Influence of clamping-induced ischemia and reperfusion on the response of a mouse melanoma to radiation and hyperthermia

Purpose: To study the response of a mouse melanoma to radiation and hyperthermia under acute hypoxia and reperfusion. Materials and methods: B16F1 melanoma of 100 ± 10mm³, in C57BL mouse, were locally exposed to 10 Gy gamma radiation (RT), 43°C for 30 min (HT) in a water bath, or RT followed immediately by HT, under clamping (acute hypoxia) or 1 h after reperfusion. Tumour regression, volume doubling time (VDT), growth delay (GD), apoptosis and microvascular density (MVD) were studied. Results: Under clamping, HT increased the VDT and GD to > 20 days above control and resulted in > 50% regression (PR) in all the tumours, whilst RT + HT synergistically enhanced VDT and GD. Under reperfusion, HT produced 25% PR against 16% by RT, with no increase in VDT and GD compared to RT. RT + HT significantly enhanced VDT and GD above that of RT or HT, but did not further increase PR of reperfused tumours. HT under clamping caused > 50% increase in apoptic cells over control and decreased MVD to 1/3rd of control. RT + HT further enhanced apoptotic cells to > 70% and reduced MVD to 1/6th of control. Conclusions: These results suggest that combination of radiotherapy with hyperthermia could benefit treatment of tumours with ischemia-induced acute hypoxia.     

The Dutch Deep Hyperthermia Trial: results in cervical cancer.

BACKGROUND: Radiotherapy plus hyperthermia was compared to radiotherapy alone in the Dutch Deep Hyperthermia Trial, in patients with advanced bladder, cervical, and rectal tumours. The overall results, published elsewhere, demonstrate that addition of hyperthermia to radiotherapy improves both pelvic control and overall survival rates. The therapeutic gain appeared especially worthwhile in locally advanced cervical tumours. Here, the results in patients with cervical cancer are summarized and discussed, and further details provided. METHODS: From 1990-1996, 114 patients with cervical cancer were entered into this prospective randomized trial. RT was applied to a median total dose of 68 Gy. HT was given once weekly. The median follow-up time was 43 months. All randomized patients were included in the statistical analysis, which was done by intention to treat. The primary end points of the trial were complete response (CR) and duration of pelvic control (PC), secondary end points were overall survival (OS) and toxicity. Besides, an economic evaluation was performed. RESULTS: CR rates were 57% following RT and 83% following RT + HT(p = 0.003). The difference in PC was maintained during follow-up, with 3-year LC rates of 41% following RT and 61% following RT + HT. The 3-year OS rates were 27% and 51% following RT and RT + HT, respectively (p = 0.009). When the patients were divided into two subgroups by whether or not the planned RT was completed, a beneficial effect of hyperthermia was observed in both subgroups. Radiation toxicity was not enhanced by HT. Additional hyperthermia proved to be cost-effective, with maximum discounted cost-per-life-year gained of about Euro 4000. CONCLUSION: Hyperthermia in addition to standard radiotherapy of locally advanced cervical tumours results in therapeutic gain and is cost-effective.     

Cervical cancer: radiotherapy and hyperthermia.

BACKGROUND: For many years, the standard treatment of advanced cervical cancer has been radiotherapy (RT), including brachytherapy. The achievement of locoregional tumour control is essential for cure. Results of RT in early stages are reasonably satisfactory, but locoregional failure rates for stage IIIb and IVa are high. In several randomized trials, the addition of hyperthermia (HT) to RT has been investigated. RANDOMIZED TRIALS: The Dutch Deep Hyperthermia Trial was completed in 1996. In this trial a beneficial effect of additional hyperthermia was clearly demonstrated. Three-year locoregional control and overall survival rates were significantly higher in the RT + HT group than in the RT alone group, while radiation toxicity was not affected. Cost-per-life-year-gained was less than 4,000 Euros. The results of this trial have led to the acceptance of RT plus HT as standard treatment for advanced cervical cancer in the Netherlands. Five trials conducted in Asia have been published, of which three showed significant better complete response, locoregional tumour control and/or disease-free survival rates. One trial showed a trend of better locoregional tumour control and one did not show any benefit. CONCLUSION: Hyperthermia added to standard radiotherapy of locally advanced cervical tumours results in considerable therapeutic gain and is cost-effective. For a beneficial effect, the use of an adequate heating technique is an important requirement.     

