A Patient's Guide: Combining Heat Therapy with Radiation for Prostate Cancer

Table of Contents

• Introduction: Why Combine Heat and Radiation?
• How This Review Was Conducted
• How Heat Makes Radiation More Effective
• What Laboratory and Animal Studies Show
• Clinical Results: Patient Outcomes with Combined Therapy
• Safety and Side Effects of the Combined Treatment
• The Technology Behind the Heat: Methods and Challenges
• Overall Conclusions and Future Directions
• Source Information

Introduction: Why Combine Heat and Radiation?

Radiation therapy (RT) is a standard and often curative treatment for prostate cancer. However, a portion of patients—especially those with high-risk features—may experience a local relapse, where the cancer returns in the prostate area. To combat this, doctors have tried increasing radiation doses or adding hormone therapy (androgen deprivation therapy or ADT). While these strategies can improve tumor control, they also come with a risk of increased side effects.

This creates a major challenge: how to improve cure rates without making treatment more toxic. This is known as improving the therapeutic ratio. One promising strategy is to combine radiation with hyperthermia (HT), which is the controlled application of heat to raise tissue temperature above the normal body level.

Heat therapy acts as a radiosensitizer, meaning it makes cancer cells more vulnerable to radiation. Research in other cancers, like cervical, rectal, and bladder cancer, has shown that adding HT can improve local control rates by 10–20% and even boost survival. For prostate cancer, recent advances in heating technology make this combination an innovative approach worth exploring to potentially achieve better results with acceptable side effects.

How This Review Was Conducted

The authors performed a systematic review, which is a rigorous method of gathering and analyzing all relevant published research on a specific topic. They searched the PubMed database on July 21, 2021, using the terms "prostate cancer" AND "radiotherapy" AND "hyperthermia."

This search initially identified 126 scientific records. After screening, 54 were excluded because they did not directly address the combination of RT and HT for prostate cancer. The final review included studies published in English that were available in full text, following established reporting guidelines to ensure transparency and completeness.

How Heat Makes Radiation More Effective

From a biological perspective, heat (applied at 41–43°C) boosts radiation's effectiveness through several key mechanisms. First, it causes blood vessels to dilate, increasing oxygen supply to the tumor. Since oxygen makes cells more sensitive to radiation, this reduces the problem of tumor hypoxia (low oxygen).

Second, heat interferes with cancer cells' ability to repair the DNA damage caused by radiation. It inhibits specific repair pathways known as base excision repair (BER) and homologous recombination (HR). The dominant effect depends on the temperature: improved oxygenation is more important around 41°C, while DNA repair inhibition becomes more significant around 43°C.

Furthermore, heat has a direct cell-killing effect on radiation-resistant cells and can stimulate the immune system, potentially activating immune cells against the cancer. It's estimated that adding HT can make radiation as effective as if an extra 10 Gy of dose had been given—a substantial increase without actually raising the physical radiation dose to healthy tissues.

What Laboratory and Animal Studies Show

Experiments on prostate cancer cells and in animals provide strong evidence for the synergy between heat and radiation. In one key lab study using DU145 prostate cancer cells, a 90-minute heat session at 43°C followed by a 4 Gy radiation dose led to significantly more DNA damage and cell death (64.48% apoptotic cells) compared to radiation alone (27.70%).

Even in radioresistant prostate cancer stem cells, the combination drastically reduced the number of surviving colonies—by up to a factor of 100 compared to radiation alone. In mice with implanted human prostate tumors, the combined treatment was most effective at slowing tumor growth. The median time for tumors to double in size was 35.5 days with HT+RT, compared to 25.5 days with RT alone and 18 days with HT alone, confirming at least an additive benefit.

Another study in rats showed that performing HT both before and after a brachytherapy (internal radiation) seed implant resulted in a 53.7-day delay in tumor growth, better than a single HT session before treatment (44-day delay).

Clinical Results: Patient Outcomes with Combined Therapy

The review analyzed clinical studies where patients received combined HT and RT, primarily those with high-risk initial disease or with a local recurrence after previous surgery or radiation. The table below summarizes key findings from several important studies.

Key Clinical Studies and Their Outcomes:

• Deger et al. (2002): 57 patients received interstitial HT (heating seeds placed in the prostate) weekly along with external beam RT (68.4 Gy). The 2-year biochemical relapse-free survival (bRFS) was an excellent 95%, and median PSA dropped from 11.6 to 0.5 ng/mL at 48 months.
• Hurwitz et al. (2010): 37 patients with stage T2b-T3b cancer received transrectal ultrasound HT twice during a 70 Gy RT course. The 7-year failure-free survival was 61%, and overall survival was 94%. This compares favorably to historical data where RT alone (70 Gy) resulted in only a 43% control rate at 6 years.
• Van Vulpen et al. (2004): Patients with locally advanced cancer (T3, T4) received weekly HT with 70 Gy RT, without hormone therapy. They still achieved a 70% bRFS rate at 3 years.
• Yahara et al. (2018): In high/very high-risk patients, combined treatment led to a 78% 3-year bRFS, compared to 72% for matched patients treated with RT alone.
• Kalapurakal et al. (2004): For patients with hormone-resistant or recurrent disease, the combined approach achieved a 77% local control rate.
• Tilly et al. (2002): At 6 years, the bRFS was 60% for primary treatment and 43% for salvage treatment after prostatectomy.

