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+/-10 mm3, in C57BL mouse, were locally exposed to 10Gy gamma radiation (RT), 43 degrees 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.     

A phase II trial testing the thermal dose parameter CEM43° 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°C to > 90% of the tumour sites monitored (CEM43°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 ≥ 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 1 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°T₉₀ > 0.5 after initial HT (`heatable' patients), twice a week to a maximum of 10 HT or CEM43°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 ≥ 75% (p, = 0.02). Of the 25 heatable tumours that achieved CEM43°T,₉₀ ≥ 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°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.     

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.     

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.     

Hyperthermia and radiotherapy with or without chemotherapy in locally advanced cervical cancer: a systematic review with conventional and network meta-analyses

Purpose: A systematic review with conventional and network meta-analyses (NMA) was conducted to examine the outcomes of loco-regional hyperthermia (HT) with radiotherapy (RT) and/or chemotherapy (CT) in locally advanced cervix cancer, IIB–IVA (LACC).

Methods and materials: A total of 217 abstracts were screened from five databases and reported as per PRISMA guidelines. Only randomised trials with HT and RT?±?CT were considered. The outcomes evaluated were complete response (CR), long-term loco-regional control (LRC), patients alive, acute and late grade III/IV toxicities.

Results: Eight articles were finally retained. Six randomised trials with HTRT (n?=?215) vs. RT (n?=?212) were subjected to meta-analysis. The risk difference for achieving CR and LRC was greater by 22% (p?p?p?=?.001). No other end points were reported. Bayesian NMA, incorporating 13 studies (n?=?1000 patients) for CR and 12 studies for patients alive (n?=?807 patients), comparing HTCTRT, HTRT, CTRT and RT alone, was conducted. The pairwise comparison of various groups showed that HTRTCT was the best option for both CR and patient survival. This was also evident on ranking treatment modalities based on the “surface under cumulative ranking” values.

Conclusions: In LACC, HTRT demonstrates a therapeutic advantage over RT without significant acute or late morbidities. On NMA, HTCTRT appears promising, but needs further confirmation through prospective randomised trials.     

Intracavity hyperthermia in nasopharyngeal cancer: A phase III clinical study

Purpose: To compare the local tumour control, survival, and acute mucous toxicity of nasopharyngeal cancer (NPC) patients treated with conventional radiotherapy (RT) combined with intracavity hyperthermia versus conventional RT alone.

Methods and materials: Previously untreated NPC patients were assigned randomly into the conventional RT group and the hyperthermia group. In addition to curative RT, hyperthermia group patients received intracavity hyperthermia before or after RT; T90 was 42.5°–43°C for 50 min twice a week for 7 weeks.

Results: From August 2001 to July 2006, 180 eligible patients with NPC were enrolled in this study. The complete response (CR) rate in the two arms (RT plus hyperthermia versus conventional RT) was 95.6% and 81.1%, respectively (p = 0.003, χ² test). CR rates for T2 and T3 patients in the hyperthermia group were 97.1% and 96.9%, respectively, while in the conventional RT group they were 79.5% and 76.7%, respectively. The difference between the two groups was statistically significant (p = 0.03 and p = 0.024, respectively). The 5-year local control rate was 91.1% and 78.9% for the two arms, respectively (p = 0.022). Oral mucous toxicity in both arms was comparable. The 5-year PFS and 5-year OS rate for the hyperthermia arm vs. the conventional arm were 72.7% versus 63.1% (p = 0.039) and 78.2% versus 70.3% (p = 0.14), respectively.

Conclusions: Conventional RT treatment followed by intracavity hyperthermia was well tolerated by the NPC patients. The addition of hyperthermia improved the local tumour control, and our results indicated a positive impact on PFS of NPC patients.     

