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Purpose In this study, we hypothesized that systemic antitumor immunity might be enhanced by combining pulsed-wave ultrasound hyperthermia (pUSHT) with OK-432 and that the induced antitumor immunity could confer protection against tumorigenesis. These hypotheses were tested in bilateral and rechallenged tumor models. Methods and Materials Bilateral and rechallenged tumor models were applied in the studies. In the bilateral tumor model, BALB/c mice were inoculated in both flanks with CT26-luc tumor cells. The tumors in the right flank were treated with 4 courses of pUSHT with or without OK-432. In the rechallenged tumor model, tumor cells were implanted into the right flank. Once formed, the tumors were treated with pUSHT with OK-432, followed by surgical resection. New tumor cells were then implanted into the contralateral flank. The antitumor response was evaluated via infiltrated immune cells and the severity of necrosis/apoptosis in tumors. Results In the bilateral tumor model, the tumor growth rate and growth activity of both treated (100% reduction) and untreated tumors (90.5% reduction) were significantly inhibited with the combination treatment compared with the sham control group, and the systemic antitumor effect was prolonged. The survival rate was significantly enhanced (sham control, 8 days; OK plus pUSHT, >20 days). IFNγ+ CD4 (treated tumor, 8.6-fold; untreated tumor, 4-fold), IFNγ+ CD8 (treated tumor, 6.7-fold; untreated tumor, 2.6-fold), and T cell and NK cell (treated tumor, 4-fold; untreated tumor, 2.5-fold) infiltration was increased in the combination group compared with the control group. In the rechallenged tumor model, new tumors failed to form with the combination treatment. Conclusion This experimental study combining pUSHT and OK-432 explored a new therapeutic strategy for controlling colon cancer metastasis. The results show that the combination treatment may produce an effective antitumor immune response.

Purpose To evaluate the feasibility of magnetic resonance–guided high-intensity focused ultrasound (MR-HIFU) mild hyperthermia in deep tissue targets for enhancing radiation therapy and chemotherapy in the context of recurrent rectal cancer. A preclinical study was performed to evaluate the safety and performance of MR-HIFU mild hyperthermia. A prospective imaging study was performed in volunteers with rectal cancer to evaluate MR thermometry quality near the rectum and accessibility of rectal tumors using MR-HIFU. Methods and Materials Mild hyperthermia was performed in pig thigh (9 sonications, 6 pigs) using a clinical MR-HIFU system. Targets near the rectal wall and deep thigh were evaluated. Thermal maps obtained in 6 planes every 3.2 seconds were used to control sonications in 18-mm diameter treatment regions at temperatures of 42°C to 42.5°C for 10 to 60 minutes. Volunteer imaging-only studies to assess the quality of MR thermometry (without heating) were approved by the institutional research ethics board. Anatomic and MR thermometry images were acquired in consenting volunteers with rectal cancer. In 3 of 6 study participants, rectal filling with saline was used to reduce motion-related MR thermometry artifacts near the tumor. Results In pigs, mean target temperature matched the desired hyperthermia temperature within 0.2°C; temporal standard deviation ≤0.5°C. With optimized control thresholds, no undesired tissue damage was observed. In human volunteers, MR temperature measurements had adequate precision and stability, especially when rectal filling was used to reduce bowel motion. Conclusions In pigs, MR-HIFU can safely deliver mild hyperthermia (41°C-43°C) to a targeted volume for 30 minutes. In humans, careful patient selection and preparation will enable adequate targeting for recurrent rectal cancers and sufficient MR temperature mapping stability to control mild hyperthermia. These results enable human trials of MR-HIFU hyperthermia.

Hyperthermia is the clinical application of heat, in which tumor temperatures are raised to 40°C to 45°C. This proven radiation and chemosensitizer significantly improves clinical outcome for several tumor sites. Earlier studies of the use of pre-treatment planning for hyperthermia showed good qualitative but disappointing quantitative reliability. The purpose of this study was to investigate whether hyperthermia treatment planning (HTP) can be used more reliably for online adaptive treatment planning during locoregional hyperthermia treatments. This study included 78 treatment sessions for 15 patients with non-muscle-invasive bladder cancer. At the start of treatments, temperature rise measurements were performed with 3 different antenna settings optimized for each patient, from which the absorbed power (specific absorption rate [SAR]) was derived. HTP was performed based on a computed tomography (CT) scan in treatment position with the bladder catheter in situ. The SAR along the thermocouple tracks was extracted from the simulated SAR distributions. Correlations between measured and simulated (average) SAR values were determined. To evaluate phase steering, correlations between the changes in simulated and measured SAR values averaged over the thermocouple probe were determined for all 3 combinations of antenna settings. For 42% of the individual treatment sessions, the correlation coefficient between measured and simulated SAR profiles was higher than 0.5, whereas 58% showed a weak correlation (R of

Purpose To assess the impact on local tumor control of intraoperative ultrasonographic plaque visualization and selective application of transpupillary thermotherapy (TTT) in the treatment of posterior uveal melanoma with iodine-125 (I-125) episcleral plaque brachytherapy (EPB). Methods and Materials Retrospective analysis of 526 patients treated with I-125 EPB for posterior uveal melanoma. Clinical features, dosimetric parameters, TTT treatments, and local tumor control outcomes were recorded. Statistical analysis was performed using Cox proportional hazards and Kaplan-Meier life table method. Results The study included 270 men (51%) and 256 women (49%), with a median age of 63 years (mean, 62 years; range, 16-91 years). Median dose to the tumor apex was 94.4 Gy (mean, 97.8; range, 43.9-183.9) and to the tumor base was 257.9 Gy (mean, 275.6; range, 124.2-729.8). Plaque tilt >1 mm away from the sclera at plaque removal was detected in 142 cases (27%). Supplemental TTT was performed in 72 patients (13.7%). One or 2 TTT sessions were required in 71 TTT cases (98.6%). After a median follow-up of 45.9 months (mean, 53.4 months; range, 6-175 months), local tumor recurrence was detected in 19 patients (3.6%). Local tumor recurrence was associated with lower dose to the tumor base ( P =.02). Conclusions Ultrasound-guided plaque localization of I-125 EPB is associated with excellent local tumor control. Detection of plaque tilt by ultrasonography at plaque removal allows supplemental TTT to be used in patients at potentially higher risk for local recurrence while sparing the majority of patients who are at low risk. Most patients require only 1 or 2 TTT sessions.

