Liver - 03327
Original Paper
Immune-related Effects of Local Hyperthermia
in Patients with Primary Liver Cancer
Valentina V Ostapenko1, Hiroto Tanaka2, Motoshige Miyano1, Takahiro Nishide1, Hiroki Ueda2
Iwao Nishide1, Yoshimasa Tanaka1, Masatoshi Mune2, Susumu Yukawa2
1Shouseikai Nishide Hospital, and 2Third Department of Internal Medicine Corresponding Author: Dr. Valentina Ostapenko, Shouseikai Nishide Hospital Tel: +81 724 32 0777, Fax: +81 724 36 3074, E-mail: [email protected] KEY WORDS:
Background/Aims: To investigate immune-related
decreased significantly (p<0.05), whereas the rela- effects of local hyperthermia (HT) with hepatocellu- tive amount of CD4+ T cells showed a tendency to decrease (p=0.063), and CD8 - to increase (p=0.088).
Methodology: Immune status after 7 HT was stud-
An activation of NK cells was observed in patients ied in 11 patients (M/F - 9/2; 1st group). The effects who had a low or normal pretreatment level of acti- were also evaluated during one HT session in 4 of vation. In the 2nd group, there was a significant ABBREVIATIONS:
decrease in the CD4/CD8 ratio by the end of the The HT treatment was performed by means of an 8- treatment (p<0.05) and increased activity of NK MHz capacitive heating device, Thermotron RF8 cells as early as 20 min after the onset of HT (Japan). The mean time of one HT session was 60 min. HT was performed 1-2 times a week. In both Conclusions: Our results suggest that HT stimu-
groups the percentage of T and B cells, CD4+, CD8+ lates the immunity of cancer patients by several subsets of T cells, the CD4/CD8 ratio and activation means and therefore may exhibit indirect anticancer effect. In addition, activation of NK cells by HT may Results: In the 1st group, CD4/CD8 ratio was be associated with improved quality of life.
Heating: The HT treatment was performed by
The rate of hepatocellular carcinoma (HCC) has means of an 8-MHz capacitive heating device, "Ther- been increasing in Japan. Most cases are associated motron RF-8" (Yamamoto Vinita Co., Ltd., Osaka, with HCV infection. The mechanism of HCV-related Japan). The electromagnetic power ranging from 614 carcinogenesis and disease progression are not well to 1363 W was applied between two 30-cm electrodes understood, although it is thought that not only virus- placed on opposite sides of the patient's upper abdom- induced but also immunologically mediated mecha- inal region. Overlying water boluses were placed between the electrode and the skin to improve the Such local methods as transcatheter arterial homogeneity of the heating. A saline solution main- embolization (TAE) and percutaneous ethanol injec- tained at 2-15°C was circulated in the boluses to avoid tion therapy (PEIT) are widely used in the treatment overheating of the skin. For premedication, 50mg of inoperable HCC. However, it has been reported that indomethacin (i.r.) was administered 30 min before the TAE procedure might suppress a host immunity HT. A 1% xylocaine topical gel was applied to the skin response against cancer in HCC patients (3). Recently to decrease the sensation of heat. Blood pressure and local hyperthermia (HT) has been widely used for can- pulse were monitored during treatment. The time of cer treatment as a way to increase a tumor's radio- one HT session was 40-60 min. HT was performed 1-2 and chemosensitivity (4,5). In contrast to most other times a week. A total of 8 sessions delivered 1-2 times cancer treatment modalities, HT is also known to a week, were performed (1 course). Thermometry was cause an activation of the immune system (6-10).
