Hyperthermic Extracorporeal Applied Tumor Therapy (HEATT®) in Hospice Eligible Cancer Patients

doi:10.21203/rs.3.rs-4137794/v1

Download PDF

Research Article

Hyperthermic Extracorporeal Applied Tumor Therapy (HEATT®) in Hospice Eligible Cancer Patients

https://doi.org/10.21203/rs.3.rs-4137794/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Previous research has indicated elevated temperatures of 42°C induce cell death, apoptosis, or senescence of responsive cancers, providing a mechanism for tumor destruction and management. Veno-venous perfusion-induced systemic hyperthermia (VV-PISH) may be the key to improving advanced tumor responsiveness as solo therapy or as an adjunct to previously failed chemotherapy, radiation, and immunotherapy alone, or in combination. The most recent iteration of VV-PISH, Hyperthermic Extracorporeal Applied Tumor Therapy (HEATT^®), provides homogeneous heating of all tissues with electrolyte and pH control, and continues to prove safe and effective. This consecutive series of 13 hospice-eligible patients confirms that HEATT^® is safe and efficacious in a near end-of-life diverse population; 8/13 exceeded expected median survival, 6/13 exceeded the 6-month predicted end-of-life, and 5/13 exceeded 12 months. Several lessons learned allowed inclusion and exclusion criteria refinement. Utilization of HEATT^® in all eligible patients should be considered as a part of integrative oncology care.

Hyperthermia

whole-body hyperthermia (WBHT)

veno-venous perfusion-induced systemic hyperthermia (VV-PISH)

Hyperthermic Extracorporeal Applied Tumor Therapy (HEATT®)

metastatic cancer

hospice

In 1979, Parks et. al. first reported the use of an extracorporeal circuit to heat perfused blood to 41.5°C for 6 hours to achieve systemic hyperthermia [1]. 97 whole-body hyperthermia (WBHT) therapy sessions, most with adjuvant therapies, achieved anti-tumor effects in 6 of 25 patients [1]. A recent systematic review of complementary medical hyperthermia in oncology provided comprehensive information regarding the evolution of hyperthermia [2]. Whole-body, perfusion-induced systemic hyperthermia can play a pivotal role in the treatment of metastatic cancers, especially when part of an integrated cancer treatment plan.

Vertrees and Zwischenberger, working with molecular biology, cell cultures, and rodents established 120 minutes at 42°C to be a lethal threshold for solid-organ derived tumors [3]. Additional studies in swine models developed an extracorporeal technique capable of safely raising the animal’s average core temperature to 42°C thus exploiting the potential vulnerability of tumors to hyperthermia [4–8]. The optimum delivery technique was veno-venous perfusion-induced systemic hyperthermia (VV-PISH) where blood was circulated from a cannula located in a deep vein (i.e., inferior vena cava) through an extracorporeal circuit that contained a heat exchanger, dialysis cartridge, and charcoal sorbent, and then returned through a cannula in a different central vein (i.e., superior vena cava) in proximity to the heart. With this technique, heated blood was mixed into the pulmonary circulation, then perfused throughout the body by cardiac output, thus raising all tissues in the body, including tumors, to the target temperature [4].

The initial VV-PISH human study (an FDA-approved clinical trial), was for 10 patients with unresponsive stage IIIB-IV non-small cell lung cancer (IDE G960257) [3, 9]. VV-PISH achieved and sustained an average core temperature of 42°C for two hours and was then cooled to normal range. The side effects of treatment were minor without major complications, and results indicated improved patient median survival of 450 days versus concurrent controls of 96 days. Some patients were able to resume further anti-neoplastic therapies [3, 9].

