Year : 2019 | Volume
: 10 | Issue : 4 | Page : 174--185
Abstracts of 11th biennial conference of indian association of hyperthermic oncology and medicine, february 15-16, 2020, Nanavati Hospital, Mumbai
|How to cite this article:|
. Abstracts of 11th biennial conference of indian association of hyperthermic oncology and medicine, february 15-16, 2020, Nanavati Hospital, Mumbai.J Radiat Cancer Res 2019;10:174-185
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. Abstracts of 11th biennial conference of indian association of hyperthermic oncology and medicine, february 15-16, 2020, Nanavati Hospital, Mumbai. J Radiat Cancer Res [serial online] 2019 [cited 2020 Jul 8 ];10:174-185
Available from: http://www.journalrcr.org/text.asp?2019/10/4/174/278413
Modulated Electro-Hyperthermia – Towards the Immunogenic Hyperthermic Action
Professor, Chair, Department of Biotechnics, St.Istvan University, Hungary, Chief Science Officer (CSO), Oncotherm GmbH/Kft., Hungary/Germany
Memorial oration of Dr. BB. Singh – It is my honor to present a talk in memory of Dr. B.B. Singh who held a first class Master's degree in Physics and Ph. D. in the field of radiation biology from the University of London. His pioneering research work has resulted in an entirely new additional arm in the treatment of cancer by radiation comprising of non-chemotherapeutic drugs and mild hyperthermia.
The modulated electro-hyperthermia (mEHT, trade name oncothermia®) represents a new paradigm of hyperthermia treatment for solid tumors. The mEHT heats the malignant cells selectively, contrary to the conventional isothermal approach it follows the natural heterogeneity of the tumor-structure by selective energy-absorption, focusing on the cellular selection of the malignant cells. It has long history from the laboratory experiments to the human therapies. The mEHT uses sophisticated mechanisms of focusing the electric field on the cellular membrane helped by modulation technique. The main medical task to treat advanced malignant diseases requests treating systemically being effective on the possible micro and macro metastases all over the body. The local technics of mEHT effects on the distant metastases using tumor-specific immune reactions.
A capacitive impedance coupled electromagnetic heating method is the base of the mEHT technics, using 13.56 MHz radiofrequency amplitude modulated with time-fractal (1/f) pattern.
The mEHT causes massive apoptosis by exciting death-toll receptors and transient reaction potential channels of the membrane. The large number of apoptotic bodies together with the correct time sequences of cell membrane exposure of Calreticulin, release of HMGB1 protein and membrane expression of HSP70 forming a damage associated molecular pattern and causing immunogenic cell-death. This immune-activation process causes abscopal effect with concomitant application of (anyway ineffective) immune-stimulators. The immune actions are well proven in laboratory experiments, and in some clinical applications for advanced metastatic cancers including brain tumors too.
The method mEHT extends the local hyperthermia treatment to systemic, making available to treat advanced cancers with distant metastases.
Evolution of Magnetic Hyperthermia for Cancer Therapy: Past, Present and Future Prospective
Ruby Gupta1 and Deepika Sharma2*
1Research Scholar, Institute of Nano Science and Technology, Habitat Centre, Phase- 10, Sector- 6, Mohali, Punjab – 160062 2Scientist C, Institute of Nano Science and Technology, Habitat Centre, Phase- 10, Sector- 6, Mohali, Punjab – 160062
Over the years, much research has been done to prove the Magnetic hyperthermia as a cancer treatment. Magnetic hyperthermia-based cancer therapy (MHCT) was first attempted in 1957 to treat cancers that had metastasized to the lymph nodes and is built upon the principles of localized heat generation on the application of alternating magnetic field (AMF) in the presence of magnetic nanoparticles (MNPs). Controlling the magnetic properties of a nanoparticle efficiently via its particle size to achieve optimized heat under AMF is the central point for MHCT. In our lab, we have shown the successful use of stevioside (a natural plant-based glycoside) as a promising biosurfactant to control the magnetic properties of Fe3O4 nanoparticles by controlling the particle size. Our results showed that stevioside coating onto nanoparticles, besides enhancing cellular uptake in glioma cells, also exhibited significant improvement in the calorimetric hyperthermia activity, through particle size reduction, which is essential for MHCT. The stevioside-coated nanomagnets were further investigated for in-vitro MHCT (405 kHz, 168 Oe), showing their efficacy to induce cell death of rat C6 glioma cells after 30 min at a target temperature T = 43°C. The surface modification of the stevioside molecule was further done to enhance the water stability of nanomaterials that resulted in a remarkable specific absorption rate of 191.25 W/g. At present we are also evaluating the application of citric acid-coated Manganese doped magnetic nanoclusters for bimodal GBM therapy by MHCT and photothermal therapy. The results obtained so far are suggestive of their great potential for use in localized hyperthermia treatment of solid tumors, either alone or in combination with other adjuvant therapies. We believe that, in the future, advancements in magnetic nanosystems might contribute towards establishing magnetic hyperthermia as a potential treatment for cancer.
Iron oxide based Magnetic Nano-formulations for Improvement of Cancer Radiotherapy
Neena G. Shetake, Amit Kumar and B. N. Pandey
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai-85, India
E-mail : firstname.lastname@example.org
Despite of the advances in therapeutic modalities, cancer still remains one of the major causes of death all over the world. Amongst the conventional cancer treatment options, radiotherapy is regarded as one of the most important modalities of cancer management, but its success is limited by several factors, such as (i) non-targeted or non-specificity to tumor cells, (ii) associated normal tissue damage, (iii) development of resistance to radiation, etc. Therefore, development of better targeted and multi-prong approaches to overcome the limitations of current modalities has become indispensable. Nanoparticles are excellent platforms for targeted co-delivery of one or more anti-cancer agents due to their several bio-physical properties, such as, (i) high surface to volume ratio, (ii) amenability for functionalization with different capping agents, etc. Amongst nanoparticles, iron oxide nanoparticles are in the focus of intense research because of their additional property of super-paramagnetism, owing to which they can be used as contrast agents for magnetic resonance imaging and for magnetic hyperthermia therapy of cancer. In the present study we have synthesized and thoroughly characterized oleic acid functionalized iron oxide nanoparticles (MN-OA, size: 10nm) and demonstrated their magnetic hyperthermia efficacy in WEHI-164 (fibrosarcoma) cancer cells and its tumor model. We have elucidated the mechanism of hyperthermic killing, which was found to be mediated through down-regulation of HSP90 and its pro-survival client protein, AKT. Moreover, these nanoparticles showed excellent cancer radio-sensitizing ability as evident from the significant decrease in the clonogenic survival (~ 91%) of cancer cells as compared to only MN-OA or only 2 Gy treatments. Moreover, MN-OA+2Gy showed significant induction of G2-M cell cycle arrest, apoptosis and mitotic catastrophe in WEHI-164 cells. The mechanism of radio-sensitization was found to be mediated by binding of MN-OA with HSP90 and down-regulation of its client proteins involved in the cell cycle progression (Cyclin B1 and CDC2) and DNA-double strand break repair (e.g. RAD51 and BRCA1). These results were validated in murine fibrosarcoma model as well. Thus, these in vitro and in vivo data revealed the role of HSP90 and its client proteins in the mechanism of tumor radio-sensitization by MN-OA.