Simultaneous superficial hyperthermia and external radiotherapy: report of thermal dosimetry and tolerance to treatment

Background : In vitro and animal studies indicate that a moderate temperature of 41°C maintained for ～ 1h will provide radiosensitization if radiation (RT) and hyperthermia (HT) are delivered simultaneously, but not with sequential treatment. A minimum tumour temperature of 41°C is a more feasible goal than the goal of >42°C needed for sequential treatment. Methods and materials: Forty-four patients with 47 recurrent superficial cancers received simultaneous external beam radiotherapy and superficial hyperthermia on successive IRB approved phase I/II studies. All lesions had failed previous therapy, 35 were previously irradiated (mean dose 52.7Gy). Hyperthermia was delivered with 915MHz microwave or 1-3.5MHz ultrasound using commercially available applicators. The average dimensions of 19 lesions treated with microwave were 4.7 3.6 1.7cm and the average dimensions of 28 lesions treated with ultrasound were 8.0 6.1 2.9cm. The most common sites were chest wall (15 cases) and head and neck (21 cases). Temperatures were monitored at an average of six intratumoral locations using multisensor probes. The median number of hyperthermia treatments was three and the median radiation dose 30Gy. Radiation dose per fraction was 4Gy with hyperthermia and 2Gy or 4Gy (depending on protocol) on non-hyperthermia days. Results: Six different measures of minimum monitored temperature and duration were found to be highly correlated with each other. There was nearly a one-to-one correspondence between minimum tumour time at or above 41°C (Min t41) and minimum tumour Sapareto Dewey equivalent time at 42°C (Min teq42). After four sessions 63% of cases had a per session average Sapareto Dewey equivalent time at 41°C which exceeded 60min in all monitored tumour locations. The complete and partial response rate in evaluable lesions were respectively 21/41 (51% ) and 7/41 (17% ) and were best correlated with site (chest wall showing best response). Toxicity consisted of 10/47 (21% ) slow healing soft tissue ulcers which healed in all cases but required a median of 7 months. The most important predictors for chronic ulceration were cumulative radiation dose >80Gy and complete response to treatment. Conclusions: Minimum tumour temperatures maintained for durations compatible in vitro with thermal radiosensitization (if RT and HT are delivered simultaneously) are clinically feasible and tolerable for broad but superficial lesions amenable to externally applied ultrasound or microwave hyperthermia. The current in-house protocol is evaluating the impact of more than four hyperthermia sessions on the overall thermal dose distribution and toxicity.     

Is hyperthermia combined with radiotherapy adequate in elderly patients with muscle-invasive bladder cancers? Thermo-radiobiological implications from an audit of initial results

Abstract

Purpose: The aim of this study was to evaluate the outcomes of loco-regional hyperthermia (HT) with radiotherapy (RT) and/or chemotherapy (CT) in elderly patients with muscle-invasive bladder cancers (MIBC). Material and methods: Twenty consecutive MIBC patients were treated with HTRT (n?=?8) or HTCTRT (n?=?12) following transurethral resection of their bladder tumours. Weekly HT was administered prior to RT to a mean temperature of 40.6–42.7?°C for 60?min. A mean RT dose of 54.6?Gy (SD?±?4.2) was delivered. Single-agent cisplatin (n?=?2) or carboplatin (n?=?10) was used in HTCTRT patients. Results: The median age was 81 years. HTRT patients received a mean RT dose of 51.0?Gy compared to 57.1?Gy with HTCTRT (p?<?0.001) in a shorter overall treatment time (OTT) (30.8?±?6.9 versus 43.9?±?4.0 days, p?<?0.001). All HTRT patients had long-term local disease control, while 41.6% of HTCTRT recurred during follow-up. None of the HTRT patients experienced grade III/IV acute and late toxicities, while these were evident in two and one HTCTRT patients respectively. Taken together, the 3-year bladder preservation, local disease-free survival, cause-specific survival and overall survival were 86.6%, 60.7%, 55% and 39.5% respectively. Even though the mean biological effective dose (BED) for both groups was similar (57.8?Gy₁₅), the thermo-radiobiological BED estimated from HT-induced reduction of α/β was significantly higher for HTRT patients (91?±?4.4 versus 85.8?±?4.3?Gy₃, p?=?0.018). Conclusions: Thermal radiosensitisation with consequent reduction in α/β results in a higher thermo-radiobiological BED with a relatively higher RT dose/fraction and shorter OTT. This translates into a favourable outcome in elderly MIBC patients. Any benefit of CT in these patients needs further investigation.     

Heme oxygenase-1 (Hsp32) is involved in the protection of small intestine by whole body mild hyperthermia from ischemia/reperfusion injury in rat

Aim: The aim of the present study was to explore whether heme oxygenase-1 (HO-1) is involved in the hyperthermia-provided protection of the small intestine from ischemia/reperfusion injury in rats.

