Hyperthermia as an Adjunctive Therapy in Oncology

Introduction:

Hyperthermia has gained increasing attention as an adjunctive therapy in oncology. Hyperthermia has exhibited promising potential in augmenting tumor response and enhancing patient outcomes when used alongside radiation therapy, chemotherapy, and immunotherapy. This article presents a comprehensive overview of hyperthermia as an adjunctive therapy in oncology.

What Is Hyperthermia Treatment?

Hyperthermia is a therapeutic technique that entails increasing the temperature of body tissue to selectively target and eliminate cancer cells while minimizing harm to surrounding healthy tissues. It is known by various names, including:

1. Thermal therapy.

2. Thermal ablation.

3. Thermotherapy.

Hyperthermia treatments utilize different techniques to generate heat for the targeted therapy. These techniques encompass:

• Microwave Energy Probes: Probes are employed to generate microwave energy, which is used to heat the affected tissue.

• Radio Waves: Radiofrequency waves are utilized to create heat and raise the temperature of the targeted area.

• Laser: The focused application of laser energy generates heat and selectively destroys cancer cells.

• Ultrasound: Ultrasound waves produce heat in the targeted tissue, effectively damaging cancer cells.

• Perfusion: In this technique, fluids such as blood or chemotherapy drugs are heated and then introduced into the body to raise the temperature locally in the targeted area.

• Whole-Body Hyperthermia: This method involves exposing the entire body to a heated chamber, hot water bath, or heated blankets to increase the body temperature.

In these approaches, hyperthermia aims to achieve a temperature of up to 113 °F (45 °C) to induce thermal damage and destroy cancer cells while minimizing harm to normal tissues. By carefully controlling the heat application, hyperthermia treatment offers a promising strategy in oncology for the targeted elimination of cancer cells.

What Are the Types of Hyperthermia?

Hyperthermia can be employed to treat localized areas, large regions, or the entire body, depending on the patient's specific needs.

1. Local Hyperthermia:

In local hyperthermia, heat is applied to a small body area, tailored to the tumor's location. Different techniques are utilized based on the tumor's position:

• External Hyperthermia: This method is used for tumors on or beneath the skin. Heat-producing devices are placed around or near the treatment area to raise the temperature.

• Intraluminal or Endocavitary Hyperthermia: This approach can treat tumor within or near body cavities, such as the esophagus or rectum. Probes generating heat are inserted into the cavity and positioned within the tumor.

• Interstitial Hyperthermia: This technique treats tumors deep within the body, including brain tumors. Under anesthesia, probes or needles are inserted into the tumor with the assistance of imaging techniques such as ultrasound, ensuring accurate placement of the probes. The heat source is then introduced into the probe.

2. Regional Hyperthermia:

Regional hyperthermia involves heating large body areas, such as a cavity, organ, or limb. Various techniques are utilized:

• Deep Tissue Techniques: This approach treats internal cancers like cervical or bladder cancer. Heat-delivering devices are placed around the cavity or organ, focusing energy on raising the temperature of the target area.

• Regional Perfusion: Cancers in the limbs (e.g., melanoma) or specific organs (e.g., liver or lung) can be treated using this technique. Blood is removed, heated, and returned to the limb or organ. Chemotherapy is often administered concurrently.

• Continuous Hyperthermic Peritoneal Perfusion: This treatment targets cancer within the peritoneal cavity, encompassing the abdominal space containing the intestines, stomach, and liver. During surgery and under anesthesia, heated chemotherapy drugs flow through the peritoneal cavity, raising the temperature in the region to approximately 106 to 108°F (41 to 42°C).

3. Whole-Body Hyperthermia:

Whole-body hyperthermia is utilized for treating cancer that has spread throughout the body. Patients are either placed in a thermal chamber or wrapped in hot water blankets, raising their body temperature to around 107 to 108°F (41 to 42°C) for short durations.

How Does Hyperthermia Work as a Therapeutic Intervention in Oncology?

Hyperthermia demonstrates its therapeutic benefits through a variety of mechanisms. Initially, increased temperatures directly trigger the demise of cancer cells by impairing cellular structures, proteins, and DNA. Furthermore, hyperthermia amplifies the efficacy of radiation therapy by augmenting tumor oxygenation, facilitating DNA damage, and impeding DNA repair mechanisms. In addition, hyperthermia stimulates the immune system, fostering heightened immune responses against cancer cells and potentially eliminating micrometastases.

What Are the Mechanisms of Hyperthermia When Combined With Chemotherapy?

Combining hyperthermia with chemotherapy enhances drug cytotoxicity. Increased tissue temperature improves drug permeability by increasing cell membrane fluidity in tumors. Hyperthermia at 43°C synergistically enhances cisplatin cytotoxicity through modulation of the Ctr1 transporter. Regional chemotherapy with hyperthermia, like HIPEC or HIVEC, utilizes heated drugs to exert antitumor effects in the abdominal cavity or bladder.

What Are the Mechanisms of Hyperthermia When Combined With Radiotherapy?

When combined with chemotherapy, hyperthermia enhances tumor cells' sensitivity to ionizing radiation through several mechanisms. Hyperthermia increases tumor oxygenation by improving blood flow and reducing the radioresistance of hypoxic tumor cells. Optimal temperatures during hyperthermia improve oxygenation and vascular perfusion, thereby increasing radiosensitivity.

Heat-induced changes in protein structure inhibit DNA damage repair and suppress tumor cell survival mechanisms. Hyperthermia induces the synthesis of heat shock protein (Hsp) 70, interfering with telomere activity and promoting cancer cell apoptosis. Tumor cells in the G0 and S phases of the cell cycle are more sensitive to hyperthermia than radiation. Additionally, radiation therapy reduces the thermal tolerance of tumor cells, enhancing the efficacy of hyperthermia.

What Are the Mechanisms of Hyperthermia When Combined With Immunotherapy?

Temperature plays a significant role in enhancing the efficacy of immunotherapy. Hyperthermia can modulate the immunosuppressive tumor microenvironment by improving tumor oxygenation and stimulating an antitumor immune response.

Mild hyperthermia activates innate immune cells such as macrophages, dendritic cells, and natural killer cells, increasing cytotoxicity and tumor cell recognition. Adaptive immune cells, including T-cells and B-cells, are also activated by heat, promoting antitumor immune responses.

Hyperthermia facilitates immune cell infiltration into tumor sites by enhancing immune cell trafficking and increasing endothelial cell activation and permeability.

What Are the Side Effects of Hyperthermia?

Perfusion techniques in hyperthermia treatment can occasionally lead to side effects such as swelling, blood clots, bleeding, or damage to normal tissues in the treated area. Fortunately, most of these side effects tend to improve after the completion of treatment.

Whole-body hyperthermia frequently causes side effects like diarrhea, nausea, and vomiting. In some cases, more severe but less common side effects can occur, including complications related to the heart and blood vessels.

Conclusion:

Hyperthermia as an adjunctive therapy in oncology shows excellent promise, improving outcomes by enhancing tumor oxygenation, sensitizing cancer cells to radiation, amplifying chemotherapy effectiveness, and stimulating the immune system. Further research is needed to optimize protocols, refine combinations, and determine specific roles in different cancers. Hyperthermia has the potential to revolutionize treatments and improve patients' quality of life.