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Thermal Chemotherapy for Tumors - Current Status and Prospects
Drug treatment for tumors, commonly known as chemotherapy, is currently one of the main methods for treating tumors. With the increasing incidence of malignant tumors, research in related fields is very active worldwide. The emergence of new drugs and the standardization and improvement of chemotherapy regimens have led to a certain degree of improvement in the survival rate and survival time of cancer patients.
Release time:
2022-08-26
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I. Background
Drug treatment for tumors, commonly known as chemotherapy, is one of the main methods for treating tumors today. With the increasing incidence of malignant tumors, research in related fields is very active worldwide. The emergence of new drugs and the standardization and improvement of chemotherapy regimens have led to a certain degree of improvement in the survival rate and survival time of tumor patients. Certain tumors, such as Hodgkin's lymphoma and testicular germ cell cancer, may be cured through proper chemotherapy; ...
However, like surgical operations and radiation therapy, tumor chemotherapy also has its limitations. For example: the drugs have significant toxic side effects, immune suppression, primary and/or secondary resistance of tumor cells, etc. Among these, the development of resistance to chemotherapy drugs by tumor cells is the main reason for chemotherapy failure. Research has found that the mechanisms of tumor resistance to chemotherapy are very complex, including: 1. Reduced concentration of chemotherapy drugs within tumor cells. 2. Increased repair of DNA damage within cells. 3. Increased metabolism and detoxification of chemotherapy drugs within cells. 4. Mutations and amplifications of target genes, etc.
Tumor hyperthermia refers to the use of various methods to raise the temperature of the whole body and/or tumor tissue (locally), utilizing thermal effects and their secondary effects to treat malignant tumors. Modern research on tumor hyperthermia began to become active in the early 1960s and has made many groundbreaking advances. In recent decades, scientists have used various cell and animal models to explore and study the principles and methods of thermal effect in treating tumors, establishing a cellular and molecular biological basis for tumor hyperthermia; at the same time, they have sought the best treatment conditions and regimens through animal and clinical experiments.
As research into the mechanisms of hyperthermia in treating tumors continues to deepen, people are gradually able to understand the effects of thermal effects on the structure, function, and growth metabolism of cancer cells from the molecular biology and genetic levels, thus providing scientific explanations for the phenomena of thermal effect in treating tumors. A large number of in vitro experiments and clinical data show that hyperthermia has synergistic and supplementary effects on tumor treatment methods such as chemotherapy, radiotherapy, and surgery. Coupled with the trend of multidisciplinary comprehensive treatment in the field of tumor therapy, tumor hyperthermia has developed rapidly in recent years, becoming another important auxiliary treatment method for tumors after surgery, radiotherapy, chemotherapy, and biological therapy.
It has been found that the principles of hyperthermia in treating malignant tumors mainly include: 1. Inducing apoptosis in tumor cells, — directly killing tumor cells. 2. Enhancing the efficacy of chemotherapy. 3. Enhancing the efficacy of radiotherapy. 4. Enhancing the immune function of the body. For whole-body hyperthermia, whole-body warming can also inhibit tumor angiogenesis and metastatic tendencies, as well as have a bone marrow protective effect. Among these, the characteristic of hyperthermia enhancing the efficacy of chemotherapy drugs is of particular interest, and thus research in related fields is relatively extensive and in-depth.
Experiments have shown that thermal effects can enhance the cytotoxicity of chemotherapy drugs through the following pathways: 1. High temperatures change the permeability of tumor cell membranes, making it easier for drugs to enter tumor cells and increasing the intracellular drug concentration. 2. Promoting the chemical (addition) reactions of drugs with targets (such as DNA), enhancing drug efficacy. 3. Inhibiting the repair of gene damage caused by chemotherapy drugs in cancer cells. 4. Thermal effects inhibit the expression of P-glycoprotein (P-gp) related genes and their protein synthesis in tumor cells, reversing and reducing the occurrence of drug resistance in tumor cells.
Since hyperthermic chemotherapy can not only enhance the efficacy of tumor chemotherapy but also reverse the drug resistance of tumor cells to chemotherapy, overcoming some shortcomings of conventional chemotherapy, it provides a rescue method for patients with advanced tumors who have developed resistance or systemic metastasis. Therefore, strengthening research in related fields is of great significance.
