April 25, 2016
New Studies Use Heat to Fight Cancer Tumors
Studies have found raising the temperature of organs and cells seems to make some cancer treatments more effective.
Heating tumors up by just a few degrees appears to help the body fight some types of cancer more effectively, new research has shown.
Increasing body temperature is an ages-old treatment known as hyperthermia, and it has been used to treat tumors and other diseases since the days of Hippocrates. But figuring out how to apply the heat in a controlled way has been a challenge.
Interest in hyperthermia had lulled for decades after a series of disappointing clinical trials, but recent encouraging studies have led to a resurgence in the field.
In recent years, clinical and lab studies have found that increasing the temperature of particular organs and cells appears to increase the effectiveness of chemotherapy and radiation, as well as of the body’s immune system. And new cancer drugs are being developed that are activated using heat, but only when the medicine reaches the targeted tumor—potentially enabling higher effective doses to be administered while minimizing side effects to normal tissue.
“If we can treat earlier with less toxicity, killing tumors before they get large, and trigger [greater] immune response, then we’ll have something really interesting,” says Brant Inman, a urology professor at Duke Cancer Institute, in Durham, N.C., who is studying hyperthermia.
Hyperthermia generally refers to treatments in which the temperature of a particular organ, tissue or bodily region is raised anywhere from a few degrees into what is known as the fever or febrile range of about 102 to 105 degrees Fahrenheit, to a much greater increase into “ablative” temperatures of up to about 200 degrees Fahrenheit, which burns and kills tumor tissue. Currently, hyperthermia treatment is sometimes used in combination with radiation therapy for a variety of cancers and is used experimentally for other tumors, Dr. Inman says.
Hyperthermia addresses a common problem with treating some types of cancer, which is that chemotherapy isn’t always taken up well by tumors. However, when an organ such as the bladder can be heated in isolation, the hyperthermia treatment, alone or in combination with another treatment, holds promise as a potential treatment.
In recent years, hyperthermia has been studied extensively in bladder cancer, particularly a noninvasive type that hasn’t spread into the muscle of the bladder. A small European study of 51 patients with bladder cancer, many who had failed a type of standard immunotherapy called BCG, showed that hyperthermia coupled with chemotherapy appeared to be safe and effective.
Two more recent randomized controlled trials, small ones in the Netherlands and in the U.K., were encouraging despite mixed findings. The Dutch study, of patients with bladder cancer at risk of recurrence, found hyperthermia in the febrile range plus chemotherapy was superior to BCG and resulted in a significant reduction in recurrence of the disease. The British study, of 104 patients who received hyperthermia after failing BCG treatment, didn’t find a statistically significant effect. John Kelly, a urology professor at University College London and the chief investigator of the U.K. trial, says there was a benefit in some but not all patients.
Several devices can be used to deliver hyperthermia treatment. In the bladder, chemotherapy is delivered using a catheter, and the delivery system heats either the bladder or the chemotherapy as it enters the organ. In the U.K. study, patients received it for an hour, once a week for six weeks. Patients are awake and generally don’t require any analgesia, the main side effect being some irritation during urinating in the day or two following treatment, Dr. Kelly said.
Currently, he and colleagues in the U.K. and Spain are running a study of more than 350 patients testing chemotherapy with hyperthermia versus chemotherapy alone. His Spanish collaborators are running another trial as well, in which patients are pretreated using hyperthermia before the surgical removal of a tumor, in hopes it will decrease the chance of recurrence.
If hyperthermia is shown to help treat bladder cancer, “it’s another option, and with the range of chemotherapy and novel agents it may be a much better option,” Dr. Kelly said. “Taken together, the studies tell us that hyperthermia is effective in bladder cancer, and further work will help establish which patients benefit most.”
Heat appears to make some chemotherapy more effective for several reasons. In part it may be that the tumor tissue becomes more open to the uptake of chemotherapy: The tumor blood vessels dilate, taking up chemotherapy, and the hyperthermia can damage the cancer DNA within the cells, Dr. Kelly said.
In addition, each tumor cell has protective mechanisms in place that fight the drug. Heat appears to weaken the cells’ ability to protect themselves, making the same drug even more toxic and potentially more effective, says Duke’s Dr. Inman.
In early, unpublished work with pigs, Dr. Inman and his team have found that heating up the bladder and delivering novel drugs at higher levels “looks pretty promising,” he says. The team also is researching melanoma, prostate cancer and breast cancer in mice and rats.
Experimental drugs at various stages of testing use heat to activate chemotherapy after the medicine has reached its target. Some evidence suggests that such drugs could allow a dose to be given that is 10 to 30 times as high as a free-floating drug, while reducing toxicity to other parts of the body, said Dr. Inman, who is involved in some of these clinical trials.
Also of growing interest is the use of hyperthermia in combination with immunotherapy treatments. Heating the body activates the immune system, increasing interactions between immune cells designed to alert the body when it is under attack and mobilizing immune cells such as T and B cells to tissues where they are needed, according to Sharon Evans, an oncology professor in the department of immunology at Roswell Park Cancer Institute in Buffalo, N.Y.
“If you expose body to fever in the febrile temp range, this tickles and provokes the immune response at almost every level that leads to enhanced protection,” Dr. Evans said.
In work that came out last month, Dr. Evans and colleagues showed that applying an ablative tool reaching temperatures of close to 200 degrees Fahrenheit to the tumor prior to surgically removing it, reduced recurrence and increased cure rates compared with surgery alone.
“The intriguing thing is that the thermal therapy wasn’t just directly killing tumor cells. It was invoking the immune response, which had an impact even outside the treatment region,” Dr. Evans said. The ablative tool appears to be “increasing the ability of the immune system to fight cancer all across the body, not just in tumors lying within the immediate treatment zone.”
The team’s continuing work, still unpublished, focuses on mechanisms of tumor resistance to treatment. The goal would be to strategically change the tumor environment, using hyperthermia before immunotherapy, so that the environment is preconditioned to be the most beneficial for the body’s immune system and destroy malignant cancer.