41 Hyperthermia and Chemotherapy

In recent years, the understanding of the biology of cancer has dramatically increased, leading to renewed interest in developing screening and early detection methods as well as providing new therapeutic targets. In parallel, the discovery of several new chemotherapeutic agents with novel mechanisms of action and promising activity against various types of cancers have renewed interest in combined therapies. Many would argue that chemotherapy for advanced metastatic disease should not be offered because of the relative ineffectiveness of even the best regimens. However, this leaves a large number of patients with only supportive therapy for their disease—an unacceptable situation.

The combination of two therapies into one therapy, such as the combination of hyperthermic treatment with standard chemotherapeutics, can produce a wide spectrum of results, ranging from enhanced cell kill to stimulated cellular growth. Combination therapies can result in subtractive, zero, individual, additive, and synergistic effects. When the therapies are administered simultaneously, the possibility exists for immediate interactions that can render both interventions worthless (zero effect). For example, it is conceivable that a drug can stimulate sufficient HSP up-regulation that all cells will become refractory to the coincident heat therapy, resulting in a very limited cell death (subtrac-tive). On the other hand, heat could possibly alter the structure of a drug, making it nontoxic. The sequential application of therapies will decrease the likelihood of unacceptable interactions; however, interactions are still possible. Should a drug therapy follow hyperthermia, it is possible that the induced inherent thermoprotection will shield the cell from the effects of the pharmaceutical and vice versa. However, it is also conceivable that in this mode cell death could be present from both interventions (individual). The most salubrious effect is that of synergism. This would occur when both therapies resulted in a cell kill that exceeds the sum of both individual therapies. An example would be if a drug synchronizes all cells of a tumor to enter a specific phase of the cell cycle then a subsequent therapy is timed to destroy all cells in that phase of the cell cycle. Such an interaction is very desirable in its effect on tumor cells. However, if this circumstance occurs it is quite possible that an increased amount of damage will also occur to normal host cells as well—an undesirable situation.

Historically, hyperthermia was administered with a few select drugs where efficiency was studied. In an interesting study treating dogs with spontaneous malignant melanoma, Page et al., concluded that melphalan combined with whole-body hyperthermia can be safely administered, although a reduction in dose is necessary (51). In a corollary to these results, Orlandi et al., determined that thermal enhancement of melphalan cytotoxicity could be mediated at least in part by an inhibition of p34cdc2 kinase activity, which prevents cell progression into mitosis (140).

Furthermore, it has been shown that greater tumor cell killing, tumor growth delay, and prolonged survival are produced by a combination of radiation, thermosensitive liposome-entrapped melphalan, and hyperthermia compared with animals receiving single-modality or bimodality treatments. Chelvi and Ralhan concluded that this multimodality approach will be potentially useful for more effective management of melanoma (141). Averill et al., showed that increased melphalan cytotoxicity in multidrug-resistant (MDR) cells was accompanied by changes in membrane permeability to the drug (142). Cyclo-sporine A caused an increase in melphalan uptake in MDR cells and a decrease in melphalan efflux out of cells leading to an overall increase in intracellular drug accumulation, and that hyperthermia caused marked enhancement of mel-phalan cytotoxicity when cyclosporine A was present. Larrivee and Averill determined that heat alone increased both melphalan uptake and drug efflux in cells and suggested that the combination of cyclosporine A and hyperthermia could be very useful in overcoming melphalan resistance by increasing intracellular drug accumulation in MDR cells (143). Turcotte and Averill-Bates discovered that a major advantage arising from the use of regional hyperthermia is the ability to target drug cytotoxicity to the tumor volume (144). A useful finding is that ethacrynic acid, heat, and/or melphalan are also effective against MDR cells with overexpression of P-glycoprotein. Together, these aforementioned studies demonstrate that there is potentially great therapeutic benefit combining heat therapy with chemotherapeutics.

