Addition Of Hyperthermia Research Articles

Abstract 2825: Experimental hyperthermic intraperitoneal chemotherapy in mice: Establishment of a novel ovarian cancer xenograft model

Abstract Introduction: The peritoneum is a common metastatic site for several abdominal cancers, including ovarian and colorectal cancer. Peritoneal metastasis is associated with poor prognosis and poor response to therapy. A potentially curative treatment is cytoreductive surgery (CRS) to remove all visible tumor tissue, followed by perfusion with hyperthermic intraperitoneal chemotherapy (HIPEC) to eliminate small residual tumors and free-floating tumor cells. Hyperthermia can enhance the cytotoxic effect of the drug, inhibit DNA repair and activate the immune system. At the current time, there is no standardized protocol for performing HIPEC, and there is a large variation regarding key parameters, such as choice of drug, drug concentration, treatment duration, carrier solution, volume and temperature. The impact of these parameters is unknown, and in vivo models can be a helpful tool to better understand some of these parameters to improve this treatment strategy. Methods: HIPEC was established in a murine xenograft model of ovarian cancer to evaluate the response to intraperitoneal perfusion of cisplatin and mitomycin C for 30 min at 41.5°C (HIPEC) and 37°C (NIPEC) compared to no treatment or intraperitoneal perfusion with saline at 41.5°C. The luciferase transfected B76 ovarian cancer cell line was injected intraperitoneally and treatment was performed on day 4 when the tumors were < 2 mm. Treatment efficacy was assessed by weekly luminescence measurement, tumor weight at an early time point (day 17), and overall survival. Results: Intraperitoneal perfusion with cisplatin or mitomycin C significantly inhibited tumor growth as assessed by luminescence, tumor weight on day 17, as well as increased overall survival of the mice compared to control treatment from 25-27 days to 36 days for cisplatin and 37 days for mitomycin C. No significant differences in tumor growth or survival were observed by the addition of hyperthermia. However, a slight reduction of tumor weight at day 17 was observed in the HIPEC groups. Conclusion: We have established a functional closed HIPEC model in mice bearing peritoneal metastases from the B76 ovarian cancer cell line which accurately mimics many features of the procedure in patients. Intraperitoneal perfusion of both cisplatin and mitomycin C efficaciously inhibited tumor growth and improved overall survival of the mice. Addition of hyperthermia caused an additional modest, temporary growth inhibition which did not translate into improved long-term outcome. Citation Format: Karianne Giller Fleten, Yvonne Andersson, Emil Løvstakken, Theodor M. Herud, Stein Waagene, Kjersti Flatmark. Experimental hyperthermic intraperitoneal chemotherapy in mice: Establishment of a novel ovarian cancer xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2825.

HSP27 modulates tumoural immune evasion by enhancing STAT3-mediated upregulation of PD-L1 and NLRC5 in ovarian cancer.

Multiple preclinical studies have demonstrated that the addition of hyperthermia (HT) to immunotherapy could enhance tumour immunogenicity and stimulate an antitumour immune response, primarily via heat shock proteins (HSPs). However, antitumour immune responses are often impeded by immune evasion mechanisms, such as the overexpression of programmed death-ligand1 (PD-L1) and the loss of major histocompatibility complex class 1 (MHC-1) expression. In this context, we sought to investigate the effect of HT on PD-L1 and NOD-like receptor family CARD domain containing 5 (NLRC5) identified as the key transcriptional activator of MHC-1 genes, and their interaction in ovarian cancer. A coculture of ovarian cancer cell lines (IGROV1 and SKOV3) with peripheral blood mononuclear cells was set up. Then, culture media conditioned with IGROV1 or SKOV3 subjected to HT was tested on untreated cell cultures. Knocking down heat shock protein B1 (HSPB1 or HSP27), heat shock protein A1 (HSPA1 or HSP70), and pharmacological inhibition of STAT3 phosphorylation were performed. Subsequently, we measured expression levels of PD-L1, NLRC5, and proinflammatory cytokines. The correlation between PD-L1 and NLRC5 expression in ovarian cancer was evaluated using the Cancer Genome Atlas database. We found that HT produces a concomitant decrease in PD-L1 and NLRC5 expression in coculture. Notably, however, the conditioned media by heat-shocked cells increases their expression. HSP27 knockdown can reverse this increase. Adding STAT3 phosphorylation inhibitor significantly enhanced the expression inhibition of PD-L1 and NLRC5 induced by HSP27 silencing. Correlation analysis showed a positive correlation in ovarian cancer between NLRC5 and PD-L1. These findings demonstrate that HSP27 modulates PD-L1 and NLRC5 expression through the activation of a common regulator 'STAT3'. Moreover, the positive correlation between PD-L1 and NLRC5 led us to conclude that the upregulation of PD-L1 and the downregulation of MHC class I are two mutually exclusive mechanisms of immune evasion in ovarian cancer.

