{"id":14507,"date":"2026-03-19T13:27:53","date_gmt":"2026-03-19T12:27:53","guid":{"rendered":"https:\/\/www.proefschriftmaken.nl\/us_portfolio\/arlene-oei-2\/"},"modified":"2026-08-14T17:46:48","modified_gmt":"2026-08-14T15:46:48","slug":"arlene-oei","status":"publish","type":"us_portfolio","link":"https:\/\/www.proefschriftmaken.nl\/en\/portfolio\/arlene-oei\/","title":{"rendered":"Arlene Oei"},"content":{"rendered":"","protected":false},"featured_media":7998,"template":"","meta":{"_acf_changed":false},"university_us_portfolio":[26],"class_list":["post-14507","us_portfolio","type-us_portfolio","status-publish","has-post-thumbnail","hentry","university_us_portfolio-universiteit-van-amsterdam"],"acf":{"main_text":"","naam_van_het_proefschift":"Tumor cells can\u2019t stand the heat","samenvatting":"Baarmoederhalskanker is wereldwijd een van de meest voorkomende kankers bij vrouwen. De huidige behandelmethoden resulteren in een vijfjaarsoverleving van 65% voor baarmoederhalskanker. Dit betekent dat 35% van de pati\u00ebnten komt te overlijden. Er is dus behoefte aan verbetering van de huidige behandelingen. Hyperthermie wordt al sinds begin tachtiger jaren klinisch toegepast voor diverse tumor-typen en verschillende klinische trials hebben bewezen dat hyperthermie een succesvolle behandeling is voor pati\u00ebnten met lokale baarmoederhalskanker in een gevorderd stadium. Hyperthermie wordt toegepast op pati\u00ebnten die contra-indicaties hebben voor het krijgen van de standaard chemo-radiotherapie, bijvoorbeeld op pati\u00ebnten met nierfalen. Hyperthermie wordt ook omschreven als misschien wel de beste klinisch beschikbare methode, om cellen gevoeliger te maken voor radiotherapie en chemotherapie. Desondanks is hyperthermie geen standaardbehandeling. In dit proefschrift wordt uitgelegd hoe hyperthermie kankercellen gevoeliger maakt voor radiotherapie en chemotherapie. Als eerste wordt het mechanisme waardoor hyperthermie zo effectief is onder de loep genomen, waarbij diverse hypotheses worden getest (DEEL I). Daarnaast wordt in dit proefschrift beschreven waarom de combinatie van radiotherapie of chemotherapie met hyperthermie zo succesvol is in de behandeling van baarmoederhalskanker. Tevens wordt toegelicht hoe de huidige behandelstrategie\u00ebn met hyperthermie kunnen worden verbeterd (DEEL II). Tot slot worden de voordelen van het toevoegen van hyperthermie aan combinatietherapie\u00ebn onderzocht om zo tot een nog effectievere behandeling te komen (DEEL III).\n\nWerkingsmechanisme van hyperthermie\nHyperthermie activeert verschillende mechanismen die tumorcellen gevoeliger maken voor de huidige anti-kanker behandelmethoden. Enerzijds kan hyperthermie de toevoer van zuurstof in tumoren verhogen, waardoor er meer reactieve zuurstofradicalen DNA-schade kunnen induceren en de DNA-schade kunnen fixeren. Aan de andere kant kan hyperthermie diverse DNA-herstelmechanismen uitschakelen, dit wordt beschreven in Hoofdstuk 2. Verschillende in vitro en in vivo experimenten en klinische trials hebben bewezen dat hyperthermie werkt. Het is misschien wel de beste manier om tumorcellen gevoeliger te maken voor bestraling. Desalniettemin, zijn de werkingsmechanismen van hyperthermie nog grotendeels onbekend. Hyperthermie kan de homologe recombinatie remmen, dat is een van de belangrijkste DNA-herstelmechanismen, maar hyperthermie heeft mogelijk ook invloed op andere DNA-herstel routes. Het feit dat hyperthermie de homologe recombinatie kan remmen en de daaruit volgende discussies of hyperthermie wel of geen invloed heeft op de andere belangrijke DNA-herstel route, de niet homologe \u2018end joining\u2019, is de basis geweest voor de experimenten beschreven in Hoofdstuk 3. In deze experimenten werd de gevoeligheid van cellen zonder homologe recombinatie \u2013 door mutaties in het BRCA2 gen \u2013 vergeleken met de gevoeligheid van BRCA2 wild-type cellen. Theoretisch gezien, als hyperthermie uitsluitend de homologe recombinatie remt, zouden BRCA2 wild-type cellen behandeld met hyperthermie dezelfde respons moeten geven als de