Intraesophageal Hyperthermia-Enhanced Direct Tumor Chemotherapy: An Interview With Feng Zhang, MD, PhD

IO360: How does intraesophageal chemotherapy work? How do you perform the procedure, and with what devices?

Zhang: Image-guided minimally invasive interventional oncology techniques enable delivery of high doses of chemotherapeutics into target tissue with improved tumoricidal activity but fewer systemic side effects, so we designed and performed a study to develop a technique of intraesophageal hyperthermia-enhanced direct tumor chemotherapy. First we created a novel animal model with othotopic esophageal cancers using nude rats through a transesophageal approach. We used the same procedure and device for tumor cell injection and chemotherapeutic drug delivery into the tumors. A 0.035˝ guidewire was transorally introduced into the esophagus, and then a custom microcatheter was advanced into the cervical esophagus over the guidewire.

After withdrawing the guidewire, a custom microcoaxial needle that had a curved tip was positioned into the target esophagus through the microcatheter. Under real-time ultrasound imaging guidance, the curved needle tip was advanced into the cervical esophageal wall with a controlled penetration depth of 3 mm, at which point 5×106-1×107 luciferase/red fluorescence protein-positive esophageal squamous cancer cells in 100-µl Matrigel matrix (Corning) were injected into the target esophageal site. When the volume of tumors grew to approximately 50 mm3, chemotherapeutic drugs were directly injected into the esophageal tumor through the intraesophageal delivery needle under ultrasound imaging guidance. The chemotherapeutic agent was injected into the tumor at a rate of 100ul/3min using a Hamilton microsyringe.

IO360: What were the challenges that you were trying to overcome when you developed this technique?

Zhang: Esophageal cancer remains one of the leading causes of cancer-related mortality, with an estimated 455,800 new cases and 400,200 deaths per year worldwide. Surgery offers limited benefit for advanced esophageal cancers, with extremely poor overall 5-year survival ranging from 15% to 25%. Radiation therapy as a palliative treatment is even less effective than surgical resection, and is associated with a significant likelihood of major complications such as esophagotracheal fistula. 

Recent efforts have focused on combination treatment with surgery, radiation therapy, and systemic chemotherapy to achieve better local control of disease and improve overall survival of patients with this deadly disease. However, randomized clinical trials have shown mixed results with respect to progression-free or overall survival benefit with such combination therapies. It is well known that systemic chemotherapy is often unable to deliver sufficient chemotherapeutic drugs into target tumors and is often plagued by low chemosensitivity, chemoresistance, and high risk of systemic toxicities to other vital organs. 

Recent studies have confirmed that nonablative hyperthermia around 42°C can significantly enhance the sensitivity of cancer cells to chemotherapeutic drugs and reverse chemoresistance. In current clinical trials, nonablative hyperthermia for treatment of malignancies is generated by either systemic whole body or external hyperthermia. However, because of the deep anatomic location of the esophagus which is surrounded by vital organs including the heart, lungs, trachea and spine, it is difficult to generate highly focused heat only at the site of esophageal tumors using systemic or external hyperthermia. Generation of external hyperthermia within the esophagus poses the risk of injury to adjacent vital organs, such as the spinal cord. We have developed a magnetic resonance imaging-heating guidewire, which can be used not only for high-resolution luminal wall imaging and guiding interventions, but may also be applied as an intraluminal heating source for enhancing local gene/chemotherapy treatment. 

IO360: Could you describe the design and methods of the study?

Zhang: We divided the study into three stages: (1) in-vitro evaluation using human esophageal squamous cancer cells to establish “proof-of-principle” of the new concept of radiofrequency hyperthermia-enhanced anticancer effect of chemotherapeutics; (2) in-vivo confirmation of this new concept by using mouse models with subcutaneous esophageal squamous cancer xenografts; and (3) preclinical validation of the feasibility of the new technique with a novel rat model of molecular imaging-detectable orthotopic esophageal cancer.

For the rats with orthotopic esophageal cancer, immediately after drug delivery, intraesophageal radiofrequency hyperthermia was generated by inserting a 0.022-inch magnetic resonance imaging–heating-guidewire into the esophagus with its heating element centered at the tumor. The magnetic resonance imaging–heating-guidewire is made of a coaxial copper cable with 3-cm extension of its inner conductor. When external radiofrequency thermal energy is delivered, the wire can create a very localized and controlled heat source, with the heating core at the junction of the inner conductor and outer conductor of the wire. The radiofrequency power distribution is homogeneous within a distance of 1cm around the heating spot of the wire. A fiberoptic temperature probe was placed in the esophagus alongside the magnetic resonance imaging-heating-guidewire to simultaneously monitor temperature. The intraesophageal radiofrequency heating was set at 41±1°C for 30 minutes. We used optical imaging to follow tumor response at days 0, 7, and 14 after treatments. Optical imaging was conducted on a Bruker In-Vivo Xtreme Imaging Systems (Bruker Corp.). Ultrasound imaging was then performed to assess tumor growth at days 0, 7 and 14 after treatment. The axial (X) and longitudinal (Y) diameters of tumors, as well as tumor depths (Z) were measured on the ultrasound images with maximal tumor sizes. Each animal was imaged at day 0 before treatment and days 7 and 14 after treatment.