II. Thermal Effects Enhance the Cytotoxicity of Chemotherapy Drugs
According to the Arrhenius equation, which describes the relationship between temperature and the rate of chemical reactions, heating is beneficial for the chemical reactions between chemotherapy drugs and biological molecules, thereby increasing the cytotoxicity of chemotherapy drugs. This characteristic of chemotherapy drugs is known as the thermal enhancement effect. This characteristic is particularly prominent in alkylating agents and platinum-based drugs; some antibiotics and antimetabolites also exhibit thermal enhancement effects. However, due to the different molecular mechanisms of pharmacological actions of different drugs, some drugs, such as vincristine and paclitaxel, show no change in cytotoxicity between 37-45°C. Recent experiments have shown that under heated conditions, some low-cost and commonly used anti-tumor drugs, such as mafosfamide, cyclophosphamide, ifosfamide, and cisplatin, have significantly increased cytotoxicity, and they have killing effects on different pathological types of tumor cell lines.
Figure 1 shows the survival rate of Fsa-II tumor cells under the same dose of cisplatin and different temperatures (37-43°C): as the temperature increases, the tumor-killing effect of the drug becomes stronger, and the cell survival rate decreases. Figure 2 shows that whole-body hyperthermia enhances the inhibitory effects of mafosfamide, cyclophosphamide, ifosfamide, cisplatin, mechlorethamine, and bleomycin on tumors: under whole-body hyperthermia (41.5°C × 30 minutes), the time required for C3Hf/Sed mice to grow Fsa-II tumors to a certain volume is significantly prolonged compared to without hyperthermia.
The thermal enhancement effect of drugs can be expressed using the thermal enhancement ratio (TER), where TER = the slope of the cell survival curve under hyperthermic conditions divided by the slope of the chemotherapy cell survival curve at 37°C (normal body temperature). The table below lists the thermal enhancement ratios of several commonly used chemotherapy drugs.
Table: Thermal Enhancement Ratios of Several Drugs in Treating Different Animal Tumor Models
Drug TER TER Tumor Author
(40-42°C) (42.5-44°C)
Cyclophosphamide 1.52-2.28 1.27-2.74 RIF-1, Mammary-Ca, Honess 1982, Monge 1988
Fsa-II, Lewis Lung-Ca Hazen 1981, Urano 1985
Mechlorethamine 1.5-2.96 2.71-2.74 RIF-1, KHT, Fsa-II Honess 1982, Honess 1985, Urano 1991
Mafosfamide 1.5-3.9 ---- RIF-1, KHT, Fsa-II Honess 1985, Urano 1995
Cisplatin 1.48-3.9 1.39-4.96 BT4A, Mammary-Ca, Mella 1985, Douple 1982
Lewis Lung-Ca, SCC VII, Herman 1988, Nishimura 1990
R1-RMS Lindegaard 1992, van Bree 1996
Bleomycin 1.24 1.65-2.90 AdenoCa284, SCC, von Sazazepauski 1981,
Fas-II Hassanzadeh 1982, Urano 1990
Mitomycin C 1.0 2.8 Mammary-Ca, Fsa-II Monge 1989, Urano 1994
5-Fluorouracil 1.0 1.0 Human leukemia, Mini 1986, Rose 1979,
Colon-Ca, Fsa-II Urano 1991
Doxorubicin 1.0 1.0 Mammary-Ca, Fsa-II Monge 1988, Urano 1994
Moreover, clinical trials have also confirmed (see below) that the combined application of hyperthermia and chemotherapy can not only improve the efficacy of tumor treatment (CR + PR); but also reverse the resistance of tumor cells to chemotherapy drugs and enhance the control rate of tumors [5-8].
III. The Principle of Hyperthermia Enhancing Chemotherapy Efficacy
Research has found that the thermal effect mainly enhances the cytotoxic effects of chemotherapy drugs through the following pathways:
1. Increase the concentration of chemotherapy drugs inside cells.
A sufficient number of drug molecules entering the cell is a basic condition for the drug to exert its effect. The sensitivity of tumor cells to a certain drug partly depends on the cell's ability to absorb and acquire that drug. One of the main reasons cancer cells develop resistance to chemotherapy drugs is that the drug cannot reach an effective concentration inside the cell.