On the Development of 434 Mhz Phased Array Applicator for Hyperthermia Treatment of Locally Advanced Breast Cancer
Divya Baskaran and Kavitha Arunachalam
Department of Engineering Design, Indian Institute of Technology Madras, Chennai, India.
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Rapid rise in the incidence of locally advanced breast cancer (LABC) in India and lack of phased array (PA) prototype for hyperthermia treatment (HT) of LABC motivated us to design a PA applicator with good hotspot control, large focal spot size and ability to treat varied patient population and tumor location. The PA works on the principle of radio detection and ranging (RADAR) and is constructed using dielectric loaded patch antenna as the basic element. The performance of the PA to steer and selectively deposit power at the tumor target was evaluated using numerical breast models of varying sizes and tissue heterogeneity, and tumor of size 40 mm and above to simulate LABC. Hotspot to target ratio <1.34, average power absorption ratio > 3.93 and TC25 >80% was achieved for all the patient models. The PA applicator was fabricated for experimental verification. The ability to selectively heat a target volume was assessed using 3D breast phantom fabricated based on the anonymized magnetic resonance image (MRI) data of patient with LABC. A 6.55°C temperature rise from the baseline temperature was achieved in the tumor target locations that were predefined in the breast phantom. Temperature rise in the healthy tissue immediately surrounding the tumor target was less than 4°C and regions far away from the tumor target was less than 2°C, which indicates selective power deposition in the tumor site with acceptably low thermal dose in the healthy tissue regions. Hyperthermia phantom heating experiments demonstrated that the proposed PA applicator for HT of LABC can be used for targeted heating of the intact breast with LABC with acceptably low temperature rise in the surrounding healthy tissues in good agreement with the simulations. However, rigorous validation with anatomically realistic breast phantom is required before moving towards preclinical trials.
Report on the Addition of Modulated Electro-Hyperthermia to Chemoradiotherapy for Hiv-Positive/-Negative Cervical Cancer Patients in South Africa
CA Minnaar1,2 and JA Kotzen2 and A Baeyens1,3
1University of the Witwatersrand, Department of Radiobiology, 17 Jubilee road, Parktown, 2193, South Africa, 2Wits Donald Gordon Academic Hospital, 18 Eton Road, Parktown, 2193, South Africa, 3University of Ghent, Department of Human of Structure and Repair, Corneel Heymanslaan 10, 9000 Ghent, Belgium.
In a resource-constrained setting with high risk patients (obese; Human Immunodeficiency Virus (HIV) positive; malnourished), investigations into feasible radiosensitisers are warranted. Modulated electro-hyperthermia (mEHT) is a capacitive coupled heating technology that uses amplitude modulated radio waves to induce mild local heating of tumours. A Phase III clinical trial investigated the addition of mEHT to chemoradiotherapy for FIGO stage IIB to IIIB cervical cancer patients (staged clinically) in a public hospital in South Africa. 210 participants were randomised to receive chemoradiotherapy with/without mEHT and 101 participants in each group were eligible for six month local disease free survival (LDFS) analysis. Inclusion criteria: Signed informed consent; HIV-positive patients with a CD4 count >200 cells/mm3 and/or on antiretroviral treatment; normal renal function. Patients with bilateral hydronephrosis and fistulas were excluded. Tumour response at six months post treatment was assessed by 18F-FDG PET/CT. All participants have reached six months post treatment. Six month LDFS and local disease control (LDC; censored for survival) were significantly higher in the group treated with mEHT (LDFS: n=39[38.6%]; LDC: n=40[45.5%]), than in the Control Group (LDFS: n=20[19.8%] n=20[24.1%]); (LDFS: p=0.003; LDC: p=0.003). In the participants who have reached three years post-treatment, three year disease-free survival is significantly higher in the mEHT group: 18[58%] versus 16[35%], (HR: 1.97; p=0.042).The addition of mEHT to the treatment protocols did not significantly increase the toxicity profile of chemoradiotherapy. mEHT effectively and safely sensitises LACC tumours to chemoradiotherapy and could therefore drastically improve the outcomes for locally advanced, high-risk cervical cancer patients in resource-constrained settings.
Hyperthermia'S Benefits in the Portfolio of Cancer Therapies with the Focus on Enhancing Immunological Therapies (Including Checkpoint Inhibitors /Car-T)
Univ. Mannheim, Germany
Hyperthermia as a therapy concept in chronical diseases including cancer exists already for a long time. But one has to differentiate between the various forms of hyperthermia and the intended rationale. Hyperthermia to enhance effects of local radiation is a very different form of hyperthermia than whole body hyperthermia with the objective to boost the immunological status of a patient. The presentation will briefly differentiate the various hyperthermia forms, the temperatures desired and achievable and its different rationales. The focus, however, will be on the potential that hyperthermia offers to boost the effect of novel immunological therapy concepts that have emerged lately such as checkpoint inhibitors. Some interesting synergies of how hyperthermia can influence the T-cell response just came up in the last years. The beneficial potential of upregulating a body's temperature is still not entirely understood but likely it is not without reason that evolution developed fever in its immunological arsenal against adverse developments in its microenvironment and/or cellular level. Finally, as an outlook, the presentation will briefly discuss those forms of hyperthermia that use electromagnetic fields to generate the heat which may have effects due to their inherent frequency characteristics. There exists a controversial and open discussion into this theme.
