anyone really care how an oncologist defines “response” or “progression”? In fact, this discussion is far from a debate about abstract semantics. In the patient with progressive cancer involving multiple new lesions and worsening symptoms, it would be clear to all that the current management paradigm is not working and requires change. However, a highly rational argument can be advanced that the mere increase in a single tumor mass from 2 cm to 2.5 cm, in the absence of symptoms or unacceptable treatment-associated adverse events, should not necessarily mandate a change in treatment. The biologically plausible justification here is that the existing treatment may be controlling all but perhaps a slowly growing single resistant malignant clone.
Concerns with the appropriate descriptions of cancer trial outcomes are not restricted to the oncology literature. Perhaps not surprisingly, even high-quality non-medical news media experience difficulty explaining a complex study design (eg, double-blind placebo-controlled randomized phase II study) and what a statistically significant outcome may mean to an individual patient.
At times it is almost comical to read the contortions journalists go through in attempting to objectively describe to a lay audience how “drug A” could result in a significant (statistically defined) improvement in progression-free survival, but not overall survival. Similarly, when the news report states the study revealed “drug B” may improve survival, it is reasonable for a patient to be confused, since her/his question will be: But will it improve my survival?
The apparent requirement to find a very simple statement that appears to objectively describe a clinical trial outcome may unfortunately do little more than confuse the audience (patients, family, and the public). Consider, for example, the potential damage done by well-intentioned members of the media who elect to inappropriately simplify the finding of a landmark study that revealed a statistically significant median 4-month improvement in overall survival associated with the administration of “drug D” to patients with “cancer C” by declaring that patients with cancer C given drug D may have their lives extended “by up to 4 months.”10
There are no easy answers to these language conundrums. Yet the search for better terminology begins with considering the need for improvement.
Maurie Markman, MD, editor-in-chief, is senior vice president for Clinical Affairs and national director for Medical Oncology at Cancer Treatment Centers of America, and clinical professor of Medicine, Drexel University College of Medicine. email@example.com