Radiotherapy in the Treatment of Subcutaneous Melanoma

Simple SummaryThe non-surgical treatment of cutaneous and/or subcutaneous melanoma lesions involves a multitude of local treatments, including radiotherapy. This is often used when other local methods fail, and there are currently no clear guidelines or evidence-based recommendations to support its use in this setting. This review, collecting the retrospective and prospective experiences on radiotherapy alone or in combination with other methods, aims to provide a scenario of the possible advantages and disadvantages related to its use in the treatment of skin/subcutaneous melanoma lesions.Malignant melanoma frequently develops cutaneous and/or subcutaneous metastases during the course of the disease. These may present as non-nodal locoregional metastases (microsatellite, satellite, or in-transit) included in stage III or as distant metastases in stage IV. Their presentation is heterogeneous and associated with significant morbidity resulting from both disease-related functional damage and treatment side effects. The standard treatment is surgical excision, whereas local therapies or systemic therapies have a role when surgery is not indicated. Radiotherapy can be used in the local management of ITM, subcutaneous relapses, or distant metastases to provide symptom relief and prolong regional disease control. To increase the local response without increasing toxicity, the addition of hyperthermia and intralesional therapies to radiotherapy appear to be very promising. Boron neutron capture therapy, based on nuclear neutron capture and boron isotope fission reaction, could be an alternative to standard treatments, but its use in clinical practice is still limited. The potential benefit of combining radiotherapy with targeted therapies and immunotherapy has yet to be explored in this lesion setting. This review explores the role of radiotherapy in the treatment of cutaneous and subcutaneous lesions, its impact on outcomes, and its association with other treatment modalities.

A Phase I Prospective Clinical Trial Using Volumetric Magnetic Resonance-Guided High Intensity Focused Ultrasound (MR-HIFU) Hyperthermia (HT) Combined with Radiotherapy and Chemotherapy for Recurrent Rectal Cancer

Non-operable locally recurrent rectal cancer following chemotherapy (CT), radiation therapy (RT) and surgery (Sx) presents an extremely challenging clinical scenario as it portends both poor outcomes and challenging palliation. The addition of HT may improve the local control and quality of life by providing additional sensitization. Herein, we report on the results of our first in human phase I prospective clinical trial of MR-HIFU hyperthermia combined with RT and CT for non-operable recurrent rectal cancer. This ethics-approved study enrolled 6 patients with recurrent inoperable rectal cancer following CT, RT and Sx who were candidates for re-irradiation and chemotherapy; and with an MRI-visible and HIFU-accessible lesion. Patients were prescribed 30.6 Gy delivered in 1.8Gy fractions delivered daily with concurrent oral capecitabine. MR-HIFU HT was delivered immediately before RT on days 1, 8, and 15 under procedural sedation. Brief Pain Inventory (BPI) and Functional Assessment of Cancer Therapy-Colorectal cancer (FACT-C) were collected prospectively at baseline and 1, 2, 3, 4 and 12 weeks after treatment. Statistical analysis was performed using paired-samples t-test and repeated measures ANOVA. A p value of ≤ 0.05 was considered significant. Median age of patients was 59.5 (range: 39-76). All had received previous CT, RT and Sx for a prior adenocarcinoma of rectum. 1 patient withdrew from the study due to pre-existing pain issues and received only 1/3 planned HT treatments. There were no intraoperative complications, no adverse events or unintended tissue damage attributable to HT, RT, or CT. Table 1 shows the best single continuous HT and mean temperatures (T90, T10), cumulative time in range (TIR), cumulative number of equivalent minutes at 43oC (CEM43) and day 90 imaging response. There were no attributable grade 2-5 toxicities associated with the intervention. 2 patients had transient grade 1 GI toxicity following intervention. At 90 day follow up, 2 patients had partial response, 2 patients had stable disease and 1 patient had progressive disease. There was no statistically significant difference found using repeated measures ANOVA in FACT-C scores (p = 0.63) and BPI (p = 0.45). Table 1 – HT quality and T2 weighted MRI response. The addition of MR-HIFU HT to re-irradiation with chemotherapy is a novel, feasible and safe treatment modality with no negative impact on patients’ quality of life. Further investigation with a phase II clinical trial in primary rectal cancer may be warranted.Abstract 3424; TableBest Session TemperatureCumulative TIR 40-45°CCumulative CEM43,T50Radiologic ResponsePtMean [oC]T90 [oC]T10 [oC][min][min]0140.6 ± 1.040.1 ± 1.642.1 ± 1.022.72.5PR0242.5 ± 0.241.6 ± 0.243.3 ± 0.251.841.3SD0341.9 ± 0.540.9 ± 2.043.1 ± 0.449.017.7PD0441.5 ± 0.539.9 ± 0.542.8 ± 0.516.36.8Withdrew0539.4 ± 0.638.9 ± 0.940.2 ± 0.54.20.4SD0642.3 ± 0.740.5 ± 0.743.7 ± 0.732.313.5PR Open table in a new tab