We have investigated differences in the efficacy of combined treatment with cis-diamminedichloroplatinum(II) (cDDP) and local hyperthermia (HT) in nonirradiated and preirradiated experimental tumors. Survival of R-1 rhabdomyosarcoma cells was assessed after treatment with various cDDP-concentrations at 37 degrees C and 42 degrees C in vitro. Rats bearing R-1 rhabdomyosarcomas of 190 mm3 (SE 15 mm3) were treated with cDDP (6 mg/kg i.p.), HT (1 h at 43 degrees C), or cDDP+HT (45 min interval) without preirradiation or at day 16 after the first dose of fractionated irradiation. Fractionated irradiation consisted of four daily doses of 5 Gy of x-rays each and tumor volumes had regrown to their original volume at the time of treatment. Experimental endpoint was tumor growth delay (TGD). Hyperthermia-enhanced cDDP cytotoxicity in vitro by a factor of about 5. Treatment with cDDP or HT alone resulted in a similar TGD in non- and preirradiated tumors (7.2 vs. 7.4 days and 1.1 vs. 0.9 days, respectively). In non- as well as in preirradiated tumors, HT given in combination with cDDP significantly enhanced the effect of cDDP, prolonging the TGD (11.1 days (p = 0.0001) and 16.2 days (p < 0.0001), respectively) corresponding to a TGD-enhancement of 1.54 and 2.19, respectively. The TGD after cDDP+HT in preirradiated tumors was significantly longer than in nonirradiated tumors (p = 0.0003). In this tumor model, HT enhanced the antitumor effect of cDDP. Previous radiation treatment did not reduce the HT-enhanced effect of cDDP. Combined cDDP and HT may be useful in the treatment of nonirradiated tumors as well as previously irradiated tumors

Purpose : The biological rationale for combining locoregional hyperthermia (HT) with cisplatin (CDDP) is the potentiating effect of HT on CDDP uptake and cytotoxicity. Feasibility, toxicity, and preliminary results of a clinical trial of weekly loco-regional HT in combination with cisplatin are described in this article. Methods and Materials : Patients with a previously irradiated unresectable local recurrent cervical carcinoma or locally advanced bladder carcinoma were treated with weekly cycles of locoregional HT (70 MHz four antenna phased array system) for 1 h and CDDP 50 mg/m 2 IV for a maximum of 12 courses. Results : Fourteen patients, 10 patients with recurrent cervical carcinoma and 4 with a locally advanced bladder carcinoma, were entered in this study. A total of 100 cycles were given. Overall toxicity was acceptable ; Grade 3 (WHO) toxicity (gastrointestinal, hematological, and neurotoxicity) was observed in 5 out of 14 patients. No Grade 4 toxicity was seen. Subcutaneously fatty necrosis due to HT occurred in 11% of the cycles, while two patients developed skin burns. Two out of 10 patients with recurrent cervical carcinoma were not evaluable for response. Four out of eight evaluable cervical carcinoma patients responded (two pathologic complete responses, one pathologic confirmed partial response, one partial response): response rate 50% (95% confidence interval 15.7-84.3%). Salvage surgery became possible in three out of four responding patients, whose tumors were previously considered unresectable. Two out of the four evaluable patients with locally advanced bladder carcinoma responded (two partial responses). Conclusions : Weekly loco-regional HT and CDDP 50 mg/m 2 /week for a maximum of 12 courses is feasible with an acceptable toxicity, which seems not to be enhanced by the addition of loco-regional HT. The encouraging preliminary results of this treatment schedule warrant further study, especially in patients with previously irradiated recurrent cervical carcinomas.

Purpose To assess the efficacy of radiotherapy (RT) combined with regional hyperthermia (HT) guided by radiofrequency (RF)-output power and intraesophageal temperature and evaluate the potential contribution of HT to clinical outcomes in patients with Stage III non–small-cell lung cancer (NSCLC). Methods and Materials Thirty-five patients with Stage III NSCLC treated with RT plus regional HT were retrospectively analyzed. Twenty-two of the 35 patients underwent intraesophageal temperature measurements. Patients with subcutaneous fat of 2.5 cm or greater, older age, or other serious complications did not undergo this therapy. The 8-MHz RF-capacitive heating device was applied, and in all patients, both the upper and lower electrodes were 30 cm in diameter, placed on opposite sides of the whole thoracic region, and treatment posture was the prone position. The HT was applied within 15 minutes after RT once or twice a week. Results All thermal parameters, minimum, maximum, and mean of the four intraesophageal temperature measurements at the end of each session and the proportion of the time during which at least one of the four intraesophageal measurements was 41°C or higher in the total period of each session of HT, of the intraesophageal temperature significantly correlated with median RF-output power. Median RF-output power (≥1,200 W) was a statistically significant prognostic factor for overall, local recurrence–free, and distant metastasis–free survival. Conclusions The RT combined with regional HT using a higher RF-output power could contribute to better clinical outcomes in patients with Stage III NSCLC. The RF-output power thus may be used as a promising parameter to assess the treatment of deep regional HT if deep heating using this device is performed with the same size electrodes and in the same body posture.

Purpose Perillyl alcohol (POH) (4-isopropenyl-cyclohexenecarbinol) is a member of the monoterpenes, which are present in various fruits and vegetables. POH has been demonstrated to be cytotoxic against a variety of experimental cancer cells in vitro and in vivo. Phase I clinical trials have indicated that POH may be useful for human tumor treatment. The purpose of our study was to reveal whether the anticancer effect of POH could be enhanced by hyperthermia. Methods and materials SCK mammary carcinoma cells of A/J mice were used. The effects of POH or hyperthermia alone were studied by incubating the cells during exponential growth phase in culture with 0.25–1.0 mM of POH at 37°C for varying lengths of time or heating cells at 41–43°C for varying lengths of time. The combined effect of POH and hyperthermia was investigated by heating the cells with 1 mM of POH at 41–43°C for varying lengths of time. The effects of the treatments were evaluated using the clonogenic cell survival assay and three types of apoptosis assays. Results An incubation of SCK cells with 1 mM of POH at 37°C for 60 min or hyperthermia at 43°C for 1 h decreased clonogenic cell survival to 40% and 60%, respectively. When the cells were heated at 43°C for 1 h in the presence of 1 mM of POH, clonogenic cell survival decreased to 0.2%, indicating that hyperthermia potentiated the effect of POH to cause clonogenic cell death. Hyperthermia also markedly increased the degree of POH-induced apoptosis. Conclusion Hyperthermia synergistically potentiates the cytotoxicity of naturally occurring POH against cancer cells.

