Tumour perfusion assessment during regional hyperthermia treatment: Comparison of temperature probe measurement with H215O-PET perfusion

Purpose: Hyperthermia treatment might increase tumour oxygenation and perfusion, as has been reported for experimental tumours. The present study was performed to investigate this hypothesis in patients undergoing regional hyperthermia treatment.

Methods: Thirteen patients with primary or recurrent pelvic tumours were included in this study. Prior to and up to one hour after regional hyperthermia, perfusion was quantitatively determined by H₂¹⁵O-PET. The fused CT-PET images were used to extract tumour time-activity curves and to identify the catheter position. Perfusion was calculated from the total tumour time-activity curves and for the time-activity curves at the catheter site. Additionally, perfusion was calculated from the temperature-time curves measured using temperature probes.

Results: Perfusion values calculated using H₂¹⁵O-PET and those deduced from temperature probe measurements are significantly correlated with a correlation coefficient, R = 0.21. The perfusion values deduced from the temperature measured in a body cavity do not provide information about average tumour perfusion. Perfusion values deduced from the temperature are overestimated for very poorly perfused tissues and underestimated for highly perfused tissues.

Conclusions: Temperature measurement during hyperthermia may allow only determination of intermediate perfusion values.     

Tumour oxygenation is increased by hyperthermia at mild temperatures

The effects of hyperthermia on the oxygenation status in R3230 AC tumours of Fischer rats were measured using a polarographic oxygen electrode system. The median pO₂ in about 10mm diameter tumours grown s.c. in the leg of rats was 3·7 ± 0·3 mm Hg and it significantly increased upon heating at modest temperatures. For example, the tumour pO₂ measured within 10–15 min after heating for 30 min at 42·5°C was about three-fold greater than that in the control tumours. About 62% of pO₂ values measured in control tumours were < 5 mm Hg. After heating at 42·5°C for 30min, 37% of pO₂ values were < 5 mm Hg. Such an increase in tumour oxygenation or reoxygenation of hypoxic cells appeared to result from an increase in tumour blood flow caused by the mild temperature hyperthermia. The presence of hypoxic cells in tumours is believed to be a major factor in limiting the effectiveness of radiotherapy, certain chemotherapy drugs and phototherapy. Hyperthermia at mild temperatures easily achievable with the use of presently available clinical hyperthermia devices may be an effective means to overcome the hypoxic protection in the treatment of human tumours.     

Tumour oxygenation is increased by hyperthermia at mild temperatures

The effects of hyperthermia on the oxygenation status in R3230 AC tumours of Fischer rats were measured using a polarographic oxygen electrode system. The median pO₂ in about 10 mm diameter tumours grown s.c. in the leg of rats was 3.7 ± 0.3 mm Hg and it significantly increased upon heating at modest temperatures. For example, the tumour pO₂ measured within 10–15 min after heating for 30 min at 42.5°C was about three-fold greater than that in the control tumours. About 62% of pO₂ values measured in control tumours were <5 mm Hg. After heating at 42.5°C for 30 min, 37% of pO₂ values were <5 mm Hg. Such an increase in tumour oxygenation or reoxygenation of hypoxic cells appeared to result from an increase in tumour blood flow caused by the mild temperature hyperthermia. The presence of hypoxic cells in tumours is believed to be a major factor in limiting the effectiveness of radiotherapy, certain chemotherapy drugs and phototherapy. Hyperthermia at mild temperatures easily achievable with the use of presently available clinical hyperthermia devices may be an effective means to overcome the hypoxic protection in the treatment of human tumours.     