onbehandelde BRCA2 gemuteerde cellen. Echter, BRCA2 wild-type cellen behandeld met hyperthermie toonden geen gelijke cel overleving in vergelijking tot de overleving van BRCA2 gemuteerde cellen. Bovendien hadden de BRCA2 gemuteerde cellen die met hyperthermie werden behandeld een lagere overleving dan de onbehandelde BRCA2 gemuteerde cellen. Dit duidt erop dat hyperthermie toch meer doet dan alleen het verstoren van de homologe recombinatie. Zodoende werd de andere zeer belangrijke DNA-herstel route, de niet homologe \u2018end joining\u2019 bestudeerd. Hieruit blijkt dat na hyperthermie in cellen die volledig afhankelijk zijn van niet homologe \u2018end joining\u2019 \u2013 omdat deze cellen niet beschikken over werkende homologe recombinatie \u2013 de eiwitlevels van de niet homologe \u2018end joining\u2019 omlaag gaan. In de cellen die daarentegen wel over beide herstelroutes beschikken, gaat na hyperthermie de homologe recombinatie omhoog, en lijken deze cellen voor reparatie van de DNA-schade over te schakelen naar de niet homologe \u2018end joining\u2019. Daarnaast was er tot dusver geen duidelijkheid of hyperthermie dubbelstrengsbreuken in het DNA kon induceren. Er wordt namelijk in verscheidene gevallen een lichte verhoging gevonden van het \u03b3-H2AX eiwit na hyperthermie. Dit is een veel bestudeerd eiwit (histon H2AX) dat onmiddellijk gefosforyleerd wordt (dan genaamd \u03b3-H2AX) op het moment dat er een dubbelstrengsbreuk plaatsvindt. Anderen claimen dat dit vals-positieve gekleurde eiwitten zijn en deze positieve spots geen indicatie zijn voor dubbelstrengsbreuken. De resultaten beschreven in hoofdstuk 3 laten, met behulp van een andere techniek (de comet assay), zien dat hyperthermie geen breuken induceert en bevestigt hierdoor de tweede theorie, namelijk dat het vals-positieve gekleurde eiwitten kunnen zijn die worden gedetecteerd met de \u03b3-H2AX kleuring.\n\nIn voorgaande hoofdstukken kwam niet aan de orde waarom hyperthermie bijzonder effectief is in het bestrijden van baarmoederhalskanker. Om dit te onderzoeken, zijn diverse HPV-positieve en HPV-negatieve baarmoederhalskanker cellijnen getest op hun gevoeligheid voor hyperthermie met verschillende temperaturen en behandelduren, dit wordt beschreven in Hoofdstuk 4. De data gepresenteerd in dit hoofdstuk suggereren dat hyperthermie de mogelijkheid heeft om de onderdrukking van het tumor suppressor eiwit p53 door het virale E6 eiwit weg te nemen. Daarom is hyperthermie waarschijnlijk essentieel in de behandeling van HPV-positieve baarmoederhalskanker.\n\nDosis, volgorde en tijdsinterval tussen radiotherapie en hyperthermie\nPati\u00ebnten met baarmoederhalskanker die contra-indicaties hebben voor cisplatinum-bevattende chemotherapie, komen in aanmerking voor behandeling met radiotherapie en hyperthermie. Echter, er is geen wereldwijde consensus over de optimale behandelvolgorde en het tijdsinterval tussen radiotherapie en hyperthermie. In Europa wordt meestal de tumor eerst bestraald alvorens hyperthermie plaatsvindt, terwijl in de Verenigde Staten de therapie\u00ebn in de omgekeerde volgorde worden toegepast. De achterliggende gedachte om eerst te bestralen is om eerst DNA-schade te veroorzaken, en dan hyperthermie te gebruiken om de DNA-herstelmechanismen lam te leggen. De rationale achter de omgekeerde volgorde wordt ondersteund door het feit dat wanneer eerst hyperthermie wordt gegeven dit leidt tot een verhoogde zuurstoftoevoer en daarmee een grotere hoeveelheid zuurstofradicalen, met als gevolg dat er meer indirecte DNA-schade wordt gecre\u00eberd en gefixeerd door radiotherapie. Het vraagstuk welke volgorde de beste uitkomsten biedt, vraagt om uitgebreid onderzoek. In Hoofdstuk 5 is niet alleen gekeken naar de volgorde tussen beide behandelingen, ook het tijdsinterval tussen radiotherapie en hyperthermie is geanalyseerd op verschillende cellijnen. De resultaten laten zien dat de verschillende volgorden geen verschil geven, noch in de cel overleving, noch in welke fase van de celcyclus de cellen zich bevinden, noch in de hoeveelheid DNA-schade, maar een korter tijdinterval tussen beide behandelingen resulteerde in meer celdood van kankercellen. Beide uitkomsten zijn te verwachten als de hyperthermie vooral interfereert met een traag DNA-herstel mechanisme. Echter, de re-oxygenatie kan niet uit in vitro experimenten worden beoordeeld, daarom kan nog steeds niet worden geconcludeerd wat vanuit een klinisch perspectief het dominante mechanisme is.