Experimental Feasibility of Ultrasound Guided Microwave Hyperthermia Treatment Delivery
Divya Baskaran1, AliArshad Kothawala2, Arun Kumar Thittai2, and Kavitha Arunachalam1
1Department of Engineering Design, Indian Institute of Technology Madras, Chennai, India. 2Department of Applied Mechanics, Indian Institute of Technology Madras, Chennai, India.
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The objective of this work is to demonstrate the feasibility of ultrasound (US) image guided hyperthermia treatment (HT) to provide real-time temperature feedback to the user to precisely control power deposition in tissue during HT delivery. A 434 MHz phased array (PA) applicator with 18 antennas arranged in 3 rings with 6 antennas per ring and cylindrical human muscle tissue mimicking phantom were used in this study. The required amplitude and phase excitation of each antenna in the PA applicator for targeted power deposition inside the phantom were calculated using electromagnetic simulations and multi objective genetic algorithm based optimization technique. A subset of 9 antennas in the 18-antenna PA was connected to an in-house 9-channel hyperthermia delivery system. Heating experiments were carried out with microwave sources OFF for the initial 600 s, ON for the next 1200 s and OFF for the remaining time. A linear array US transducer operating at 5 MHz center frequency was placed on top of the muscle phantom during PA heating. A conventional focused imaging with a fixed transmit focus was used to acquire raw radio frequency (RF) data at 1-minute interval with sampling frequency of 20 MHz. The raw RF data was beamformed using a delay and sum (DAS) beamformer and the signal was processed using regularized log spectral difference (RLSD) technique. The ground truth measurements for the phantom heating experiments were gathered using an 8-channel fibre optic thermometry (FOT) probes placed inside the phantom. The transient temperature profile measured by FOT probes and US transducer during the heating experiment was compared. Preliminary experimental study demonstrates the feasibility of extracting spatio-temporal evolution of temperature distribution at depth from the processed US images and the potential of US based image-guided non-invasive 3D thermometry for real time feedback control during HT delivery.
Intracavitary Tandem Applicator for Sequential Delivery of Microwave Hyperthermia and Hdr Brachytherapy
Shabeeb Ahamed KP1 and Kavitha Arunachalam2
1Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 2Department of Engineering Design, Indian Institute of Technology Madras, Chennai
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Hyperthermia (HT), which involves selective heating of target to 40−45 °C for 60 minutes, has a strong biological and clinical rationale to be combined with Radiation Therapy (RT) and Chemotherapy(CT). Unlike external heating devices, endocavitary applicators can deliver higher thermal or radiation doses to tumor targets with minimum dose to the neighboring healthy tissues for tumors within or adjacent to natural body cavities. An intracavitary tandem applicator is presented, which can deliver microwave (MW) Hyperthermia and HDR brachytherapy sequentially. Tandem, once placed within the patient at the tumor site, can be used for both heat delivery and HDR brachytherapy. The developed applicator includes an intracavitary tandem of standard HDR brachytherapy tandem dimensions, a microwave antenna along with cooling channels for circulating cooling water, and supporting accessories for aligning antenna centrally to the tandem and an insert within which tubings from HDR brachytherapy after loaders can be inserted for radiation delivery. Different types of antennas at multiple operating frequencies are also presented so as to deliver targeted thermal dose to varying tumor sizes. MW antennas are numerically evaluated in terms of power reflection characteristics and specific absorption rate (SAR), and experimentally validated using tissue-mimicking phantom. The fabricated applicators resonate at the designed frequencies with less than 1 percentage power reflection. The 25% axial SAR varied from 37 mm to 60 mm for varying antenna profiles and the radial SAR was measured to be 16 mm which can be used to deliver HT for tumors of varying sizes.
Role of Focused Ultrasound Heating in Nanoparticle-based Cancer Chemo-Immunotherapy
Associate Professor and Endowed Chair, Centre for Veterinary Health Sciences, Oklahoma State University, 90 SU
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Magnetic resonance and ultrasound (US)-guided focused ultrasound (FUS) is a clinically relevant therapeutic technology that provides a spatially accurate mechanical stress and heating of a solid tumor, without causing collateral toxicity to healthy tissues. FUS can also promote immunogenic recognition of tumor cells by aiding the translocation of damage associated membrane proteins. Our research has shown that FUS-induced local heating and stress and combination with lipid-based nanoparticles can modify the tumor microenvironment to impart several benefits including enhanced solid cancer chemotherapy, tumor antigen release, and anti-tumor immunity compared to conventional therapy in pre-clinical models. In this seminar, I will discuss the concepts and techniques, and also provide examples of clinical translation in canine cancer treatment.
Chemoradiation with Hyperthermia in the Treatment of Head and Neck Cancer
Nanavati Super Specialty Hospital, Mumbai
The management of head and neck cancer requires skilled integration of multiple modalities such as surgery, radiation, chemotherapy and hyperthermia. Chemoradiation can benefit from the addition of a proven modality such as hyperthermia in increasing survival, disease-free survival and quality of life without increasing the risk of complication. The purpose of this retrospective study was to evaluate the feasibility and efficacy of hyperthermia with chemoradiation in advanced head and neck cancers.
Between January 2004 and May 2008 40 patients with advanced head and neck cancers were allocated for hyperthermia with chemoradiotherapy. All patients underwent radiation on a telecobalt machine. A total dose of 70 Gy in 7 weeks with conventional fractionation was given with weekly chemotherapy of cisplatin 50 mg or paclitaxel 60 mg. Patients underwent hyperthermia on a radiofrequency machine at 8.2 MHz for 30 min at 41○–43○C with 10 min pre-cooling to 5○C.
