Why heat keeps proving itself in cancer, and keeps getting ignored
Forty years of data, a clear mechanism, but a commercial model that never paid for the trial the field needed
Heating a tumor to 41.5 °C sounds like fringe medicine. It is not. Oncologic use of hyperthermia has evidence that most treatments marketed as “emerging” never reach. The puzzle I keep coming back to, as a medical doctor, scientist, and now as someone trying to fund a trial for it, is the gap between that evidence and how rarely the treatment is used.
What heat actually does
Heat already does a lot on its own, but its best-proven value is as a sensitizer for the treatments we already use. At 39–41 °C, it starts to activate antitumor immunity by improving antigen presentation and increasing immune cell infiltration into the tumor. At around 41 °C, it impairs the DNA repair machinery that tumor cells rely on to survive radiation and cytotoxic chemotherapy. In a systematic review I co-authored, we mapped these effects onto the hallmarks of cancer and found that induced hyperthermia modulates seven of the ten (Gorbaslieva et al., 2025). Others reach the same picture from different angles: localized heat acting on the hallmarks of cancer (Hannon et al., 2021), and the argument for treating regional hyperthermia as a targeted therapy built around blocking DNA repair (Issels et al., 2016).
These reviews also make a point I find more honest than most of the field’s marketing: the effect is temperature-dependent. Heat too hard and you lose effect and cause harm; heat too little and the effect is too small. This treatment has a therapeutic window that demands strict control.
The radiotherapy evidence
The cleanest data come from radiation. In the Dutch Deep Hyperthermia Trial, adding hyperthermia to radiotherapy for locally advanced cervical cancer raised the complete response rate from 57% to 83%, and three-year survival from 27% to 51% (van der Zee & González, 2002). Radiation toxicity did not increase.
The meta-analyses point the same way. About a 25-percentage-point gain in complete response for head and neck cancer (Datta et al., 2016a), and 60% versus 38% complete response in locally recurrent breast cancer (Datta et al., 2016b), both without a meaningful rise in late toxicity.
Almost never used....
The chemotherapy evidence
Chemotherapy has its own randomized signal. EORTC 62961 added regional hyperthermia to neoadjuvant chemotherapy in high-risk soft-tissue sarcoma and improved local control (Issels et al., 2010). At a median follow-up of 11 years, five-year survival was 63% versus 51% (Issels et al., 2018). That is the first phase 3 trial to show heat adds to chemotherapy, and the benefit held up over a decade.
Almost nowhere used....
Why a treatment this good stays at the margin
If a drug carried this profile across three tumor types, it would be standard of care. Hyperthermia is not, and the reasons are operational, not scientific.
The field grew up around selling devices. A hospital buys a machine once. There is no recurring revenue to fund the large, well-designed trials that change guidelines, so the trials stayed small, academic, often non-randomized or controlled, single-center, and heterogeneous in how they heated and how they measured dose. Those are exactly the features a reviewer uses to discount a literature. The credibility gap is real, but it is a funding-and-design gap, not a biology gap.
The bet
This is the part I now live in. The indication I care about most, metastatic pancreatic cancer, has only low-quality evidence. Across 14 studies, median survival was 11.7 versus 5.6 months in favor of the hyperthermia arms, but the studies were too heterogeneous to draw firm conclusions (van der Horst et al., 2017). The honest reading is “signal, not proof.”
However, what the field has never had is a properly powered, properly funded randomized controlled trial, professionally executed with a business model behind it that can pay for the next one. That, more than any new physics, is what would move hyperthermia from the margin into the protocol.
The question was never really whether heat works. Four decades of data already answer that. The open question is whether anyone will build the commercial engine to run the trial that proves it at the scale oncology demands before it commits.
We are trying to do just that. Setting up a randomized, controlled, multicenter, well-powered trial. I will keep you posted....
Disclosures. I am CEO and shareholder of ElmediX, a Belgian MedTech company developing whole-body hyperthermia for metastatic pancreatic cancer, and a co-author of one of the reviews I cite here (Gorbaslieva et al., 2025). This is my reading of the evidence regardless of those interests, but you should know about them.
References
Datta, N. R., Rogers, S., Gómez Ordóñez, S., Puric, E., & Bodis, S. (2016a). Hyperthermia and radiotherapy in the management of head and neck cancers: A systematic review and meta-analysis. International Journal of Hyperthermia, 32(1), 31–40. https://doi.org/10.3109/02656736.2015.1099746
Datta, N. R., Puric, E., Klingbiel, D., Gomez, S., & Bodis, S. (2016b). Hyperthermia and radiation therapy in locoregional recurrent breast cancers: A systematic review and meta-analysis. International Journal of Radiation Oncology, Biology, Physics, 94(5), 1073–1087. https://doi.org/10.1016/j.ijrobp.2015.12.361
Issels, R. D., Lindner, L. H., Verweij, J., Wust, P., Reichardt, P., Schem, B. C., … Hohenberger, P. (2010). Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: A randomised phase 3 multicentre study. The Lancet Oncology, 11(6), 561–570. https://doi.org/10.1016/S1470-2045(10)70071-1
Issels, R. D., Lindner, L. H., Verweij, J., Wessalowski, R., Reichardt, P., Wust, P., … Gronchi, A. (2018). Effect of neoadjuvant chemotherapy plus regional hyperthermia on long-term outcomes among patients with localized high-risk soft tissue sarcoma: The EORTC 62961-ESHO 95 randomized clinical trial. JAMA Oncology, 4(4), 483–492. https://doi.org/10.1001/jamaoncol.2017.4996
van der Horst, A., Versteijne, E., Besselink, M. G. H., Daams, J. G., Bulle, E. B., Bijlsma, M. F., … van Tienhoven, G. (2017). The clinical benefit of hyperthermia in pancreatic cancer: A systematic review. International Journal of Hyperthermia, 34(7), 969–979. https://doi.org/10.1080/02656736.2017.1401126
van der Zee, J., & González González, D. (2002). The Dutch Deep Hyperthermia Trial: Results in cervical cancer. International Journal of Hyperthermia, 18(1), 1–12. https://doi.org/10.1080/02656730110091919
Gorbaslieva, I., Quisenaerts, T., Bogers, J. J. P. M., Peeters, M., Saldien, V., & Ysebaert, D. (2025). Temperature-dependent effects of induced hyperthermia, including whole-body hyperthermia, on the hallmarks of cancer: A systematic review. Cancers, 17(23), 3824. https://doi.org/10.3390/cancers17233824
Hannon, G., Tansi, F. L., Hilger, I., & Prina-Mello, A. (2021). The effects of localized heat on the hallmarks of cancer. Advanced Therapeutics, 4(7), 2000267. https://doi.org/10.1002/adtp.202000267
Issels, R., Kampmann, E., Kanaar, R., & Lindner, L. H. (2016). Hallmarks of hyperthermia in driving the future of clinical hyperthermia as targeted therapy: Translation into clinical application. International Journal of Hyperthermia, 32(1), 89–95. https://doi.org/10.3109/02656736.2015.1119317