ABSTRACT
Recent clinical trials have shown that adaptive drug therapies can be more efficient than a standard cancer treatment based on a continuous use of maximum tolerated doses (MTD). The adaptive therapy paradigm is not based on a preset schedule; instead, the doses are administered based on the current state of tumour. But the adaptive treatment policies examined so far have been largely ad hoc. We propose a method for systematically optimizing adaptive policies based on an evolutionary game theory model of cancer dynamics. Given a set of treatment objectives, we use the framework of dynamic programming to find the optimal treatment strategies. In particular, we optimize the total drug usage and time to recovery by solving a Hamilton-Jacobi-Bellman equation. We compare MTD-based treatment strategy with optimal adaptive treatment policies and show that the latter can significantly decrease the total amount of drugs prescribed while also increasing the fraction of initial tumour states from which the recovery is possible. We conclude that the use of optimal control theory to improve adaptive policies is a promising concept in cancer treatment and should be integrated into clinical trial design.
Subject(s)
Biological Evolution , Game Theory , Neoplasms/drug therapy , Humans , Neural Networks, Computer , Nonlinear DynamicsABSTRACT
BACKGROUND: Gastrointestinal stromal tumors (GIST) comprise about 80% of gastrointestinal sarcomas. In patients with localized disease, surgery is considered as "Gold Standard" treatment. Organ-sparing radical en-block resection is widely accepted practice. Since lymph node dissection is not routinely indicated, minimally invasive approach is of particular interest. The aim of this study is to investigate the short-term outcomes of different surgical treatment of GISTs. METHODS: We analyzed data of 116 patients who received surgical treatment for localized forms of GIST. Tumors were located in the stomach in 87 (75%) cases, in the small intestine in 26 (22.4%) cases, and extragastrointestinal GISTs were found in 3 (2.6%) patients. Four different approaches were used-open surgery (OpS, n=48), laparoscopic surgery (LS, n=40), endoscopic procedures (EP, n=22) and hybrid rendezvous (HR, n=6). Patient demographics, clinical presentation of tumors, characteristics of operation procedures (duration, intraoperative blood loss, frequency of R0-resection and fragmentation of tumor), postoperative complications and length of hospital stay were examined in all these groups. RESULTS: Radical treatment (R0-resection) was performed in all patients. There were no cases of tumor ruptures during surgical procedure. Mean size of GIST in OpS was 9.1±2.0 [2-35] cm; in LS: 4.9±0.8 (1.5-15) cm; in HR: 3.5±0.8 (2-4.5) cm and in EP: 2.3±0.3 (0.4-3.5) cm. Intraoperative blood loss in OpS was 369.7±209.5 [0-4,000] mL; LS: 63.9±16.0 [0-150] mL; in HR: 96.7±44.3 [50-200] mL; in EP: 33.3±11.0 [0-150] mL. Duration of operation in OpS was 160±20.4 [50-310] min; in LS: 104.7±12.7 [50-185]; in HR: 176.7±44.0 [110-260] min and in EP: 89.8±15.5 [25-190] min. Complication rate in OpS was 5 (10.4%); in LS: 3 (7.5%); in HR: 0% and in EP: 3 (13.6%). Length of hospital stay in OpS was 13.8±2.2 [7-52] days; in LS: 11, 4±2.2 [4-21] days; in HR: 11±3.2 [7-15] days and in EP: 11, 9±2.1 [5-22] days. There were no postoperative deaths. CONCLUSIONS: There is a diversity of surgical approaches for GISTs treatment. From our point of view, the main selection criteria for certain procedure are size, localization, growth type of the tumor and status of overlying mucosa. Nevertheless, due to relative rarity and heterogeneity of this pathology, individualization is necessary in each specific case. Laparoscopic and endoscopic surgery is proved to be safe and feasible for resection of the gastric GISTs, with a reasonable operation time, low blood loss, and an acceptable complication rate. Immediate results indicate that all interventions were performed radically without mortality or serious morbidity.