No patient had life-threatening complications. Only 38 out of 40 patients were eligible for assessment of immediate response as one patient died during treatment and the other did not complete treatment. Complete response was 76.23% (29 pts), and 23.68% (9 pts) had partial response. Overall survival by the Kaplan Meir method was 75.69% at 1 year and 63.08% at 2 years. No enhanced mucosal or thermal toxicities were documented as compared to our earlier experience with chemoradiation. Conclusion: This retrospective analysis demonstrates the feasibility and efficacy of chemoradiation with hyperthermia in advanced head and neck cancer. The study is encouraging enough to start a randomised trial to compare chemoradiation with triple modality of treatment.
This retrospective analysis demonstrates the feasibility of chemoradiation with hyperthermia in advanced head and neck cancer. Head and neck cancer with very high tumour burden have a gloomy survival prospect. The study is encouraging enough to start a randomised trial to compare chemoradiation with chemohyperthermia and radiation.
The Evidence So Far, An Appraisal of Clinical Trials
Radiation Oncologist, Ex-Gujarat Cancer and Research Institute, Ahmadabad
Hyperthermia is one of the oldest methods of treatment of cancer. Unfortunately, there are very few studies in the field till date. The role of superficial hyperthermia and deep hyperthermia is well established in some of the reviewed studies.
The studies have shown very good outcomes in form of improvement in overall survival, disease free survival, improvement in quality of life with inclusion of Hyperthermia along with Radiotherapy and/or chemotherapy. In recurrent and/ or locally advanced tumors, Hyperthermia has proven its efficacy.
But still the modality has no or minimal acceptance amongst the oncologists worldwide. Many of the major Guidelines have not included the modality as the standard care of treatment yet. Though it is believed to be the fourth pillar of cancer treatment, there are only one or two centers in India who offers the treatment.
Many more studies with large number of patient data are required. The place in NCCN guideline as a standard treatment modality will help in acceptance amongst the oncologist.
Hif-1A: Key Promotor of Malignant Progression, Central Driver of Metabolic Reprogramming, and Putative Role in Hyperthermia Treatment
Department of Radiation Oncology, Medical Center, University of Freiburg, Germany, Department of Radiation Oncology, University Medical Center, Mainz, Germany
The identification and purification of the hypoxia-inducible transcription factor-1α (HIF-1α) by the pioneering work of Semenza and Wang was a milestone in our understanding of how mammalian cells sense O2 deficiency (hypoxia) and adapt -within minutes- to low oxygen (O2) levels in order to maintain cellular metabolism and vital functions, The center of the transcriptional response to hypoxia is the active HIF-1 complex, which is composed of HIF-1α, the limiting component, and HIF-1 . In this complex, the two subunits are heterodimerized and bind to recognition sequences in the DNA (HRE = hypoxia responsive elements) that are present in a large cohort of genes, and thus are activated during hypoxia. So far, >200 target genes have been identified whose products are involved -inter alia- in embryonal development, cell survival, angiogenesis, erythropoiesis, bone formation, enhanced anaerobic glycolysis, high altitude adaptation, and wound repair. The physiological regulation of HIF-1α was investigated independently by G. Semenza. W. Kaelin and P. Ratcliffe, the winners of the 2019 Nobel Prize in Physiology and Medicine. Hypoxia is widespread within most solid tumors. This stress situation is sufficient to activate HIF-1α that mediates - in a counterproductive/fatal manner - the activation of survival pathways in cancer cells. In cancers, HIF-1α can also be induced by O2-independent (normoxic) genetic deregulations that activate (PI3K/AKT-mTOR, MEK/ERK) or deactivate (AMPK) signaling pathways, activate oncogenes (cMYC, RAS) and/or inactivate tumors suppressors (mutant- p53, mutant- PTEN, mutant-pVHL). In 70-80% of malignant tumors, normoxic and hypoxic HIF-1α- overexpression triggers the Warburg-effect (i.e., aerobic glycolysis in the presence of oxygen and functioning mitochondria), a major driver of the cancer progression machinery, sustained and uncontrolled growth, invasion and metastasis, Survival advantages and malignant progression, resistance to conventional cancer therapies, and escape from antitumors immune responses ultimately lead to poor patient outcome. The effect of heat (39-43°C) on HIF-1α expression has been reported previously in several preclinical investigations [8-11]. As a key result, heat increased HIF-1α upregulation independently of oxygen in most studies shedding some light on possible molecular mechanisms of tumor recurrences following hyperthermia treatment. In contrast to these data, in canine sarcomas there was an (unexpected) inverse relationship between hyperthermia level and the direction of HIF- expression. From this data review there is clear indication, that there is a lack of valid clinical information on possibly deleterious HIF-1α upregulation upon hyperthermia treatment (39-43°C).
Current Clinical Status and Future Direction of Hyperthermia in Japan
1Department of Therapeutic Radiology, University Hospital of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu 807-8555, Japan
In the 1960s, the cytotoxic effect of heat was confirmed using cultured cells. Many basic studies have demonstrated the following biological merits of hyperthermia in the treatment of cancer i) in most cells, applying heat of 42°C–43°C lowers the survival rate of cells depending on the duration of heat application, and heat sensitivity does not vary with tissue type; ii) tumor tissue is more easily heated than normal tissue; iii) hypoxic cells are more susceptible to heat than aerobic cells; iv) the recovery of cells from radiation or chemotherapeutic agents is prevented by heat; and v) sensitivity to heat and radiation differs with the cell cycle.
In 1984, the Japanese Society of Hyperthermic Oncology (JSHO) was established, and a lot of clinical trials were started. In 1990, Japanese health insurance coverage for hyperthermia was achieved. The capacitive heating device is commonly used in Japan. This situation is different from the other countries. When using this device, the patient is placed between two electrodes connected to a high-power RF generator. The overheating of subcutaneous fat tissue and pain near the electrode edge are major problems for deep regional capacitive heating devices. We investigated various optimization methods to achieve higher temperature rise in the deep heating target in this device. In addition, the correlations between the clinical outcomes and thermal parameters were confirmed in clinical studies using this device in various type of cancer patients treated with radiotherapy plus hyperthermia.
Clinical Practice Guideline for Hyperthermia is planning to be published by the JSHO. These Guidelines are established according to Evidence-Based Medicine and written by members of the Committee for Clinical Practice Guidelines for hyperthermia in the JSHO. The guidelines include clinical questions and recommendations. This guideline may contribute that Japanese clinicians recognize the clinical merit of hyperthermia.
