Going Beyond RECIST – Part 1

Are Volumetric Assessments a True Reflection of Drug Response?

[Part 1 of our 3 Part series on Going Beyond RECIST: a look at volumetric and functional tumor analysis in oncology clinical trials.]

Medical imaging is an integral part of oncology clinical trial design due to its non-invasive nature and its ability to detect biological and physiological phenomena. Traditionally, anatomical quantitative image analysis relied on linear measurements of tumor size. However, these unidimensional size measurements often fail to completely capture morphological and other physiological and metabolic changes that occur in response to treatment, particularly for today’s new targeted cancer therapies. Volume-based measurements and functional imaging, which encompass the whole tumor and reflect physiological changes, can be used to make both morphological and functional measurements, and in certain instances, may allow clinicians to more accurately assess response.

Adding Value to Clinical Trials

As volumetric imaging methods continue to be studied, questions arise about whether volume measurements can truly improve trial quality or just add to overall costs and complexity.

Volumetric imaging offers greater measurement sensitivity and potential earlier detection of response, which is important for both ethical and practical reasons. [Mozley 2010] Determining patient response early allows a patient to stop an ineffective treatment sooner (and potentially transition to an alternate, more effective treatment) and prevents premature termination of an effective treatment. Although volumetric imaging may be more complex, and therefore more costly to perform, the greater sensitivity associated with volumetric measurements can increase the statistical power per subject. This means fewer subjects are necessary per trial, and each subject may be enrolled for a shorter period, decreasing overall trial time and cost. This also potentially enables more new therapeutics to travel through the drug pipeline and at a faster rate. [Mozley 2010] [Mozley 2012, Goldmacher 2012, QIBA Profile vCT]

Are Volumetric Measurements Medically Meaningful?

In order for volumetric imaging to add value to a clinical trial, the data generated must be able to impact clinical decision-making and be associated with clinical outcomes. Although the issue of value is still being determined, several studies suggest that volumetric assessment does indeed add value. For example, a retrospective analysis of 42 lung cancer patients participating in an open-label phase 2 study found that volumetric measurements on first follow-up (4 weeks after starting treatment) were better able to predict overall survival than RECIST measurements. [Hayes 2016]  Patients who were classified as partial responders had a 1-year overall survival rate of 70%, while those classified as non-responders had a 1-year survival rate of 46%. There was no difference in survival rates among partial responders and non-responders according to RECIST. [Hayes 2016] This study suggests that a positive response to treatment, as measured through changes in tumor volume, may correlate with clinical benefit.

As advanced imaging endpoints continue through the validation and standardization process, it is our hope that they eventually achieve surrogate endpoint status, ultimately adding to the arsenal of therapeutic response tools available to clinicians in the clinical trial setting.

Post Author:

Dr. Nathalie Faye, Medical Director, Median Technologies

References

Hayes SA, Pietanza MC, O’Driscoll D, Zheng J, Moskowitz CS, and Kris MG. (2016) Eur. J Radiol. 85, 524-533.

Mozley PD, Schwartz LH, Bendtsen C, Zhao B, Petrick N, and Buckler AJ. (2010) Ann Oncol. 21, 1751-1755.

Mozley PD, Bendtsen C, Zhao B, et al. (2012) Transl Oncol. 5, 19-25