\n\nVolgend op de conclusie uit het voorgaande hoofdstuk dat het tijdinterval tussen radiotherapie en hyperthermie belangrijk is om de cel overleving te minimaliseren, is dit ook in een klinische setting onderzocht. Daarvoor is een retrospectieve studie uitgevoerd op pati\u00ebnten met baarmoederhalskanker die zijn behandeld met hyperthermie en radiotherapie. Resultaten van deze studie worden gepresenteerd in Hoofdstuk 6. Deze klinische resultaten bevestigen de in vitro resultaten uit Hoofdstuk 5, omdat een kort tijdsinterval resulteerde in lager voorkomen van recidieven en een hogere gemiddelde overlevingskans.\n\nNieuwe combinatiebehandelingen met hyperthermie\nHet laatste deel van dit proefschrift onderzoekt de opties voor combinatiebehandelingen ten behoeve van pati\u00ebnten voor wie volledige bestralingsdoses niet meer mogelijk waren. Dit kan het geval zijn als tumoren in gebieden liggen die voorheen al zijn bestraald. Combinaties van cisplatinum met hyperthermie en de toevoeging van een PARP-inhibitor resulteren zowel in vitro als in vivo in een effectievere therapie, zonder ernstige bijwerkingen (Hoofdstuk 7). Cisplatinum is \u00e9\u00e9n van de oudste en wereldwijd meest gebruikte chemotherapeutica, maar het middel kan ernstige en permanente bijwerkingen hebben. Daarom werd onderzocht of het mogelijk is de kwaliteit van leven van pati\u00ebnten te verbeteren zonder de effectiviteit van de behandelingen te verminderen met behulp van nieuwe combinatiebehandelingen. In Hoofdstuk 8 leidde de toevoeging van PARP-inhibitor aan de combinatie van hyperthermie en cisplatinum ertoe dat cisplatinum doseringen met een factor tien konden worden gereduceerd, zonder de effectiviteit van de therapie te verminderen. Behandelen met hogere temperaturen resulteert in meer celdood. Hyperthermie is dus effectiever naar gelang de behandeltemperatuur die bereikt wordt hoger is. Hoe hoog de bereikte behandeltemperatuur is, wordt in overleg met de pati\u00ebnt tijdens de behandeling bepaald. Dit varieert per tumorsoort en is afhankelijk van de ligging van de tumor. Naast de voorafgaand beschreven opties om de behandeluitkomsten met hyperthermie te verbeteren, is een andere mogelijk om de werkzaamheid van hyperthermie te versterken met het gebruik van een remmer van het Heat Shock Protein 90 (HSP90-remmer). De resultaten in Hoofdstuk 9 demonstreren dat de toevoeging van HSP90-remmer de gevoeligheid voor radiotherapie en chemotherapie door hyperthermie verhoogt.\n\nIn Hoofdstuk 10 van dit proefschrift wordt ook besproken dat het vernietigen van alle tumorcellen een grote uitdaging blijft, aangezien veel anti-kankerbehandelingen niet alle tumorcellen kunnen uitschakelen. Het behandelen van deze therapie-ongevoelige cellen blijft daardoor een belangrijk probleem. Deze categorie tumorcellen heeft de mogelijkheid om recidieven of metastasen te veroorzaken en worden ook wel de kanker-initi\u00ebrende cellen of kanker stamcellen genoemd. Deze therapie-ongevoelige kankercellen bevinden zich onder meer in zuurstofarme (hypoxische) en voedingsstofarme gebieden van de tumor. Dit zijn helaas precies de locaties waar radiotherapie en chemotherapie het minst effectief zijn. Een belangrijk gegeven is dat hyperthermie vaak wordt beschreven als een zeer goede behandeling om hypoxie te verminderen in tumoren, waardoor de omstandigheden in het hypoxische gebied, de comfort-zone van deze hypoxische cellen, wordt veranderd. Het is cruciaal om deze therapie-ongevoelige cellen te elimineren en daarom wordt in deze thesis een combinatiebehandeling inclusief hyperthermie voorgesteld als een veelbelovende behandeling om juist deze cellen aan te pakken