Considerations in evaluating tumor growth effects of targeted therapies

Newer targeted therapies are often cytostatic or cytolentic (slowing proliferation) [60], resulting in disease stabilization, improved quality of life and extended survival. Examples of such drugs include sorefinib (Nexavar) [61], axitinib (Inlyta) for renal cell carcinoma [62], and mTOR inhibitors (everolimus (Afinitor) [63] and temsirolimus (Torisel)). Dasitinib (Sprycel) and sorefinib (Nexavar) are active in prostate cancer. Dasatinib is active in chronic granulocytic leukemia and GIST, inhibits BCR/ABL tyrosine kinase, KIT, PDGFR and Src ty-rosine kinase amongst other targets. The Src tyrosine kinase is instrumental in driving hormone-independent prostate cancers [64]. Dasatinib is active in castrate resistant prostate cancer and may be administered safely with docetaxel [65, 66].

These newer therapies target not only the tumor cell but also modify the supporting stroma and microvasculature. The cytostatic/cytolentic effects may leave the tumor dimensionally intact, stable on imaging studies but with slower or absent growth for extended periods of time. Some imaging techniques such as PET and MRI [67], able to quantify such metabolic effects, may enhance clinical evaluation while CT images appear unchanged.

There is mounting evidence that stabilization of tumor growth significantly prolongs overall survival to a degree similar to patients experiencing an objective response judged by RE-CIST or RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors). This raises concern and new calls for modification of current RECIST categories to include new definitions for targeted responses [68].

Simple reductions in PSA levels as defined by Bubley [35] have not yet been validated as a surrogate end point for use in clinical trials of agents with novel mechanisms of action. As indicated, cytotoxic chemotherapy alone, in combination with molecular-targeted agents, or the sole use of targeted therapies, produces different and at times transient and paradoxical changes in serum PSA and further studies are needed to further define this issue.

As questions have emerged concerning the utility of PSA levels as a surrogate end point, the Prostate Cancer Clinical Trials Working Group reviewed the criteria for outcome measures in clinical trials that evaluate systemic treatment for patients with progressive prostate cancer. Recommendations conclude that PSA responses may be delayed in trials of non-cytotox-ic agents, and rising PSA levels in the absence of other signs of progression should not lead to discontinuation of trials. This recommendation might lead to much consternation between the patient and doctor where discussion of the latest PSA value is often the primary subject during follow-up visits.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook

Post a comment