The effect of mild temperature hyperthermia on tumour hypoxia and blood perfusion: relevance for radiotherapy,vascular targeting and imaging

Clinically achievable mild temperature local hyperthermia (<43°C) has been demonstrated to be an effective adjuvant to radiotherapy in pre-clinical and clinical studies. In this article, we briefly review the recent progress in the following areas: (1) the effect of mild temperature hyperthermia (MTH) on tumour hypoxia and blood perfusion as assessed by dual marker immunohistochemistry (IHC); (2) the kinetics of MTH induced changes in tumour hypoxia; (3) the potential role of heat-induced tumour reoxygenation on radio- and chemo-sensitisation; (4) the potential role of MTH in combination with vascular targeting agents (VTAs) on tumour response; and (5) non-invasive detection of changes in tumour oxygenation and blood perfusion. It is shown that MTH, by itself or in combination with VTAs, leads to changes in tumour perfusion and oxygenation with potential for radio- and chemo-sensitisation.     

Tumor associated mesenchymal stem cells protects ovarian cancer cells from hyperthermia through CXCL12

Hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promise in treatment of ovarian carcinosis. Despite its efficiency for the treatment of peritoneal carcinosis from digestive tract neoplasia, it has failed to demonstrate significant benefit in ovarian cancers. It is therefore essential to understand the mechanism underlying resistance to HIPEC in ovarian cancers. Mesenchymal stem cells (MSC) play an important role in the development of ovarian cancer metastasis and resistance to treatments. A recent study suggests that MSCs may be cytotoxic for cancer cells upon heat shock. In contrast, we describe the protective role of MSC against hyperthermia. Using cytokine arrays we determined that the tumor associated MSC (TAMC) secrete pro‐tumoral cytokines. We studied the effect of hyperthermia in co‐culture setting of TAMC or BM‐MCS associated with ovarian cancer cell lines (SKOV3 and CaOV3) with polyvariate flow cytometry. We demonstrate that hyperthermia does not challenge survival of TAMC or bone marrow derived MSC (BM‐MSC). Both TAMC and BM‐MSC displayed strong protective effect inducing thermotolerance in ovarian cancer cells (OCC). Transwell experiments demonstrated the role of secreted factors. We showed that CXCL12 was inducing thermotolerance and that inhibition of CXCL12/CXCR4 interaction restored cytotoxicity of hyperthermia in co‐culture experiments. Contrary to the previous published study we demonstrated that TAMC and BM‐MSC co‐cultured with OCC induced thermotolerance in a CXCL12 dependant manner. Targeting the interaction between stromal and cancer cells through CXCL12 inhibition might restore hyperthermia sensitivity in ovarian cancers, and thus improve HIPEC efficiency.     

热疗联合腹腔灌注化疗治疗晚期胃肠道恶性肿瘤的疗效观察

目的：观察热疗联合腹腔灌注化疗治疗晚期胃肠道恶性肿瘤的疗效.方法：60例晚期胃肠道恶性肿瘤患者随机分为热疗联合化疗组（A组30例）和单纯腹腔化疗组（B组30例）.结果：热疗联合腹腔化疗组胃癌有效率、肠癌有效率及总有效率分别为58.8％、69.2％及63.3％,明显高于单纯腹腔化疗组的40.0％、33.3％及36.7％,差异有统计学意义（P＜0.05）.结论：热疗联合腹腔化疗相比单纯腹腔化疗可有效缓解病情,改善晚期肿瘤患者生活质量,值得临床推广应用.     

Limitations and significance of thermal washout data obtained during microwave and ultrasound hyperthermia