en daarmee hun DNA-herstellende eigenschappen te verminderen.","summary":"place within seconds after DNA is damaged and will be finished within a few hours. Therefore, our in vitro data on HR proficient cells suggest that the fast repair is less affected by mild hyperthermia alone. However, as re-oxygenation cannot be studied in in vitro experiments, the issue of the dominant mechanism in a clinical setting remains undecided. Furthermore, this result only concerns tumor cells and not normal tissue toxicity. The optimal time interval and sequence also covers the best balance between targeting the tumor tissue as much as possible, with tolerable damage to the normal tissue. Finally, direct cell death due to radiotherapy and hyperthermia does not give insight in tumor relapse. The in vitro experiments did show more cell death after a shorter time interval, but then again, this has not yet been tested in respect to the normal tissue. Research studying the effects on normal tissue toxicity is ongoing.\n\nThe importance of limiting the time interval between radiotherapy and hyperthermia was not only demonstrated in in vitro results. In patients, the optimal window between radiotherapy and hyperthermia to gain a beneficial effect is even shorter. This difference between tumor cells in vitro and patients is that, unlike the situation in human beings, cultured tumor cells are treated under optimal conditions, i.e. the temperature distribution is homogeneous and oxygen levels are perfectly regulated. The clinical lesson to be learned is that shortening the time interval between radiotherapy and hyperthermia is essential in achieving a higher overall survival. A limitation of the patient study was the relatively small number of patients (n=58). Moreover, among all patients with inoperable cervical cancer, these patients even had more dismal prognostic factors, which coincides with their contraindication against receiving chemotherapy. This group included a large number of elderly and physically unfit patients. If hyperthermia becomes a standard treatment for a larger group of patients, the impact of sequence and time interval must be re-evaluated prospectively in a randomized trial which includes patients with various ages and with different physical status. The impact should be compared for patients with different ages and various physical conditions as the sequence and time interval between radiotherapy and hyperthermia might be even more important in younger and physically fitter patients, effects may be larger and perhaps last longer, as the response of blood flow to hyperthermia may be better in younger patients.\n\nHPV+ tumors, a special target for hyperthermia?\nRemarkably, cervical carcinoma has a favorable clinical outcomes after combinational therapies including hyperthermia (Datta et al, 2016). In this thesis (Chapter 4), we explored one possible mechanism explaining the success of hyperthermia in this particular tumor type. Whereas hyperthermia interferes with the complex formation of HPV-E6 and p53 in HPV+ cervical carcinoma cell lines, thereby rescuing p53 to become active and induce tumor cells death, a new logical question rises whether hyperthermia has this effect on all HPV+ tumor types, such as anal cancer and tumors of the head and neck. These questions are definitely high ranking on our list of topics to be investigated in future projects. According to our results, hyperthermia is rather unique in interrupting the tumor promoting complex formation of E6 and p53; neither radiotherapy nor chemotherapy, or the combination of both is able to do so. Therefore, it may be important to support clinical application of hyperthermia in all patients with HPV+ tumors and not only for a selected group of patients. Whereas cervical carcinoma has a significantly better outcome when combined with hyperthermia, head and neck tumors which are caused by HPV have already been found to respond very well to radiotherapy alone. It would therefore be extremely interesting to investigate if hyperthermia could further increase