Methods: Intestinal damage was induced in male Sprague-Dawley rats by clamping both the superior mesenteric artery and the celiac trunk for 30?min, followed by reperfusion. Whole-body hyperthermia was induced in anesthetized rats by placement in a temperature-controlled water bath. Whole-body hyperthermia to a core temperature of 42–43°C for 15?min was followed by passive cooling. We started the hyperthermic treatment 6?h before the vascular clamping. The severity of the mucosal injury was evaluated by several biochemical markers and histological findings. Hyperthermia-induced heat-shock proteins were detected by Western blotting. We also investigated the effect of zinc protoporphyrin IX (an HO-1 inhibitor) on the protective effect of hyperthermia.

Results: The rats, which were killed after ischemia/reperfusion, had severe intestinal inflammation. Hyperthermia significantly induced the production of Hsp70 and HO-1 in intestinal mucosa and significantly reduced ischemia/reperfusion-induced mucosal injury. The combination of zinc protoporphyrin IX with hyperthermia extinguished the protective effects of hyperthermia on ischemia/reperfusion injury.

Conclusion: Hyperthermia protects against ischemia/reperfusion injury in rat small intestine through the expression of heat-shock proteins, especially HO-1.     

Development of a novel method to enhance the therapeutic effect on tumours by simultaneous action of radiation and heating

Abstract

Purpose: This paper describes the development of a new type of electromagnetic hyperthermia applicator delivering dose control within large application fields and increased effectiveness by providing simultaneous action of radiation and heating (SRH) in malignant tumours, and development of a dosimetric feedback method to support SRH. Materials and methods: Single and phased arrays of flexible applicators have been developed to allow simultaneous hyperthermia and external beam therapy. A frequency of 434?MHz is used to heat near-surface and moderately deep-seated tumours and 70?MHz for deep-seated tumours. Phase and amplitude control allows focusing of electromagnetic energy (EM) to deep-seated tumours. The specific absorption rate (SAR) dose distribution can be modified to achieve uniform heating of tumours with complex shapes and heterogeneous tissue properties. A lithium fluoride thermoluminescent dosimeter (TLD) in a flexible film cassette has been developed for real-time dose measurement. Results: Four types of 434?MHz applicators were manufactured with 3, 4, 9 or 12 independent applicators. Two types of 70?MHz applicators were made with 4 or 6 independent applicators. Phantom tests demonstrated the ability to control the SAR pattern by phase and amplitude control. Placement of the dosimeter between bolus and phantom increased the phantom surface temperature up to 3?°C and showed that the ratio of absorbed energy in TLD to dose in water approaches (0.83?±?3%) for photon energies >60?keV. Conclusions: Simultaneous and controlled radiation and local hyperthermia is technically feasible in a preclinical setting, a clinical feasibility test is the next step.     

Definitive radiotherapy plus regional hyperthermia for high-risk and very high-risk prostate carcinoma: Thermal parameters correlated with biochemical relapse-free survival

Abstract

Purpose: The aim of this study was to assess the efficacy of definitive radiotherapy (RT) plus regional hyperthermia (HT) and investigate the potential contribution of HT to clinical outcomes in patients with prostate carcinoma. Materials and methods: Following our institution’s treatment protocol, HT was combined with RT to improve clinical outcomes in selected patients with high-risk or very high-risk prostate cancer. Data from 82 patients treated with RT plus HT and 64 patients treated with RT alone were retrospectively analysed. Results: Median follow-up duration was 61 months. The 5-year biochemical disease-free survival (bDFS) rate for the 82 patients treated with RT plus HT was 78%, whereas bDFS for the 64 patients treated with RT alone was 72%; this difference was not significant. Among the 75 patients treated with RT plus HT who underwent intra-rectal temperature measurements, higher thermal parameters were significant prognostic indicators of improved bDFS by univariate analysis. A higher CEM43?°CT90 thermal parameter and a T stage of T1–2 were significant prognostic factors based on multivariate analysis. The 5-year bDFS rates for the 40 patients with a higher CEM43?°CT90 and the 64 patients treated with RT alone were significantly different, whereas 5-year bDFS for the 35 patients with a lower CEM43?°CT90 and the 64 patients treated with RT alone were not. Conclusions: The addition of HT with higher thermal parameters to RT may improve bDFS for patients with high-risk or very high-risk prostate cancer. These findings also demonstrate the importance of careful selection of treatable patients with higher thermal parameters.     