A second FDA trial addressed safety and efficacy in 10 women with ovarian cancer, who had failed first-line chemotherapy and surgery options, second-line chemotherapy, and remained eligible for a third-line (or more) therapy [10]. The VV-PISH extracorporeal circuit used also included a more efficient dialyser and heat exchanger; thus was rebranded as Hyperthermic Extracorporeal Applied Tumor Treatment (HEATT®). Patients were intubated and exposed to HEATT® using multiple temperature sensors to achieve a core temperature of 42°C for 120 minutes before cooling to 38°C. HEATT® was used 1 to 6 times depending upon patient response. Median overall survival following the initial HEATT® procedure was 596 days compared to matched historical controls of 267 days. Additionally, 7 of 10 patients received additional chemotherapy post-completion of HEATT® therapy and demonstrated an improved response to agents previously ineffective. Based on these studies, the FDA accepted our findings of safety and efficacy to apply HEATT to 42^°C as therapy.

This article reports the ongoing results of 13 hospice-eligible patients who failed first-line and second-line chemotherapy, plus multiple naturopathic treatments, with unresponsive, advanced cancers, treated once with HEATT®.

Once a patient met safety criteria by the selection committee, a complete review of medical records and an in-person evaluation at the treatment location was completed. The goals of this visit were as follows: correct any electrolyte and hematologic deficiencies prior to treatment, establish a baseline physical activity of the patient, and achieve an understanding of the patient's current medical condition in person. Common pre-treatment findings were coagulation abnormalities and effects of cachexia (anemia, low protein and albumin, muscle wasting).

HEATT® was conducted under general anesthesia with catheters placed for both monitoring and blood sampling in the arterial and venous systems. Blood samples were withdrawn every 15 minutes and analyzed for electrolytes, metabolites, blood gases, and coagulation (activated clotting time, and PT, PTT, INR). A urinary bladder drainage catheter with an integrated temperature probe was inserted into the bladder along with temperature probes placed in both auditory canals, rectum, nasopharynx, and distal esophagus; the average of these temperatures is regarded as the average core temperature (Tc) (Fig. 1).

An interventional radiologist inserted perfusion cannula (15–17 Fr) into the common femoral vein under fluoroscopic guidance (positioned at L-2) to drain blood from the patient. Another perfusion cannula (13–15 Fr.) was inserted into the internal jugular vein, positioned near the superior vena cava-right atrium (SVC-RA) junction, for blood return. These cannulas were then connected to the HEATT® circuit. The patient was anticoagulated with heparin (3 mg/Kg) with the target ACT of 6 times baseline seconds and was then retreated when it fell to under 3 times baseline seconds.

HEATT® was delivered with an extracorporeal circuit that consists of a standard cardiac bypass machine (Cobe Century Heart Lung Machine with 4-pump heads; Medtronic, Minneapolis MN), heater/cooler (CardioQuip MCH-1000 HT; CardioQuip, College Station, TX), a dialyzer (Optiflux F8, Fresenius Medical Care, Waltham, MA), column dialysate regeneration with activated carbon and dialysate fluids. HEATT® blood flow was slowly increased up to 30% (maximum 50%) of estimated cardiac output. Once the temperature was stabilized at 38°C, the heparin was reversed with protamine sulfate, cannulas were removed, and the patient was extubated and moved to the recovery area.

The consecutive clinical series examines the utilization of HEATT® in hospice-eligible patients (n = 13) with unresponsive, advanced cancer. Patients had failed at least first-line and second-line chemotherapy and, if received, immunotherapy plus multiple naturopathic treatments prior to referral. Exclusion criteria included: central nervous system metastases, stroke within the past 6 months, myocardial infarction within the past 6 months, uncontrolled hypertension, uncontrolled diabetes mellitus, active infection, sepsis, and organ failure.

