Many years ago, it was discovered that a moderate increase in tissue temperature can markedly improve the cancer cell killing power of ionizing radiation. The temperature increase needed is not extreme. It is only necessary to increase temperature from 37°C (98.6°F) to something in the range of 41-43°C (106-109°F), which is the just a little warmer than a hot shower. Like a hot shower, it brings more blood into the warmed tissues, which may be the reason for its benefit.
The Theory
Blood flows to warm tissue in an effort to carry away the excess heat. Skin and muscle can easily tolerate temperatures of 44-46°C for an hour or more in a limited volume. But cancerous tissue does not have a good blood supply, so the heat accumulates preferentially there and cripples those cells. Those cancer cells are more susceptible to killing by radiation (or chemotherapy). The increased blood flow also increases the oxygenation that is necessary for radiation to work, while protecting healthy cells. There is also be a direct cancer cell killing effect attributable to protein denaturation and inhibition of DNA repair. By denaturing the proteins that activate DNA repair, the cancer cells undergo "mitotic catastrophe" when they try to replicate. Sublethal radiation damage becomes lethal. At the same time, cancer cells are directly destroyed via several other mechanisms: senescence, apoptosis, and necrosis.
When subjected to heat stress, cells, whether cancerous or healthy, release protective heat shock proteins (HSP) both inside the cell and into the extracellular space. HSP is responsible for thermal resistance, which is why hyperthermia is not used at every radiation sessions in most studies. (Negating the protective effect using HSP inhibitors is an active area of oncological research.) In the studies below, hyperthermia was given only a few times during the course of an extended radiation schedule. On the other hand, HSP in the extracellular space chaperones cancer antigens to the immune system. Much of the benefit is thought to arise from a bystander or abscopal effect.
Hyperthermia would ideally be delivered at the same time as radiation (see the brachytherapy study below). But it can also be delivered up to 3 hours
before radiation. It has also been used within a short time
after radiation because it renders lethal what would otherwise be sublethal damage, and because of immune stimulation.
Not all types of cancer cells are vulnerable to hyperthermia. In
a lab study, it was shown that prostate cancer cells were sensitive to hyperthermia (and hypothermia).
A mathematical model showed that raising the tumor temperature to 42°C and delivering 76 Gy of radiation would be equivalent in cancer killing to raising the radiation dose to 86 Gy - effectively adding 10 Gy of cancer-killing power without increasing toxicity.
While it's important to have a theoretical framework showing why it should be beneficial, it is more important to demonstrate that benefit in clinical practice. There are four situations in which combining hyperthermia and radiation may be useful in prostate cancer treatment: (1) Primary prostate treatment, (2) Salvage prostate bed treatment, (3) whole pelvic treatment, and (4) Palliative treatment of metastases.
Primary Prostate Treatment
Many of the studies on hyperthermia + radiation occurred in the 1990s when radiation doses were usually inadequate for cure, and there have been no randomized studies. The few studies tell us more about treatment-related toxicity than efficacy.
Hurwitz et al. used just two transrectal ultrasound hyperthermia treatments before radiation on 37 locally-advanced patients who also received 66 Gy of radiation and 6 months of ADT. They found that heating the rectal wall to 42°C for about an hour was tolerable, and they allowed the interior temperature probe to go up to 43°C for 10 minutes. Toxicity was mild, with no patients suffering from serious (Grade 3) urinary or rectal toxicity. There was no relation between late-term rectal toxicity and rectal wall temperature. There was a relationship with
acute rectal toxicity, although there was no toxicity greater than grade 2 (
see this link). The
same authors also found that perfusion of blood into the prostate increased most among those with the most hypoxic prostate tumors.
With longer follow-up,
Hurwitz et al. reported that two-year recurrence-free survival was 84% with hyperthermia compared to only 64% in historical controls without hyperthermia. 7-year recurrence-free survival was 61% with hyperthermia (they didn't have a comparable 7-year historical control). The authors noted a relation existed between the maximum heating achieved in a patient and his recurrence-free survival.
Maluta et al. reported on 144 patients with locally advanced prostate cancer treated with 74 Gy of conformal external beam radiation, with ADT used short term in more than 60% of those patients. Hyperthermic therapy was given once a week for the first four weeks of EBRT. They noted no significant side effects, other than those associated with ADT and radiation. There was no toxicity greater than grade 2.
Kukielka et al. reported on 73 prostate cancer patients (54 primary therapy for low- and intermediate-risk, 19 locally recurrent after primary EBRT) treated with hyperthermia + high dose rate brachytherapy. They found no complications other than those normally associated with brachytherapy. There was no toxicity above grade 2.
It has been proposed that tumors within the prostate, identified with mpMRI or PET scan, can receive a hyperthermia boost prior to radiation. Tis may prove useful in overcoming hypoxia.
Salvage Prostate Treatment
Kukielka et al. separately reported on 25 locally radio-recurrent patients treated with hyperthermia + high dose rate brachytherapy. The brachytherapy dose was 30 Gy in 3 fractions, and hyperthermia was applied before each fraction. There were no complications higher than grade 2. Two-year biochemical control was 74%.
There is
an ongoing trial in Europe of hyperthermia in patients receiving salvage radiation (70 Gy) using 41°C for 60 minutes in the prostate fossa.
With
Dr. King's analysis that suggests that current post-prostatectomy salvage radiation doses (of about 70 Gy) are inadequate, there may be a unique opportunity to raise the biologically effective dose without increasing radiation toxicity.
