Mechanisms of cryoablation: clinical consequences on malignant tumors

Abstract

While the destructive actions of a cryoablative freeze cycle are long recognized, more recent evidence has revealed a complex set of molecular responses that provides a path for optimization. The importance of optimization relates to the observation that the cryosurgical treatment of tumors yields success only equivalent to alternative therapies. This is also true of all existing therapies of cancer, which while applied with curative intent; provide only disease suppression for periods ranging from months to years. Recent research has led to an important new understanding of the nature of cancer, which has implications for primary therapies, including cryosurgical treatment. We now recognize that a cancer is a highly organized tissue dependent on other supporting cells for its establishment, growth and invasion. Further, cancer stem cells are now recognized as an origin of disease and prove resistant to many treatment modalities. Growth is dependent on endothelial cells essential to blood vessel formation, fibroblasts production of growth factors, and protective functions of cells of the immune system. This review discusses the biology of cancer, which has profound implications for the diverse therapies of the disease, including cryosurgery. We also describe the cryosurgical treatment of diverse cancers, citing results, types of adjunctive therapy intended to improve clinical outcomes, and comment briefly on other energy-based ablative therapies. With an expanded view of tumor complexity we identify those elements key to effective cryoablation and strategies designed to optimize cancer cell mortality with a consideration of the now recognized hallmarks of cancer.

Keywords: Cryoablation; Cryosensitizers; Cryosurgery; Cryotherapy; Prostate cancer.

Figure 1. Transrectal Ultrasound Images of a Human Prostate Cryoablation Procedure

Upper Image: Transverse view of prostate illustrating two “ice balls” advancing toward the rectum (bottom of image). The white hyperechoic rim (HER) represents the boundary between frozen (black shadowed area) and unfrozen tissue. Tissue temperature at the distal edge of the HER is nominally 0°C and approximately −15°C along the proximal edge of the HER. The position of the cryoprobe is obscured by the advancing ice. Lower Image: Sagital view the freezing process in the human prostate. Note the position of the cryoprobe shaft projecting from the frozen tissue mass.

Figure 2. Freeze Response Profiles of an Androgen Sensitive and Insensitive Human Prostate Cancer Phenotype

Androgen sensitive LNCaP cells (dotted lines) are a p53 positive and androgen receptor positive prostate cancer phenotype whereas PC-3 cells (solid lines) are p53 negative and androgen receptor negative. The androgen insensitive PC-3 cells have been shown to be more tolerant to freezing injury as illustrated by their recovery following exposure to −25°C and −40°C in comparison to the LNCaP cells which are completely destroyed at those temperatures.