The average blood flow through the HEATT circuit was 1.36 ± 0.22 L/min/m². The average flow through the dialysis loop was 0.24 ± 0.05 L/min. The average time to achieve target temperature was 59.2 ± 6.4 minutes, average time of target temperature was 117.7 ± 3.5 minutes and took 45.8 ± 8.8 minutes to cool to normal range. Mean sodium and chloride concentrations remained within normal limits throughout HEATT^®. Potassium, magnesium, phosphorous, pH, and ionized calcium also controlled to within normal ranges throughout the operation either removal through dialysis or supplemental administration. The blood pressures showed a negative change during target temperature; systolic time course showed a -10.8% change, diastolic time-course − 11.8%, and the mean BP-time course showed a -10% change over the duration of the perfusion. On induction, most demonstrated low CVP (4% change from baseline value) presumably secondary to dehydration from chronic illness. These changes in systemic pressures are due to the vasodilatory effect of hyperthermia. When the hematocrit fell below 30% the following is the sequence of interventions used to maintain sufficient pressures; blood, colloids, crystalloids the vasopressors (Neo-Synephrine was the drug of choice). As patients were anemic on admission, blood usage averaged 2.85 ± 0.8 units per patient. Patients were extubated on the table of on day one. Discharge occurred on day 1–4 depending upon ambulatory status and travel arrangements. Return to pre-treatment status ranged from 2 days to 2 weeks depending upon severity of metastatic burden and pre-treatment status. All patients were followed by their referring physician until death.

Of the 13 patients, 8 exceeded the expected median survival of 90 days for a hospice-eligible patient. Additionally, 6 out of the 13 patients exceeded the predicted maximum 6-month end-of-life with 5 of the 6 patients exceeding a year. Included patients varied in cancer type: ovarian, colo-rectal, breast, lipo-sarcoma, lung, pancreas, and cholangiocarcinoma. Of this cohort, the longest survival lengths were recorded at 416, 530, 614, and 639 days post-HEATT® prior to death. There was one death within 30 days – the patient had multiple pulmonary metastasis while taking bevacizumab (Avastin®) but failed to report this contraindication and stop dosage before treatment. Pulmonary hemorrhage upon systemic anticoagulation forced early stoppage with subsequent respiratory failure.

As the study progressed, a Karnofsky score of less than 70, frailty (defined in this population as unable to independently walk across a room, equating to a FAST < 60), and age greater than 80 years resulted in a poor response or survival. The most impactful takeaway from this consecutive patient series was updated exclusion criteria that included the following: obstruction of a hollow viscus/duct, frailty, and age > 80. Frailty was the most common major contributor to poor survival in this series. Although both the small bowel obstruction and the biliary obstruction were palliated pre-HEATT® with stenting, follow-up imaging revealed tumor compression was not relieved after HEATT®.

No complications specific to hyperthermia were witnessed during this study. Technical challenges that arose during the administration of HEATT® were related to proper cannula and catheter placement. Utilization of interventional radiologists for cannula placement addressed the challenges of distorted anatomy from tumor displacement. With updated criteria from the series findings, 4 out of the 5 deaths prior to the 90-day expected hospice survival timeline would now meet the updated exclusion criteria that includes hollow viscus obstruction, age > 80, and frailty measures (FAST < 60, Karnofsky score < 70 (Table 1).

Table 1

A chart to provide updated contraindications discovered during this series.
Patient Identification Number	Days Lived Post-HEATT	Patient contraindications that meet updated criteria
Patient 1	86 days	Frailty (bedridden) and age
Patient 6	55 days	Frailty and small bowel obstruction
Patient 8	67 days	Obstruction of biliary tree
Patient 12	63 days	Frailty and cachexia

Historically, metastatic cancers have been difficult to treat with traditional cancer therapies including surgery, radiation, chemotherapy, and immunotherapy. A study published in 2020 reported on 92-novel cancer drugs approved by the FDA and determined that the median absolute survival benefit was 2.4 months [11]. Systemic hyperthermia is a broad category of techniques that utilizes elevated body heat to treat metastatic cancers. Hyperthermia techniques are subdivided based on the amount of tissue they cover: local, regional, and whole-body. Whole-body hyperthermia has been evaluated in several forms including radiant heat induced, immersion conduction, and radiation induced [12].