It is common in clinical hyperthermia to calculate an ‘effective blood flow’ by neglecting tissue thermal conduction and fitting thermal washout data to a simple, perfusion-dominated exponential model. We have applied this approach to characterize thermal dissipative mechanisms in patients treated at the Harvard-MIT Hyperthermia Center, by analysing thermal washout curves which were obtained during treatment sessions by momentarily interrupting the applied heating. Unfortunately, these measurements of ‘effective blood flow’ in patient sessions have given inconsistent results. These inconsistencies arise from uncertainties inherent in the clinical situation: the actual thermal boundary conditions and the spatiotemporal characteristics of the heating field. To quantify these observations a Green's function solution to the tissue bioheat equation has been derived, to enable temperature fields produced by various heating geometries to be easily calculated. This has been applied to the analysis of temperature decay curves following local energy deposition representative of ultrasound and microwave hyperthermia therapy devices. These results show that thermal washout data are as dependent on patient-and session-specific parameters as on tissue properties and perfusion. For measurements of effective blood flow following ultrasonic heating, errors are dependent on the measurement position within the heated volume, heating geometry, and duration of heating prior to the decay; for microwave heating, results are dependent on the position of the measurement point within the heated field, the heating frequency, and the surface boundary conditions, whether heated, cooled, or insulated. Thus, any effective tissue property calculated without correctly modelling the heating geometry, boundary conditions and initial conditions will be of a qualitative rather than quantitative nature, and may lead to erroneous and misleading conclusions concerning tissue and tumour response.     

Interstitial brachytherapy and hyperthermia for malignant gliomas

Interstitial brachytherapy has well-known radiobiological and radiophysical advantages that has made delivery of high doses of radiation to malignant brain tumors a possibility [1]. Over the past 10 years a great deal of clinical information attesting to the usefulness of brachytherapy in the treatment of malignant gliomas has been accrued.     

Simultaneous radiotherapy and superficial hyperthermia for high-risk breast carcinoma: A randomised comparison of treatment sequelae in heated versus non-heated sectors of the chest wall hyperthermia

Purpose: In vitro data demonstrate that heat-induced radiosensitisation is maximised if hyperthermia and radiotherapy are given simultaneously, with the radiation fraction delivered midway through a hyperthermia session, rather than sequentially. The long-term normal tissue toxicity of full-dose simultaneous thermoradiotherapy is unknown.

Materials and methods: Patients with locally advanced breast cancer (T3, T4 or more than three involved nodes or local recurrence), no prior radiotherapy, received between four and eight sessions of simultaneous thermoradiotherapy. Hyperthermia always included the primary tumour site. In addition an electively heated sector (EHS) was included. The EHS was randomised to either medial or lateral to the tumour site, with the other side an irradiated but unheated control. As per our usual practice, patients received surgery and/or chemotherapy prior to radiotherapy. Radiation doses were 46–50?Gy followed by a boost of ≤16?Gy at 1.8–2?Gy per fraction. EHS and control sectors received the same dose.

Results: A total of 57 evaluable cases with average follow-up of 79 months experienced two local and two nodal recurrences. There was no significant difference in ≥grade 2 toxicity for heated versus control sectors (LR χ^2?=?0.78, p?=?0.38) with no relationship between number of hyperthermia sessions and toxicity (LR χ^2?=?2.90, p?=?0.09).

Conclusions: Simultaneous full-dose thermoradiotherapy for breast cancer is feasible and well tolerated, with no significant difference in late toxicity between electively heated and unheated control sectors. All patients had hyperthermia to the primary tumour site with excellent local control.     

多西他赛联合腹腔热灌注化疗加热疗治疗晚期卵巢癌

  目的  观察多西他赛联合腹腔内顺铂热灌注化疗加热疗治疗晚期卵巢癌的疗效与不良反应。   方法  无法手术及复发晚期卵巢癌患者83例,随机分成两组:热疗组42例,行多西他赛静脉化疗后即刻行腹腔内顺铂热灌注化疗并加腹部局部射频热疗;对照组41例,单纯给予多西他赛静脉化疗加腹腔内顺铂热灌注化疗。   结果  热疗组和对照组的总有效率分别是81.0%和58.1%,其中总有效率显著提高（P < 0.05）,腹水控制率分别为78.3%和66.7%,CA125下降率分别为84.2%和61.5%（P < 0.05）,主要不良反应为消化道不良反应及骨髓抑制,无显著性差异。   结论  多西他赛联合顺铂腹腔内灌注加热疗明显提高晚期卵巢癌的疗效,不增加不良反应,值得进一步推广。      