Purpose To present a preliminary report on the feasibility, efficacy, and toxicity of irradiation (RT) and hyperthermia (HT) in patients with locally advanced, hormone-refractory prostate cancer (LAHRPC) who may or may not have received prior RT. Methods and materials Between 1997 and 2002, 13 consecutive patients with LAHRPC or RT-recurrent prostate cancer were treated with RT and HT on a Phase I–II protocol. Eight patients had RT-recurrent LAHRPC (Group A) and 5 had LAHRPC without prior RT (Group B). All patients had large and clinically symptomatic tumors. The median RT dose was 39.6 Gy and 66.6 Gy in Groups A and B, respectively. External deep HT was delivered using a BSD-2000 Sigma-60 applicator. The median number of HT treatments was 8 in group A and 10 in group B. Results The median follow-up was 14 and 13 months for Groups A and B, respectively. All patients achieved a complete or partial response (CR/PR) and complete palliation of symptoms. Eleven patients had follow-up CT scans that demonstrated a CR in six and a PR in five. Two patients, who died of metastasis, did not have CT scans and had a PR on digital rectal examination. Two patients demonstrated a biochemical CR. The median duration of the CR/PR among Group A patients was 12 months after therapy. Three patients in Group A developed tumor recurrence at 9, 17, and 27 months after repeat RT to doses of 39.6, 36, and 50 Gy, respectively. At last follow-up, no Group B patient developed local recurrence. Grade 1-2 rectal bleeding was noted in 3 patients. RT and HT were generally well tolerated by all patients who had not previously undergone RT. Of the 8 patients who had, 6 (75%) tolerated retreatment well with minimal or no complications. Two patients in the repeat RT group had severe complications. One patient with lymphoma and factor XI deficiency developed Grade 4 hemorrhagic cystitis. Another previously irradiated patient developed a rectovesical fistula 4 months after retreatment, after disappearance of a large, invasive, and necrotic tumor. Conclusion This preliminary report demonstrates the feasibility and efficacy of RT and HT in patients with LAHRPC, who may or may not have received prior RT. Presently, such patients who have undergone previous RT have no effective treatment options. RT and HT were generally well tolerated by patients who were not previously undergone RT. Of those who had been, most (6 of 8) tolerated retreatment well with minimal or no complications. The high-risk factors for treatment- and tumor regression-related side effects include the presence of large necrotic tumors, previous RT with a large dose/fraction, and the presence of bleeding disorders. Despite the size of these large tumors, RT and HT resulted in significant tumor shrinkage, rapid serum prostate-specific antigen decline, durable treatment responses, and durable palliation of symptoms. Additional clinical studies are warranted.

Purpose: To assess the therapeutic gain (at the TCD 50 level) that can be obtained by boosting thermoradiotherapy with intravenous glucose infusion at different temperatures. This completes our series of studies to determine the optimal conditions and the effectiveness of glucose administration at clinically achievable glucose levels and treatment temperatures. Methods and Materials: Subcutaneous rat rhabdomyosarcoma BA1112 was irradiated with graded single doses of 300-kV X-rays (dose range 0–60 Gy). Fifteen minutes after irradiation, a 100-min intravenous infusion was started, consisting of either glucose (20% solution, 2.4–3 g/kg/h) or saline as a control. Then heat was applied to the tumors at 42°C or 43°C (water bath) during a subsequent 100-min period of infusion. Tumor control was scored as the absence of palpable growth at 100 days after treatment. Results: Glucose infusion enhanced tumor control independent of temperature in the range 42–43°C. At 42°C, the TCD 50 for X-irradiation decreased by 5.9 Gy (SEM 1.8 Gy), from 41.6 (1.6) to 35.7 (1.5) Gy, and at 43°C from 33.3 (1.6) to 27.3 (1.5) Gy, representing a glucose enhancement ratio of approximately 1.2. At doses corresponding to the TCD 50 at either 42 or 43°C, the addition of glucose increased tumor control from 50% to 70%. An enhancement ratio of 2.1 was found for the combination of irradiation, glucose infusion, and heating at 43°C, with respect to irradiation alone (TCD 50 56.3 Gy, reanalyzed earlier data). The contribution of combined heat and glucose to tumor control represented an additive effect, probably on the hypoxic cell population. Conclusion: Moderate glucose administration (blood concentration 300 mg/100 mL) sizably improves experimental tumor control after combined X-irradiation and hyperthermia under clinically feasible conditions. Clinical treatment should benefit from this additional modality, in particular if unsatisfactory local control rates are due to insufficient heating. The therapeutic gain has to be evaluated further in clinical studies.

Purpose: The relationship between apoptosis induced by 42°C and 44°C hyperthermia alone or in combination with verapamil and changes in intracellular Ca 2+ concentration ([Ca 2+ ]i) was investigated in U937 cells. Methods: Apoptosis induced by hyperthermia was assessed according to DNA fragmentation, nuclear morphologic changes, and expression of phosphatidylserine on the outside plasma cell membrane. These changes were measured by flow cytometry. The [Ca 2+ ]i of individual cells after hyperthermia was monitored by a digital image-analyzing technique using Fura-2. Results: Hyperthermia-induced apoptosis reached a plateau after 6 h and was found to be both time and temperature-dependent. DNA fragmentation was maximum at 44°C after 30 min. Verapamil enhanced the apoptosis induced by 42°C and 44°C hyperthermia in normal cells and by 44°C hyperthermia in thermotolerant cells. The number of cells containing higher [Ca 2+ ]i (more than 200 nM) was significantly increased by hyperthermia and further elevated by the addition of verapamil in both normal and thermotolerant cells. Apoptosis induced by hyperthermia was markedly decreased by an intracellular Ca 2+ chelator, BAPTA-AM, in a dose-dependent manner. Conclusion: These results indicate that [Ca 2+ ]i increase plays a crucial role in apoptosis induced by hyperthermia and the combined treatment with verapamil in normal and thermotolerant U937 cells. Furthermore, hyperthermia-combined drug therapy has potential significance in cancer therapy.

Purpose: To determine the feasibility of combining external beam radiotherapy, continuous infusion 5-fluorouracil (5-FU), and external microwave hyperthermia in patients with locally advanced, unresectable, or recurrent adenocarcinoma of the rectum. Methods and Materials: From 7/95 through 2/99, 15 patients were enrolled in the study. The treatment regimen consisted of continuous infusion 5-FU 250 mg/m 2 /d 7 days/week beginning on day 1, external beam radiotherapy to the pelvis, 4500 cGy, 180 cGy/d 5 days/week using a 3 or 4-field technique, and external microwave hyperthermia on days 3, 8, 15, 22, and 29. Chemotherapy was stopped on the last day of radiotherapy. Surgical resection, if feasible, was scheduled 3–6 weeks after completing thermochemoradiotherapy. For this regimen to be considered feasible, no more than 2 of the 15 patients should fail to complete therapy due to life-threatening toxicity. Toxicity was scored using National Cancer Institute Criteria. Results: All patients completed the chemoradiotherapy portion of the protocol. Eleven of the 15 patients completed all 5 hyperthermia treatments. Of the 4 patients who did not receive the full course of hyperthermia, only 1 patient had treatment stopped due to life-threatening toxicity. The other 3 patients did not complete hyperthermia due to scheduling errors ( n = 2) or patient request ( n = 1). Five of 15 patients required a treatment interruption due to toxicity ≥ Grade 3. Seven patients experienced lesser degrees of toxicity which did not require treatment interruption. Three patients experienced no side effects. The most common toxicities were dermatitis and diarrhea. Of the 14 patients in whom surgery was planned, 11 (79%) were resectable. There was one pathologic complete response. Conclusions: It is feasible to deliver thermochemoradiotherapy, as prescribed in this study, to patients with locally advanced, unresectable, or recurrent rectal cancer. The therapy is moderately toxic, with one-third of patients requiring temporary treatment interruptions. The regimen appears active against rectal cancer, and appears to warrant further consideration as a treatment option for this patient population.