Enhanced effects of aminolaevulinic acid-based photodynamic therapy through local hyperthermia in rat tumours

The possibility of enhancing aminolaevulinic acid (ALA)-based photodynamic therapy (PDT) by simultaneous application of localised hyperthermia (HT) was evaluated. Treatments of rat DS-sarcomas included: (i) control, (ii) ALA administration (375 mg kg(-1), i.p.), no illumination, (iii) 'nonthermal' illumination, (iv) ALA-PDT: that is, ALA administration, 'nonthermal' illumination, (v) localised HT, 43 degrees C, 60 min (vi) ALA-PDT+HT: ALA administration with full spectrum irradiation resulting in ALA-PDT and HT. Tumour volume was monitored for 90 days or until a target volume (3.5 ml) was reached. No differences were seen between the first three groups, with all tumours reaching the target volume by 8-11 days. A total of 13 and 15% of tumours did not reach the target volume by day 90 following HT or ALA-PDT treatment, respectively. ALA-PDT+HT showed the greatest antitumour effect (P=0.0001), with 61% of the tumours not reaching the target volume. Viability and in vitro growth were also assessed in cells from tumours excised after treatment. ALA-PDT+HT reduced the fraction of viable tumour cells by 85%, and in vitro culture showed pronounced growth delay compared to control cells. These results demonstrate an enhanced antitumour effect upon ALA+HT, which appears to involve direct cell toxicity rather than solely vascular damage.     

Long-term improvement in treatment outcome after radiotherapy and hyperthermia in locoregionally advanced cervix cancer: an update of the Dutch Deep Hyperthermia Trial

PURPOSE: The local failure rate in patients with locoregionally advanced cervical cancer is 41-72% after radiotherapy (RT) alone, whereas local control is a prerequisite for cure. The Dutch Deep Hyperthermia Trial showed that combining RT with hyperthermia (HT) improved 3-year local control rates of 41-61%, as we reported earlier. In this study, we evaluate long-term results of the Dutch Deep Hyperthermia Trial after 12 years of follow-up. METHODS AND MATERIALS: From 1990 to 1996, a total of 114 women with locoregionally advanced cervical carcinoma were randomly assigned to RT or RT+HT. The RT was applied to a median total dose of 68 Gy. The HT was given once weekly. The primary end point was local control. Secondary end points were overall survival and late toxicity. RESULTS: At the 12-year follow-up, local control remained better in the RT+HT group (37% vs. 56%; p=0.01). Survival was persistently better after 12 years: 20% (RT) and 37% (RT+HT; p=0.03). World Health Organization (WHO) performance status was a significant prognostic factor for local control. The WHO performance status, International Federation of Gynaecology and Obstetrics (FIGO) stage, and tumor diameter were significant for survival. The benefit of HT remained significant after correction for these factors. European Organization for Research and Treatment of Cancer Grade 3 or higher radiation-induced late toxicities were similar in both groups. CONCLUSIONS: For locoregionally advanced cervical cancer, the addition of HT to RT resulted in long-term major improvement in local control and survival without increasing late toxicity. This combined treatment should be considered for patients who are unfit to receive chemotherapy. For other patients, the optimal treatment strategy is the subject of ongoing research.     

N3 (TNM-UICC) metastatic neck nodes managed by combined radiation therapy and hyperthermia: clinical results and analysis of treatment parameters