The effect of hydralazine dose on blood perfusion changes during hyperthermia

Experiments were performed to determine the dose-related effects of the intravenous administration of a vasodilator (hydralazine) on normal muscle blood perfusion during localized hyperthermia. Fourteen anaesthetized outbred canines were investigated, seven receiving the recommended dose level of 0–5 mg/kg and seven receiving one-quarter of that level. The changes in blood perfusion were estimated using two methods: calculation of an effective blood perfusion magnitude and the use of state and parameter estimation techniques. Both methods showed that the changes in blood perfusion induced by the hydralazine were significant, and that the differences between the results for the two drug doses were not significantly different. This suggests that low doses may be useful in humans, giving the same resultant blood perfusion increase but with a decreased patient risk relative to standard therapeutic doses of hydralazine.

While the trends in the blood perfusion changes were the same for both calculation methods the effective perfusion method frequently yielded blood perfusion magnitudes significantly different from those obtained using the state and parameter estimation technique. The differences are postulated to be due to the fact that the effective perfusion values include conduction effects, thus overpredicting the amount of perfusion present. Thus, while the effective blood perfusion can be used as a qualitative indication of blood perfusion changes under certain conditions, we do not recommend its use as a quantitative measure of perfusion.     

Transurethral hyperthermia for benign prostatic hyperplasia: Long term results

Transurethral resection of the prostate (TURP) is the only recognized treatment in patients with benign prostatic hyperplasia (BPH). Transurethral hyperthermia (TUHT) was used as an alternative treatment in patient who refused TURP. From 1987 to 1988, 21 BPH patients with moderate to severe symptoms and signs of prostatism were treated with TUHT in a phase I trial. Mean pre-treatment subjective and objective values were: Total symptom score (TSS) 13.5, obstructive symptom score (OSS) 6.5, irritative symptom score (TSS) 7.0, peak flow rate (PFR) 11.6 cc/sec, post-voiding residual volume (PRV) 187 cc, and prostate volume (PV) 93 cc. TUHT was given for a total of 177 sessions (mean 8.4), each of 60 min duration at a steady state. Temperature was recorded continuously on the urethral surface, in all treatments. It ranged from T_min 40.3d`C to T<sub>max</sub> = 49.2d`C and T_mean = 44.1d`C. The mean minimum temperature of ≥ 42d`C was obtained in 98% of the TUHT sessions. Treatments were given on an outpatient basis without sedation or anaesthesia. Treatment tolerance was excellent with minor acute toxicity common (71% of patients), of no clinical importance and with no late complications. Of the 21 patients treated, 17 (81%) had an objective and 15 (71%) a subjective improvement recorded at 6 months post-treatment. This statistically highly significant improvement included: 61% decrease in TSS; 66% decrease in OSS; 55% decrease in ISS; 42% increase in PFR; 55% decrease in PRV; and 21% decrease in PV. Of the 17 patients with objective improvement, nine have maintained their response to TUHT for a minimum period of over six years, two relapsed at 11 and 40 months, respectively, and six patients died of cardiovascular causes maintaining their response to death. This study has demonstrated TUHT treatment efficacy with no major or clinically important toxicity in BPH patients. A relative weakness of this report is a lack of verification of objective study parameters in the patients at seven years post-treatment. Prospective randomized trials are needed to define the role of TUHT in the management of BPH patients.     