Purpose: The aim of our study was to investigate if the efficacy of paclitaxel and paclitaxel-radiation treatments in vivo could be enhanced by hyperthermia. Materials and Methods: Paclitaxel was administered i.p. in doses from 30 to 60 mg/kg b.w. to (C3D2F1) mice bearing spontaneous mammary carcinoma. Local hyperthermia (41°, 42°, 43°C) was carried out by immersing tumor-bearing legs in a water bath for 1 h. Single X-ray treatments from 10 to 90 Gy were performed. Tumor growth delay (TGD) or tumor control dose (TCD 50 , radiation dose needed to induce local tumor control in 50% of irradiated animals) were the endpoints. Results: A significant increase of dose-dependent growth delay was observed in paclitaxel and 43°C hyperthermia combined treatments, and a superadditive effect was seen with paclitaxel 45 mg/kg. Combined treatments with hyperthermia at 41° and 42°C were less effective. Administration of paclitaxel 24 h, 4 h, and 15 min before or 15 min and 4 h after hyperthermic treatments produced similar results (TGDs varying from 22.1 to 17 days), and administering paclitaxel 48 h before or 24 h after hyperthermic treatments decreased TGDs (about 10 days). Trimodality treatment (paclitaxel 45 mg/kg, hyperthermia, and X-ray), with a TCD 50 of 14.1 Gy, in respect to the TCD 50 of 53.1 obtained with X-ray alone, was the most effective. Conclusions: Hyperthermia enhanced the effectiveness of paclitaxel in all the tested protocols. Our results show a superadditive effect of paclitaxel 45 mg/kg combined with a hyperthermic treatment of 1 h at 43°C. Trimodality treatment, evaluated in terms of percentage of cures, shows a very high enhancement ratio.

Purpose: To investigate the toxicity of combretastatin A-4 disodium phosphate (CA-4) and its vascular effects in the subcutaneous (s.c.) BT 4 An rat glioma, and additionally, to determine the tumor response of CA-4 combined with hyperthermia. Methods and Materials: For assessment of drug toxicity, rats were given 50, 75, or 100 mg/kg CA-4 and followed by daily registration of weight and side effects. Interstitial tumor blood flow was determined by laser Doppler flowmetry in rats injected with 50 mg/kg CA-4. In the tumor response study we administered CA-4 50 mg/kg alone or combined with hyperthermia (waterbath 44°C for 60 min) 0 or 3 h later. Results: We found that CA-4, at a well-tolerated dose of 50 mg/kg, induced a considerable time-dependent decrease in the tumor blood flow. Tumor blood flow was reduced by 47–55% during the first 110 min after injecting CA-4, and thereafter remained decreased until the measurements were terminated. Administering CA-4 3 h before hyperthermia yielded the best tumor response and increased tumor growth time significantly compared with simultaneous administration of CA-4 and hyperthermia ( p = 0.03). Interestingly, CA-4 alone did not influence tumor growth. Conclusion: CA-4 induces a gradual reduction in tumor blood flow which can be exploited to sensitize the BT 4 An tumor for hyperthermia.

Purpose: Complete serum and single growth factors have been reported to protect cells against the effects of hyperthermia. The phenomenon is not very well understood, especially with regard to the relative importance of the various serum components. There is also a need to clarify the possible involvement of changes in proliferation. The influence of serum and growth factors on radiation sensitivity has not been studied in detail. The present communication is an attempt to at least partly fill these gaps. Cells were exposed to X-rays and/or heat after incubation in sufficiently supplemented medium and media lacking certain serum components. Differences in clonogenic survival were recorded and related to the proliferative status under the various conditions. Methods and Materials: Human melanoma cells (MeWo) were used throughout. Cells were incubated for 3 or 6 days (a) in Ham’s F12 medium with 20% fetal calf serum; (b) in medium without serum, but supplemented with the following components: insulin, transferrin, Na-selenite, and a lipid–protein complex; (c) to (f) in media lacking one or the other of these components; (g) in unsupplemented medium. Colony formation ability served as a measure of cell survival after exposure to radiation (250 kV X-rays) and/or hyperthermia (heating at 43°C). In parallel, cell proliferation was characterized by the bromodeoxyuridine (BrdU) labeling index and the Ki-67 growth fraction, both determined by two-parameter flow cytometry. Results and Conclusions: Sensitivity was hardly influenced by 3 days of incubation in medium containing no supplement at all, whereas after 6 days under the same conditions survival curves both of irradiated and hyperthermia-treated cells had a strongly reduced shoulder or were considerably steeper. Experiments with media lacking only one or the other serum component, showed that deprivation of insulin, transferrin, and sodium selenite led to no more than a modest increase in cell killing, whereas the effects in medium lacking lipid–protein complex were about the same as in medium containing no supplement at all. Sensitivity changes did not seem to be due to the lack of serum or certain of its components per se, but were very well correlated with changes in proliferation as characterized by BrdU labeling index or the Ki-67 growth fraction.

Purpose: Long duration mild hyperthermia has been shown to be an effective radiosensitizer when given concurrently with low dose rate irradiation. Pulsed simulated low dose rate (PSLDR) is now being used clinically, and we have set out to determine whether concurrent mild hyperthermia can be an effective radiosensitizer for the PSLDR protocol. Materials and Methods: Human glioma cells (U-87MG) were grown to plateau phase and treated in plateau phase in order to minimize cell cycle redistribution during protracted treatments. Low dose rate (LDR) irradiation and 41°C hyperthermia were delivered by having a radium irradiator inside a temperature-controlled incubator. PSLDR was given using a 150 kVp X-ray unit and maintaining the cells at 41°C between irradiations. The duration of irradiation and concurrent heating depended on total dose and extended up to 48 h. Results: When 41°C hyperthermia was given currently with LDR or PSLDR, the thermal enhancement ratios (TER) were about the same if the average dose rate for PSLDR was the same as for LDR. At higher average dose rates for PSLDR the TERs became less. Conclusions: Our data show that concurrent mild hyperthermia can be an effective sensitizer for PSLDR. This sensitization can be as effective as for LDR if the same average dose rate is used and the TER increases with decreasing dose rate. Thus mild hyperthermia combined with PSLDR may be an effective clinical protocol.