Whole Pelvic Treatment
In 2005,
Tilly et al. reported on 22 patients who received regional hyperthermia along with 68.4 Gy of radiation for locally advanced or recurrent prostate cancer. None had positive lymph nodes. Acute toxicity was high, while late toxicity was mild. Thermal parameters were not correlated with toxicity, but higher temperatures were associated with better PSA control.
This reflects an underexplored opportunity in both primary and salvage treatment, and especially when cancerous lymph nodes have been detected by pelvic lymph node dissection (PLND) or imaging. Because of toxicity considerations, the pelvic lymph node area is only treated with about 50 Gy of conventionally fractionated radiation, which may be inadequate to kill all traces of the relatively radioresistant cancer. Hyperthermia may be able to boost the effective cancer-killing dose. In addition, it can be used less broadly to radiosensitize any specific positive lymph nodes that have already been identified.
Metastasis-directed Treatment
Chi et al. reported the first clinical trial where 57 patients were randomized to receive hyperthermia along with their radiation (30 Gy in 10 fractions) of painful bone metastases. Those who received hyperthermia, received it within 2 hours
after radiation treatments twice weekly for 2 weeks. Their hyperthermia system used radiowaves (RF) to heat the metastases to the target temperature for 40 minutes. Pain palliation was the goal. The trial was ended early because the adjuvant hyperthermia was clearly superior. Complete pain palliation after 3 months was achieved in 59% of those who received hyperthermia, but only 32% of those who received radiation alone. Among those who had a complete pain response, median time to return of pain was 55 days among those who received radiation alone, but was not reached in the 24 weeks of follow-up among those who received hyperthermia.
Hyperthermia Technologies
Historically, technology kept hyperthermia therapy from gaining wide acceptance. Patients often suffered burns.The hyperthermia did not penetrate deep enough, and could not be accurately maintained. There were no guidelines for its use, and it was labor intensive to closely monitor each treatment. With low-toxicity radiation dose-escalation achieved with IGRT/IMRT, there was less need for the adjuvant thermal treatment. There are several technologies used to achieve hyperthermic temperatures. Hurwitz et al. used transrectal ultrasound with multiple temperature probes. Kukielka used RF implants directly into the prostate done at the same time as the brachytherapy implants. Others have investigated implanted ferromagnetic seeds that heat up when exposed to an alternating magnetic field. Chi et al. used RF at the surface to warm metastases.
Temperature inside the body can now be monitored from measurements taken from the surface, rather than internal temperature probes. Hyperthermia is prescribed in terms of cumulative equivalent minutes at 43°C achieved in 90% of the target area (CEM43T90). For each °C
above 43°C, the time required for an equivalent effect is halved; for each °C
below 43°C, the time required for an equivalent effect is fourfold higher. Typical CEM43T90 is at least 10 minutes. It is difficult to maintain the hyperthermic temperature because blood flow is continuously trying to carry away the excess heat. The patient typically spends about an hour on the table.
The problem with RF and MW energy is that much of their energy is deposited at the skin, causing burns. Microwaves do not penetrate deeply but can pinpoint a small area. RF can go deeper, but can only be used in wider areas. Ultrasound (US) is the technological breakthrough that enabled hyperthermia to treat deeper and wider areas, and it allows for greater accuracy. Low frequency US can penetrate deeply. Multiple US beams can be made to converge at the target tissue without overheating adjacent tissue. The only drawbacks of US are that it is strongly absorbed by bone, and it is interrupted and reflected by air pockets. This means that the spine and bones of pelvis must be avoided. It can also not be used across the rectum, unless the rectum is filled with a water balloon.
Treating the pelvic lymph node area may be problematic. It is large area deep within the body which may be difficult to heat and keep heated for a therapeutic length of time. Also, pelvic bones must be avoided.
Many hyperthermia clinics use the
Sonotherm 1000. Its US can penetrate up to depths of 8 cm, which should be adequate to reach the entire prostate, and prostate bed. Similar to a multileaf collimator and intensity modulation used in radiation, it has an array of US transducers that can shape and focus the beams.
Research Directions and Treatment Centers
Because radiation technology has progressed so rapidly, it is now usually possible to curatively treat most patients with dose-escalated radiation without dose-limiting toxicity. Still, there may be instances where gross tumors have been identified within the prostate. Those tumors may exhibit a relatively radioresistant Gleason pattern 5, or they may have poor blood flow. There are opportunities for using hyperthermia to increase the biologically effective dose in the post-primary radiation and post-prostatectomy salvage situation and, if the technology can be worked out, to the whole pelvic region where radiation doses have historically been held low to avoid toxicity. Adjuvant hyperthermia for metastasis-directed therapy for pain palliation looks like a very promising use.
Although adjuvant hyperthermia is more popular in Europe, there are several centers in the US that are using it, notably
UCSF, Washington University, Cleveland Clinic, Dana-Farber, Duke, and
Thomas Jefferson University. One private clinic I spoke with suggests daily treatments, for which there is no substantiation, may render the therapy less effective, and seems to be a money-grabbing ploy.
It seems that the technology has improved to the point that randomized clinical trials should be instituted. There seem to be only two clinical trials currently running in the US. Mark Hurwitz at Thomas Jefferson University is lead investigator on
a trial using salvage high dose rate brachytherapy with interstitial hyperthermia in patients who are recurrent after radiation. Joe Hsu at UCSF is running
a similar trial that is no longer open to recruitment.
Adjuvant hyperthermia is now Medicare-approved. If not covered by Medicare or insurance, patients may pay about $900 per treatment.
Thanks to BJ Choi at The Center for Thermal Oncology for explaining their protocol.