Whole body, veno-venous perfusion-induced systemic hyperthermia is a unique, reliable delivery system that achieves homogeneous tissue heating to 42° and has consistently shown noteworthy, anti-neoplastic effects. Perfusion-induced systemic hyperthermia or HEATT® has the potential to slow or destroy cancer growth and metastasis [13]. Topical or surface heating cannot attain the internal organ temperature necessary to reach the required therapeutic target temperature (42°C for 120 minutes) without sustaining significant damage to the outer conductive tissues (skin and muscle tissue).

Hyperthermia increases tumor blood flow and temperature is enhanced tumor vascular permeability, increased oxygenation, decreased interstitial fluid pressure, and normalizing of the pH [14]. Additionally, at the biochemical level, hyperthermia has been shown to increase immune cell trafficking into tumors, regulate lymphocyte trafficking, alter cytokine activity, increase metabolic rate, and upregulate gene expression favoring apoptosis [15–18].

VV-PISH in general, and HEATT® specifically, efficiently supply a stable thermal dose (41.8 ± 0.8°C for 120 minutes) to visceral, cranial, and thoracic organs, as well as peripheral tissues like skeletal muscle and bone marrow [13]. Multiple designated temperature monitoring points and average body temperature are used in real-time as feedback control, preventing prolonged periods in elevated or insufficiently heated temperature ranges, and serum solute maintenance and control further limit the risk of hemodynamic instability [19]. While hyperthermia was used in isolation for this series, recent literature suggests that using hyperthermia in combination with chemotherapy or immunotherapy may yield greater results [20].

Deleterious systemic consequences of perfusion hyperthermia include the possibility of thermal organ damage, significantly expanded circulating volume, deranged serum electrolytes, hemodynamic instability, deranged coagulation, acidosis, hypoxia, and hypercarbia [8]. Although successful in extending the length of survival in terminally ill cancer patients, early VV-PISH-focused studies noted hemodynamic instability [6, 8]. This instability was presumably from vasodilatation as the elevated total body temperature led to significant changes in heart rate (HR), cardiac index (CI), central venous pressure (CVP), mean pulmonary arterial pressure (MPAP), and pulmonary capillary wedge pressure (PCWP). Hyperthermia-induced hemodynamic instability improved after body temperature returned to normal, but PCWP remained elevated. In this series, using the latest HEATT® technology, management of hypotension with fluid replacement, correction of anemia, and/or vasoconstrictors substantially decreased these responses.

This study was originally designed to evaluate if the resultant modified whole-body VV-PISH circuit and management, HEATT®, could be delivered safely and effectively in hospice-eligible patients with unresponsive, advanced cancer. Through core temperature control, the normalization of electrolytes, and the removal of tissue breakdown products during HEATT®, it was possible to deliver a predictable thermal dose without the negative physiologic sequelae previously associated with this degree of systemic heating. Therefore, we were able to safely heat the patient’s blood to achieve a therapeutic window of 42°C for 120 minutes duration.

Pre-HEATT® physical activity provided a good screening tool for treatment tolerance and post-HEATT® return to pre-treatment activity, it did not predict post-HEATT® time-to-return to baseline activity. For the target population of unresponsive hospice eligible patients, their physical activity and reserve capacity can change remarkably from the initial screening interview to treatment date. The in-person evaluation immediately prior to treatment allowed the opportunity to counsel or divert patients whose risk/benefit assessment had deteriorated, changing the initial risk profile.

One source of variability was the diagnosis of hospice-eligibility. Hospice eligible is a judgement call by the dominant care provider predicting a median survival of 3 months and maximum 6 months for comfort care [21]. Because of this ambiguity and variability among different medical professionals regarding comfort care, palliation and hospice eligibility, plus the strong signal of efficacy seen in this series, we now evaluate any patient with unresponsive, advanced cancer. Based on this series, we expanded our contraindications to target improved benefit from HEATT®.