Purpose: To assess treatment outcome for patients with locally advanced or recurrent gynecological malignancies treated with continuous low-dose-rate (LDR) remote afterloading brachytherapy using the Martinez Universal Perineal Interstitial Template (MUPIT). Materials and Methods: Between 7/85 and 6/94, 69 patients with either locally advanced or recurrent malignancies of the cervix, endometrium, vagina, or female urethra were treated by 5 different physicians using the MUPIT with (24 patients) or without (45 patients) interstitial hyperthermia. Fifty-four patients had no prior treatment with radiation and received a combination of external beam irradiation (EBRT) and an interstitial implant. The combined median dose was 71 Gy (range 56–99 Gy), median EBRT dose was 39 Gy (range 30–74 Gy), and the median implant dose was 32 Gy (range 17–40 Gy). Fifteen patients with prior radiation treatment received an implant alone. The total median dose including previous EBRT was 91 Gy (range 70–130 Gy) and the median implant dose was 35 Gy (range 25–55 Gy). Results: With a median follow-up of 4.7 yr in survivors, the 3-yr actuarial local control (LC), disease-specific survival (DSS), and overall survival (OS) for all patients was 60%, 55%, and 41% respectively. The clinical complete response rate was 78% and in these patients the 3-year actuarial LC, DSS, and OS was 78%, 79%, and 63% respectively. On univariate analysis for local control, disease volume and hemoglobin were found to be statistically significant. On multivariate analysis, however, only disease volume remained significant ( p = 0.011). There was no statistically significant difference in local control whether patients had received any prior treatment with radiation ( p = 0.34), had recurrent disease ( p = 0.13), or which physician performed the implant ( p = 0.45). The grade 4 complication rate (small bowel obstruction requiring surgery, fistulas, soft tissue necrosis) for all patients was 14%. With a dose rate less than 70 cGy/hour, the grade 4 complication rate was 3% vs. 24% with dose rate ≥ 70 cGy/hour ( p = 0.013). Conclusion: Patients with locally advanced or recurrent gynecological malignancies treated with the remote afterloader LDR MUPIT applicator can expect reasonable rates of local control that are not operator-dependent. Complication rates with this approach are acceptable and appear to be related to the dose rate.

Purpose/Objective: Peripheral neuropathies have emerged as the major dose-limiting complication reported after intraoperative radiation therapy (IORT). The combination of IORT with hyperthermia may further increase the risk of peripheral nerve injury. The objective of this study was to evaluate histopathological and histomorphometric changes in the sciatic nerve of dogs, after IORT with or without hyperthermia treatment. Methods and Materials: Young adult beagle dogs were randomized into five groups of 3-5 dogs each to receive IORT doses of 16, 20, 24, 28, or 32 Gy, Six groups of 4-5 dogs each received IORT doses of 12, 16, 20, 24, or 28 Gy simultaneously with 44 degrees C of intraoperative hyperthermia (IOHT) for 60 min. One group of dogs acted as hyperthermia-alone controls. Two years after the treatment, dogs were euthanized, and histopathological and morphometric analyses were performed. Results: Qualitative histological analysis showed prominant changes such as focal necrosis, mineralization, fibrosis, and severe fiber loss in dogs which received combined treatment. Histomorphometric results showed a significantly higher decrease in axon and myelin and small blood vessels, with a corresponding increase in connective tissue in dogs receiving IORT plus hyperthermia treatment, The effective dose for 50% of nerve fiber loss (ED50) in dogs exposed to IORT only was 25.3 Gy, The ED50 for nerve fiber loss in dogs exposed to IORT combined with IOHT was 14.8 Gy, The thermal enhancement ratio (TER) was 1.7. Conclusion: The probability of developing peripheral neuropathies in a large animal model is higher when IORT is combined with IOHT, when compared to IORT application alone. To minimize the risk of peripheral neuropathy, clinical treatment protocols for the combination of IORT and hyperthermia should not assume a thermal enhancement ratio (TER) to be lower than 1.5, (C) 1999 Elsevier Science Inc.

Purpose: To determine the most effective combination of carbogen breathing with mild temperature hyperthermia (MTH) to increase the oxygenation and radiation response in murine tumors. Methods and Materials: MTH at 41.5°C for 60 min was applied by immersion of the tumor in a precisely controlled water bath. The tumor pO 2 was measured with a polarographic microelectrode. The radiation response of the tumor was determined using the in vivo / in vitro assay for surviving tumor cells. Results: In the FSaII fibrosarcoma the median pO 2 increased from a control value of 6.5 ± 0.5 mm Hg to 16.6 ± 1.1 mm Hg immediately after MTH and was 10.9 ± 1.3 mm Hg 24 h later. Carbogen breathing for 5 min increased the FSaII pO 2 to 19.9 ± 2.1 mm Hg. Carbogen breathing for 5 min beginning immediately after MTH increased the median pO 2 more than 5 times to 35.4 ± 3.8 mm Hg. This combined treatment also substantially increased the response of the tumors to a radiation exposure of 20 Gy. In another tumor model, the SCK mammary carcinoma, MTH treatment increased the median pO 2 from the control level of 4.4 ± 0.2 mm Hg to 12.6 ± 1.2 mm Hg, and it returned to 4.3 ± 0.3 mm Hg 24 h later. Carbogen breathing for 5 min increased the SCK tumor pO 2 to 17.1 ± 1.4 mm Hg. The median SCK pO 2 was increased about 7 times to 31.2 ± 4.2 mm Hg when MTH was followed immediately with carbogen breathing for 5 min. The radiation response was also markedly increased by this combination. When the animals breathed carbogen for 15 or 30 min, the pO 2 and radiosensitivity in both tumor types either remained the same or was lower than that after 5 min of breathing. In addition, both FSaII and SCK tumors were radiosensitized 24 h after MTH treatment alone or with 5 min of carbogen breathing. Conclusions: A shorter carbogen breathing time immediately after MTH causes the most tumor radiosensitization. The results of this study also demonstrate that MTH increases radiosensitivity with and without carbogen breathing up to 24 h after the mild hyperthermia treatment.