Review of the Clinical Evidences of Modulated Electro-Hyperthermia (mEHT) Method: An Update for the Practicing Oncologist.

Background: Modulated electro-hyperthermia (mEHT) is a variation of the conventional hyperthermia which selectively targets the malignant cell membranes in order to heat the malignant tissue and sensitize the tissue to oncology treatments. Although widely applied, the formulation of guidelines for the use thereof is still in progress for many tumors.Aim: In this paper we review the literature on the effects of mEHT in cancer patients on local disease control and survival.Methodology: Our review on data presents the collected experience with capacitive hyperthermia treatments with the EHY-2000+ device (OncoTherm Ltd., Germany). A literature search was conducted in Pubmed and articles were grouped and discussed according to: trial type, animal studies, in vitro studies, and reviews. Search results from Conference s; Trial Registries; Thesis and Dissertations and the Oncothermia Journal were included in the discussions.Results: Modulated electro-hyperthermia is a safe form of hyperthermia which has shown to effectively sensitizes deep tumors, regardless of the thickness of the adipose layers. The technology has demonstrated equal benefits compared to other forms of hyperthermia for a variety of tumors. Given the effective heating ability to moderate temperatures, the improved tumor perfusion, and ability to increase drug absorption, mEHT is a safe and effective heating technology which can be easily applied to sensitize tumors which have demonstrated benefits with the addition of hyperthermia. Modulated electro-hyperthermia also appears to improve local control and survival rates and appears to induce an abscopal (systemic) response to ionizing radiation.Conclusion: Based on clinical studies, the method mEHT is a feasible hyperthermia technology for oncological applications. Concomitant utilization of mEHT is supported by the preclinical and clinical data.

Анализ результатов рандомизированных исследований по гипертермии в онкологии

The review presents statistics of published randomized phase III trials on the addition of hyperthermia (HT) to other cancer therapies, and analyzes the results of these trials. In total, 47 comparisons could be made for treatments with or without HT. These trials were done in a large variety of solid tumors, and in centers in Asia, Europe, North America and Australia. In general, these studies were relatively small – 17 studies included more than 100 patients. The total number of patients was 5099. In the majority of the studies, HT was applied with electromagnetic radiation. Most studies (74 %) have shown that additional HT significantly improves the results of radiation, chemo- and chemoradiotherapy in patients with, in general, locally advanced relapsed and metastatic forms of malignant tumors. Improved results were reported for complete and overall response, loco-regional tumor control, disease free and overall survival, and, in one study, for palliative effects. In these randomized trials also acute and/or late toxicity has been investigated. In the majority of the trials, addition of HT did not result in significant increases of toxic effects. The economic consequences of HT as part of cancer treatment are discussed. Twenty-six percent of the studies failed to show a significant beneficial effect of HT which are discussed in more detail. In 4 studies with a trend of a better outcome in the plus HT treatment arm, with an absolute difference of 10 % or more, the lack of significance is probably due to a low number of patients included. In other studies, there was an unbalanced distribution of tumor characteristics over the two study arms, with worse prognostic factors in the plus HT arm, inadequate techniques, using too high frequency of electromagnetic radiation, and/or a small applicator, and/or a short heating time, so that a sufficient energy deposition in the tumor volume could not be achieved. These results make clear that it is important to develop guidelines for the application of HT, in addition to the existing ones. In view of the different principles of operation of HT applicators, it is important that such guidelines will become available for each individual device. Further, it is important to conduct larger randomized trials. Larger studies would probably increase the number of significant and also more relevant outcomes, and promote a wider acceptance of HT as part of cancer treatment.