clinical outcomes for this specific tumor type. Elucidating whether hyperthermia has similar effects in all HPV+ tumor types would be essential, in order to prevent over-treating patients. As there are also multiple investigations testing the effectiveness of hyperthermia in both HPV+ and HPV- head and neck tumors, also in clinical trials, the current clinical outcomes of treated head and neck tumors need to be improved. The effect on E6 is certainly not the only effect of heat. In HPV- tumors hyperthermia induces p53 dependent apoptosis as well. This raises the question whether hyperthermia affects MDM2, which is an important p53 regulator. This issue remains to be investigated.\n\nHyperthermia to target CSC?\nTreatment failure after local radiotherapy and systemic chemotherapy in women with cervical cancer is caused by distant metastases, regional failure and local recurrence. The initial response to treatment is usually favorable, but recurrences still occur, probably caused by a small percentage of cells that become therapy-resistant. These therapy-resistant cells, typically localized in the hypoxic area of the tumor, often show similar characteristics to normal tissue stem cells, and are therefore referred to as cancer stem cells (CSCs). These CSCs have the capacity to re-populate and re-establish an entirely new tumor. In Chapter 10, we argued that hyperthermia targets exactly the areas in which radioresistant cells are located, and may therefore strengthen the forces in the battle against CSCs. Indeed, in tumors located in previously irradiated areas, low doses of radiation combined with hyperthermia proved to be just as effective as high doses of radiation. This protocol is chosen to prevent too much normal tissue toxicity caused by ionizing radiation. Hyperthermia can then be added to prevent cells from becoming radioresistant. It would therefore be interesting to investigate whether hyperthermia can sensitize CSCs to chemotherapy and radiotherapy. In vitro and in vivo experiments are needed to confirm this hypothesis. This could shed light on why hyperthermia can increase the local disease free survival in clinical trials raises the question whether hyperthermia should be applied already in primary tumors to avoid cells from getting therapy-resistant (by reaching all areas of the tumor with the combinational anti-cancer treatment), or whether hyperthermia is more effective when specifically applied to treat when radioresistant cells are known to be present and posing a problem for conventional therapies. The outcome of this debate depends on whether hyperthermia has the ability not only to reduce hypoxia in primary tumors, but more importantly, to make usually well oxygenated recurrences and metastases more vulnerable to conventional therapy by targeting the CSCs. This approach can not only increase tumor response and time to recurrence, but can also increase cancer cure rates, if hyperthermia actually can kill all remaining tumor cells.\n\nMultimodality treatments to improve the effectiveness of hyperthermia\nAs mentioned before, hyperthermia is not effective as a single modality treatment of cancer, but is very effective after combination with radiotherapy or chemotherapy. If tumor recurrence is located in previously irradiated areas, it is preferred to avoid radiotherapy. Combinational treatments with hyperthermia, cisplatin and PARP-inhibitors have been investigated in in vitro and in vivo experiments. Once radiotherapy is contraindicated for treatment, hyperthermia and cisplatin is an established combination for retreatment of these therapy resistant tumors. The rationale to combine hyperthermia with PARP-inhibitors, originates from the induction of synthetic lethality by treating BRCA-deficient cancer cells with PARP-inhibitors. Since PARP plays a crucial role in the repair of single strand breaks, treatment with a PARP-inhibitor will convert single strand breaks into double strand breaks. These will normally be repaired by HR, in which BRCA-proteins are essential. Therefore, patients who have