In clinical studies of melphalan and hyperthermia, we see varied responses. Robins et al., found that melphalan was well tolerated at 41.8°C, and that clinical results were consistent with preclinical predictions providing a foundation for further trials (145). Hafstrom and Naredi reported rather disappointing results with the combination treatment, where 2 patients died within the first postoperative month, 5 patients were reoperated on owing to postoperative bleeding, and 3 of 6 patients with liver metastases from malignant melanoma or leiomyosarcoma, and none of 5 patients with liver metastases from colorectal cancer, showed a partial response (146). In the Robins et al., follow-up study, combining TNF-a, melphalan, and whole-body hyperthermia (41.8°C for 60 min), responses included two complete remissions (malignant melanoma, TNF dose level I; breast cancer, TNF dose level II) and two disease stabilizations (both malignant melanoma, TNF dose level I) (147). Hyperthermia affected the pharmacokinetics of intraperitoneal (IP) melphalan by decreasing the quantity of peritoneal fluid melphalan without increasing the plasma quantity, though it increased intraabdominal tissue concentrations (148). Lindner et al., documented conflicting results when melphalan was used in conjunction with isolated hepatic perfusion and TNF-a, where they show considerable toxicity, and question the effectiveness in patients with colorectal liver metastasis (149). Results in patients with melanoma and leiomyosarcoma were different and warrant further study. Libutti et al., treated these patients who had unresectable hepatic malignancies with a perfusion hyperthermia technique, TNF, and mel-phalan, with favorable results (150). Pilati and colleagues show that under hyperthermic conditions, neither an increase in liver parenchyma toxicity nor changes in melphalan pharmacokinetics were observed, and suggested that these findings support the use of hyperthermia in the clinical environment (151). Isolated limb perfusions with TNF-a and melphalan for recurrent melanomas resulted in a high complete response rate and a low limb-recurrence rate in patients at the cost of only mild toxicity (152).

Another chemotherapeutic agent used in conjunction with hyperthermia for the treatment of cancers is mitomycin C. Mitomycin C exerts its mode of action as an alkalizing agent that, upon activation, binds to guanine and cytosine moieties of DNA, resulting in the inhibition of DNA synthesis. Herman et al., studied the combined effect of mitomycin C and hyperthermia and determined that a considerable potential therapeutic efficacy with the addition of hyperther-mia to mitomycin C exists (153). These results show that hyperthermic intra-peritoneal chemotherapy (HIPEC) with mitomycin C is a safe and reliable treatment for peritoneal seedings in severely advanced gastrointestinal cancers and encourage us to proceed with this new therapeutic modality (154). These outcomes indicate that the use of selected anticancer drugs with hyperthermia and radiation can produce highly cytotoxic interactions that markedly modify the effect of radiation (155).

Sakaguchi et al., determined that the enhancement was prominent in cases of drugs and hyperthermia combined and speculated that hyperthermochemo-therapy, using mitomycin C has a potential to attack selectively hypoxic cells present in a solid tumor (156). Loggie et al., was an early proponent of HIPEC for advanced gastrointestinal and ovarian cancers (26). In a laboratory study, Takeuchi et al., determined that increased antitumor response was achieved with the combination of mitomycin C, flavone acetic acid, and hyperthermia because of a decrease in blood flow to the tumor and subsequent hypoxic conditions (157). Studying the combined effect on gastric cells, Shchepotin et al., determined that hyperthermia did not enhance the effect of mitomycin C and urged further investigation on gastric cancer (158). In a clinical trial for peritoneal carcinomatosis, Gilly et al., determined that in 9 out of 10 patients with preoperative malignant ascites, it cleared after treatment (159). One-year survival rate was 54.2%. They state that HIPEC with mitomycin C "is a safe and reliable treatment for peritoneal carcinomatosis in far advanced digestive cancers." Francois reported 42 cases of gastric cancer with peritoneal carcinosis treated with HIPEC (10 mg/L mitomycin C at 46°C-49°C for 90 min) and suggests even in light of numerous complications that HIPEC with mitomycin C is a new treatment for carcinosis of gastric origin (160). Paroni et al., demonstrated that local hyperthermia enhances the systemic absorption of mitomycin C during intravesical chemotherapy for bladder cancer (161). For resectable gastric cancers with stage 1 and 2 carcinomatosis, 1-, 2-, and 3-yr actuarial survival rates were 80%, 61%, and 41%, respectively, and Sayag-Beaujard et al., concluded that HIPEC appears to be an interesting therapeutic option in patients with digestive cancers and small malignant peritoneal granulations (162).

The latest generation of antineoplastic agents has produced significant advances in both understanding and survival from cancer and needs to be studied in relation to hyperthermia. Recent studies suggest that, irrespective of the primary site of action of a drug, cell death by most pharmacologic agents is mediated by activation of the signal transduction pathway for apoptosis. A study by Barry et al., emphasizes this point (134). Their results suggest two signal pathways for apoptosis, one directly associated with drug action and a second that requires cell cycle-related events.

