New Breast Cancer Therapy Boosts Drugs' Effects, Dramatically Shrinks Tumors
DURHAM, N.C. – Patients of Kimberly Blackwell, M.D., jokingly call their treatment table the "booby Jacuzzi." The name may be a bit crass, but then a close brush with mortality entitles these women to call the life-saving contraption whatever they want.
Humor aside, they have come to the Duke Comprehensive Cancer Center with the earnest hope of preserving their lives, if not their breasts, from the ravages of deadly breast cancers – termed "inflammatory" and "locally advanced" tumors -- that often resist traditional treatments. Sixty to 70 percent of its victims do not survive past five years. Twenty-one women came to Duke for a unique phase I trial in search of better odds.
Propped on pillows and serenaded by the music of their choice, the women lie upon a massage-like table for one hour as radio frequency energy warms their breasts, which lie in a sunken pool of water. The heat triggers the chemotherapy they have just received to settle inside the tumor, where it trickles out of its protective coating -- a tiny fat bubble called a liposome – and attacks the tumor's genetic machinery.
The body's normal tissues remain unheated, so the drug is not preferentially delivered there. Hence, the drugs slowly leak out into normal tissues over a period of three or four weeks – long enough for the liver and spleen to blunt its toxic side effects.
In several cases, the treatment has remarkably destroyed all visible signs of the tumor. In others, the treatment has saved women's breasts from surgical removal. In every case, it has halted the tumor from growing, said Blackwell, a Duke medical oncologist who runs the protocol with a team of a dozen colleagues.
The results are far more dramatic than any of the team envisioned, based on their pre-clinical studies, said Blackwell, who presents their phase I clinical trial data on May 18 at the American Society of Clinical Oncology in Orlando. Twenty-one women with newly diagnosed breast cancers participated in the 12-week hyperthermia trial, funded by the National Cancer Institute.
"Encapsulating the chemotherapy inside of liposomes enables us to deliver 30 times more chemotherapy than we normally could to the tumor site, without poisoning the rest of the body," said Blackwell. "Heat also boosts the drugs' potency by interfering with mechanisms that control a cancer cell's ability to replicate."
The only clinical trial of its kind in the nation, Blackwell said it is the first to combine "hyperthermia" (heat therapy) together with chemotherapy and fat liposomes in patients with newly diagnosed, large and invasive breast tumors. 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.
Already, the Duke researchers have shown that traditional chemotherapy agents, which have little effect on cancer in mice, are highly effective in mice when encapsulated in liposomes and heated, said Mark Dewhirst, Ph.D., director of the hyperthermia program at Duke.
Simple as it appears, heat triggers a series of complex events that are critical to the tumor's demise, said Dewhirst, whose decades of animal research gave rise to the current trial. First, heating the breast draws liposomes out of the bloodstream and directly to the site of the tumor, thus concentrating the drug-packed liposomes where they are needed the most.
"A tumor's blood vessels are much leakier than normal blood vessels," Dewhirst said. "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."
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, including those in the current trial. And finally, heat amplifies the level of DNA damage that chemotherapy inflicts upon the cell by inhibiting enzymes that normally repair such DNA damage.
Hyperthermia, however, is not the only powerhouse in this new treatment equation, said Dewhirst. Liposomes themselves are quite beneficial to patients because their unique formulation reduces the amount of drugs that enter the heart, nerves and other critical tissues, where they could cause substantial harm.
Building on liposomes' natural merits, Dewhirst and his collaborator David Needham, Ph.D., have developed a new generation of liposomes that melt quickly when heated, thereby dumping their contents directly into the tumor within 20 seconds of heating. The precisely determined melting point of 40 degrees Celsius (104 degrees Fahrenheit) is warm enough to engage the benefits of heat but cool enough to prevent burning the patient's skin. This is exactly the temperature to which a Jacuzzi is typically heated; hence the treatment's nickname.
"By delivering the drugs to the precise site of the tumor, and releasing them at a precise point in time, we'll be able to best utilize their tumor-fighting abilities where they are needed most," said Ellen Jones, M.D., a radiation oncologist who delivers the hyperthermia treatments to patients at Duke.
Indeed, doctors have long known that placing enough chemotherapy in a dish of cancer cells kills virtually all of them. The problem has been delivering enough drugs to the tumors to kill cancer cells without poisoning the patient or causing undue side effects.
The current study, and subsequent trials utilizing the new "melting" liposome, is designed to circumvent these problems, Dewhirst said. So far, patients generally have experienced less nausea, fatigue and cardiac toxicity than with traditional chemotherapy, presumably because one of the drugs, doxorubicin, is encased in liposomes. (Its liposomal formulation is called Myocet.) Both Myocet and Taxol, the second drug, work by preventing cancer cells from properly dividing and thus replicating, said Jones.
In addition, results show the combined therapy has halted tumor growth in all women and has at least partially shrunk tumors in half the women. Eleven percent of women have had complete pathologic responses, meaning no cancer was found in the breast tissue upon analyzing its surgical remains. Thirty-three percent of patients had complete clinical responses, meaning visible signs of the tumor could no longer be detected, and 17 percent of patients were converted from mastectomy candidates to lumpectomy candidates.
These numbers are significant, Blackwell said, considering that most of these women were told by their surgeons that they had inoperable tumors. Inoperable generally means the tumors are either so large or invasive that they have permeated the skin, chest wall, or surrounding muscles. The treatment goal was to shrink tumors enough for surgeons to successfully remove them without mutilating the surrounding tissue or leaving behind errant cancer cells.
The new treatment reverses the traditional order of cancer therapy, which starts with surgery and ends with chemotherapy and radiation, said Jones. The new model, called "neo-adjuvant" therapy (treatment before surgery) is a more logical sequence of treatment because it requires less invasive surgery and offers patients with refractory tumors a wider range of options, Blackwell said.
Her treatment program begins with a traditional infusion of chemotherapy, followed by a CT scan of the breast to pinpoint the tumor's precise location. Next, a plastic tube or "catheter" is placed inside the tumor, in which doctors place a thermometer to monitor the tumor's temperature during hyperthermia. Patients then undergo hyperthermia on a one-of-a kind treatment table designed and built by Duke engineer Thaddeus Samulski, Ph.D. Samulski also designed the table's heating apparatus and software, through which he delivers radio frequency energy that heats the tumor via a pool of salt water. The water helps distribute the heat evenly around the breast to avoid burning and helps direct the radio frequency energy into the breast. Hyperthermia drug treatments are given every three weeks for four cycles.
After the fourth and final hyperthermia treatment, radiation oncologists measure the tumor shrinkage and recommend the least invasive type of surgery to remove their patients' tumors. Surgery is followed by additional chemotherapy and radiation to kill any undetected cancer cells in the breast and surrounding tissue.
"We use the best and newest agents up front, then the standard and traditional treatments at the tail end," Blackwell said. "It's like a guarantee policy to ensure that the patients receive every possible benefit we have to offer them."