Chemotherapy drugs generally pass through the cell membrane into the cytoplasm or nucleus by passive diffusion. Experiments have shown that thermal effects can increase the fluidity and permeability of the lipid bilayer structure of the cell membrane, increasing the concentration of drugs such as cisplatin, mafosfamide, and doxorubicin inside the cells [9-11], and increasing the content of chemotherapy drugs within tumor tissues [12, 13].
2. Promote the adduct formation of drugs with cancer cell DNA.
The process by which electrophilic groups in alkylating agents and platinum-based drug molecules form covalent bonds with corresponding sites on cellular DNA macromolecules is called the adduct reaction. The presence of adducts can block DNA replication and transcription, thereby inducing apoptosis. Experiments have shown that thermal effects at 43°C can increase the formation of platinum-DNA adducts by 170-410% (with cisplatin, oxaliplatin, and carboplatin increasing by 410%, 180%, and 170% respectively) [14, 15], and inhibit the clearance of adducts [16, 17].
3. Inhibit the repair of DNA damage in cancer cells:
Poly(ADP-ribose) polymerase (PARP) is a multifunctional enzyme widely present in eukaryotic cells. When cellular DNA is damaged, PARP acts as an intracellular molecular sensor, recognizing and binding to the site of DNA breaks, and is activated. Activated PARP can catalyze the poly(ADP-ribosyl)ation of various nuclear receptor proteins such as histone H1, topoisomerase I and II, DNA polymerase, RNA polymerase, DNA ligase, Ca2+/Mg2+-dependent nucleases, and PARP itself, transmitting damage information and triggering a cascade reaction caused by the damage, ultimately determining the fate of the cell: repair the damage or undergo apoptosis. After PARP is activated by single-strand or double-strand DNA breaks, it catalyzes the transfer of ADP-ribose from nicotinamide adenine dinucleotide (NAD+) to the carboxyl end of glutamic acid residues in certain nuclear proteins, and subsequently ADP-ribose polymerizes with them, releasing nicotinamide (NIC). This process requires ATP to provide energy. Thus, NAD+ is the rate-limiting substrate for PARP. Experiments have confirmed that hyperthermia can reduce the concentrations of NAD+ and ATP within cells, and can therefore reduce PARP activity by more than 50% [18], inhibiting the repair of DNA damage in cancer cells and promoting apoptosis [19].
4. Reduce and reverse the occurrence of drug resistance in tumor cells.
The multidrug resistance (MDR) of tumor cells to chemotherapy drugs refers to the phenomenon where tumor cells develop resistance to one drug while simultaneously exhibiting cross-resistance to other drugs that share common characteristics or have different structures and mechanisms. The high expression of P-glycoprotein (P-gp) encoded by the MDR1 gene is a major cause of MDR. P-gp is an energy-dependent drug efflux pump or "translocator enzyme"; it can pump anticancer drugs out of the cell using energy provided by ATP, thereby weakening or eliminating their cytotoxic effects and leading to resistance. Experiments have confirmed that heating combined with chemotherapy can inhibit the gene expression of P-gp, reduce the content of P-gp in the cell membranes of multidrug-resistant cell lines [20, 21], reverse the multidrug resistance of tumor cells, and induce apoptosis [22, 23].
IV. Clinical Applications of Hyperthermic Chemotherapy
In the past decade, due to the recognition of the thermal enhancement effect of anticancer drugs, the oncology community has regarded hyperthermic chemotherapy as an important development direction to improve the efficacy of chemotherapy and overcome resistance. Additionally, in recent years, progress in research on the principles of hyperthermia in treating malignant tumors, the development trend of comprehensive cancer treatment, and the emergence and promotion of low-toxicity, reliable hyperthermia equipment have made clinical application research in this field quite active, with related research reports increasing year by year, and preliminary progress is encouraging.