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.     

Altered interhemispheric resting state functional connectivity during passive hyperthermia

Abstract

Purpose: This study examines the effect of passive hyperthermia on interhemispheric resting state functional connectivity and the correlation between interhemispheric resting state functional connectivity and efficiency of a succedent working memory task. Materials and methods: We performed voxel-mirrored homotopic connectivity (VMHC) analyses on resting state MRI data and a one-back task from 14 healthy subjects in both HT (hyperthermia, 50?°C) conditions and normal control (NC, 25?°C) conditions. The group analyses of the differences for VMHC between the two conditions and the correlation analysis between the VMHC and the reaction time (RT) of the one-back task were performed with the statistical parametric mapping software package and the software REST. Results: Compared with NC conditions, HT conditions increased VMHC in the cuneus, the postcentral gyrus, and the fusiform gyrus. No region showed decreased VMHC in the HT group in comparison with the NC group. For NC conditions, negative correlations were demonstrated between RT of the one-back task and VMHC in bilateral superior temporal gyrus, and bilateral middle frontal gyrus; for HT conditions, negative correlations were demonstrated between RT and VMHC in bilateral inferior frontal gyrus, bilateral middle frontal gyrus, as well as cerebellum posterior lobe. Conclusion: Passive heat stress can impact the interhemispheric information interactions at resting state and the VMHC deficits may play an important role in cognitive dysfunction.     

Regional hyperthermia combined with radiotherapy for locally advanced non-small cell lung cancers: a multi-institutional prospective randomized trial of the International Atomic Energy Agency

Background An International Atomic Energy Agency (IAEA)-sponsored, multi-institutional prospective randomized trial was conducted to clarify whether the combination of hyperthermia and radiotherapy improves the local response rate of locally advanced non-small cell lung cancer (NSCLC) compared with that obtained by radiotherapy alone. Methods Between October 1998 and April 2002, 80 patients with locally advanced NSCLC were randomized to receive either standard radiation therapy alone (RT) or radiation therapy combined with hyperthermia (RT + HT). The primary endpoint was the local response rate. The secondary endpoints were local progression-free survival and overall survival. Results The median follow-up period was 204 days for all patients and 450 days for surviving patients. There were no significant differences between the two arms with regard to local response rate (P = 0.49) or overall survival rate (P = 0.868). However, local progression-free survival was significantly better in the RT+HT arm (P = 0.036). Toxicity was generally mild and no grade 3 late toxicity was observed in either arm. Conclusion Although improvement of local progression-free survival was observed in the RT+HT arm, this prospective randomized study failed to show any substantial benefit from the addition of hyperthermia to radiotherapy in the treatment of locally advanced NSCLC.     

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.     

Comparison of radiological and pathohistological response to neoadjuvant chemotherapy combined with regional hyperthermia (RHT) and study of response dependence on the applied thermal parameters in patients with soft tissue sarcomas (STS)

Purpose: To compare the radiological criteria RECIST, WHO, and tumor volume for evaluation of tumor response in patients with soft tissue sarcomas (STS) showing either good or poor pathohistological response to neoadjuvant chemotherapy combined with regional hyperthermia, and to examine the dependence of the findings on the applied thermal dose.

Materials and methods:19 patients with pathohistological complete response (no vital tumor cells, group 1) and 27 with pathohistological no response (<25% necrosis, group 2) were selected from our previous clinical trials. The change in tumor size before and after therapy was determined. Intratumoral temperature (T₉₀) and thermal dose (CEM 43°C T₉₀) were calculated for 13 patients.

Results: In the first group, 6 partial response (PR) and 13 stable disease (SD) according to RECIST, 7 PR and 12 SD according to WHO, 7 PR and 12 SD according to volumetric criteria were evaluated. In the second group, the results were 10 PR and 17 SD (RECIST), 9 PR and 18 SD (WHO), 8 PR and 19 SD (volume). The concordance of these criteria was 73.7% in group 1 and 74% in group 2. PR and SD were equally distributed in both groups (p > 0.421). Thermal parameters were not different between the groups (p > 0.327).

