Development of a Perfusion-induced Systemic Hyperthermia Delivery Apparatus

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer-related deaths in men and women. The prognosis for patients with advanced stage non-small cell lung cancer (NSCLC), which accounts for 75% of all new lung cancer cases, is dismal with currently available chemotherapy regimens providing only a 9-12 month median survival. Thus, our long term goal is to develop a more effective treatment for late stage NSCLC. One potential candidate for advanced lung cancer therapy is hyperthermia. Our group developed a venovenous perfusion-induced systemic hyperthermia (vv-PISH) system. In a previous phase I clinical trial, the vv-PISH significantly improved median survival in advanced stage NSCLC patients by 363 days. Although our vv-PISH system functioned adequately in the clinical trial, the vv-PISH system was too complex with a multi-site cannulation and numerous dialysis problems. Our Phase I STTR results showed the feasibility of a simple and inexpensive vv-PISH system in delivering a predictable therapeutic hyperthermia dose. The objective of this Phase II STTR proposal is to establish the feasibility of our finalized vv-PISH circuit to safely deliver therapeutic hyperthermia. Specific Aim 1: To finalize and produce an integrated, clinical vv-PISH prototype. In this specific aim, our system will be finalized to incorporate new developments and integrate off the shelf components into a vv-PISH prototype suitable for preclinical and clinical testing. We will assemble the: 1) peristaltic roller pump (MC3 pump), 2) adult ECMO heat exchanger (ECMOtherm-II(tm)), 3) hemofilter (Renaflow II(r)), 4) water heater (Hemotherm(r)), and 5) double lumen cannula (Avalon Elite(tm)). Once assembled, we will perform bench testing to confirm that design requirements are met. Specific Aim 2: To determine the temperature control performance and in vivo safety of the clinical vv-PISH circuit. In this specific aim, we will establish the safety and reproducibility of the vv-PISH circuit in achieving the target therapeutic dose (42 C for 120 minutes) in adult swine. We will examine major organ function during hyperthermia, and end organ damage or emboli will be examined in a detailed necropsy. Adult swine will also be monitored for five days after hyperthermia administration. Parameters used to assess the safety of the vv-PISH system will include: 1) survival, 2) multiple organ function, and 3) quality of life. This outcomes study is an essential part of the preclinical testing that must precede the clinical trial. Specific Aim 3: To determine the clinical feasibility of the vv-PISH circuit in a prospective randomized clinical trial. In this specific aim, a phase I clinical trial will be performed to test the clinical feasibility of the vv-PISH circuit. Advanced stage (IIIb or IV) NSCLC patients will be randomized into: 1) standard of care treatment consisting of cisplatin and etoposide chemotherapy with concurrent radiation therapy (n=10) and 2) standard of care therapy followed by systemic hyperthermia treatment via our vv-PISH clinical prototype (n=10). Hyperthermia will be given 2 weeks after the last chemotherapy dose. The impact of this work is that we have developed a new treatment strategy for a relatively unresponsive cancer. PUBLIC HEALTH RELEVANCE: Advanced stage lung cancer, which has a median survival of only 10 months, is present in 75% of all new cases. We developed a new circuit to deliver whole body hyperthermia which significantly increased advanced lung cancer patient survival in a previous phase I clinical trial. Since our Phase I STTR results showed the feasibility of a more simple and inexpensive hyperthermia delivery system, the goal of this Phase II STTR proposal is to establish the feasibility of our finalized circuit to safely deliver therapeutic hyperthermia.