In an attempt to improve the control of N3 (TNM-UICC) fixed and inoperable metastatic nodes, local microwave hyperthermia (HT) was combined with radiation therapy (RT). From February 1981 to January 1985, 34 patients, with N3 metastatic nodes from primary tumours in the head and neck, were treated according to two different prospective, non-randomized protocols: 23 patients received HT combined with the first course of conventionally fractionated radical RT (40 Gy + HT--2 week interval--20-30 Gy), and 11 patients received HT combined with palliative RT (20-50 Gy + HT). All the patients were treated with the same microwave applicator (MA-150) on the BSD-1000 unit, at a frequency of 280-300 MHz. Temperatures were measured by means of 2-3 Bowman probes placed within the tumour (core and periphery) and 5-6 probes on the skin surface. HT sessions were delivered after RT (less than 20 min), 2 or 3 times weekly, for a duration of 30 min after steady-state temperatures were obtained. Twenty-seven patients out of 34 were evaluable, with a follow-up of at least 3 months (range 3-39 months; median 10 months). Clinical results at 3 months revealed 59 per cent complete responses, 30 per cent partial responses, and 11 per cent with progressive disease. Analyses of response rates showed: a marginally significant difference (P = 0.095) between RT alone (historical control) and the entire group of patients treated with RT plus HT; a significant difference (P = 0.034) if RT alone is compared with Protocol A (RT greater than or equal to 60 Gy + HT); no significant difference between the two protocols employing HT, despite the different RT doses utilized; no significant differences in response rates, as a function of minimal intratumoural temperatures achieved, number of weekly HT sessions or total number of HT sessions; and a significantly lower response rate for nodes with maximum diameter greater than 6 cm (P = 0.043). No important differences in acute side effects between irradiated and heated regions in the same patient were noted. Late side effects in patients treated with RT plus HT included three cases (9 per cent) of severe fibrosis, possibly as a consequence of excessive maximum tumour temperature (greater than 46 degrees C).     

Regional hyperthermia for advanced tumors: a clinical study of 353 patients

A Phase I study using deep regional hyperthermia (HT) with an annular phased array was conducted in 14 U.S. medical centers from 1980 through 1986. There were 353 patients whose average age was 57 years. All patients had advanced recurrent or persistent tumors. Prior frequently complex, multimodality anti-cancer therapy was received by 71% of the patients. Gastrointestinal adenocarcinoma was present in 146 (41%) patients, genitourinary tumors in 86 (24%), soft tissue sarcomas in 46 (13%), malignant melanoma in 21 (6%) and 15% had other tumors. The sites treated included: pelvis 55%, abdomen 21%, liver 14%, thorax 6%, and other sites 3%. All patients received deep regional HT with an average frequency of 55 MHz. A total of 1412 HT treatments was administered to these 353 patients with an aim to increase the temperature in the volume of interest to greater than 42 degrees C for greater than or equal to 30 minutes. Thermal dose (TD in equivalent minutes at 42.5 degrees C) was less than 50 in 104 (29%), greater than or equal to 50 less than 100 in 30 (11%), greater than or equal to 100 in 26 (7%), and greater than 200 in 34 (10%). The remaining 150 (42%) patients had TD = 0. In addition to HT, 260 (74%) received radiotherapy (RT). RT was given at 180 or 200 cGy daily with an average total dose of 33.4 Gy. A total of 42 (12%) patients were given chemotherapy (CT) with HT, and 15 (4%) CT + HT + RT/HT alone was given to 47 (13%) patients. Complete response (CR) was obtained in 35 (10%) and partial response (PR) in 59 (17%) patients. CR was 12% in patients who received RT, vs 2% in those who did not receive it, p = 0.003. Radiation dose was an important factor influencing response, p less than 0.001. Thermal dose was not an important parameter influencing tumor response. A duration of CR ranged from 4 to 73 weeks with an average duration of 31 weeks and the median duration of 28 weeks. The overall 2-year survival was 13% with the median survival of 42 weeks. Patients with CR and PR had a 2 year survival of 41%, and a median survival of 71 weeks. This compared with 8% 2-year survival and 24 weeks median survival in patients who did not have CR or PR, p less than 0.001. Of the patients presenting with significant pain, 62% had complete or partial pain relief.(ABSTRACT TRUNCATED AT 400 WORDS)     

Cervical cancer: Radiotherapy and hyperthermia

Background: For many years, the standard treatment of advanced cervical cancer has been radiotherapy (RT), including brachytherapy. The achievement of locoregional tumour control is essential for cure. Results of RT in early stages are reasonably satisfactory, but locoregional failure rates for stage IIIb and IVa are high. In several randomized trials, the addition of hyperthermia (HT) to RT has been investigated.