腹腔灌注化疗联合微波体外聚焦热疗治疗晚期腹盆腔恶性肿瘤近期疗效观察

为观察腹腔灌注化疗联合微波体外聚焦热疗治疗晚期腹、盆腔恶性肿瘤的近期疗效,2005年5月~2007年5月青岛市胶州中心医院放疗科对115例晚期腹、盆腔肿瘤患者进行治疗,随机分为热化疗组(55例)和单纯腹腔化疗组(60例)。结果热化疗组卵巢癌有效率、胃肠癌有效率及总有效率为63.6%、59.1%和60.0%,均明显高于化疗组的46.2%、36.2%和38.3%,差异有统计学意义,P值均<0.05。热化疗组疼痛缓解方面、体质量增加及KPS评分提高等均明显高于单纯化疗组,而食欲减退发生率却明显低于化疗组,差异均有统计学意义,P值均<0.01。热化疗组恶心呕吐的发生率明显低于化疗组,差异有统计学意义,P<0.05;口腔炎、腹泻、骨髓抑制、神经毒副反应及肾功能受损等的发生率热化疗组也低于化疗组,但差异无统计学意义,P值均>0.05。初步观察结果提示,热化疗组无论是肿瘤缓解率、患者生活质量的改善,还是毒副反应的减轻都明显优于单纯腹腔化疗组,值得临床推广应用。     

Implantable helical coil microwave antenna for interstitial hyperthermia

An implantable helical coil microwave antenna has been developed for improved localization and control of interstitial hyperthermia for deep-seated tumours. A helical coil structure was employed as an extension of the inner conductor at the terminal portion of a miniature semi-rigid coaxial cable. The antennas were constructed with three different connection configurations of the helical coil to the feedline, and with several coil turn densities during the optimization of heating characteristics. In order to compare relative antenna heating performance, a set of quantitative parameters was introduced. Power deposition profiles of 2450 MHz helical coil antennas were studied in both phantom models and muscle tissue in vivo, and compared to those of commonly used dipole antennas. Optimal antenna performance was obtained with a 10-turn per 1 cm helical coil connected to the inner conductor at the tip and separated from the outer conductor by a 0.1 cm gap (HCS-10). These antennas produced a well-localized heating pattern with a sharp falloff of temperature in both directions axially from the coil element. For half-wavelength insertion depths, the effective heating length (50 per cent of maximum SAR) of HCS-10 antennas matched that of standard dipole antennas, but was shifted down towards the tip. For shorter and deeper antenna insertion depths the HCS-10 heating pattern remained similarly localized to the region surrounding the helical coil with minimal cold zone at the tip. In contrast, the dipole antenna heating pattern changed significantly depending on insertion depth, with an unavoidable 0.2–0.7 cm cold region at the antenna tip and elevated surface temperatures for short insertion depths.     

Reirradiation and hyperthermia for radiation-associated sarcoma

BACKGROUND:

The objective of this study was to evaluate the role of reirradiation and hyperthermia in the treatment of radiation‐associated sarcoma (RAS) in the thoracic region, which is an increasing, yet extremely rare condition with a poor prognosis.

METHODS:

Between 1979 and 2009, 16 patients with RAS in the thoracic region were treated in the Academic Medical Center and the Institute Verbeeten with reirradiation and hyperthermia. In 13 patients, this treatment was given for unresectable disease and 3 times after resection as adjuvant treatment. The median latency period between the original malignancy diagnosis and the RAS diagnosis was 86 months (range 19‐212 months). Histology was angiosarcoma in 11 patients (69%). The literature on reirradiation with or without hyperthermia for RAS was reviewed.

RESULTS:

The median survival was 15.5 months (range, 3‐204 months). Four patients were not evaluable for response. The response rate for the remaining 12 patients was 75% (7 complete responses and 2 partial responses). Six patients remained free of local failure until death (5 months and 7 months) or last follow‐up (8 months, 11 months, 39 months, and 68 months).

CONCLUSIONS:

The current study indicates that combined reirradiation and hyperthermia for RAS in the thoracic region is feasible. The high response rate and the possibility of durable local control suggest that this treatment is promising. Cancer 2012;. © 2011 American Cancer Society.     