Purpose: The kinetics of the accumulation of inducible 72-kD heat shock protein (hsp72) and the activation of heat shock transcriptional factor (HSF) after hyperthermia and/or CDDP treatment in two human glioblastoma cell lines, A-172 having the wild-type p53 gene and T98G having the mutated p53 gene were evaluated. Methods and Materials: Western blot analysis of hsp72, gel-mobility shift assay of HSF, cell survival, and development of thermotolerance were examined. Results: The prominent suppression of heat-induced hsp72 accumulation by CDDP was seen in A-172 cells, but not in T98G cells. This was due to the p53-dependent inhibition of heat-induced HSF activation by CDDP. The interactive hyperthermic enhancement of CDDP cytotoxicity was observed in A-172 cells, but not in T98G cells. In addition, the heat-induced thermotolerance was suppressed by the presence of CDDP in the pretreatment. Conclusion: Suppression of heat-induced hsp72 accumulation by CDDP contributes to an interactive hyperthermic enhancement of CDDP cytotoxicity in the cells bearing the wild-type p53 gene.

Purpose: To determine the feasibility of measuring temperature noninvasively with magnetic resonance imaging during hyperthermia treatment of human tumors. Methods: The proton chemical shift detected using phase-difference magnetic resonance imaging (MRI) was used to measure temperature in phantoms and human tumors during treatment with hyperthermia. Four adult patients having high-grade primary sarcoma tumors of the lower leg received 5 hyperthermia treatments in the MR scanner using an MRI-compatible radiofrequency heating applicator. Prior to each treatment, an average of 3 fiberoptic temperature probes were invasively placed into the tumor (or phantom). Hyperthermia was applied concurrent with MR thermometry. Following completion of the treatment, regions of interest (ROI) were defined on MR phase images at each temperature probe location, in bone marrow, and in gel standards placed outside the heated region. The median phase difference (compared to pretreatment baseline images) was calculated for each ROI. This phase difference was corrected for phase drift observed in standards and bone marrow. The observed phase difference, with and without corrections, was correlated with the fiberoptic temperature measurements. Results: The phase difference observed with MRI was found to correlate with temperature. Phantom measurements demonstrated a linear regression coefficient of 4.70° phase difference per ° Celsius, with an R2 = 0.998. After human images with artifact were excluded, the linear regression demonstrated a correlation coefficient of 5.5° phase difference per ° Celsius, with an R2 = 0.84. In both phantom and human treatments, temperature measured via corrected phase difference closely tracked measurements obtained with fiberoptic probes during the hyperthermia treatments. Conclusions: Proton chemical shift imaging with current MRI and hyperthermia technology can be used to monitor and control temperature during treatment of large tumors in the distal lower extremity.

PURPOSE To determine if adjuvant interstitial hyperthermia (HT) significantly improves survival of patients with glioblastoma undergoing brachytherapy boost after conventional radiotherapy. METHODS AND MATERIALS Adults with newly-diagnosed, focal, supratentorial glioblastoma < or = 5 cm in diameter were registered postoperatively on a Phase II/III randomized trial and treated with partial brain radiotherapy to 59.4 Gy with oral hydroxyurea. Those patients whose tumor was still implantable after teletherapy were randomized to brachytherapy boost (60 Gy at 0.40-0.60 Gy/h) +/- HT for 30 min immediately before and after brachytherapy. Time to progression (TTP) and survival from date of diagnosis were estimated using the Kaplan-Meier method. RESULTS From 1990 to 1995, 112 eligible patients were entered in the trial. Patient ages ranged from 21-78 years (median, 54 years) and KPS ranged from 70-100 (median, 90). Most commonly due to tumor progression or patient refusal, 33 patients were never randomized. Of the patients, 39 were randomized to brachytherapy ("no heat") and 40 to brachytherapy + HT ("heat"). By intent to treat, TTP and survival were significantly longer for "heat" than "no heat" (p = 0.04 and p = 0.04). For the 33 "no heat" patients and 35 "heat" patients who underwent brachytherapy boost, TTP and survival were significantly longer for "heat" than "no heat" (p = 0.045 and p = 0.02, respectively; median survival 85 weeks vs. 76 weeks; 2-year survival 31% vs. 15%). A multivariate analysis for these 68 patients adjusting for age and KPS showed that improved survival was significantly associated with randomization to "heat" (p = 0.008; hazard ratio 0.51). There were no Grade 5 toxicities, 2 Grade 4 toxicities (1 on each arm), and 7 Grade 3 toxicities (1 on "no heat" and 6 on the "heat" arm). CONCLUSION Adjuvant interstitial brain HT, given before and after brachytherapy boost, after conventional radiotherapy significantly improves survival of patients with focal glioblastoma, with acceptable toxicity.

Purpose: To determine whether intracellular pH (pH i ) is affected during hyperthermia in substrate-attached cells and whether acute extracellular acidification potentiates the cytotoxicity of hyperthermia via an effect on pH i . Methods and Materials: The pH i was determined in cells attached to extracellular matrix proteins loaded with the flourescent indicator dye BCECF at 37°C and during 42°C hyperthermia at an extracellular pH (pH e ) of 6.7 or 7.3 in cells. Effects on pH i during hyperthermia are compared to effects on clonogenic survival after hyperthermia at pH e 7.3 and 6.7 of cells grown at pH e 7.3, or of cells grown and monitored at pH e 6.7. Results: The results show that pH i values are affected by substrate attachments. Cells attached to extracellular matrix proteins had better signal stability, low dye leakage and evidence of homeostatic regulation of pH i during heating. The net decrease in pH i in cells grown and assayed at pH e = 7.3 during 42°C hyperthermia was 0.28 units and the decrease in low pH adapted cells heated at pH e = 6.7 was 0.14 units. Acute acidification from pH e = 7.3 to pH e = 6.7 at 37°C caused an initial reduction of 0.5-0.8 unit in pH i , but a partial recovery followed during the next 60–90 min. Concurrent 42°C hyperthermia caused the same initial reduction in pH i in acutely acidified cells, but inhibited the partial recovery that occurred during the next 60–90 min at 37°C. After 4 h at 37°C, the net change in pH i in acutely acidified cells was 0.30 pH unit, but at 42°C is 0.63 pH units. The net change in pH i correlated inversely with clonogenic survival. Conclusions: Hyperthermia causes a pH i reduction in cells which was smaller in magnitude by 50% in low pH adapted cells. Hyperthermia inhibited the partial recovery from acute acidification that was observed at 37°C in substrate attached cells, in parallel with a lower subsequent clonogenic survival.