These studies, while not all randomized trials, consistently suggest that adding HT can improve outcomes, particularly in challenging clinical situations.

Safety and Side Effects of the Combined Treatment

A critical finding of this review is that adding hyperthermia to radiation did not lead to a dramatic increase in severe side effects. Reported toxicity rates were generally manageable.

Acute (Short-term) Genitourinary (GU) Side Effects: Grade 2 issues (moderately bothersome) ranged from 0% to 55% across studies. Severe (Grade 3) acute GU toxicity was rare in the primary treatment setting, reported in only 1% to 4% of patients. In the salvage (re-treatment) setting, the rate was higher but still limited, up to 18% in one study.

Acute Gastrointestinal (GI) Side Effects: Grade 2 issues like diarrhea were more common, up to 48% in one trial. Grade 3 acute GI effects were mainly seen in re-irradiation patients (14% in one study).

Long-term (Late) Side Effects: Importantly, no late Grade 3 toxicities were reported across the studies. Only two cases of severe (Grade 4) late toxicity were noted, both in complex salvage cases: one hemorrhagic cystitis in a patient with a bleeding disorder, and one rectovesical fistula.

Heat-Specific Side Effects: These were mostly mild. Skin burns (Grade 1 or 2) occurred in some patients, with one study reporting 68% Grade 1 and 9% Grade 2 skin reactions. These typically healed on their own. Pain during heat application was a challenge in some early studies, sometimes limiting the ability to reach the target temperature.

The interim analysis of the ongoing HT-Prostate trial (NCT0415905) for salvage treatment reported low acute toxicity: 10% Grade 2 GU, 4% Grade 2 GI, and 42% Grade 1 heat-related issues like skin pain.

The Technology Behind the Heat: Methods and Challenges

Delivering effective and targeted heat to the prostate is a technical challenge. The studies in this review used several methods, all based on electromagnetic heating (like radiofrequency or microwaves).

The main approaches were:

1. Regional Hyperthermia: Devices with multiple antennas or applicators are placed around the patient's pelvis (e.g., annular phased arrays or capacitive systems). This heats a larger area.
2. Local Hyperthermia: Heat is applied more directly to the prostate.
   • Interstitial: Tiny heating probes or "thermoseeds" are implanted directly into the prostate, often alongside brachytherapy seeds.
   • Transrectal/Transurethral Ultrasound: A probe inserted into the rectum or urethra delivers focused ultrasound energy to heat the prostate.

The goal is to achieve and maintain a temperature between 41-43°C in the entire tumor for 30-60 minutes. A major hurdle is the uneven heating caused by differing blood flow and tissue properties, which can create unwanted "hot spots" in normal tissues (like fat or muscle) and "cold spots" in the tumor.

Advanced techniques are being developed to overcome this. MR-guided focused ultrasound is particularly promising because it uses magnetic resonance imaging (MRI) to visualize the tumor in real-time and precisely steer powerful ultrasound beams to heat it uniformly, potentially improving effectiveness and safety.

Overall Conclusions and Future Directions

This systematic review gathers compelling evidence that combining hyperthermia with radiotherapy is a promising strategy for prostate cancer treatment. The biological rationale is strong: heat sensitizes cancer cells to radiation, inhibits repair, and may stimulate immunity.

Clinical data, though primarily from non-randomized studies, consistently show that the combination can improve tumor control rates in both primary treatment for high-risk disease and in salvage settings for recurrent cancer. Crucially, this benefit appears achievable without a substantial increase in severe long-term side effects.

The main limitations of the current evidence are the lack of large, randomized Phase III trials specifically for prostate cancer and the technical challenges in delivering uniform, effective heat. However, ongoing technological advances, especially in image-guided focused ultrasound, are actively addressing these hurdles.

For patients, this means: Hyperthermia combined with radiation is an emerging and well-tolerated option that may offer improved outcomes, particularly if you have high-risk localized prostate cancer or a local recurrence. You should discuss with your radiation oncologist whether this approach is available and suitable for your specific case, considering the technology used by your treatment center.

Source Information

Original Article Title: Combined hyperthermia and radiotherapy for prostate cancer: a systematic review
Authors: Jennifer Le Guevelou, Monica Emilia Chirila, Vérane Achard, Pauline Coralie Guillemin, Orane Lorton, Johannes W. E. Uiterwijk, Giovanna Dipasquale, Rares Salomir & Thomas Zilli
Publication: International Journal of Hyperthermia, Volume 39, 2022, Pages 547-556.
DOI: 10.1080/02656736.2022.2053212

This patient-friendly article is based on the peer-reviewed research systematic review cited above. It aims to translate the key findings, data, and context for an educated patient audience, preserving the full scope and details of the original publication.