In this consecutive series of hospice eligible cancer patients, HEATT® demonstrates an increase in the length of survival in responding patients with metastatic cancers after the failure of prior therapy options, with some patients living approximately 12 to 18 months longer than expected. HEATT® has continued to demonstrate safety and efficacy using the current protocol. Recent experience evolves exclusion criteria to include hollow viscus obstruction, age > 80, and frailty measures (FAST < 60, Karnofsky score < 70).

This improved survival in hospice-eligible patients with unresponsive, advanced cancer further supports the utilization of HEATT® in patients meeting current criteria. HEATT^® improves survival and quality of life in advanced cancer; including those unresponsive to conventional therapy, integrative oncology treatments, and hospice-eligible patients.

Competing Interests: The system and methods of Verthermia® are protected by four issued US patents (11,065,379; 11,185,622; 11,191,883, and 11,239,551). Two other US patent applications are in process, and one international or PCT (Patent Cooperation Treaty) application is in process, also. Currently, Verthermia® has two registered US trademarks, and two other US trademark applications are in process. Verthermia® has also filed an application for an international trademark. Joseph B. Zwischenberger is Chief Medical Officer of Verthermia Corporation. Roger Vertrees is Chief Science Officer of Verthermia Corporation

Funding: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author Contributions: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by all authors. The manuscript was written by all authors. All authors read and approved the final manuscript.

Data Availability: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval: This is a retrospective chart review. The IRB Research Committee has confirmed that no ethical approval is required as retrospective studies are conducted on already available data.