Randomized trials: The Dutch Deep Hyperthermia Trial was completed in 1996. In this trial a beneficial effect of additional hyperthermia was clearly demonstrated. Three-year locoregional control and overall survival rates were significantly higher in the RT?+?HT group than in the RT alone group, while radiation toxicity was not affected. Cost-per-life-year-gained was less than 4000 Euros. The results of this trial have led to the acceptance of RT plus HT as standard treatment for advanced cervical cancer in the Netherlands.

?Five trials conducted in Asia have been published, of which three showed significant better complete response, locoregional tumour control and/or disease-free survival rates. One trial showed a trend of better locoregional tumour control and one did not show any benefit.

Conclusion: Hyperthermia added to standard radiotherapy of locally advanced cervical tumours results in considerable therapeutic gain and is cost-effective. For a beneficial effect, the use of an adequate heating technique is an important requirement.     

A phase II trial testing the thermal dose parameter CEM43 degrees T90 as a predictor of response in soft tissue sarcomas treated with pre-operative thermoradiotherapy.

We prospectively evaluated whether delivering a thermal dose of > 10 cumulative equivalent minutes at 43 degrees C to >90% of the tumour sites monitored (CEM43 degrees T90) would produce a pathologic complete response (pCR) in > 75% of high-grade soft tissue sarcomas treated pre-operatively with thermoradiotherapy. The impact of thermal dose on local failure (LF), distant metastasis (DM), and toxicity was also assessed. Thirty-five patients > or = 18 years old with grade 2 or 3 soft tissue sarcomas accessible for invasive thermometry were enrolled on the protocol. All patients received megavoltage external beam radiotherapy (RT) in daily fractions of 1.8-2.0 Gy, five times a week, to a median total dose of 50 Gy and an initial hyperthermia treatment (HT) of I h duration utilizing the BSD 2000 with Sigma 60 or MAPA applicators at frequencies of 60-140 MHz. Further HT was given for patients with CEM43 degrees T90 > 0.5 after initial HT ('heatable' patients), twice a week to a maximum of 10 HT or CEM43 degrees T90 > 100. Of the 35 patients entered, 30 had heatable tumours, one of which was inevaluable for pCR or LF as the patient died of DM prior to surgery, leaving 29 evaluable patients. Of these 29 patients, 15 (52%) had a pCR (95% CI: 37-73%), significantly less than the projected rate of > or = 75% (p = 0.02). Of the 25 heatable tumours that achieved CEM43 degrees T90 > or = 10, 14 (56%) had a pCR (95% CI: 39-78%) significantly less than the projected rate (p = 0.06). Three of the 29 patients (10%) with heatable tumours had a LF, versus 1/5 unheatable tumours (p = 0.48). Fourteen of the 30 patients (47%) with heatable tumours developed DM, versus 2/5 unheatable tumours (p = 1.00). Ten of the 30 patients (33%) with heatable tumours developed treatment-induced toxicity. Thus, no correlation of thermal dose with histologic response was observed. Prospective control of CEM43 degrees T90 failed to achieve the projected pCR rate following pre-operative thermoradiotherapy for high-grade soft tissue sarcomas, despite excellent local control. Possible explanations for this outcome are discussed.     