Conclusions: SD or PR in radiological response assessment does not correlate with the pathohistological response after neoadjuvant thermochemotherapy. RECIST, WHO and volumetric criteria for response evaluation in STS are in substantial agreement. For irregularly shaped lesions, volumetric criteria seem to be more appropriate.     

Preclinical evaluation of the novel hypoxic marker 99mTc-HL91 (prognox) in murine and xenograft systems in vivo

Purpose: The ^99mTc-labelled amine oxime ^99mTc-HL91 (Prognox™) is under investigation as a potential noninvasive clinical marker of tumour hypoxia whose uptake can be monitored by gamma camera imaging. The aim was to assess its retention in 3 tumours under control and enhanced oxygenation conditions.Materials and Methods: The SaF murine sarcoma, grown subcutaneously in CBA mice, and human colon carcinoma HT29 and lung adenocarcinoma A549, grown as xenografts in SCID mice, were used at 6–8 mm diameter. Oxygenation status was enhanced by giving 500 mg/kg nicotinamide i.p. and breathing carbogen until the point of assay. Oxygenation/hypoxia was measured using the Eppendorf pO₂ histograph (KIMOC 6650) with at least 5 tracks and at least 70 values, and expressing pO₂ values as % < 2.5 mmHg. ^99mTc-HL91 (0.8 or 8 MBq per mouse) was injected i.v. immediately before nicotinamide or saline, and animals were killed 2 h after injection. Tumour, skin, muscle, and blood samples were counted and isotope retention was expressed as % injected dose per gram. ¹⁴C-labelled uncomplexed HL91 was used similarly (0.2–0.4 MBq per mouse) and samples were solubilised and decolourised before counting.Results: Nicotinamide and carbogen treatment reduced ^99mTc-HL91 retention in all tumours to 54%–64% of control; it also reduced the proportion of pO₂ values < 2.5 mmHg in all tumours. The mean proportion of pO₂ values < 2.5 mmHg correlated very well with the mean ratio of tumour to blood retention at 2 h for all tumours, both unperturbed and oxygen-enhanced (r = 0.996, p < 0.001). Retention of ¹⁴C-HL91 in SaF tumour was unchanged by nicotinamide and carbogen, confirming that ^99mTc complexation of the ligand is required for hypoxia specificity.Conclusion There is excellent correlation between ^99mTc-HL91 retention and hypoxia, as measured by the Eppendorf histograph, over the range of 50%–90% of values < 2.5 mmHg in 3 different tumour models, including 2 human xenografts. ^99mTc complexation of the ligand is required for hypoxia specificity. ^99mTc-HL91 (Prognox™) shows good potential as a clinical marker for hypoxia and warrants further development.     

Multi-institutional clinical studies on hyperthermia combined with radiotherapy or chemotherapy in advanced cancer of deep-seated organs

Multi-institutional studies on clinical hyperthermia of deep-seated tumours were undertaken using 8 MHz radiofrequency capacitive heating devices (Thermotron RF-8) at seven institutions. Each institute was designated to treat specific organs. This paper contains the accumulations of the results obtained at different institutions charged for different tumours. Deep-seated tumours in the lung, stomach, pancreas, liver, urinary bladder and rectum were treated. A total of 177 cases examined from January 1985 to December 1988 included 96 cases (54%) treated with radiotherapy plus hyperthermia, among which 14 cases were pre-operative. Of 177 cases, 81 (46%) were treated with chemotherapy plus hyperthermia. Complete response (CR) and partial response (PR) were obtained in 80% of the cases with lung cancer, 39% with stomach cancer, 56% with liver cancer, 35 % with pancreas cancer, 71 % with urinary bladder cancer, 100% with primary rectal cancer, and 47% with recurrent rectal cancer. Thermometry was performed using two techniques; one is direct measurement of intratumour temperature in lung and liver cancers, the other is indirect measurement of intracavitary temperature for stomach, pancreas, urinary bladder and rectal cancers. Intratumour temperatures were measured in 30 of the 43 tumours of the lung and liver. The maximum tumour temperature was > 42°C in 23 (77%) of the 30 tumours. Intracavitary temperatures were measured in 133 (99%) of the 134 tumours of stomach, pancreas, urinary bladder and rectum. An intracavitary temperature > 42°C was obtained in 98 (73-7%) of the 133 tumours. The contribution of hyperthermia in improving the quality of life of patients under terminal care was also investigated. It was indicated that hyperthermia was one of the most effective treatment techniques for advanced or inoperable cases. In this study local control rate (LCR) was mainly discussed because the period of follow-up was only 3 years. Side-effects were observed in 37 cases (21 %); main side-effects were fatty induration, pain during treatment and burn. However, no side-effects were severe enough to interrupt therapy.     