Parks LC, Minaberry D, Smith DP, Neely WA. Treatment of far-advanced bronchogenic carcinoma by extracorporeally induced systemic hyperthermia. J Thorac Cardiovasc Surg. 1979;78(6):883-892. doi:10.1016/S0022-5223(19)38032-8
Liebl CM, Kutschan S, Dörfler J, Käsmann L, Hübner J. Systematic review about complementary medical hyperthermia in oncology. Clin Exp Med. 2022;22(4):519-565. doi:10.1007/s10238-022-00846-9
Zwischenberger JB, Vertrees RA, Woodson LC, Bedell EA, Alpard SK, McQuitty SK, Chernin JM. Percutaneous venovenous perfusion-induced systemic hyperthermia for advanced non–small cell lung cancer: initial clinical experience. Ann Thorac Surg. 2001;72(1):234-242. doi:10.1016/S0003-4975(01)02673-X
Vertrees RA, Tao W, Pencil SD, Sites JP, Althoff DP, Zwischenberger JB. Induction of whole body hyperthermia with venovenous perfusion. ASAIO J 1996; 42:250-254.
Vertrees RA, Brunston RL Jr., Tao W, Deyo DJ, Zwischenberger JB. Parallel dialysis normalizes serum chemistries during veno-venous perfusion-induced hyperthermia. ASAIO J 1997;43:M806-M811
Vertrees RA, Bidani A, Deyo DJ, Tao W, Zwischenberger JB. Venovenous perfusion-induced systemic hyperthermia: hemodynamics, blood flow, and thermal gradients. Ann Thorac Surg. 2000;70(2):644-652. doi:10.1016/S0003-4975(00)01381-3
Vertrees RA, Deyo DJ, Quast M, Lightfoot KM, Boor PJ, Zwischenberger JB. Development of a human to murine orthotopic xenotransplanted lung cancer model. J Investigative Surg 2000;13:349-358
Vertrees RA, Zwischenberger JB, Woodson LC, Bedell EA, Deyo DJ, Chernin JM. Veno-venous perfusion-induced systemic hyperthermia: case report with perfusion considerations. Perfusion 2001;16:243-248.
Zwischenberger JB, Vertrees RA, Bedell EA, McQuitty CK, Chernin JM, Woodson LC. Percutaneous venovenous perfusion-induced systemic hyperthermia for lung cancer: a phase I safety study. Ann Thorac Surg. 2004;77(6):1916-1925. doi:10.1016/j.athoracsur.2003.10.111
Investigational Device Exemption Report, IDE G130024, 6/13/2022
Ladanie A, Schmitt AM, Speich B, et al. Clinical Trial Evidence Supporting US Food and Drug Administration Approval of Novel Cancer Therapies Between 2000 and 2016. JAMA Netw Open. 2020;3(11):e2024406. Published 2020 Nov 2. doi:10.1001/jamanetworkopen.2020.24406
Cheng Y, Weng S, Yu L, Zhu N, Yang M, Yuan Y. The Role of Hyperthermia in the Multidisciplinary Treatment of Malignant Tumors. Integr Cancer Ther. 2019;18:1534735419876345. doi:10.1177/1534735419876345
Vertrees RA, Zwischenberger JB, Winetz JA. Hyperthermic Extracorporeal Applied Tumor Therapy for Six Cycles for Recurrent Metastatic Peritoneal Serous Papillary Carcinoma. Cureus. 2023;15(1):e34100. Published 2023 Jan 23. doi:10.7759/cureus.34100
Mikucki ME, Fisher DT, Ku AW, Appenheimer MM, Muhitch JB, Evans SS. Preconditioning thermal therapy: flipping the switch on IL-6 for anti-tumour immunity. Int J Hyperthermia. 2013;29:464–473.
Evans SS, Wang WC, Bain MD, Burd R, Ostberg JR, Repasky EA. Fever-range hyperthermia dynamically regulates lymphocyte delivery to high endothelial venules. Blood. 2001;97:2727–2733.
Narikawa M, Umemura M, Tanaka R, et al. Acute hyperthermia inhibits TGF-β1-induced cardiac fibroblast activation via suppression of akt signaling. Sci Rep. 2018;8:6277.
Vertrees RA, Das GC, Coscio AM, Xie J, Zwischenberger JB, Boor PJ. A mechanism of hyperthermia-induced apoptosis in ras-transformed lung cells. Mol Carcinog. 2005;44:111–121
Song CW, Park HJ, Lee CK, Griffin R. Implications of increased tumor blood flow and oxygenation caused by mild temperature hyperthermia in tumor treatment. Int J Hyperthermia. 2005 Dec;21(8):761-7. doi: 10.1080/02656730500204487. PMID: 16338859
Ballard-Croft C, Wang D, Jones C, Sumpter LR, Zhou X, Thomas J, Topaz S, Zwischenberger J. Physiologic response to a simplified venovenous perfusion-induced systemic hyperthermia system. ASAIO J. 2012;58(6):601-606. doi:10.1097/MAT.0b013e318271badb
Lassche G, Crezee J, Van Herpen CML. Whole-body hyperthermia in combination with systemic therapy in advanced solid malignancies. Crit Rev Oncol Hematol. 2019;139:67-74. doi:10.1016/j.critrevonc.2019.04.023
Tatum PE, Mills SS. Hospice and Palliative Care: An Overview. Med Clin North Am. 2020;104(3):359-373. doi:10.1016/j.mcna.2020.01.001

Competing interest reported. The system and methods of Verthermia® are protected by four issued US patents (11,065,379; 11,185,622; 11,191,883, and 11,239,551). Two other US patent applications are in process, and one international or PCT (Patent Cooperation Treaty) application is in process, also. Currently, Verthermia® has two registered US trademarks, and two other US trademark applications are in process. Verthermia® has also filed an application for an international trademark. Joseph B. Zwischenberger is Chief Medical Officer of Verthermia Corporation. Roger Vertrees is Chief Science Officer of Verthermia Corporation. However, there was no funding or financial interests in relation to the publication of this paper.

Download PDF

Version 1

posted

You are reading this latest preprint version

Hyperthermic Extracorporeal Applied Tumor Therapy (HEATT®) in Hospice Eligible Cancer Patients

Status:

Version 1

Abstract

Figures

Introduction

Methods

Results

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1