Combining hyperthermia with radiation therapy produces effective local control of recurrent breast cancer, with manageable side effects, even in patients with extensive disease whose previous therapies had failed, a Cleveland Clinic study has found. Hyperthermia’s benefits are most apparent in patients whose prior treatment included radiation.
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The retrospective study’s results can guide clinicians managing these difficult cases. Therapeutic decision-making in cases of locally recurrent breast cancer must take into account the increased risk of side effects in patients who often already have undergone substantial amounts of chemo- and radiotherapy, and who may have considerable tumor volumes, both of which complicate treatment.
Hyperthermia’s ability to increase cancer cells’ radiosensitivity means lower radiation doses can result in greater tumor control than radiation alone.
“This is the first research from Cleveland Clinic that has shown we can achieve excellent results in terms of tumor control in patients with extensive disease,” says Taussig Cancer Institute radiation oncologist Jennifer Yu, MD, PhD, the study’s corresponding author, founder and Director of the Center for Hyperthermia, President of the Society for Thermal Medicine, and a cancer researcher in the Lerner Research Institute’s Department of Cancer Biology. “Many of the patients that we’ve treated have failed other types of treatments. They failed their initial radiation and many types of chemotherapy; some have failed hormone therapy as well, and they have no other treatment options.”
Dr. Yu and her colleagues found that thermoradiotherapy produced either a complete disappearance of disease or a measurable reduction in a majority of the study’s patients, including some of the most challenging cases.
The study included 36 patients with recurrent breast cancer who received hyperthermia and radiation at Cleveland Clinic between 2011 and 2017. Median length of follow-up was 11 months.
Prior to recurrence, 33 of those patients (91.7%) had been treated with chemotherapy, 30 (83.3%) received radiation therapy (median dose 60.4 Gy, range 50.4–66.0 Gy), and 29 (80.5%) had a partial, complete or double mastectomy.
After recurrence, 13 patients were treated with electron therapy, 12 received intensity-modulated radiation therapy (IMRT) and 11 received conventional photon therapy with or without regional nodal irradiation. The median radiation dose and median fraction size were 35.5 Gy and 3.0 Gy, respectively. IMRT enables treatment of patients with extensive recurrences that require complex radiation fields while minimizing collateral dosing to nearby organs.
Hyperthermia, lasting 60 minutes per session, was given twice per week. For patients with extensive volumes of disease, hyperthermia was delivered using two to three hyperthermia fields. A 915 MHz microwave unit was used to heat the treated area and thermistors placed on the tumor’s surface recorded the temperature. Hyperthermia’s effectiveness depends in part on maintaining target temperature during the treatment period. The study’s median T90 — the temperature exceeded by 90% of the measured temperature readings — was 40.2°C.
Hyperthermia improves cancer control by increasing cancer cell death caused by radiation and chemotherapy and altering the tumor microenvironment. Specifically, hyperthermia has been shown to:
• Help activate and recruit cytotoxic immune cells to tumor regions.
• Enhance tumor cell perfusion to increase drug delivery.
• Increase tumor cell oxygenation to improve radiation efficacy.
• Impair DNA damage repair in cancer cells, ultimately leading to cancer cell death.
“Our main goal was to show that hyperthermia can improve tumor control in patients that have breast cancer, particularly for patients that needed repeat radiation — those patients who have progressed after prior radiation treatment,” Dr. Yu explains.
In the Cleveland Clinic Cancer Center study, thermoradiotherapy produced an overall response rate of 61.1%. Previous studies reported higher overall response rates; Dr. Yu and her colleagues explain that the Cleveland Clinic study’s response rate may have been influenced by the inclusion of patients with large tumor burdens, for whom only a partial response is likely.
Seventeen patients (47.2%) experienced a complete response. Five patients (13.9%) had a partial response. Eleven patients’ disease (30.6%) remained stable, while three patients (8.3%) developed progressive disease.
The most common acute side effects of treatment included pain (36.1%), erythema (27.8%) and edema (16.7%). The most common long-term side effects were hyperpigmentation/tanning (22.2%), lymphedema (16.7%) and scarring/fibrosis (13.9%).
Hyperthermia currently is not part of standard first-line treatment for breast cancer because effective therapies already are available for many patients with early-stage disease, Dr. Yu says.
“For some of the early-stage breast cancers, the tumor control and survival rates are so good to begin with that people try to reduce treatment, as opposed to add more,” she says.
However, the situation with recurrent and aggressive disease is significantly more challenging because it is more difficult to achieve remission with existing therapies.
“For recurrent breast cancers, there is no standard per se,” Dr. Yu says. Therefore, “hyperthermia should be considered for recurrent or aggressive breast cancer because it can improve cancer control with minimal toxicity.”
Her recommendations are based on data from phase III clinical trials and multiple meta analyses that found hyperthermia and radiation to yield improved complete responses compared to radiation alone. Prior studies have shown a complete response rate of about 60% for thermoradiotherapy compared to about 40% for radiation alone in patients with superficial breast cancers.
“With thermoradiotherapy, a complete response rate is 150% of the response rate for radiation alone,” she says. “For patients that have had prior radiation, you’re looking at [achieving] complete responses in about 2/3 of patients and that is very, very high.”
Dr. Yu’s team is currently conducting a preclinical study to assess if hyperthermia can improve immune response to various cancers. On the clinical side, the researchers are examining how hyperthermia affects patients with sarcoma, skin cancer and bone metastases. She emphasizes that timely referral for thermoradiotherapy, early in the course of disease, is critical to its success.
“If patients came to us sooner for hyperthermia and radiation, their tumors would be smaller and, therefore, there would be less area that we would need to treat,” she says. Early treatment is beneficial in two ways, she adds, “It is easier for us to control a smaller tumor and the side effects of treatment are also reduced.”
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