HDR brachytherapy combined with interstitial hyperthermia in locally advanced cervical cancer patients initially treated with concomitant radiochemotherapy: A phase I study

Background and purpose: The aim of this study was to investigate whether hyperthermia (HT) combined with interstitial brachytherapy (ISBT) has any influence on acute and late side effects in patients with advanced cervical cancer. Local control (LC) and disease-free survival (DFS) were also analysed.

Materials and methods: Following the completion of radiochemotherapy, patients with cervical cancer (FIGO stages I–III) were assigned to two treatment groups, either ISBT combined with interstitial hyperthermia (ISHT) or ISBT alone as a control group. Selection criterion for the ISBT combined with HT group was advanced cervical cancer with poor response to external beam radiotherapy. A total of 76 patients were included in the statistical analysis. Once a week, HT (at a temperature above 42.5°C) was administered for 45?min before and during high dose rate (HDR) brachytherapy (BT) in 43 patients. Four HT treatments were administered.

Results: The median follow-up time was 43 months (range 4–73 months). Significant differences were not observed for the distribution of early and late complications between the HT and no HT groups. Despite this, LC was similar in both groups. The 5-year DFS for the BT and BT?+?HT groups was 73.6% and 65.8%, respectively. The 5-year LC for the BT and BT?+?HT groups was 89% and 83%, respectively. For the majority of patients the maximum temperature level of 44–45°C was achieved during the ISHT.

Conclusions: ISHT is well tolerated and does not affect treatment-related early or late complications.     

Immune correlates of clinical benefit in a phase I study of hyperthermia with adoptive T cell immunotherapy in patients with solid tumors

Abstract

Purpose: To characterize the T cell receptor (TCR) repertoire, serum cytokine levels, peripheral blood T lymphocyte populations, safety, and clinical efficacy of hyperthermia (HT) combined with autologous adoptive cell therapy (ACT) and either salvage chemotherapy (CT) or anti-PD-1 antibody in patients with previously treated advanced solid tumors.

Materials and methods: Thirty-three (33) patients with ovarian, pancreatic, gastric, colorectal, cervical, or endometrial cancer were recruited into the following therapeutic groups: HT?+?ACT (n?=?10), HT?+?ACT?+?anti-PD-1 inhibitor (pembrolizumab) (n?=?11) and HT?+?ACT?+?CT (n?=?12). Peripheral blood was collected to analyze TCR repertoire, measurements of cytokines levels and lymphocyte sub-populations before and after treatment.

Results: The objective response rate (ORR) was 30% (10/33), including three complete responses (CR) (9.1%) and seven partial responses (PR) (21.2%) and a disease control rate (DCR?=?CR?+?PR?+?SD) of 66.7% (22 of 33). The most common adverse reactions, blistering, subcutaneous fat induration, local heat-related pain, vomiting and sinus tachycardia, were observed in association with HT. IL-2, IL-4, TNF-α, and IFN-γ levels in peripheral blood were significantly increased among the clinical responders (p?<?0.05) while IL-6 and IL-10 were elevated among those with progressive disease (p?<?0.05). Peripheral blood CD8⁺/CD28⁺ T cells increased (p?=?0.002), while the CD4⁺/CD25⁺/CD127⁺Treg cells decreased after therapy (p?=?0.012). TCR diversity was substantially increased among the clinical responders.

Conclusions: Combining HT with ACT plus either CT or anti-PD-1 antibody was safe, generated clinical responses in previously treated advanced cancers, and promoted TCR repertoire diversity and favorable changes in serum IL-2, IL-4, TNF-α, and IFN-γ levels in clinical responders.