**6. Rationale for chemotherapy and hyperthermia association**

164 Hyperthermia

cervix cancer and gliomas. 1) Hyperthermia increases perfusion and oxygenation of neoplastic hypoxic cells, which are three times more resistant to ionizing radiation than normal cells. Consequently, the action of radiotherapy becomes 1.5-5 times more efficient. Hyperthermia has a direct cytotoxic action on cancer: due to the pathologic blood vessels, the thermal elevation persists inside the tumor, whereas neighboring normal tissues, adequately perfused, are cooled: at 43 °C, normal cells are not damaged, whereas tumor cells are damaged at the cell nucleus, plasmatic membrane and cytoskeleton, up to apoptosis. Hyperthermia acts mostly at an acid pH and in the S phase of the cell cycle, when cells are radioresistant. This means that radiotherapy and hyperthermia are complementary in their action: radiotherapy forms free radicals, which damage the DNA of tumor cells, whereas hyperthermia inhibits its reparation. 2) Hyperthermic inhibition of repairing radiation damage has been suggested as an essential factor causing the synergistic cell-killing effect of X-rays and hyperthermia. Heating cells before X-irradiation has been shown to inhibit the repair of DNA strand breaks as well as the excision of base damage1. There are several DNA repair pathways involved in restoration of damage after ionizing irradiation and the kinetics of all of them are affected by heat shock. However, this does not imply that the inhibition of each of these pathways is relevant to the effect of heat on cellular radiosensitivity. Data reported by Kampinga et al showed that thermal inhibition of the non-homologous end-joining pathway plays a role in heat radiosensitization. Furthermore, limited data suggest that the homologous recombination pathway may not be a major heat target. The inhibition of base-excision damage repair could be, by deduction, the crucial step in the mechanism of radiosensitization by heat (63). 3) Hyperthermia enhances the sensitivity of cells to radiation and drugs and this sensitization is not directly related to altered heat-shock proteins (HSP) expression. Elevating HSP prior to heating makes cells thermo- tolerant and altering their expression will affect the extent of thermal action because the HSP will attenuate the heat-induced protein damage, responsible for radiation and drug sensitization. Nuclear protein damage is considered to be responsible for hyperthermic effects on DNA

In an effort to provide a clearer picture of the interaction between hyperthermia and radiation, asynchronous CHO cell survivals for a matrix of doses of radiation and hyperthermia were determined. The survival matrix was then analyzed by fitting a survival function that was the product of survivals due to hyperthermia alone, to radiation alone and to the interaction of hyperthermia and radiation. This survival function is an expression for the survival surface, a surface in the space defined by the three axes of logarithm of cell survival, hyperthermia dose and radiation dose. The survival surface is a three dimensional

The two principal rationales for applying hyperthermia in cancer therapy are that: (a) the S phase, which is relatively radioresistant, is the most sensitive phase to hyperthermia, and can be selectively radiosensitized by combining hyperthermia with x-irradiation; the cycling tumor cells in S phase which would normally survive an x-ray dose could thus be killed by subjecting these cells to hyperthermia; and (b) the relatively radioresistant hypoxic cells in the tumor may be selectively destroyed by combinations of hyperthermia and x-irradiation. Both of these rationales have been mentioned as reasons for using high LET irradiation in cancer therapy; therefore where such irradiation may be of use, hyperthermia may also be advantageous.

repair, especially base-excision damage repair (64).

extension of the two-dimensional survival curve (65).

Hyperthermia can also be used to activate cytotoxic effects of chemotherapy within tumors, thereby sparing normal tissue, when the drugs are encapsulated in thermally sensitive nanoparticles. Hyperthermic drug sensitization can be seen for several anti-cancer drugs, in particular alkylating agents. The combined action between heat and drugs arises from multiple events such as drug accumulation, drug detoxification pathways and repair of drug-induced DNA adducts. Cells with acquired drug resistance can be made responsive to the same drugs again by combining drugs with heat. Hyperthermia, which increases tumor tissue perfusion, facilitates the absorption of chemotherapeutic drugs through cell membrane. The heat accelerates chemical reactions, so that chemotherapy becomes more effective, without being more toxic. Hyperthermia allows the response of tumors resistant to various chemotherapeutic drugs: doxorubicin, cisplatin, bleomycin, mitomycin c, nitrosoureas, cyclophosphamide. Use of liposomes, including adriamycin (Caelyx®) administered i.v., hyperthermia fuses and frees their content inside the heated tumor bed, thus obtaining a target chemotherapy, with reduction of side effects.

On March 18, 2010, the Celsion Corporation (http://www.celsion.com, accessed 17 November 2010) announced that an abstract about the phase I/II trial of ThermoDox® in recurrent chest wall cancer has been accepted for presentation at the American Society of Clinical Oncology (ASCO) 2010 Annual Meeting. The abstract presents the background, rationale and design of the DIGNITY study which is ongoing and evaluating ThermoDox® in combination with hyperthermia in women with recurrent breast cancer on their chest wall (66).

In a separate trial with a similar design being conducted at Duke University Medical Center, researchers are reporting convincing evidence of clinical activity. The DIGNITY clinical trial is a phase I/II, open label, dose- escalating trial to evaluate the safety and efficacy of ThermoDox® with hyperthermia for the treatment of recurrent chest wall breast cancer, an aggressive form of cancer with a poor prognosis and limited treatment options. The primary end point in the DIGNITY trial is durable complete local response at the tumor site. Once the safe dose is determined, Celsion intends to enroll up to 100 patients to establish efficacy. The results from the DIGNITY trial are expected to build on the promising data from the phase I dose-escalation study currently being conducted at Duke University Medical Center. ThermoDox® has also demonstrated evidence of efficacy in a phase I study for primary liver cancer. Celsion has been granted FDA orphan drug designation for ThermoDox® and is conducting a pivotal 600 patient global phase III study in primary liver cancer under an FDA special protocol assessment, thus obtaining a target chemotherapy, with reduction of side effects. It has been demonstrated that hyperthermia also has an anti-angiogenic action and an immunotherapeutic role, due to thermal shock proteins, which are produced by stressed tumor cells. Finally, hyperthermia substains the action of genic therapy (67).

Hyperthermia and Radiology 167

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The immunotherapeutic role of hyperthermia is not yet completely understood. Especially, the effects on natural killer (NK) cell cytotoxicity against tumor cell targets have not been fully demonstrated. At treatment temperatures above 40 °C, both enhancing and inhibitory effects of cytotoxic activity of NK cells against tumor cells have been reported. In particular, an enhancement of human NK cytotoxicity against tumor cell targets has been demonstrated using a temperature of 39.5 °C10. Data in the literature indicate a strong potential for heat-induced enhancement of NK cell activity in mediating the improved clinical response. A better understanding in this field should be achieved in order to maximize the clinical benefits obtained by using hyperthermia for cancer therapy (68).