Comparative Evaluation of Heating Technologies Currently Available in the Clinic
H. Crezee1 and H.P. Kok1
1Department of radiation Oncology, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
The therapeutic application of heat is very effective in the treatment of malignant tumors. Both hyperthermia i.e. heating to 39-45°C to induce sensitization to radiotherapy and chemotherapy, and thermal ablation, where temperatures beyond 50°C destroy tumor cells directly, are applied clinically. An effective treatment requires high quality heating equipment, precise thermal dosimetry, and adequate quality assurance. Several types of devices have been developed and clinically used which vary considerably in technique, heating depth, ability to focus, and in the size of the heating focus. Clinical heating techniques involve electromagnetic and ultrasonic heating, hyperthermic perfusion and conductive heating. Thermal therapies can be subdivided into 3 broad categories: local heating, locoregional heating, or whole body heating. Local heating techniques include interstitial, intraluminal, superficial and nanoparticle heating, and electroporation. Locoregional heating techniques include phased array systems, capacitive systems and isolated perfusion. Whole body techniques focus on prevention of heat loss supplemented with energy deposition in the body, e.g. by infrared radiation. Devices have progressed from single source applicators to sophisticate multiple source instruments to meet heating requirements for specific tumor sites. Real-time temperature feedback combined with reliable treatment planning is required to guide the applicator settings and the desired tumor target temperature distribution.
High Intensity Focused Ultrasound (Hifu) for Prostate Cancer – Current Status and Future Directions
Consulting Surgeon, Nanavati Hospital, Mumbai
Hyperthermia refers to the heating of tissue in an effort to produce meaningful clinical outcomes. It is providing clinicians and researchers newer avenues to explore to provide cutting edge diagnostic and therapeutic options to patients. In oncology, the use of hyperthermia is getting more widespread with ablative technologies beginning to provide a good alternative to surgery or radiation in selected cases. Liver and kidney tumor ablations are quite commonly performed using radio-frequency probes to heat and kill neoplastic cells.
Prostate cancer (PCa) is the most common solid organ cancer among men in the western world and is increasing in incidence in India as well. Approximately one in eight men will be diagnosed with PCa at some point during their lifetime. Treatment for localized prostate cancer by radical prostatectomy or radiation therapy offers excellent oncological outcomes. However, side-effects with respect to urinary and sexual function can have a tremendous impact on patient's quality of life following these treatments.
High Intensity Focused Ultrasound (HIFU), ablates tissue by delivering focused ultrasound waves. The energy produced by the device is absorbed by tissue and converted into heat. It can reach temperatures of up to 100oC in a few seconds, and leads to tissue necrosis. It has been used for the past 3 decades for prostate ablation and we will discuss its mechanism and uses in prostate cancer.
Three commercially available HIFU devices are available at present: Ablatherm, Focal One (both from Edap Technomed, Lyon, France) and Sonablate (Sonocare, Indianapolis, IN, USA). The basic mechanisms of these devices are similar and they provide precise and accurate focal ablation.
Generally a machine consists of 2 separate modules: the treatment module, which include the patient's bed with the endorectal ultrasound probe and the planning module, used for planning and monitoring of treatment. The system has a 7.5MHz imaging transducer and a 3 MHz ablation transducer incorporated in a single ultrasound probe.
Integrated safety features such as the patient movement detector and rectal wall distance monitoring are available in advanced systems. These stop the treatment if the patient moves or the rectum is too close to the ablation area. The rectum is cooled to a temperature of 14-15 degrees Celsius throughout the procedure, minimizing injuries to the rectum. The maximum depth that can be reached by the ultrasound waves depends on the exact machine used and this can be a limitation when ablating anterior tumors.
Newer machines integrating MRI imaging and with a potential for fusion biopsy and targeting are also available nowadays.
Procedures are performed under general anesthesia to minimize patient movement. The patient is positioned appropriately depending on the system used. The endorectal probe is inserted and the prostate is mapped out with an ultrasound scan. After selecting the area for treatment, rectal cooling is begun, and ablation occurs through the same ultrasound probe. The process is controlled via a computer in the Ablatherm machine or manually in the Sonablate machine. The tissue is heated to 80-100 degrees Celsius allowing for complete coagulative necrosis of the area. The patient requires a catheter for 5-7days to allow the necrotic tissue to slough off through it. Simultaneous or prior (2-3weeks before) transurethral resection of the prostate (TURP) is generally recommended for those with larger prostates (>40-50cc) or significant urinary symptoms preoperatively. The TURP helps reduce the risk of post-HIFU urinary retention which can be significant.
Whole-gland prostate ablation via and endorectal probe by HIFU began in Europe in the 1990s. It was initially used as an alternative to surgery for unfit and older men, however with time its use became more widespread.
H Ro et al, reported their 15-year follow up experience with 704 patients with localized disease. Mean follow-up was 5.3. They reported a cancer-specific survival of 99%, metastasis-free survival of 95%, and 10-year salvage treatment-free rates of 98% in low risk, 72% in intermediate risk and 68% in high risk patients. Re-treatment with HIFU was seen in 15% cases. The rates of long-term urinary incontinence (>3months post-procedure) were only 3.26%, however about 20% patients developed bladder neck contractures and 0.23% developed recto-urethral fistula.
In a study from France, Crouzet et al reported 8-year biochemical-free survival rates of 76%, 63%, and 57% for low-, intermediate-, and high-risk patients, respectively. At 10 years following HIFU, the PCa-specific survival rate and metastasis-free survival rate were 97% and 94%, respectively. Sixty percent of patients received one HIFU session, 38% received two sessions, and 2% received three sessions.
Despite the good oncological outcomes, only half the men retained potency after treatment, which reflects the side effects of whole gland treatment for the prostate. As the side-effects were not significantly different from traditional whole-gland treatments like surgery or radiation, the use of whole-gland HIFU has remained restricted to selected centers in Germany and France.