Gemcitabine (dFdC) is a deoxycytidine nucleoside analogue that has a marked effect on several enzymes involved in DNA synthesis and repair (163). It requires intracellular activation by phosphorylation into its active triphosphate dFdCTP form, which is incorporated into DNA at the penultimate position and blocks further elongation of the DNA strand (164). This drug inhibits cellular proliferation in S phase, which causes cells to accumulate at the G1-S-phase boundary (165). Gemcitabine can also be incorporated in RNA-inducing apoptosis (166). This drug is active against human tumor xenograft models of lung, breast, and colon carcinoma (167). Again, the combination should show at least an additive effect because gemcitabine halts cells in the S phase of the cell cycle, which is the most receptive phase for heat kill.

Latz et al., demonstrated that treatment of cells with gemcitabine immediately before irradiation eliminates, or at least greatly reduces, the variation in radioresistance during S phase (168). This reversal of S-phase radioresistance could imply that gemcitabine interferes with the potentially lethal damage repair-fixation pathway, setting the stage for additional kill by another agent. They suggest that hyperthermia or densely ionizing radiation in combination with gemcitabine could prove of value in this situation.

Several investigators have coupled hyperthermia with gemcitabine in both lab and clinical studies with varied results. Haveman et al., showed that simultaneous application led to decreased cytotoxicity, whereas an interval of 20 h or 24 h between exposure to dFdCyd and hyperthermia led to enhanced cell killing (169). Mohamed et al., showed that moderate hyperthermia (41.5°C for 30 min) increases the cytotoxicity of gemcitabine on mouse fibrosarcoma (27).

van der Heijden et al., showed a synergistic interaction for hyperthermia and gemcitabine on human transitional cell carcinoma cell lines (170). Hyperther-mia alone did not cause decreased cell proliferation. Synergism was most prominent with low drug doses. In a clinical case report, 2-yr follow-up of a patient that received IP perfusion (saline heated to 42°C containing cisplatin, etoposide, and mitomycin C, followed by 24 courses of postoperative chemotherapy with gemcitabine) for pseudomyxoma peritonei to be in good condition with no signs of progression (171). In a recent study, we report that the combined therapy is synergistic in effect because of hyperthermia-enhancing gem-citabine-induced apoptosis (172). We support this conclusion by documenting that the cancer cell line had significantly more Hoechst-positive (apoptotic) cells, and that TUNEL, DNA fragmentation, and Annexin-V all corroborate the presence of apoptosis. Western blot comparing the effect of hyperthermia in cancer cells to normal cells revealed that TRAIL and FAS-L displayed significant increases (threefold and twofold, respectively); that caspase-3 showed a decrease in uncleaved form and an increase in cleaved form, and a 50-fold increase in activity effectively blocked with the caspase-3 inhibitor DEVD-fmk; that caspase-9 showed near depletion of uncleaved form; and that PARP degradation was clearly visible during heating. After hyperthermia, gene expression demonstrates a 5.7-fold increase in TRAIL and insignificant changes in TNF-a, FAS-L, and caspase-3, -8, and -9 in transformed cells (172). Additionally, Vertrees et al., demonstrated that the combination of hyperthermia and gemcitabine, when given in a series of experiments, delayed further tumor development as long as the dual therapy was administered; however, when the therapy was withdrawn, normal tumor development resumed (172).

The mechanism of action of taxanes (paclitaxel or docetaxel) is promotion of microtubule assembly and stabilization resulting in interference with mitosis. This drug has displayed antitumor activity against nude mouse xenografts of melanoma, breast, colon, lung, pancreas, and ovarian cancer cells. Hyperther-mia should theoretically increase the cell kill when used with the taxanes because the cell after taxane exposure would be held in S phase, making it susceptible to heat-induced destruction. However, studies where paclitaxel and hyperthermia (41.8°C for 60 min) were administered together showed no thermal enhancement of cytotoxicity in human and murine cell lines. The authors did show that paclitaxel and docetaxel were heat stable at 41.8°C and 43°C (173). Cividalli and colleagues demonstrate that hyperthermia had a superadditive effect on paclitaxel (45 mg/kg) combined with a hyperthermic treatment (43°C for 60 min) (174). An additional study of the taxanes showed that paclitaxel cytotoxicity was not enhanced by hyperthermia (41.5°C for 30 min), but that docetaxel cytotoxicity was (27). By way of explaining a possible mechanism for the observed phenomenon, Salah-Eldin and colleagues show that both treatments disturbed the heterodimerization of Bax with Bcl-2