Dramatic Response of an Aggressive Chest Wall Recurrence to Hyperthermia, Radiation, and Chemotherapy

Hyperthermia has been demonstrated to be an effective adjuvant oncological treatment modality in combination with chemotherapy and/or radiation. Published data have demonstrated that the addition of hyperthermia can improve local control for breast cancer chest wall recurrences. We present a patient with a very aggressive estrogen receptor-negative, progesterone receptor-negative, HER2/neu receptor-negative chest wall recurrence status-post a right modified radical mastectomy. Despite having metastatic disease, in an attempt to achieve local control and provide palliation, she was treated with hyperthermia, radiation, and chemotherapy. A near complete resolution of her chest wall recurrence in a very short time period was seen with a significant improvement in her symptoms. While she unfortunately succumbed to her disease shortly thereafter, the local control that our treatment offered her allowed her quality of life to improve significantly near the end of her life.

Targeting DNA double strand break repair with hyperthermia and DNA-PKcs inhibition to enhance the effect of radiation treatment.

Radiotherapy is based on the induction of lethal DNA damage, primarily DNA double-strand breaks (DSB). Efficient DSB repair via Non-Homologous End Joining or Homologous Recombination can therefore undermine the efficacy of radiotherapy. By suppressing DNA-DSB repair with hyperthermia (HT) and DNA-PKcs inhibitor NU7441 (DNA-PKcsi), we aim to enhance the effect of radiation.The sensitizing effect of HT for 1 hour at 42°C and DNA-PKcsi [1 μM] to radiation treatment was investigated in cervical and breast cancer cells, primary breast cancer sphere cells (BCSCs) enriched for cancer stem cells, and in an in vivo human tumor model. A significant radio-enhancement effect was observed for all cell types when DNA-PKcsi and HT were applied separately, and when both were combined, HT and DNA-PKcsi enhanced radio-sensitivity to an even greater extent. Strikingly, combined treatment resulted in significantly lower survival rates, 2 to 2.5 fold increase in apoptosis, more residual DNA-DSB 6 h post treatment and a G2-phase arrest. In addition, tumor growth analysis in vivo showed significant reduction in tumor growth and elevated caspase-3 activity when radiation was combined with HT and DNA-PKcsi compared to radiation alone. Importantly, no toxic side effects of HT or DNA-PKcsi were found.In conclusion, inhibiting DNA-DSB repair using HT and DNA-PKcsi before radiotherapy leads to enhanced cytotoxicity in cancer cells. This effect was even noticed in the more radio-resistant BCSCs, which are clearly sensitized by combined treatment. Therefore, the addition of HT and DNA-PKcsi to conventional radiotherapy is promising and might contribute to more efficient tumor control and patient outcome.

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

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 Sensitizes Glioma Stem-like Cells to Radiation by Inhibiting AKT Signaling.

Glioma stem-like cells (GSC) are a subpopulation of cells in tumors that are believed to mediate self-renewal and relapse in glioblastoma (GBM), the most deadly form of primary brain cancer. In radiation oncology, hyperthermia is known to radiosensitize cells, and it is reemerging as a treatment option for patients with GBM. In this study, we investigated the mechanisms of hyperthermic radiosensitization in GSCs by a phospho-kinase array that revealed the survival kinase AKT as a critical sensitization determinant. GSCs treated with radiation alone exhibited increased AKT activation, but the addition of hyperthermia before radiotherapy reduced AKT activation and impaired GSC proliferation. Introduction of constitutively active AKT in GSCs compromised hyperthermic radiosensitization. Pharmacologic inhibition of PI3K further enhanced the radiosensitizing effects of hyperthermia. In a preclinical orthotopic transplant model of human GBM, thermoradiotherapy reduced pS6 levels, delayed tumor growth, and extended animal survival. Together, our results offer a preclinical proof-of-concept for further evaluation of combined hyperthermia and radiation for GBM treatment.