Deep regional hyperthermia of the liver. A clinical study of 49 patients

From 1981 to 1986, six medical centers participated in feasibility studies of radiofrequency deep regional hyperthermia (HT) in the treatment of hepatic metastases. A total of 49 patients, 32 men and 17 women, were treated with an annular phased array. Colon was the primary site in 74% of the patients, and adenocarcinoma was the diagnosis in 80%. More than one half of the patients had been treated previously. This included chemotherapy (CT) in 17 patients and radiotherapy (RT) in 10 patients, with a mean RT dose of 24 Gy. Upper abdominal pain was the dominant presenting symptom in 53% of patients. In the study, treatment was administered as follows: 14 (28%) patients received HT alone, 17 (35%) received HT + RT, 14 (28%) received HT + CT, and 4 (8%) received HT + RT + CT. A total of 157 HT treatments was administered at a mean frequency of 55 MHz and a mean power of 780 watts. The number of HT sessions ranged from 1 to 8, with a mean of 3.2 treatments per patient. Temperature was monitored continuously throughout each treatment session. The treatment aim was to reach and maintain a temperature of 42.5 degrees C for 30 min. In practice, owing to the difficulty in reaching this temperature, an equivalent (lower) temperature from 40 to 42 degrees C was used, extending the duration of treatment sessions to 45-60 min. Thermal dose was defined as the number of minutes at 42.5 degrees C or its equivalent. In 21 (43%) patients, a temperature less than 40 degrees C was obtained and thermal dose = 0. Thermal dose was less than or equal to 50 in 17 (35%) patients, greater than 50 less than or equal to 100 in 7 (14%), and greater than 100 in 4 (8%). RT was given at a daily dose of 1.8 Gy to a total of less than 20 Gy in 14 patients, greater than 20 less than or equal to 30 Gy in 6, and greater than 30 Gy in 1. CT consisted of 5-Fluorouracil by way of Hepatic Artery Infusion (HAI) in 9 patients, i.v. cisplatin in 5, and doxorubicin HAI in 3. Objective tumor regression (CR + PR) was seen in 6 (12%) patients. An additional 10 (20%) patients had less than 50% greater than 25% tumor regression, and 10 (20%) had complete or partial pain relief. The median duration of CR and PR was 26 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)     

Interstitial microwave hyperthermia combined with iridium-192 radiotherapy for recurrent tumors

From 1985 through 1987, 44 tumors in 39 patients with recurrent cancer were treated with interstitial microwave hyperthermia (HT) combined with interstitial 192Ir radiotherapy (RT). All patients had unresectable and previously treated tumors (mean RT dose 57.6 Gy). Diagnoses were squamous cell carcinoma in 27 (62%), adenocarcinoma in 11 (25%), melanoma in 5 (11%), and soft tissue sarcoma in 1 (2%) site. Interstitial RT dose was from 25 to 50 Gy (mean 38.3 Gy). The first HT session was scheduled immediately before the loading of 192Ir, and the second was scheduled following its removal. Each session lasted 45-60 min at therapeutic temperature (42.5 degrees C). Complete response (CR) was obtained in 28 (64%) sites and partial response (PR) in 15 (34%) sites. None of the CR patients had local recurrence. Tumor volume was the most important factor influencing CR (p less than 0.001). The treated site, radiation dose, and thermal dose were not significant factors for CR (p = 0.03). The overall median survival was 39 weeks, with a 2-year survival of 22%. The treatment was well tolerated, with two patients developing focal skin necrosis.     

Efficacy of irradiation and external hyperthermia in locally advanced, hormone-refractory or radiation recurrent prostate cancer: a preliminary report

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.     

Water-filtered infrared-A radiation: a novel technique for localized hyperthermia in combination with bacteriochlorophyll-based photodynamic therapy.

A novel application of an infrared-A (IR-A) radiation source equipped with a water-filter in the radiation path is described, which allows for tumour treatment with a simultaneous combination of localized hyperthermia (HT) and bacteriochlorophyll-serine (Bchl-ser) based photodynamic therapy (PDT). Using this system, the IR-A radiation was used to heat tumours to 43 degrees C for 60 min, while at the same time activating the Bchl-ser which was injected i.v. at a dose of 20 mg/kg, 10 min following commencement of HT. The growth of tumours undergoing this combined therapy was compared to that of tumours undergoing HT alone or sham-treated controls. Within the 90 day observation period, 100% of tumours in sham-treated animals, 80% in HT-treated animals and only 17% in HT + Bchlser-treated animals reached the end point target volume of 3.5 ml. Thus, the tumour growth inhibition effect of HT can be substantially enhanced by combination with Bchl-ser-PDT. This novel technique has proved to be well-tolerated, easy to apply and should be suitable for treatment of superficial malignancies, especially where hypoxic tumour areas are present.     

