Hyperthermia Boosts Chemo Effect in Large Breast Cancers

ORLANDO—A neoadjuvant treatment approach that involves the administration of liposomal doxorubicin (Myocet, investigational in the United States) and paclitaxel (Taxol), then heat delivery to the tumor, appears to enhance the efficacy of the chemotherapy, according to a study reported at the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 200). Lead investigator Kimberly Blackwell, MD, a medical oncologist at Duke University Comprehensive Cancer Center, called the results "impressive."

The phase I trial involved 21 stage IIB-III breast cancer patients. Patients received four cycles every 3 weeks of liposomal doxorubicin and paclitaxel, followed by 1 hour of hyperthermia via a phased array microwave system. Doses escalated from liposomal doxorubicin 30 mg/m2 plus paclitaxel 100 mg/m² up to 75/175 mg/m².

While hyperthermia has long been known to boost the effects of radiation therapy, its ability to enhance a tumor’s response to drugs encased in liposomes is just being explored in humans.

The patients receive their chemotherapy, then are placed face down on a table with their breast submerged in a sunken pool of water through which microwave energy is delivered (see Figure).

The heat activates the agents, coaxing the doxorubicin out of its liposomal coating to attack the tumor. The body’s normal tissues remain unheated; therefore, the chemotherapy works preferentially at the tumor site and affects normal tissue only gradually over 3 to 4 weeks, thus blunting the side effects.

"Encapsulating the chemotherapy inside of liposomes enables us to deliver 30 times more chemotherapy to the tumor site than we normally could, without too much toxicity," Dr. Blackwell said. "Heat also boosts the drugs’ potency by interfering with mechanisms that control a cancer cell’s ability to replicate."

Responses

The complete clinical response rate was 35%, and 11% of patients had a complete pathologic response; 55% of patients achieved a partial response, and in all the others, the treatment produced at least stable disease.

The results were more dramatic than the investigators had predicted based on preclinical studies, Dr. Blackwell said. Breast conservation therapy was made possible in 17% of patients who would have undergone mastectomy. The findings are particularly significant considering that most of these women were told by their surgeons that they had inoperable tumors, she added.

"It is very exciting that almost 100% of tumors became operable. All the patients started out with very large tumors and had minimal residual cancer left. We were impressed," she commented.

The patients have generally experienced less nausea, fatigue, and cardiac toxicity than with traditional chemotherapy, presumably because of the liposomal preparation of doxorubicin.

The researchers had previously shown that traditional chemotherapy agents, which have little effect on cancer in mice, are highly effective in mice when encapsulated in liposomes (fat bubbles) and heated, said Mark Dewhirst, PhD, director of the hyperthermia program at Duke.

The heat triggers a series of complex events that are critical to the tumor’s demise. First, heating the breast draws liposomes out of the bloodstream and directly to the tumor site. "Heat pulls the blood vessels apart even more than usual, allowing tiny particles such as liposomes to leak out and pool into the tumor’s interstitial spaces," he explained.

Second, heat increases the rate of a drug’s uptake into the cancer cell itself, through mechanisms that are not well understood. Heat also increases oxygen levels within the tumor, oxygen being critical to the proper functioning of many chemotherapy agents.

Finally, heat amplifies the level of DNA damage that chemotherapy inflicts upon the cell by inhibiting enzymes that normally would repair such DNA damage.

But hyperthermia is not the only factor, he said. Liposomes themselves are beneficial because they reduce the amount of drugs delivered to nontumor sites. Dr. Dewhirst and his colleagues have developed a new generation of liposomes that melt quickly when heated, releasing drug into the tumor within 20 seconds of heating to 40° C.

In this study, only three patients received the dose that will probably be included in future studies (75/175 mg/m²). Forty more patients are being enrolled at this dose level.