OP0014 Thermal enhancement sensitises gastric cancer stem cells to chemotherapy through ROS-modulation-induced autophagic death

Background Peritoneal metastasis in gastric cancer is hypothesised to result from residual cancer stem cells (CSCs), which play an important part in the comprehensive treatment of gastric tumour. Hyperthermia could enhance the anti-cancer effects of chemotherapy, but the precise biochemical mechanisms of the synergistic antitumour effect of chemotherapy plus hyperthermia are unclear. In this study, we investigated whether hyperthermic enhancement sensitises gastric CSCs to chemotherapy through ROS-modulation-induced autophagic death. Methods Using CD44 as a marker, we isolated CSCs by fluorescence-activated cell sorting in a MNK-45 human gastric cancer line or tumours from a NOD/SCID mouse xenograft model. After treatment with chemotherapy plus hyperthermia, the proportion change in the CD44-positive MNK-45 cell subpopulation was observed in CD44-positive MNK-45 cells or tumour cells from the mouse model. Tumorigenic ability was studied, autophagy-related gene Beclin1 and LC3 expression were evaluated, ROS production was measured, and HSP multiplex concentrations were determined in CD44-positive MNK-45 cells from the mouse model. Findings After treatment with chemotherapy plus hyperthermia, the proportion of CD44-positive MNK-45 cells significantly decreased, CD44-positive MNK-45 tumour growth was suppressed, and inhibition of tumour growth was closely associated with the decreased proportion of CD44-positive MNK-45 cells. Chemotherapy plus hyperthermia significantly increased the expression of Beclin1 and LC3 and inhibited HSP expression in tumours from the mouse xenograft model. CD44-positive MNK-45 gastric cancer cells showed a significantly higher level of ROS after compared with before hyperthermia and chemotherapy, and the decreased proportion of CD44-positive MNK-45 cells was almost completely consistent with increased expression of Beclin1 and LC3 and suppression of HSP expression after chemotherapy plus hyperthermia treatment in tumours from the mouse xenograft model. Interpretation The addition of hyperthermia can eliminate the resistance of gastric CSCs to chemotherapy. Mild thermal enhancement sensitises gastric CSCs to chemotherapy through ROS-modulation-induced autophagic death.

Systemic therapy and hyperthermia for locally advanced soft tissue sarcoma

Patients with high-risk soft tissue sarcomas (FNCLCC grades 2-3, > 5cm and deep lying) are at a high risk of local recurrence or distant metastases despite optimal surgical tumor resection. Therefore, multimodal treatment should be considered for this difficult to treat patient group. Besides surgery, radiation therapy and chemotherapy, hyperthermia has become a valid, complementary treatment option within multimodal treatment concepts. Hyperthermia in this context means the selective heating of the tumor region to temperatures of 40-43 °C for 60min by microwave radiation in addition to simultaneous chemotherapy or radiation therapy. A randomized phase III study demonstrated that the addition of hyperthermia to neoadjuvant chemotherapy improved tumor response and was associated with a minimal risk of early disease progression as compared to chemotherapy alone. The addition of hyperthermia to a multimodal treatment regimen for high-risk soft tissue sarcoma consisting of surgery, radiation therapy and chemotherapy, either in the neoadjuvant or adjuvant setting after incomplete or marginal tumor resection, significantly improved local progression-free and disease-free survival. Based on these results and due to the generally good tolerability of hyperthermia, this treatment method in combination with chemotherapy should be considered as a standard treatment option within multimodal treatment approaches for locally advanced high-risk soft tissue sarcoma.

Response of blood flow to hyperthermia in human prostate tumors: Opportunities for enhanced radiation effect and drug delivery.