Hyperthermia as an adjuvant to radiation therapy of recurrent or metastatic malignant melanoma. A multicentre randomized trial by the European Society for Hyperthermic Oncology

The ESHO protocol 3-85 is a multicentre randomized trial investigating the value of hyperthermia as an adjuvant to radiotherapy in treatment of malignant melanoma. A total of 134 metastatic of recurrent malignant melanoma lesions in 70 patients were randomized to receive radiotherapy alone (3 fractions in 8 days) or each fraction followed by hyperthermia (aimed for 43°C for 60 min). Radiation was given with high voltage photons or electrons. Tumours were stratified according to institution and size (above or below 4 cm) and randomly assigned to a total radiation dose of either 24 or 27 Gy to be given with or without hyperthermia. The endpoint was persistent complete response in the treated area. A number of 128 tumours in 68 patients were evaluable, with an observation time between 3 and 72 months. Sixty-five tumours were randomized to radiation alone and 63 to radiation + heat. Sixty received 24 Gy and 68 tumours received 27 Gy, respectively. Size was ≤4 cm in 81 and >4 cm in 47 tumours. Overall the 2-year actuarial local tumour control was 37%. Univariate analysis showed prognostic influence of hyperthermia (rad alone 28% vs. rad + heat 46%, p = 0.008) and radiation dose (24 Gy 25% vs. 27 Gy 56%, p = 0.02), but not of tumour size (small 42% vs. large 29%, p = 0.21). A Cox multivariate regression analysis showed the most important prognostic parameters to be: hyperthermia (odds ratio: 1.73 (1.07-2.78), p = 0.02), tumour size (odds ratio: 0.91 (0.85-0.99), p = 0.05) and radiation dose (odds ratio: 1.17 (1.01—1.36), p = 0.05). Analysis of the heating quality showed a significant relationship between the extent of heating and local tumour response. Addition of heat did not significantly increase the acute or late radiation reactions. The overall 5-year survival rate of the patients was 19%, but 38% in patients if all known disease was controlled, compared to 8% in the patients with persistent active disease.     

Interstitial thermoradiotherapy for recurrent or persistent tumours

Between 1984 and 1986, 31 sites in 27 patients with biopsy proven tumours were treated with a combination of interstitial microwave hyperthermia (HT) and iridium 192 implants (RT). The 31 sites treated included fifteen (48 per cent) head and neck, six (20 per cent) breast, four (13 per cent) vagina and cervix, and six (20 per cent) others. All patients had prior surgery, RT, or chemotherapy. Of the 31 sites treated, 19 (61 per cent) had complete response (CR) with no recurrence in the volume treated. Additionally, eight patients remained free of tumour from 3 to 24 months. Partial response (PR) was seen in 11 (36 per cent) sites while one (3 per cent) had lesser degree tumour regression. Tumour control rate correlated well with the dose of radiation, p = 0.02, and tumour volume, p = 0.02, but not with thermal dose. Treatment complications of significance occurred in one (3 per cent) site, which developed soft tissue necrosis. This study again has demonstrated the effectiveness of RT-HT combination in treatment of recurrent tumours.     

Efficacy of doxorubicin thermosensitive liposomes (40 degrees C) and local hyperthermia on rat rhabdomyosarcoma

The efficacy of novel thermosensitive liposomes (40 degrees C) containing doxorubicin (Dox-Lip) together with local hyperthermia (HT) was studied on solid growing rat rhabdomyosarcomas. Tumor response and systemic toxicity were evaluated by comparing to free doxorubicin (Free Dox) with or without hyperthermia. Tumors were heated with infrared-A-radiation and drugs were infused intravenously after preheating the tumors followed by a further 60 min of heating at 42.5 degrees C. Recorded temperatures at various locations in the tumors indicated that all intratumoral temperatures, especially at the back rim, were definitely >40 degrees C. After single doses, tumor growth was further inhibited by Dox-Lip+HT compared to Free Dox+HT or Free Dox alone. Repeated treatments with Dox-Lip+HT (2x2.5 mg/kg+HT/2 weeks) resulted in a statistically significant tumor growth delay and was associated with a much lower systemic toxicity. Uptake studies of drugs in blood, tumor and normal tissues showed that Dox-liposomes (40 degrees C) are long circulating liposomes in the blood. However, the enhanced tumor response did not correlate with an increased uptake of Dox-Lip+HT in the tumor. The findings suggest that repeated applications of thermosensitive liposomal doxorubicin (40 degrees C) and local hyperthermia can control primary rat rhabdomyosarcomas while reducing the systemic toxicity of free doxorubicin.     