(175). Hyperthermia, but not paclitaxel treatment, induced a gradual Bax translocation from the cytoplasm to the nucleus. Although both treatments induced a prominent cell cycle disturbance in the G2M phase, paclitaxel treatment induced typical apoptosis, and hyperthermia hardly induced apoptosis at all. Their results suggest that the subcellular redistribution of Bax and the phosphorylation of Bcl-2 depend on the type of apoptosis inducers, such as hyperthermia and paclitaxel. The report by Zoul et al., in 7 patients treated for inoperable local recurrence of breast cancer after mastectomy, irradiation, and chemotherapy or hormonal therapy indicates that the combination of weekly paclitaxel (60 mg/m2-80 mg/m2) in 3-h infusions and hyperthermia (41°C-44°C for 45 min for 6-18 cycles) may be effective in the treatment of locally recurrent breast cancer after mastectomy (176).

Irinotecan is a topoisomerase I inhibitor with a broad spectrum of clinical activity. Mohamed et al., demonstrated that the combination of moderate hyperthermia (41.5°C for 30 min) and irinotecan against a spontaneous murine fibrosarcoma results in increased cytotoxicity (27). Sumiyoshi et al., hypothesized that an antiangiogenesis strategy combining fever-range whole-body hyperther-mia (FR-WBH) and irinotecan hydrochloride could inhibit the development of metastatic disease with minimal toxicity in rats (42). They found that both the group treated with FR-WBH alone and the combined FR-WBH + irinotecan hydrochloride group had delayed onset and reduced incidence of axillary lymph node metastases, reduced lung metastases, and longer survival compared to control. Elias et al., studied 39 patients with peritoneal carcinomatosis of either gastrointestinal or peritoneal origin who underwent complete cytoreductive surgery (CRS), followed by HIPEC with a stable dose of oxaliplatin (460 mg/ m2), plus 1 of 7 escalating doses of irinotecan (from 300 mg/m2 to 700 mg/m2) (177). HIPEC was carried out with the abdomen open, for 30 min at 43°C, with 2 L/m2 of a 5% dextrose instillation in a closed continuous circuit. Irinotecan concentration in tumoral tissue increased until 400 mg/m2 and then remained stable despite dose escalations. It was 16-23 times higher than in non-bathed tissues. Intraperitoneal heated oxaliplatin (460 mg/m2) plus irinotecan (400 mg/ m2) presented an advantageous PK profile and was tolerated by patients, despite a high hematological toxicity rate. In another clinical study, 25 patients (10 women and 15 men; mean age, 53 yr) were identified who had progressive liver metastases by carcinoembryonic antigen, imaging studies, or both after irino-tecan. A 1-h hyperthermic isolated hepatic fusion (IHP) (mean hepatic temperature, 40.0°C) with 1.5 mg/kg melphalan (mean total dose, 100 mg) was administered via laparotomy. Perfusion with an oxygenated extracorporeal circuit was established with inflow via a cannula in the gastroduodenal artery and common hepatic artery inflow occlusion. Outflow was via a cannula in an isolated segment of the inferior vena cava. During IHP, portal and inferior vena cava flow were shunted to the axillary vein. Patients were assessed for radiographical response, recurrence pattern, and survival. The median number of liver metastases before IHP was 10 (range, 1-50), and the median percentage of hepatic replacement by tumor was 25%. There was one complete response and 14 partial responses in 25 patients (60%), with a median duration of 12 mo (range, 5-35 mo). Disease progressed systemically in 13 out of 25 patients at a median of 5 mo (range, 3-16 mo). The median overall survival was 12 mo (range, 1-47 mo), and the 2-yr survival was 28%. The authors concluded that in patients with progressive CRC liver metastases after irinotecan, IHP had good efficacy in terms of response rate and duration, and suggest continued evaluation of IHP with melphalan as second-line therapy in this clinical setting (178).

Carboplatin produces interstrand DNA cross-links rather than DNA-protein crosslinks. This effect is cell cycle nonspecific. The addition of heat to this drug could potentially enhance the numbers of cells killed during the heat-sensitive S phase. This drug has shown antitumor activity against breast, colon, lung, pancreas, and ovarian cancer cells. Several studies have assessed the efficiency of hyperthermia and carboplatin in both the lab and clinical venues. Robins et al., concluded from a clinical study that carboplatin with WBH (41.8°C for 60 min) is well tolerated, even at conventional carboplatin doses, and that results are consistent with preclinical predictions of an increased therapeutic index for this combination (179).

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