BRCA1\/2-deficient tumors are, theoretically, likely to benefit from PARP-inhibitor without too much normal tissue toxicity, since only the tumor cells lack functional BRCA. In Chapter 7, rats treated with cisplatin, hyperthermia and PARP-inhibitor showed a tumor growth control, without observing any side-effects. However, in four different studies (all using Olaparib), a slower tumor progression was found, but patient survival was not improved. Worse, serious side-effects such as nausea, fatigue, vomiting and anaemia were observed (Ledermann et al, 2012; Wiggans et al, 2015). In a fifth study, also treating epithelial ovarian cancer, Veliparib (another PARP-inhibitor) was used, demonstrating fewer severe side-effects, but the patient numbers were too small to draw any firm conclusions (Wiggans et al, 2015). Either lower doses of PARP-inhibitors should be applied to reduce side-effects, or the clinical effects of a newer generation PARP-inhibitors with lower toxicities should be investigated. Since hyperthermia is a local therapy that can temporarily downregulate BRCA2, we argue that hyperthermia creates a time window to treat all tumor types, including BRCA-proficient tumor types. The trimodality of cisplatin, hyperthermia and a PARP-inhibitor shows a higher tumor cell death than only thermochemotherapy (Chapter 7).\n\nCisplatin is a very effective and widely used chemotherapeutic agent. However, as cisplatin is used as a systemic therapy, it does not distinguish between tumor cells and fast replicating non-tumor cells as cisplatin targets all fast replicating cells. The \u00e2\u0080\u0093 sometimes irreversible - side-effects can be serious, as it can result into hearing impairment, sensory loss and kidney failure. The side-effects can already be reduced by so-called hyper-hydration of the patient before cisplatin is administered. However, hyper-hydration increases the clearance of the drug from the body, and may thereby reduce the effectiveness of cisplatin. As shown in Chapter 8, the addition of a PARP-inhibitor to hyperthermia and reduced cisplatin levels, is equally effective as standard cisplatin dose with hyperthermia. This finding can be clinically interesting to maintain tumor control at reduced cisplatin, thereby reducing severe and irreversible toxicity. Moreover, it would also be interesting to evaluate if addition of PARP-inhibitor can compensate for hyperthermia treatment at a lower temperature, or a high temperature for a shorter treatment time. Another approach to boost the effectiveness of hyperthermia is achieved by interfering with counteracting chaperone proteins (for example Heat Shock Proteins, HSPs) that protect cells from hyperthermia stress. Several in vitro and in vivo studies demonstrate targeting of HSPs combined with other anti-cancer treatments, can improve treatment outcome (Ciocca et al, 2010). Also, promising results are shown in clinical trials (Calderwood, 2010). As the effects of hyperthermia were temporary, a simultaneous application of HSP inhibitor would be required for further boosting effectiveness of HT. In vivo studies are the first step towards clinical application, and when results are positive this may eventually encourage to start clinical trials to validate these novel multi-modality strategies. A particularly important question is evaluation of the toxicity profile of the proposed multi-modality schedules. For instance, stress factors like hyperthermia, chemotherapy and radiotherapy can induce HSPs. As HSP90 regulates protein folding, prevents misfolding and assists in the function of various proteins, also in healthy cells, inhibition of this protein may result in some toxicity.