Local hyperthermia, radiation, and chemotherapy in recurrent breast cancer is feasible and effective except for inflammatory disease

Purpose: To investigate the feasibility and effectiveness of radiochemothermotherapy (triple-modality therapy) in patients with inoperable recurrent breast cancer.

Patients and Methods: Patients with inoperable recurrent lesions, World Health Organization (WHO) performance status of 2 or greater, life expectancy of more than 3 months, adequate bone marrow, hepatic and renal function were eligible for this Phase I/II study. Conventionally fractionated or hyperfractionated radiotherapy (RT) was performed. Once-weekly local hyperthermia (HT) combined with chemotherapy (CT; epirubicin 20 mg/m², ifosfamide 1.5 g/m²) was applied within 30 min after RT.

Results: Twenty-five patients, all heavily pretreated (18/25 preirradiated), received a mean total dose of 49 Gy. The median number of HT/CT sessions was 4. Skin toxicity was low, whereas bone marrow toxicity was significant (leucopenia Grade 3/4 in 14/1 patients). The overall response rate was 80% with a complete response (CR) rate of 44%. Response rates in patients with noninflammatory disease (n = 14; CR 10 patients, partial response [PR] 3 patients) were far better than in patients with inflammatory disease (n = 11; CR 1 patient, PR 6 patients).

Conclusions: In patients with recurrent breast cancer, triple-modality therapy is feasible with acceptable toxicity. High remission rates can be achieved in noninflammatory disease, however, local control is limited to a few months. Whether the addition of chemotherapy has a clear-cut advantage to radiothermotherapy alone remains an open question.     

p53 is involved in the inhibition of cell proliferation mediated by activin A in cultured human prostate cancer LNCaP cells

Large tumor size is a negative prognostic variable for attaining complete regression (CR) with local hyperthermia (HT) and radiotherapy (RT). Such poor prognosis lesions (i.e., >7 cm(2) or >14 cm(3)) have an expected CR rate of similar to 30+/-8%. To improve on this result we added cisplatin to HT and RT with standard fractionation (std Fx) in an earlier study, and observed a 19% CR rate in head and neck (H&N) patients. We now report the results of a second generation trial combining HT, cisplatin (40 mg/m(2)) and hyperfractionated RT in a series of 13 pretreated poor prognosis H&N patients. Therapy encompassed 44 triple modality sessions and was well tolerated: toxicity included one episode of grade-3 skin reaction and one grade 1 leukopenia. Although the overall remission rate was 92%, the CR rate was only 8%; this resulted in early closure of this trial concluding that hyperfractionated RT had no (over std Fx RT) benefit in this combined modality approach.     

Effect of hyperthermia combined with external radiation therapy in primary non-small cell lung cancer with direct bony invasion

Purpose : Local control in lung cancer directly invading the bone is extremely poor. Effects of regional hyperthermia combined with conventional external beam radiation therapy were evaluated. Materials and methods : Thirteen patients with non-small lung cancer (NSCLC) with direct bony invasion were treated with hyperthermia plus irradiation (hyperthermia group). The treatment outcome was compared with the historical treatment results in 13 patients treated with external radiation therapy alone (radiation alone group). In patients with no distant metastasis, radiation therapy at a total dose of 60-70Gy was administered to both groups. Hyperthermia was performed for 45-60min immediately after irradiation for two-four sessions with radiofrequency capacitive heating devices. Results : For primary response, 10 of the 13 tumours responded to the treatment (3 CR, 7 PR) in the hyperthermia group, whereas seven tumours responded (1 CR, 6 PR) in the radiation alone group. The 2-year local recurrence-free survival rate for clinical M 0 patients in the hyperthermia group and that in the radiation alone group were 76.1 and 16.9%, respectively. Three patients died of distant metastases within 2 years in the hyperthermia group, but two out of three tumours histologically disappeared, even in the autopsy examination. The 2-year overall survival rate for clinical M 0 patients in the hyperthermia group and that in the radiation alone group were 44.4 and 15.4%, respectively. No severe pulmonary complication was observed in either group. Conclusions : Regional hyperthermia combined with conventional irradiation could be a tool to improve local control in patients with NSCLC deeply invading the chest wall.