Clinical trials related to hyperthermia often start with cases of tumors resistant to conventional chemotherapy. The efficacy and feasibility of using hyperthermia as a rescue method for tumor patients who have developed resistance have been confirmed by corresponding clinical experiments. Hegewisch-Becker S. et al. [6] used 41.8℃ whole-body hyperthermia + oxaliplatin/5-FU/LV to treat 44 cases of metastatic colorectal cancer patients who relapsed after treatment with 5-FU/LV, irinotecan alone, or 5-FU/LV + irinotecan. The chemotherapy doses were: oxaliplatin, 85mg/m2; LV, 200mg/m2; and 5-FU, 3g/m2, continuous intravenous infusion for 48 hours; every two weeks. Whole-body hyperthermia was performed once every four weeks. Among the 41 patients with assessable efficacy, a total of 130 sessions of whole-body hyperthermia were administered (average 3.2 times/person). Results: At the above dose intensity, whole-body hyperthermia did not increase the incidence of various toxic side effects of chemotherapy; the overall response rate was 20% (2CR, 6PR), with a median survival time of 50 weeks (95% confidence interval 39-61 weeks), and the tumor control rate (CP + PR + SD) was 76%. Westermann AM. et al. [7] used 41.8℃ whole-body hyperthermia + carboplatin (AUC = 8) to treat a group of ovarian cancer patients resistant to platinum-containing chemotherapy (14 cases in total, 12 cases assessable for efficacy), repeated every four weeks. Carboplatin was administered 20 minutes after reaching the plateau phase, infused over about 20 minutes. Results: The effective rate of treatment was 36% (1CR, 4PR). The average course of effective patients was 5 (4-6) cycles.
The significance of advocating hyperthermia for appropriate cancer patients also lies in promoting the efficacy of chemotherapy or surgical treatment. After various malignant tumors have extensive abdominal metastasis, the patient's survival time will be significantly shortened, and the prognosis is poor. Multiple clinical experiments have confirmed that performing intraperitoneal hyperthermic perfusion chemotherapy on patients undergoing extensive peritoneal resection will significantly improve the efficacy of treatment and prolong the patient's disease-free survival period [24-26].
For patients with advanced or unresectable limb sarcomas, amputation is often required. Isolated Limb Hyperthermic Perfusion (HILP) for the affected limb can be an effective method for limb preservation and improving the patient's quality of life. Kim CJ. et al. used HILP + mafosfamide to treat a group of unresectable or recurrent limb osteosarcoma patients, achieving an efficacy rate of 100%, allowing 80% (4/5) of patients' affected limbs to be preserved. Various literature reports indicate that using different chemotherapy drugs + HILP to treat such conditions can achieve an overall efficacy rate of 50-100% [27].
Westermann AM. et al. [8] used 41.8℃ whole-body hyperthermia + ICE regimen to treat metastatic soft tissue sarcoma, with a total of 108 patients, 95 of whom were assessable for efficacy. The overall efficacy rate was 28.4% (4CR, 23PR); the median survival time was 393 days (95% confidence interval 327-496 days). Among them, the efficacy rate for first-line chemotherapy patients was 36%, while the efficacy rate for re-treatment patients was 24%. Compared to the literature, the efficacy was significantly improved.
Malignant pleural mesothelioma patients progress relatively quickly, and under various treatments, the median survival time averages 10.5 months. Bakhshandeh A. et al. [28] experimentally used 41.8℃ whole-body hyperthermia + ICE regimen to treat 27 cases of malignant pleural mesothelioma patients who had not metastasized after first-line chemotherapy. Among the 25 patients assessable for efficacy, the efficacy rate (CR + PR) was 20% (5PR; 95% confidence interval 8.9-39.1%); the 1-year and 2-year survival rates reached 68% and 20%, respectively.
……
5. Conclusion and Outlook
Antibiotics and various cytotoxic drugs used for treating tumors are collectively known as chemotherapy drugs in the medical field. The history of antibiotic development is essentially a cycle of drug invention, resistance, and the re-invention of new drugs, yet it has not fully overcome the emergence of resistant bacterial strains. The discovery of various β-lactamase inhibitors has significantly enhanced the efficacy of penicillin and cephalosporin drugs. Drawing inspiration from the history of antibiotics, it is equally crucial to develop various methods to combat and reverse cancer cell resistance while improving the efficacy of existing drugs, alongside the development of new drugs targeting resistant strains of malignant tumors. Hyperthermia offers us an effective approach in this regard. It is believed that through the continuous refinement and dissemination of relevant theories and knowledge, along with ongoing in-depth research in the field, hyperthermia will provide hope to more cancer patients and become a powerful tool for oncology professionals in the battle against cancer.
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(Chinese Society of Hyperthermia)
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