\n\nFuture perspectives for hyperthermia in cervical carcinoma\nThe Dutch Deep Hyperthermia Trial (van der Zee et al, 2000) demonstrated significant increased tumor control and survival benefit if hyperthermia was added to radiotherapy in cervical carcinoma. In this trial, radiotherapy was compared to radiotherapy combined with hyperthermia in patients with advanced bladder, cervical and rectal tumors. In cervical cancer patients, the complete response rate was significantly higher after radiotherapy combined with hyperthermia (83%) compared to radiotherapy alone (57%). Similar results were reported in other randomized trials evaluating the effect of combining. However, the current standard treatment of patients with locally advanced cervical cancer is not radiotherapy alone, but cisplatin based chemoradiotherapy. In the RADCHOC trial (Lutgens et al, 2016), hyperthermia combined with radiotherapy was compared to chemoradiotherapy, and did not show a significant difference between the two approaches. It should be noted that many patients in the RADCHOC trial received radiotherapy in the nearest radiotherapy facility, but had to travel sometimes several hours to receive hyperthermia in a distant facility. In our retrospective patient series, described in Chapter 6, we discovered that a long time interval between radiotherapy and hyperthermia is detrimental for treatment outcome, and that the time interval between the two modalities should preferable be as short as possible, mandating delivery of both in the same facility. Then, the outcome of thermoradiation may eventually be much better as was suggested by the RADCHOC study.\n\nTaking it to the next level, standard chemoradiotherapy versus hyperthermia plus chemoradiotherapy has also been investigated in a multicentre randomised clinical trial in Japan in locally advanced cervical carcinoma (Harima et al, 2016). A trend was seen demonstrating a higher five-year overall survival of 77.8% in the arm treated with hyperthermia and chemoradiotherapy vs. 64.8% for chemoradiotherapy alone. Complete response rates were significantly higher when hyperthermia was added to chemoradiotherapy (88% vs. 77.6%). Moreover, the triple modality was well tolerated, no additional toxicities were observed. A comparable multicentre trial randomizing between the same two arms, initiated from Duke University Medical Center, the Academic Medical Centre Amsterdam, and other international partners (Westermann et al, 2012) did show a non significant trend towards a benefit of adding hyperthermia to chemoradiation regarding local control (70% to 78%) but no benefit regarding overall survival. The latter may be due to a considerable number of patients that had para-aortic lymph node metastases beyond the heated region of the primary tumor. This warrants the development of hyperthermia techniques capable of safely heating even larger volumes, or to target the para-aortic lymph nodes separately. Considering the cytotoxicity to the normal tissue due to cisplatin-based treatment, the rationale to prefer hyperthermia over cisplatin or to give trimodality treatment with a significantly reduced cisplatin dose seems logical. Further clinical studies to confirm these data are warranted. Multiple clinical trials are under investigation. For example, a clinical trial is ongoing at the University of Texas Health Science Center, in which the effectiveness of triple-modality treatment for inoperable or metastastic pancreatic cancer is investigated (www.clinicaltrials.gov). Also, clinical trials in which combinational treatments of hyperthermia with PARP-inhibitor are explored.\n\nIn conclusion, hyperthermia is a local treatment, which has proven its effectiveness in multiple clinical trials (Datta et al, 2016) and still many new improvements are explored. Not only did several studies demonstrate favorable clinical outcomes, in none of the patients severe toxicities were reported associated with hyperthermia. A good treatment not only targets the tumor cells, it must also spare the normal tissue as much as possible to reduce toxicity, both to prolong life and maintain a good quality of life for patients after treatment. After elucidating the mechanisms responsible for the effectiveness of hyperthermia, application in clinical practice of hyperthermia may be improved, which hopefully is a step towards routine clinical practice for all patients who may benefit from hyperthermia as I feel hyperthermia is potentially beneficial for a much larger group of patients than the relatively small number of patients who are presently treated with hyperthermia.