189 Background: Tissue perfusion may be a significant factor affecting outcome of prostate cancer treatment. Hyperthermia has been shown to have beneficial anti-cancer effects when combined with other anti-neoplastic modalities including radiation, chemotherapy, and immunotherapy. For instance, hyperthermia may increase prostate perfusion resulting in radiosensitization through increased oxygenation and chemotherapy through enhanced drug delivery. We previously reported significant benefit to the addition of hyperthermia to radiation on a phase II trial for men with locally advanced prostate cancer. To better understand tissue perfusion in patients with prostate cancer and response to hyperthermia, we measured perfusion levels in patients on this trial before and after hyperthermia. Methods: Prostate perfusion was measured before and immediately after heating in a total of 21 hyperthermia treatments in 14 patients with prostate cancer. A trans-rectal ultrasound device with a water cooled jacket was used to heat the prostate. Prostate tissue temperatures were measured using three multisensory thermocouple probes. Perfusion was measured with the TDP-200 Thermal Diffusion Probe, a thermistor-based device which quantifies perfusion with a modified wash-out technique. Results: In 19 treatments in which perfusion was measured before heating, average and standard deviation was 18.3 ± 10.6 ml/100g-min and in 17 treatments in which perfusion was measured after heating, it was 30.7 ± 20.8 ml/100g-min. This represents a statistically significant increase of 68% (p = 0.018). Perfusion increased 12 of 15 treatments in which measurements were obtained before and after hyperthermia. Notably, prostate tissue that was most ischemic prior to heating experienced the largest heat-induced perfusion increase. Conclusions: Prostate perfusion increased significantly with a majority of hyperthermia treatments. Enhanced prostate oxygenation may have been a contributing factor to the benefit noted with hyperthermia in this phase II trial. The use of hyperthermia to augment prostate perfusion to enhance radiation, chemotherapy, and immunotherapy warrants further investigation.

Old and new facts about hyperthermia-induced modulations of the immune system

Hyperthermia (HT) is a potent sensitiser for radiotherapy (RT) and chemotherapy (CT) and has been proven to modulate directly or indirectly cells of the innate and adaptive immune system. We will focus in this article on how anti-tumour immunity can be induced by HT. In contrast to some in vitro assays, in vivo examinations showed that natural killer cells and phagocytes like granulocytes are directly activated against the tumour by HT. Since heat also activates dendritic cells (DCs), HT should be combined with further death stimuli (RT, CT or immune therapy) to allocate tumour antigen, derived from, for example, necrotic tumour cells, for uptake by DCs. We will outline that induction of immunogenic tumour cells and direct tumour cell killing by HT in combination with other therapies contributes to immune activation against the tumour. Studies will be presented showing that non-beneficial effects of HT on immune cells are mostly timely restricted. A special focus is set on immune activation mediated by extracellular present heat shock proteins (HSPs) carrying tumour antigens and further danger signals released by dying tumour cells. Local HT treatment in addition to further stress stimuli exerts abscopal effects and might be considered as in situ tumour vaccination. An increased natural killer (NK) cell activity, lymphocyte infiltration and HSP-mediated induction of immunogenic tumour cells have been observed in patients. Treatments with the addition of HT therefore can be considered as a personalised cancer treatment approach by specifically activating the immune system against the individual unique tumour.

Re-surgery and chest wall re-irradiation for recurrent breast cancer - a second curative approach

BackgroundRepeat radiation is a rarely used treatment strategy that must be performed with caution. The efficacy and toxicity of a second curative radiotherapy series was investigated in cases of recurrent breast cancer.MethodsForty-two patients treated from 1993 to 2003 with resection (n = 30) and postoperative re-irradiation or definitive re-irradiation (n = 12) for recurrent breast cancer were enrolled in the study. Concurrent hyperthermia was performed in 29 patients. The median age was 57 years. The median pre-radiation exposure was 54Gy. Re-irradiation was conventionally fractionated to a median total dose of 60Gy.ResultsAfter a median follow-up of 41 months (range 3-92 months) higher graded late toxicity > G3 according to CTC 3.0 and LENT-SOMA was not observed. The estimated 5-year local control rate reached 62%. The estimated 5-year overall survival rate was 59%. Significantly inferior survival was associated with recurrence within two years (40 vs. 71%, p < ([0-9]).01) and presence of macroscopic tumour load (24 vs. 75%, p = 0.03).ConclusionsRepeat radiotherapy for recurrent breast cancer with total radiation doses of 60 Gy and the addition of hyperthermia in the majority of patients was feasible, with acceptable late morbidity and improved prognosis, particularly in patients with previous resection of recurrent tumours.