To evaluate thermometry and the clinical results of radiofrequency (RF) hyperthermia for advanced malignant liver tumors.One hundred seventy-three patients with malignant liver tumors treated between 1983 and 1995 underwent hyperthermia. The 173 tumors consisted of 114 hepatocellular carcinomas (HCCs) and 59 non-HCCs (47 metastatic liver tumors and 12 cholangiocarcinomas). Eight-megahertz RF capacitive heating equipment was used for the hyperthermia. Two opposing 25-cm electrodes were generally used for heating the liver tumors. Our standard protocol was to administer hyperthermia 40-50 min twice a week for a total of eight sessions. The liver tumor temperature was measured by microthermocouples when possible. Transcatheter arterial embolization, radiotherapy, immunotherapy, and chemotherapy were combined with hyperthermia treatment in accordance with each patient's liver function.One hundred forty (81%) of the 173 patients who underwent more than four sessions of hyperthermia were evaluated in this study. Thermometry was performed in 77 (55%) of these 140 patients. The maximum tumor temperature, average tumor temperature, and minimum tumor temperature in the HCC were (mean +/- standard error) 41.2 +/- 0.2 degrees C, 40.3 +/- 1.3 degrees C, and 40.1 +/- 0.2 degrees C, respectively. The same thermometry results for non-HCC were 42.3 +/- 0.2 degrees C, 41.2 +/- 0.2 degrees C, and 40.9 +/- 0.2 degrees C, respectively. The maximum and minimum temperatures (41.8 +/- 0.2 degrees C and 40.3 +/- 0.4 degrees C) in the patients with a complete or partial response (CR or PR) were higher than those in the patients with no response or progressive disease (NR or PD) (41.3 +/- 0.5 degrees C and 39.8 +/- 0.4 degrees C), but the difference was not significant. Of the 73 cases with HCC who were evaluated by computed tomography (CT), CR was achieved in 7 (10%), PR in 15 (21%), NR in 37 (51%), and PD in 14 (19%). Of the 45 cases involving liver metastases evaluated by CT, CR was achieved in 3 (7%), PR in 17 (38%), NR in 12 (27%), and PD in 13 (29%). The 1-year cumulative survival rate for HCC patients was 30.0%, and the 5-year survival rate was 17.5%. The 1-year survival of non-HCC patients was 32.5%, and the longest survival was 30 months. The sequelae of hyperthermia included focal fat necrosis in 20 patients (12%), gastric ulceration in 4 (2%), and liver necrosis in 1 (1%). The sequelae of thermometry were severe peritoneal pain in seven patients (11%), intraperitoneal hematoma in one (1%), and pneumothorax in one (1%).Even though the thermometry results for liver tumors were not satisfactory, the treatment results are promising. Further clinical trials of RF capacitive hyperthermia for the treatment of advanced liver tumors should be encouraged.

Purpose: To determine the influence of adjuvant hyperthermia on the oxygenation status of fractionated irradiated tumors. Methods and Materials: Oxygen partial pressure (pO 2 ) in rat rhabdomyosarcomas (R1H) was measured sequentially at weekly intervals during a fractionated irradiation with 60 C-γ-rays (60 Gy/20f/4 weeks) in combination with local hyperthermia (8 f(HT) at 43°C, 1 h/4 weeks). Tumors were heated twice weekly with a 2450 MHz microwave device at 43°C, 1 h starting 10 min after irradiation. The pO 2 measurements (pO 2 -histograph, Eppendorf, Germany) were performed in anesthetized animals during mechanical ventilation and in hemodynamic steady state. All tumor pO 2 measurements were correlated to measurements of the arterial oxygen partial pressure (paO 2 ) determined by a blood gas analyzer. Results: The oxygenation status of R1H tumors decreased continuously from the start of the combined treatment, with increasing radiation dose and number of heat fractions. In untreated controls a median tumor pO 2 of 23 ± 2 mmHg (mean ± SEM) was measured. Tumor pO 2 decreased to 11 ± 2 mmHg after 30 Gy + 4 HT (2 weeks), and to 6 ± 2 mmHg after 60 Gy + 8HT (4 weeks). The increase in the frequency of pO 2 -values below 5 mmHg and the decrease in the range of the pO 2 histograms [Δp(1090)] further indicated that tumor hypoxia increased relatively rapidly from the start of combined treatment. After 60 Gy + 8HT 48 ± 5% (mean ± SEM) of the pO 2 -values recorded were below 5 mmHg. Conclusions: These findings suggest that adjuvant hyperthermia to radiatherapy induces greater changes in tumor oxygenation than radiation alone [cf. (39)]. This might be of importance for the temporary application of hyperthermia in the course of a conventional radiation treatment.

Purpose: The clinical usefulness of a newly developed ultrasound hyperthermia system was evaluated. Methods and Materials: The hyperthermia system uses a modified planer transducer operated at frequencies of 0.5, 1.0, and 1.5 MHz. The transducer has a nonvibrating part at the center to reduce the central hot spot. Frequency sweeping technique is also used to eliminate the annular hot spot around the center. Thirty-eight tumors in 29 patients were examined in this study. In 35 tumors, hyperthermia was given in conjunction with irradiation and/or chemotherapy, and in the remaining 3 tumors, hyperthermia alone was given. In all, a total of 153 hyperthermia sessions were performed. Results: The number of hyperthermia sessions per tumor ranged from 1 to 7 (mean, 4.0 ± 1.3). The number of intratumor thermometr points per session ranged from 1 to 8 (mean, 4.3 ± 1.5). The average intratumor temperature for tumors with a maximum depth of 6 cm was 42.1 ± 1.2, 41.7 ± 1.4, and 39.9 ± 2.0°C, respectively. The percentage of monitored intratumor points with temperature exceeding 42°C was 56 ± 31%, 43 ± 34%, and 21 ± 24%, respectively. Of the 30 evaluable tumors treated with combined irradiation, 12 showed complete response, 14 partial response, and 4 no change. Observed complications included pain at the treatment site in 13 of the 153 treatment sessions and vesicle formation in 3 of the 38 treatment sites. No serious complication was seen. Conclusions: These results indicate that the newly developed ultrasound hyperthermia system is clinically useful for the treatment of localized superficial and subsurface tumors with a maximum tumor depth of no more than 6 cm.