\n\nBergs JW, Krawczyk PM, Borovski T, ten Cate R, Rodermond HM, Stap J, Medema JP, Haveman J, Essers J, van Bree C, Stalpers LJ, Kanaar R, Aten JA, Franken NA (2013) Inhibition of homologous recombination by hyperthermia shunts early double strand break repair to non-homologous end-joining. DNA repair 12(1): 38-45\nCalderwood SK (2010) Heat shock proteins in breast cancer progression--a suitable case for treatment? International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 26(7): 681-5\nCiocca DR, Fanelli MA, Cuello-Carrion FD, Castro GN (2010) Heat shock proteins in prostate cancer: from tumorigenesis to the clinic. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 26(8): 737-47\nDatta NR, Rogers S, Klingbiel D, Gomez S, Puric E, Bodis S (2016) Hyperthermia and radiotherapy with or without chemotherapy in locally advanced cervical cancer: a systematic review with conventional and network meta-analyses. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 32(7): 809-21\nHarima Y, Ohguri T, Imada H, Sakurai H, Ohno T, Hiraki Y, Tuji K, Tanaka M, Terashima H (2016) A multicentre randomised clinical trial of chemoradiotherapy plus hyperthermia versus chemoradiotherapy alone in patients with locally advanced cervical cancer. International journal of hyperthermia: the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 32(7): 801-8\nHunt CR, Pandita RK, Laszlo A, Higashikubo R, Agarwal M, Kitamura T, Gupta A, Rief N, Horikoshi N, Baskaran R, Lee JH, Lobrich M, Paull TT, Roti Roti JL, Pandita TK (2007) Hyperthermia activates a subset of ataxia-telangiectasia mutated effectors independent of DNA strand breaks and heat shock protein 70 status. Cancer research 67(7): 3010-7\nKakarougkas A, Jeggo PA (2014) DNA DSB repair pathway choice: an orchestrated handover mechanism. The British journal of radiology 87(1035): 20130685\nKaneko H, Igarashi K, Kataoka K, Miura M (2005) Heat shock induces phosphorylation of histone H2AX in mammalian cells. Biochemical and biophysical research communications 328(4): 1101-6\nLaszlo A, Fleischer I (2009a) The heat-induced gamma-H2AX response does not play a role in hyperthermic cell deathing. Int J Hyperthermia 25(3): 199-209\nLaszlo A, Fleischer I (2009b) Heat-induced perturbations of DNA damage signaling pathways are modulated by molecular chaperones. Cancer research 69(5): 2042-9\nLedermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis U (2012) Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. The New England journal of medicine 366(15): 1382-92\nLutgens LC, Koper PC, Jobsen JJ, van der Steen-Banasik EM, Creutzberg CL, van den Berg HA, Ottevanger PB, van Rhoon GC, van Doorn HC, Houben R, van der Zee J (2016) Radiation therapy combined with hyperthermia versus cisplatin for locally advanced cervical cancer: Results of the randomized RADCHOC trial. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 120(3): 378-382\nOei AL, Vriend LE, Crezee J, Franken NA, Krawczyk PM (2015) Effects of hyperthermia on DNA repair pathways: one treatment to inhibit them all. Radiat Oncol 10: 165\nvan der Zee J, Gonzalez Gonzalez D, van Rhoon GC, van Dijk JD, van Putten WL, Hart AA (2000) Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumors: a prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group. Lancet 355(9210): 1119-25\nWestermann A, Mella O, Van Der Zee J, Jones EL, Van Der Steen-Banasik E, Koper P, Uitterhoeve AL, De Wit R, Van Der Velden J, Burger C, Schem BC, Van Der Wilt C, Dahl O, Prosnitz LR, Van Tinteren H (2012) Long-term survival data of triple modality treatment of stage IIB-III-IVA cervical cancer with the combination of radiotherapy, chemotherapy and hyperthermia - an update. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 28(6): 549-53\nWiggans AJ, Cass GK, Bryant A, Lawrie TA, Morrison J (2015) Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer. 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