Hyperthermia Sensitizes Breast Cancer Stem Cells to Radiation Therapy.

Abstract Background In cancer, metastatic disease and recurrence are hypothesized to result, at least in part, from the residual cancer stem cells (CSCs), also referred to as tumor-initiating cells(TICs), which evade initial treatment. In several genetically engineered mouse models that resemble human breast cancer, the tumor subpopulation CD29+/CD24+/lin- has been shown to be more tumorigenic as compared to other subpopulations by in vitro and in vivo assays. We and others have demonstrated that the tumorigenic CD29+/CD24+/lin- subpopulation repairs radiation-induced DNA strand breaks more efficiently than the other subpopulations. Therefore, we hypothesized that hyperthermia, a documented means of inhibiting DNA repair, may radiosensitize CSCs to radiation therapy(RT) by delaying and inhibiting the repair of DNA strand breaks. Methods To test this hypothesis, we assayed for tumorigenic CD29+/CD24+/lin- cells in p53null mouse mammary tumor model with and without radiation, and in combination with hyperthermia (42°C) administered as optically-activated gold nanoparticles. We then determined if there was a decrease in functional CSCs by FACS analysis and limiting dilution transplantation assays. Results These studies confirmed that CD29+/CD24+/lin- cells were more radiation resistant and that their relative proportion was increased after RT, as compared to the other cell populations. However, the addition of hyperthermia increased the sensitivity of the CD29+/CD24+/lin- subpopulation to radiation. Radiation treatment alone in vivo resulted in a decrease in tumor size, but the percentage of tumorigenic cells increased as compared to untreated controls. In contrast, following post-treatment with 20 minutes of local hyperthermia, using intravenously administered optically activated gold nanoparticles, a larger regression in tumor size was observed, without a concomitant increase in the percentage of CD29+/CD24+/lin- tumorigenic cells. Using the functional limiting dilution transplantation assay to assay for CSCs, we showed that 48 hours after treatment cells derived from tumors treated with RT exhibited an increased frequency of TICs as compared to untreated controls, and tumors treated with radiation and hyperthermia. In addition, clonogenic survival assays of this tumorigenic subpopulation had consistent results with the in vivo data. Conclusion These results suggest that localized hyperthermia serves as a simple strategy to selectively sensitize the radioresistant subpopulation of CSCs to enhance their response to radiation therapy. The mechanisms responsible for these effects of hyperthermia are currently under investigation. Supported by grant NCI R01 CA112305 and CA16303. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 506.

Thermoradiotheraphy for cancer: an effective approach

Hyperthermia (HT) means using controlled temperatures of 40-45°C for cancer treatment. HT is applied with different methods e.g. superficial-HT, locoregional deep-HT, interstitial- HT, intracavity-HT, and whole body-HT. HT can apply in different tumor sites such as breast cancer, melanoma, head and neck, cervix cancer, and glioblastoma. Literatures show that addition of HT to radiotherapy, chemotherapy, or both, will result better tumor response rate, local control, and survival rate; without increasing toxicity. HT can also improve palliative effects in patient. In recent years, due to substantial technical improvements made in achieving selected increase of temperatures in superficial and deep-seated tumors, thermometry, and treatment planning; HT is becoming more clinically accepted in Europe and the USA. HT, as an adjunct cancer treatment modality, is certainly a promising approach; however, it is not well known yet worldwide. Therefore, it seems there is need to know more about that. The purpose of this review is to provide an overview on the application of HT combined with conventional cancer treatment modalities, mainly radiotherapy. The article also introduces mechanism of HT, heating delivery modes, thermometry, and it summarizes results of randomized trials form Western research groups.