Purpose The effect of a decrease in the mean arterial blood pressure (MAP) induced by sodium nitroprusside (SNP) on the tumor temperature during hyperthermia (HT), and on the cytotoxic effect of HT, was studied in the BT4An tumor transplanted to the hind limb of BD IX rats. Experiments with two different anesthetics, pentobarbital and the midazolam/fentanyl/fluanisone combination (MFF), were performed to secure reliable conclusions. Methods and materials In the tumor response experiments local waterbath HT at 44.0 degrees C was given for 60 min. Sodium nitroprusside was administered as a continuous intravenous infusion to lower the MAP to 60 or 80 mmHg during HT. In two other experiments the temperature at the base of the tumor during HT was measured before and during SNP infusion. In animals without tumor the temperature was measured subcutaneously on the foot during HT with or without SNP-induced hypotension. Results When SNP was given to lower the MAP to 60 mmHg during HT in MFF anesthetized animals, the median tumor growth time (TGT) was 70 days, compared to 14.5 days in the HT alone group. The corresponding figures were 127 and 12.1 days with pentobarbital anesthesia. In the HT + SNP group, more than 40% cure was observed in both experiments. No cures were seen in any of the other groups. Hyperthermia alone prolonged the TGT slightly, whereas SNP given alone had no effect, compared to controls. When the MAP was lowered to 80 mmHg by SNP infusion during HT (MFF anesthesia), the median TGT was 19.9 days, which was significantly longer than that in the HT alone group (10.9 days). In the MAP range from 60 to 120 mmHg, a nearly linear relationship between the MAP and the tumor temperature was found during HT in MFF anesthetized animals. With both anesthetics, the median temperature at the base of the tumor was about 0.8 degrees C higher during HT when the MAP was lowered to 60 mmHg by SNP. In animals without tumors, the temperature subcutaneously on the foot was 0.3 and 0.4 degrees C higher during SNP infusion in the MFF and pentobarbital group, respectively. Conclusion We have developed a small animal model in inbred rats feasible for exploring the influence of a stable blood pressure reduction induced by SNP, on the effect of HT given alone or in combination with other treatment modalities to a transplantable tumor. The greatly increased cytotoxic effect of local waterbath HT in the present tumor response experiments is probably a consequence of increased tumor temperature during SNP infusion.

Purpose : The purpose of this study was to assess the effect of increasing intratumoral temperatures by the combination of local hyperthermia (LH) and whole body hyperthermia (WBH) on the radiation response of canine sarcomas. Methods and Materials : Dogs with spontaneous soft tissue sarcomas and no evidence of metastasis were randomized to be treated with radiation combined with either LH alone or LH + WBH. Dogs were accessioned for treatment at two institutions. The radiation dose was 56.25 Gy, given in 25 2.25 Gy daily fractions. Two hyperthermia treatments were given ; one during the first and one during the last week of treatment. Dogs were evaluated after treatment for local recurrence, metastasis, and complications. Results : Sixty-four dogs were treated between 1989 and 1993. The use of LH+WBH resulted in statistically significant increases in the low and middle regions of the temperature distributions. The largest increase was in the low temperatures with median CEM 43 T90 values of 4 vs. 49 min for LH vs. LH + WBH, respectively (p < 0.001). There was no difference in duration of local tumor control between hyperthermia groups (p = 0.59). The time to metastasis was shorter for dogs receiving LH + WBH (p = 0.02) ; the hazard ratio for metastatic disease for dogs in the LH + WBH group was 2.5 (95% confidence interval, 1.2-5.4) with respect to dogs in the LH group. Complications were greater in larger tumors and in tumors treated with LH + WBH. Conclusion : The combination of LH + WBH with radiation therapy, as described herein, was not associated with an increase in local tumor control in comparison to use of LH with radiation therapy. The combination of LH + WBH also appeared to alter the biology of the metastatic process and was associated with more complications than LH. We identified no rationale for further study of LH + WBH in combination with radiation for treatment of solid tumors.

Purpse: Late radiation injury to peripheral nerve may be the limiting factor in the clinical application of intraoperative radiation therapy (IORT). The combination of IORT with intraoperative hyperthermia (IOHT) raise specific concerns regarding the effects on certain normal tissues such as peripheral nerve, which might be included in the treatment field. The objective of this study was to compare the effect of IORT alone to the effect of IORT combined with IOHT on peripheral nerve in normal beagle dogs. Methods and Materials: Young adult beagle dogs were randomized into five groups of three to five dogs each to receive IORT doses of 16, 20, 24, 28, or 32 Gy to 5 cm of surgically exposed right sciatic nerve using 6 MeV electrons and six groups of four to five dogs each received IORT doses of 0, 12, 16, 20, 24, or 28 Gy simultaneously with 44°C of IOHT for 160 min. IOHT was performed using a water circulating hyperthermia device with a multichannel thermometry system on the surgically exposed exposed sciatic nerve. Neurologic and electrophysiologic examinations were done before and montly after treatment for 24 months. Electrophysiologic studies included electromyographic (EMG) exminations of motor function, as well as motor nerve conduction velocities studies. Results: Two years after treatment, the effective dose for 50% complication (ED 50 ) for limb paresis in dogs exposed to IORT only was 22 Gy. The ED 50 for paresis in dogs exposed to IORT combined with IOHT was 15 Gy. The thermal enhancement ratio (TER) was 1.5. Electrophysiologic studies showed more prominent changes such as EMG abnormalities, decrease in conduction velocity and amplitude of the action potential, and complete conduction block in dogs that received the combination of IORT and IOHT. The latency to development of peripheral neuropathies was shorter for dogs exposed to the combined treatment. Conclusion: The probability of developing peripheral neuropathies in a large animal model was higher for IORT combined with IOHT, than for IORT alone. The dose required to produce the same level of late radiation injury to the sciatic nerve was reduced by a factor of 1.5 (TER) if IORT was combined with 44°C of IOHT for 60 min.

Purpose: Recent cell culture studies by us and others suggest that some human carcinoma cells are more sensitive to heat than are rodent cell following mild hyperthermia. In studying the celllular mechanism of enhanced thermosensitivity of human tumor cells to hyperthermia, prostatic carcinoma cells of human origin were found to be more sensitive to mild hyperthermia than other human cancer cells. The present study was designed to determine the magnitude of radiosensitization of human prostatic carcinoma cells by mild hyperthermia and to examine whether the thermal radiosensitization is related to the intrinsic thermosensitivity of cancer cells. Methods and Materials: Two human prostatic carcinoma cell lines (DU-145 and PC-3) and other carcinoma cells of human origin, in particular, colon (HT-29), breast (MCF-7), lung (A-549), and brain (U-251) were exposed to temperatures of 40–41°C. Single acute dose rate radiation and fractionated radiation were combined with mild hyperthermia to determine thermal radiosensitization. The end point of the study was the colony-forming ability of single-plated cells. Results: DU-145 and PC-3 cells were found to be exceedingly thermosensitive to 41°C for 24 h, relative to other cancer cell lines. Ninety percent of the prostatic cancer cells were killed by a 24 h heat exposure. Prostatic carcinoma cells exposed to a short duration of heating at 41°C for 2 h resulted in a substantial enhancement of radiation-induced cytotoxicity. The thermal enhancement ratios (TERs) of single acute dose radiation following heat treatment 41°C for 2 h were 2.0 in DU-145 cells and 1.4 in PC-3 cells. The TERs of fractionated irradiation combined with continuous heating at 40°C were similarly in the range of 2.1 to 1.4 in prostate carcinoma cells. No significant radiosensitization was observed in MCF-7 and HT-29 cells under the same conditions. Conclusion: The present data suggest that a significant radiosensitization of prostatic cancer cells could be obtained by the combined treatment of radiatioin and mild hyperthermia. Future clinical trials should be aimed at achieving mild heating and fractionated radiation therapy.