Adjunctive therapy may consist of cytotoxic drugs, irradiation, antifreeze proteins, apoptotic promoters, or other agents. The most commonly used adjunctive therapy is a cancer chemotherapeutic agent, and the use of the drug after cryosurgery has been thought to improve survival of patients.109-111 However, a measure of caution in the use of the drug is needed. The coagulopathy or complications due to the considerable cytokine release, which follows large-volume freezing, especially of the liver, may be unfavorably affected by the administration of the cytotoxic drug.112113
Nevertheless, advantage from the use of adjunctive chemotherapy is likely. Cooper et al., in animal experiments, concluded that the administration of cyclophosphamide potentiated cell-mediated immunity.113 Clarke et al.,23 24 freezing prostate cancer cells in vitro, demonstrated that a combination of freezing and 5-fluouracil was associated with a greater reduction in cell survival than either freezing or the drug alone. Mir and Rubinsky,109 freezing melanoma cells in vitro, and exposing them to bleomycin, reported that the cold injury made the cells permeable to the drug, which is of therapeutic interest because bleomycin does not normally enter the cells.
The optimal dose and time of delivery of cancer chemotherapeutic agents is not established. The thought that the drugs can be concentrated in the tumor area, as first suggested by Benson,114 is an interesting and perhaps practical approach. The rationale is based on the failure of the microcirculation shortly after the tissue thaws. Drugs given systemically during the thawing period would become locked into the tumor area, unable to gain access to the general circulation, as vascular stasis develops. Homasson et al.,115 using bleomycin, has shown that this drug sequestration occurs in bronchial cancers. The same principle would apply to drugs injected into the thawed tissue. Such drugs do not gain access to the general circulation.
With other adjunctive agents, there is little or no demonstration of efficacy in clinical trials. Cooled cells have shown increased radio sensitivity.115,116 Though the role of irradiation as an adjunct to cryosurgery is not clear, the use of this agent should have a deleterious effect on cells in marginal survival status and should promote apoptosis. Experiments with antifreeze proteins have shown that exposure to these agents before freezing enhances the destructive effects of cold injury.117,118 During freezing, intracellular ice crystals develop at high subzero temperatures and cause damage, most likely mechanical in nature. Experiments in vivo, injecting antifreeze proteins into the tumor before freezing, show enhanced destruction from the use of the adjunctive agents.117,118 Considerable work needs to be done on the use of adjunctive agents, defining their role and efficacy, because all such agents are capable of causing cell destruction when used alone.
Another type of putative adjunctive therapy is defined in the concept of cryoimmunology, that is, the possibility that freezing tissue in situ will elicit a beneficial immunological response, as first suggested by Shulman et al.119 in the mid-1960s. In the following years, many studies have been directed at the nature of the immunological response, which certainly is complex. As cytokines are released in massive amounts, the reaction may lead to failure of organ systems, called "cryoshock" by some investigators. On the other hand, benefit in tumors in experimental animals have been shown by some investigators and denied by others and enhanced metastases due to immunologic response have been described.120-124 So the question of benefits due to an immunological response remains unsettled. Nevertheless, immunological-enhancing drugs have been considered helpful in advanced cancers,125 so it is evident that the last word on the subject has not been written.
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