Given that prostate cancer is a multifocal disease, whole gland treatment has been traditionally recommended. However, newer studies put forward the concept of the “index lesion” as the lesion of maximum size and/or grade within the prostate as driving its metastatic potential. These studies proved that the vast majority of metastatic prostate cancer was monoclonal in origin supporting this hypothesis. Therefore the concept of focal therapy (FT) by ablation of the index lesion began to be studied. This was put forth with a view to minimize the side effects associated with whole-gland therapy while maintaining oncological outcomes.
If the index lesion could be accurately identified and targeted, FT can provide a valuable treatment alternative for those men who wish to preserve their quality of life without jeopardizing cancer control. Traditional template mapping biopsies via a transperineal approach were initially used to identify potential candidates for FT. However, this is associated with a significant morbidity, need for anesthesia and significant added costs. Over the past decade, the advent of multi-parametric MRI (mpMRI) of the prostate has greatly increased the accuracy of identifying and targeting index lesions within the prostate prior to consideration of FT. Good evidence supporting the use of MRI in the diagnosis of prostate cancer is now available. For example, the PROMIS study found that MRI had a significantly better sensitivity (93% vs. 43%, p<0.001) and negative predictive value (89% vs. 74%, p<0.001) than TRUS and also concluded that fusion biopsy was better than regular TRUS biopsy in detecting clinically significant cancer. Most FT consensus groups now support the use of MRI-fusion biopsies as the minimum standard prior to proceeding for FT. However, concerns regarding the underestimation of the extent and aggressiveness of some cancers on MRI need further study and have prompted treatment margins to be larger than the lesion seen on MRI. Accurate staging prior to FT is imperative and the highly sensitive newer PET- scans like PSA or Flucyclovine play a key role in ruling out patients for FT. They can also be used to monitor progression in cases of a biochemical recurrence after FT.
Following FT, patients need to be monitored closely for a recurrence. Most centers use regular (3-monthly) PSA monitoring along with a repeat biopsy at 6-12 months following treatment. A biopsy may be repeated earlier based on PSA results or clinical progression. Three possible treatment failures can occur with FT: ablation failure when there is residual cancer in the treated area due to inability of the energy to destroy it; targeting failure when the energy was not correctly applied to the targeted area (i.e. anterior lesions) and selection failure, when the selected patient was not an appropriate candidate for FT. For patients with ablation failure, several treatment options are accepted, including repeat ablation, radical treatment with radiation therapy or surgery and active surveillance, if eligible. On the other hand, patients with either targeting or selection failure should avoid repeat ablation due to a high risk of second failure.
Various energy sources have been trialed for FT, and amongst these HIFU has the largest experience. A French center reported the largest focal HIFU data with 111 patients, who underwent hemiablation, and a mean follow up of 2 years. The infield positive biopsy rate for any cancer was 14%. Additionally, the authors reported a 95% negative follow-up biopsy for any cancer ISUP grade > 2, and a radical treatment-free survival rate of 89% at 2 years. Functional outcomes were excellent with 12-month continence of 97% and preserved erectile function in 78% of patients. Urinary tract infection (16%), transient dysuria (15%), urinary retention (12%) and transient perineal pain (9%) were the most common complications. Clavien-Dindo Grade III complications were seen in 13% of patients, who required prolonged catheterization or TURP. Several other authors have demonstrated similar functional and oncological outcomes with focal HIFU.
Up to now, most focal HIFU studies have included only low to intermediate risk PCa, owing to the fact that these men are less likely to recur systemically, and therefore local control could be curative. However a significant proportion of these low-risk men would be best served by active surveillance thereby skewing the data supporting the benefits of FT. There is no reason to believe that HIFU would not provide as effective local cancer control for high-risk cancers as it does for low to intermediate risk. Therefore, in selected patients with low volume and high risk PCa, focal HIFU might play an important role. At the University of Miami, we did select such patients for FT if they were so motivated with good oncological outcomes (manuscript under review). Guillaumier et al also showed that FT is feasible in this population with good local control of cancer. Nonetheless, all guidelines today (NCCN, AUA, EAU) do not recommend FT for patients with high risk cancer outside of a clinical trial as of now, due to the lack of available data.
There is no doubt that HIFU has been proven effective to destroy prostate tissue and in some centers remains the ablative modality of choice in patients who are unfit or unwilling for surgery or radiation. The explosion of interest in FT for prostate cancer has opened up new avenues for the use of HIFU and there is tremendous ongoing research in this space.
Hypercollar for Hyperthermia in Head and Neck Cancer
G.C. van Rhoon, G.G. Bellizzi, K. Sumser, T. Drizdal, J.A. Hernandez-Tamames, M.M. Paulides
Erasmus MC Cancer Institute, Rotterdam, The Netherlands,
E-mail : firstname.lastname@example.org.
For head and neck cancer the benefit of adding hyperthermia to radiotherapy has been demonstrated in multiple randomized phase III trials. In these trials a variety of hyperthermia equipment has been used, some specifically suited for one tumor pathology and location only. Characteristic for all equipment used in the trial was that they did not provide the ability to adapt the 3 dimensional energy absorption distribution to maximize the thermal dose in the target region. This despite the fact that multiple clinical studies have demonstrated a statistical significant thermal dose effect relationship.
With the later objective in mind the HyperCollar applicator for hyperthermia treatment of head and neck cancer has been designed. It was and still is the only applicator of which the first and all following designs have been designed and optimized by computer modelling of optimal the number and location of the radiofrequency electromagnetic antennas. An important advantage of the computer design is that it allows real-time hyperthermia treatment planning guidance of the delivered energy distribution during clinical application.
The experience with the conventional HyperCollar 3D applicator shows that despite all clinical efforts extensive monitoring of the temperature distribution in target and normal tissue during treatment of head and neck cancer remains a challenge. Therefore, the development of a MR-compatible HyperCollar 3D applicator has been started with a close focus on merging MR-Rx coils and RF-heating antennas very close to the treatment volume. The MR-HyperCollar 3D has been designed and construction is ongoing. Initial results are encouraging and will be reported.