We designed and manufactured this microintraesophageal agent delivery/radiofrequency hyperthermia heating system, which enabled us to (1) locally implant esophageal squamous cancer cells into the target esophageal segment, (2) deliver chemotherapeutics directly into the developing esophageal tumors, and (3) transfer radiofrequency heat within the esophageal lumen to locally enhance chemotherapy of the target tumors. Under real-time ultrasound imaging guidance, we inoculated luciferase/red fluorescence protein-positive esophageal squamous cancer cell suspension into the wall of the cervical esophagus via an intraesophageal approach. Ultrasound imaging detected the cell pellet in the tissue adjacent to the wall of esophagus. Approximately 3 weeks later, both ultrasound imaging and optical imaging demonstrated the presence of a tumor mass in the tissue.  

All animals survived all experiments without significant complications. Examinations of gross specimens obtained at the end of the experiments revealed tumor adherent to the wall of esophagus, which was confirmed by subsequent pathologic correlation. Optical imaging demonstrated a significant decrease in relative photon signal intensity in the combination therapy group compared with the chemotherapy-only group, RFH-only group, and phosphate buffer saline group. We also performed ultrasound imaging to evaluate changes in tumor size before and after treatments. We detected the smaller relative tumor volume in the combination therapy group compared with the chemotherapy-only group, radiofrequency hyperthermia-only group, and phosphate buffer saline group. Gross specimens obtained at the end of the experiment revealed the smallest tumor size in the combination therapy group compared to the other three groups.

IO360: What do you think the most important point is from the results in this study?

Zhang: There are three important points in this study. First, we used the MR imaging-heating guidewire to locally deliver thermal energy to esophageal cancers through an intraluminal approach. For the specific purpose of treating esophageal malignancies, the generation of intraesophageal radiofrequency hyperthermia via the MR imaging-heating guidewire offers superior advantages over external hyperthermia using electromagnetic energy or high intensity focused ultrasound. The thermal energy distribution pattern induced by the magnetic resonance imaging-heating guidewire is cylindrically symmetric and homogeneous, and thermal energy can be delivered within a distance of approximately 1-2 cm around the target site. This capability is well suited to deliver localized radiofrequency heat into the tumor alone, without causing thermal injury to adjacent vital organs (such as the spinal cord) and avoiding heat absorption by fat tissues and bones. 

Second, we created a rat model of molecular imaging-detectable orthotopic esophageal cancer, which meets the requirement that a specific animal tumor model should not only simulate the pathophysiologic properties of human esophageal cancer but reveal the appropriate interactions between cancer cells and host organs. This rat model of orthotopic esophageal cancer will be a useful tool for further laboratory investigations into esophageal malignancy. Third, we designed and manufactured a microintraesophageal agent delivery/radiofrequency heating system, which can be precisely positioned at the target site in the esophagus with real-time ultrasound imaging guidance. 

By using this micro-interventional system, we could accomplish precisely targeted injection of esophageal squamous cancer cells into the esophageal wall to create a rat model of esophageal cancer. The system also allowed local delivery of chemotherapeutics as well as radiofrequency hyperthermia to enhance the chemotherapeutic effect on esophageal cancers.

IO360: How can interventional radiologists and interventional oncologists use this information practically?

Zhang: This preclinical study created a novel alternative treatment of using intraesophageal radiofrequency hyperthermia to enhance direct intratumoral chemotherapy for esophageal cancers by simultaneous integration of radiofrequency technology, interventional oncology, and direct intratumoral chemotherapy. With the development of clinically applicable microintraesophageal agent delivery/radiofrequency heating system, it is very promising to translate this technique to the clinical practice for treating unresectable human esophageal cancers. We are glad to share our experience of creating this novel animal model with colleagues of interventional radiology and interventional oncology and we also anticipate the cooperation with industries to develop the clinically applicable intraesophageal agent delivery/radiofrequency heating system to facilitate the translation of this technique for treating human esophageal cancer.

Editor’s note: Dr. Zhang reports grants or grants pending from the National Institutes of Health.

Suggested citation: Ford J. Intraesophageal hyperthermia-enhanced direct tumor chemotherapy: an interview with Feng Zhang, MD, PhD. Intervent Oncol 360. 2016;4(10):E164-E168.