Locoregional treatment of peritoneal carcinomatosis from gastric cancer

The authors reviewed the natural history and the main features of the peritoneal carcinomatosis from gastric cancer briefly and analyzed the pertinent literature concerning the locoregional modalities for prevention and for treatment. Results of the web based voting by experts were also summarized. As regards the peritoneal perfusion with cytotoxic drugs with or without hyperthermia for preventing peritoneal carcinomatosis in high risk patients, there are some randomized clinical trials and one meta-analysis supporting a benefit of the procedure. However, disparity in methodology (drugs, dosage, duration of the treatment, addition of hyperthermia, etc.) precludes the adoption of a shared protocol to be used in the clinical practice in high risk patients. Once the peritoneal carcinomatosis is established, the approach reported in literature is the peritonectomy associated with hyperthermic perfusion. However, data supporting benefits are scanty, and limited to few centers with a specific experience in this field. With regard to the main questions addressed to the experts' panel and concerning the indications for treatment and methodology, there was a general consistency among the experts and agreement with the findings of the literature. The need for a large multicenter trial to confirm the benefit and risk of intraperitoneal chemotherapy was recognized by both the experts and the authors.

Multi-Institutional Review of Repeat Irradiation of Chest Wall and Breast for Recurrent Breast Cancer

To review the toxicity and clinical outcomes for patients who underwent repeat chest wall or breast irradiation (RT) after local recurrence. Between 1993 and 2005, 81 patients underwent repeat RT of the breast or chest wall for locally recurrent breast cancer at eight institutions. The median dose of the first course of RT was 60 Gy and was 48 Gy for the second course. The median total radiation dose was 106 Gy (range, 74.4-137.5 Gy). At the second RT course, 20% received twice-daily RT, 54% were treated with concurrent hyperthermia, and 54% received concurrent chemotherapy. The median follow-up from the second RT course was 12 months (range, 1-144 months). Four patients developed late Grade 3 or 4 toxicity. However, 25 patients had follow-up >20 months, and no late Grade 3 or 4 toxicities were noted. No treatment-related deaths occurred. The development of Grade 3 or 4 late toxicity was not associated with any repeat RT variables. The overall complete response rate was 57%. No repeat RT parameters were associated with an improved complete response rate, although a trend was noted for an improved complete response with the addition of hyperthermia that was close to reaching statistical significance (67% vs. 39%, p = 0.08). The 1-year local disease-free survival rate for patients with gross disease was 53% compared with 100% for those without gross disease (p < 0.0001). The results of our study have shown that repeat RT of the chest wall for patients with locally recurrent breast cancer is feasible, because it is associated with acceptable acute and late morbidity and encouraging local response rates.

Effect of 41°C and 43°C on cisplatin radiosensitization in two human carcinoma cell lines with different sensitivities for cisplatin

The effect of trimodality treatment consisting of hyperthermia, cisplatin and radiation was investigated in two cell lines with different sensitivities to cisplatin. Hyperthermia treatment was performed for 1 h at 41 degrees C and 43 degrees C in order to compare the effects of the two temperatures. Clonogenic assays were performed with cisplatin-sensitive SiHa human cervical carcinoma and cisplatin-resistant SW-1573 human lung carcinoma cell lines. Cells were treated with various combinations of hyperthermia, cisplatin and radiation. Radiation was performed after 1 h of simultaneous hyperthermia and cisplatin treatment. Cisplatin exposure was for 1 h or continuous without refreshment of the cisplatin-containing medium. SiHa cells were more sensitive to cisplatin than SW-1573 cells. Hyperthermia at 41 degrees C decreased survival in SW-1573 cells but was not cytotoxic in SiHa cells. Hyperthermia at 43 degrees C decreased survival dramatically in both cell lines with SiHa being the most sensitive. The addition of hyperthermia at 41 degrees C and 43 degrees C to cisplatin treatment led to enhanced cell kill in both cell lines compared with cisplatin alone. Radiosensitization was observed after continuous but not after 1 h of cisplatin treatment. Hyperthermia at 43 degrees C increased radiosensitivity whereas hyperthermia at 41 degrees C did not. A combination of 41 degrees C hyperthermia with continuous cisplatin treatment had an additive effect on SW-1573 cells but enhanced cisplatin radiosensitivity of SiHa cells. In SW-1573 cells trimodality treatment using 43 degrees C hyperthermia enhances cisplatin radiosensitivity. We conclude that hyperthermia at 43 degrees C enhances cisplatin-induced radiosensitization in both cisplatin-sensitive and -resistant cell lines. Hyperthermia at 41 degrees C was also able to increase cisplatin-induced radiosensitivity but only in the cisplatin-sensitive SiHa cell line.