Hyperthermia'S Benefits in the Portfolio of Cancer Therapies with The Focus on Enhancing Immunological Therapies (Including Checkpoint Inhibitors / Car-T)
University Mannheim, Germany
Hyperthermia as a therapy concept in chronical diseases including cancer exists already for a long time. But one has to differentiate between the various forms of hyperthermia and the intended rationale. Hyperthermia to enhance effects of local radiation is a very different form of hyperthermia than whole body hyperthermia with the objective to boost the immunological status of a patient. The presentation will briefly differentiate the various hyperthermia forms, the temperatures desired and achievable and its different rationales.
The focus, however, will be on the potential that hyperthermia offers to boost the effect of novel immunological therapy concepts that have emerged lately such as checkpoint inhibitors. Some interesting synergies of how hyperthermia can influence the T-cell response just came up in the last years. The beneficial potential of upregulating a body's temperature is still not entirely understood but likely it is not without reason that evolution developed fever in its immunological arsenal against adverse developments in its microenvironment and/or cellular level.
Finally, as an outlook, the presentation will briefly discuss those forms of hyperthermia that use electromagnetic fields to generate the heat which may have effects due to their inherent frequency characteristics. There exists a controversial and open discussion into this theme.
Results of Randomized Trials Comparing Treatments with or without Hyperthermia
J. van der Zee1 and O.K. Kurpeshev2
1Erasmus MC Cancer Institute, Rotterdam, the Netherlands, 2A. Tsyb Medical Radiological Research Center, Obninsk, and Siberian Scientific Research Institute of Hyperthermia, Novosibirsk region, Russia.
Experimental studies have shown that hyperthermia (HT) has both direct cytotoxic, and radio and chemosensitizing effects, in a large variety of tumour types. In the clinic, HT generally is added to radiotherapy (RT) and/or chemotherapy (CT) in the more advanced, or recurrent stages of the disease.
We have searched digital databases and personal files for randomized trials with main difference between the treatment arms whether or not HT was part of the treatment. We found 54 of such trials published between 1980 and 2017 and including total 5099 patients, and analyzed the results. Two thousand five hundred and sixty seven patients were treated with, and 2532 without HT. These studies investigated the addition of HT to (RT), CT or RT plus CT, or, in one study, to both RT and RT plus CT. These trials were done in a large variety of solid tumours, and in centres in Asia, Europe, North America and Australia. In general, these studies were relatively small: 36 studies included less than 100 patients, and only 7 studies included 200 patients or more. In the majority of the studies, HT was applied with electromagnetic radiation, using mainly external techniques.
In one study, five different trials were included, and of nine trials only the meta-analysis was available. One study included four treatment arms, comparing RT to RT+HT, and RT +CT to RT+CT + HT. Of two studies, both the results in the total patient population and the results in one and three subgroups, respectively, could be compared. Total 47 comparisons could be made between treatments with and without hyperthermia. For each comparison we selected the most important clinical outcome parameter which was significantly different between the two treatment arms.
Most studies (72 %) have shown that additional HT significantly improves the results of RT, CT and RT+CT in patients with, in general, locally advanced, relapsed and metastatic forms of malignant tumours. In addition, in seven of these comparisons, the difference, although not significant, was larger than 10 percent point with the better results in the plus hyperthermia arm. A beneficial effect of hyperthermia was found in a large variety of tumour types: cancer of the bladder, breast, head and neck, uterine cervix, brain, esophagus, stomach, rectum, lung, and malignant melanoma and soft tissue sarcoma. Improved results were reported for palliation in one comparison, for response in 7, for complete response in 7, for loco-regional tumour control in 5, for disease free survival in 3 and for overall survival in 11 studies. Generally, the differences were large: 10 to 53 percent point.
Most of these trials also reported acute and/or late toxicity. In the majority of the trials, addition of HT did not result in significant increases of toxic effects of RT and/or CT. Only additional toxicity from HT was reported: thermal burns which usually heal after conservative treatment. Thirteen studies failed to show a significant beneficial effect of HT. In seven studies with a trend of a better outcome in the plus HT treatment arm, with a difference of 10 percent point or more, the lack of significance is probably due to a low number of patients included. In most other studies failing to show a beneficial effect, there was an unbalanced distribution of tumour characteristics over the two study arms, with worse prognostic factors in the +HT arm, the use of inadequate techniques such as using a too high frequency of electromagnetic radiation in relation to the depth of the tumour, and/or a too small applicator, and/or a short heating time, so that a sufficient energy deposition in the target volume could not be achieved.
Almost all published comparative trials show a benefit from adding hyperthermia to radiotherapy and/or chemotherapy, in a wide variety of tumour types. The differences are large and the improvements are relevant to patients: considerably better local tumour control, disease-free survival and overall survival were achieved. Several of the trials failing to show a benefit have made clear that it is important to use adequate hyperthermia application techniques, and to follow the guidelines that have been developed. In view of the different principles of operation of the various HT application systems, it is important that such guidelines will become available for each individual device. Further, it is important to conduct larger randomized trials. Larger studies will probably increase the number of significant and also more relevant outcomes, and thereby promote a wider acceptance of HT as part of cancer treatment.
Alba Hyperthermia Technologies: New Era of Ht in Cancer Treatment
P. Pavoni. Oly
Hyperthermia (HT), heating tumors in the range 41-43°C, is a powerful radio and chemosensitizer. HT effectiveness as well as safety in combination with radiotherapy and chemotherapy has already been proven in randomized clinical trials, especially in patients with large, advanced or recurrent tumors. Despite the very strong clinical rationale and the very positive clinical results achieved so far, HT is nowadays about 1% of the radiation oncology market: Year to date 130 radiative HT systems have been installed compared to the 10.900 LINACS1 installed. The high cost HT devices together with the lack of QA systems and automated procedures which the RT world is used to, have limited the number of installed systems and clinical trial, thus hampering the achievement of the critical mass. ALBA HYPERTHERMIA has developed a hyperthermia technologies platform to overcome these limitations and finally move HT to the RT standards, opening a New era for HT in cancer treatments. In particular: ALBA 4D, representing the forefront of phased array HT system for the treatment of deep seated tumor; ALBA ON4000, the only HT system able to treat lesions at 0 to 4 cm of depth; ALBA HTPS, the first HT treatment planning system able to perform online adaptive simulations; QA equipment to guarantee ALBA HT device performances. Technical features and impact of ALBA TECHNCOLOGIES will be presented.
