Translation in solid cancer: are size-based response criteria an anachronism?

Abstract

The purpose of translation is the development of effective medicinal products based on validated science. A parallel objective is to obtain marketing authorization for the translated product. Unfortunately, in solid cancer, these two objectives are not mutually consistent as evidenced by the contrast between major advances in science and the continuing dismal record of pharmaceutical productivity. If the problem is unrelated to science, then the process of translation may require a closer examination, namely, the criteria for regulatory approval. This realization is important because, in this context, the objective of translation is regulatory approval, and science does not passively translate into useful medicinal products. Today, in solid cancer, response criteria related to tumor size are less useful than during the earlier cytotoxic drugs era; advanced imaging and biomarkers now allow for tracking of the natural history of the disease in the laboratory and the clinic. Also, it is difficult to infer clinical benefit from tumor shrinkage since it is rarely sustained. Accordingly, size-based response criteria may represent an anachronism relative to translation in solid cancer and it may be appropriate to align preclinical and clinical effort and shift the focus to local invasion and metastasis. The shift from a cancer cell-centric model to a stroma centric model offers novel opportunities not only to interupt the natural history of the disease, but also to rethink the relevance of outdated criteria of clinical response. Current evidence favors the opinion that, in solid cancer, a different, broader, and contextual approach may lead to interventions that could delay local invasion and metastasis. All elements supporting this shift, especially advanced imaging, are in place.