Enhancement of sensitivity to hyperthermia by Lonidamine in human cancer cells

Human glioma (87MG) and squamous cell carcinoma of the head and neck UMSCC-1 were shown to be sensitized to hyperthermia by Lonidamine treatment before and during hyperthermia. The degree of thermal sensitization increased with increasing heating times and temperatures. In addition, the thermal sensitization by Lonidamine as well as cellular thermal sensitivity were dependent on pH and increased with the more acidic pH. Even though plateau phase cells were more thermally resistant than exponentially growing cells, Lonidamine treatment caused thermal sensitization under both conditions. These data show that Lonidamine may hold potential to enhance the effectiveness of hyperthermia in cancer treatment and that especially in tumours with low pH an enhanced therapeutic gain may be achieved.     

Feasibility of lung cancer hyperthermia using breathable perfluorochemical (PFC) liquids. Part II: Ultrasound hyperthermia

Enhanced local control of disease in lung cancer has been shown to improve survival, and controlled clinical trials of hyperthermia adjunctive to radiotherapy in other cancers have shown improved disease control and survival over radiotherapy alone. The challenge of lung hyperthermia, however, persists. This investigation sought to demonstrate the feasibility of localized lung hyperthermia at depth via therapeutic ultrasound. The method is based on using breathable perfluorochemical liquids as acoustic coupling media in the lung, liquids that have also been shown to enable controlled liquid-filled lung convective hyperthermia (LCHT). The ability to use both lung convective hyperthermia and liquid-filled lung ultrasound hyperthermia (LUHT) provides potential flexibility in heating patterns for the hyperthermic treatment of lung cancer with concurrent radiotherapy and/or chemotherapy. Using custom ultrasound transducers designed and built for these studies, the acoustic properties of three candidate perfluorochemicals were characterized over a range of temperatures, gas contents and ultrasound frequencies and acoustic intensities. Both sound speed and attenuation were measured in the neat liquids and in isolated lungs filled with the perfluorochemicals. Successful ultrasound hyperthermia at depth was demonstrated in vivo in sheep lung lobes in intraoperative conditions. In addition, the use of ultrasound diagnostic imaging was explored as a tool for use in conjunction with lung ultrasound hyperthermia.     

热灌注化疗联合深部热疗治疗恶性腹腔积液的疗效分析

目的:总结深部热疗联合热灌注化疗治疗恶性腹腔积液的疗效。方法:将我院2012年01月-2012年10月56例恶性腹腔积液患者随机分成两组,一组单独给予顺铂腹腔内灌注化疗(单纯组),一组进行顺铂热灌注化疗联合深部热疗治疗(实验组),2个疗程后评价疗效。结果:热灌注化疗联合深部热疗治疗恶性腹腔积液总有效率(RR)为64.3%,单纯顺铂腹腔内灌注化疗组总有效率为32.1%,两组差异有统计学意义,P<0.05。热疗与化疗有良好的协同增效作用,且安全有效,毒副反应低。结论:热灌注化疗联合深部热疗治疗恶性腹腔积液疗效明显,已成为治疗恶性胸腹水的重要手段。     

A comparison of the effect of hyperthermia on DNA polymerase in hamster and human glioma cells

The hyperthermia response of two human glioma cells lines (87MG and 373MG) was compared to the CHO cell line for cell killing and DNA polymerase inactivation. Glioma cells were found to be more thermally resistant than CHO cells over a temperature range of 41–46°C. Inactivation of polymerase α and β by hyperthermia was also more resistant in glioma cells than in CHO cells. The relative order of resistance for both killing and polymerase inactivation was 373MG >87MG>CHO. While polymerase inactivation correlated with cell killing at high thermal doses, such correlation at low doses was absent; i.e. thermal killing was characterized by survival curves with shoulders while polymerase inactivation was not. Thus at low thermal doses the mechanism of thermal cell killing is probably not related to the degree of polymerase inactivation. Arrhenius analysis of the survival data showed that the inactivation energy for the glioma cells was 133–135 kcal/mol. The inactivation energies of αand β polymerase were also evaluated and were 102–104 and 140–146 kcal/mol, respectively. Further analysis of the temperature-time relationship of hyperthermia treatment resulting in 50% cell kill showed the degree of polymerase β inactivation to be a good indicator of thermal dose.