Potential of Low Dose Re-irradiation Combined with Preceding Water-Filtered Infrared A Hyperthermia: Even Repetition is Possible
M. Notter1, A.R.Thomsen2,3, P. Vaupel2,3
1Department of Radiation Oncology, Lindenhofspital Bern, Bern, Switzerland 2Department of Radiation Oncology, Medical Center, University of Freiburg, Freiburg, Germany 3German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Cancer recurrences in previously irradiated regions remain a demanding situation, in which compact tumor volumes may adequately be re-treated either by external beam radiotherapy (EBRT) or by brachytherapy in many cases. However, extensive superficial tumors are especially challenging, mainly due to the cumulative toxicity of the normal tissue involved. We apply a combined treatment method for such large-sized tumor recurrences, using superficial hyperthermia (sHT) to enhance the effect of re-irradiation (re-RT). As an example, non-resectable, locally recurrent breast cancer (LRBC) in pre-irradiated areas ranges from microscopic disease and small lesions in patients to be treated with curative intent up to cancer en cuirasse, where palliative treatment might deliberately be restricted to areas directly affecting quality of life. Hyperthermia as a radiosensitizer allows for a reduction of radiotherapy dosage and opens a chance to achieve complete and partial responses even in patients where the aim of tumor control has already been abandoned.
Between 9/2009 and 9/2019, 232 patients suffering from locally recurrent cancer in pre-irradiated areas were treated in four centers located in Switzerland and Germany. Tumor included breast cancers (n=201), angiosarcomas (n=11), head & neck cancers (n=5), melanomas (n=4), and miscellaneous recurrences (=11). 141 LBRC-patients had large lesions of >100 cm2. Response and local control rates were assessed using a novel size classification.
Treatment consisted of one combined Water filtered infrared a hyperthermia therapy (wIRA-HT) + re-RT fraction of 4 Gy every 4 to 7 days, up to a total dose of 20 Gy (range 12 – 24 Gy), as described by Notter et al. (1) and Vaupel et al. Based on experimental and clinical findings, we consider a short time interval between HT and re-RT to be crucial for optimal synergy of both modalities and thus aimed to apply external beam irradiation within 2-5 min after termination of wIRA-HT.
LBRC-patients: Overall response rates ranged from 99% in small lesions to 85% in cancer en cuirasse, with lesions extending to the back. For most patients local control after CR or infield/border progression-free stabilization after PR could be achieved during lifetime. Acute and chronic toxicity was limited to grade I and a few grade II side-effects. The low toxicity allowed for one or even several repeat re-irradiation(s) in 43 patients with re-recurrences, using the same combined treatment protocol. Treatment response was stratified according to size classes and tumor characteristics. In addition, outcome data are presented as Kaplan-Meier estimates.
Angiosarcoma: 5/11 patients with locally recurrent angiosarcoma had a manifest tumor, 3/5 obtained a CR, but 2/3 recurred outside and were then retreated. 6/11 received a secondary adjuvant re-irradiation, 5/6 are alive with no evidence of disease (4 – 96 months), 1 patient recurred outside the field after 41 months and died due to distant metastasis.
Cancer of head & neck: Overall response was 60%, but 4/5 recurred in-field/outfield.
Melanoma patients and miscellaneous localisations showed similar overall responses, and, in most cases, very good palliation was obtained as well.
Low toxicity allowed for repeating the same protocol in re-recurrences.
The combination of wIRA-HT immediately followed by hypofractionated external beam re-RT provides an effective and well-tolerated treatment option, resulting for most LBRC-patients in local control after CR or infield/border progression-free stabilization after PR. In the other patients, satisfactory palliation or - in many cases - even local tumor control was achieved during lifetime as well. While our series mainly covered patients with breast cancer, we conclude that wIRA-hyperthermia is a promising option to sensitize other superficial malignancies to re-RT, as well. Further repeated series with the same schedule are well tolerated and open the window to stabilize recurrent cancer for a long time without severe toxicity.
Integration of Pencil Beam Scanning Proton Therapy and Hyperthermia: the University of Maryland Clinical Experience
Z. Vujaskovic, D.B. Rodrigues, E. Nichols, J.W. Snider, J.K. Molitoris
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA
Hyperthermia (HT) has been used in oncology practice as an excellent adjunct to conventional radiotherapy (RT) in both the definitive and palliative settings. Hyperthermia is known to improve radiosensitivity through improved oxygenation and inhibition of radiation DNA damage repair, among other mechanisms. However, there is a paucity of safety and efficacy data for the concurrent use of proton therapy (PT) and HT due to the relative lack of institutions with capabilities for both modalities. Despite initial concerns for higher grade toxicity with this combination, as it has been likened to high-LET RT techniques, our institutions initial reports have been encouraging. We report, herein, the largest, and growing, clinical experience with concurrent Pencil Beam Scanning Proton Therapy (PBS-PT) and HT from a single institution.
At the Maryland Proton Treatment Center, PBS-PT has been utilized in over 2000 patients, of which 46 courses/sites have been delivered with concurrent superficial hyperthermia. These patients' malignancies include a wide range of histologies though sarcoma and breast cancer have been most common. PBS-PT doses ranged from 36 to 70.2 Gy(RBE) (median 57 Gy[RBE]) with some included altered/hypo-fractionation. The BSD-500 platform was utilized for all hyperthermia administrations with a bolus temperature between 39-40oC, target surface temperature 40-44oC, for 30-60 minutes (median 60) per treatment.
With a median follow-up of 8 months (range 1-31 months), concurrent hyperthermia and PBS-PT continues to be well tolerated. There were no acute/subacute grade 4-5 toxicities. Grade 3 toxicity primarily involved acute desquamation or chronic lymphedema. Most common grade 1-2 toxicities included radiation dermatitis, pain, hyperpigmentation, and GI disturbance Although short follow-up, 83 % remain alive, while 78% are locally controlled and 61% remain free of disease.
Concurrent PBS-PT and hyperthermia continue to be well tolerated in the largest experience to date of this combination. While long-term follow-up and prospective data are needed, there remains no evidence of worsened toxicity over traditional RT+hyperthermia.