In this study, the potential of local HT to enhance Laboratory data: In the first group (N=11), the
the cell-mediated immunity of HCC patients was percentage of T and B cells, CD4+ and CD8+ subsets, the CD4/CD8 ratio and activation of natural killer(NK) cells were evaluated before the 1st and 8th ses- METHODOLOGY
sions. In the 2nd group (N=4) the same immune para- Patients' characteristics: Clinical characteris-
meters were investigated during one 60-minute HT tics are summarized in Table 1.
session, namely, before the onset of heating, 20 and 40 Hepato-Gastroenterology 2005; 52:1502-1506 H.G.E. Update Medical Publishing S.A., Athens-Stuttgart Hyperthermia and Immunity in Liver Cancer Combination
FIGURE 1 NK cells activation in the course of HT in regards to
pretreatment level. Normal values of activation of NK cells are 18-40%.
Solid lines indicate data for patients with pretreatment level of activationexceeding normal range. Dashed lines indicate data for patients with pretreatment level being lower or within normal range. ation therapy; PEIT: percutaneous ethanol injection Ascitis treatment
min after onset of heating and immediately after its All patients were informed about the nature and Statistics: Data were evaluated using a paired t-
test. p values <0.05 were considered as statistically RESULTS
The Effect of Seven HT Sessions on Cell-

mediated Immunity
Data are summarized in Table 2. As shown, the
CD4+/CD8+ T cell ratio was significantly decreased
by HT (p=0.05) (Table 1). This effect was associated
to a higher degree with decreased amount of CD4+ PIVKA-II,
cells and to a lower degree with increased amount ofCD8+ T cells (NS). The percentage of the total popu-lation of both T and B cells, as well as activation of NK cells, did not significantly change in these series. At the same time, we found that the pattern of activationof NK cells was likely to be dependent on its pretreat-ment status. Namely, for patients whose pretreat- TABLE 1 Pretreatment Characteristics of the Patients and Parameters of the HT
ment level of NK activation was below or within the Location
normal value, there was a significant additional acti- TB: total bilirubin; Alb: albumin; PLT: platelets; TAE: transarterial emboliz vation caused by HT treatment (15.3±6.7% to
24.3±6.3%, p<0.05) (Figure 1). On the contrary, for
those who demonstrated an increased pretreatmentactivation level, HT treatment resulted in a decreaseor lack of change of that parameter (60.8±12.9% to 45.3±18.4, NS) (Figure 1).
The Effect of a Single HT Session on Cell-
mediated Immunity
Corresponding data are summarized in Table 3.
The CD4/CD8 ratio showed a tendency to begin decreasing already at 20 min of heating, demonstratea significantly low value at 40 min of heating and lower further by the end of HT. The decrease in theCD4/CD8 ratio was mostly due to the decrease inCD4+ fraction and less due to the tendency for CD8+ Notes: Group 2 consisted of cases 1, 5, 10 and 11.
cells to increase. The total amount of T and B cells did VV Ostapenko, H Tanaka, M Miyano, et al.
TABLE 2 Immune Parameters in the Course of HT Treatment
CD4/ CD8,%
T cells, %
B cells, %
NK activation, %
TABLE 3 Immune Parameters in HCC Patients during a Single HT Session
CD4/ CD8, %
T cells, %
B cells, %
NK activation, %
not change during the treatment. A significant NK ing is beneficial because of its activation of immune activation was evident as early as 20 min after the responses. Various immune-related effects of local HT onset of treatment, and continued to increase up to can be expected, as it has already been shown in numerous experimental and clinical investigations.
Among the clinically most relevant aspects of cell- DISCUSSION
mediated immunity are CD4+ and CD8+ populations Both carcinogenesis and tumor progression are of T cells, the CD4/CD8 ratio, T and B cells, and NK associated with a depressed immune status of the cell activity. Therefore, these parameters were chosen host. It has been suggested that a decrease of CD56+ cells and NK cells in cirrhotic livers caused by hepati- In the clinic, both CD4+ and CD8+ T cells were tis C is related to susceptibility to HCC (11,12).
shown to play an important role in antitumor defense, Depressed NK activity was also noted in patients with although the relative clinical significance of each sub- HCC, cancers of the kidney and urinary bladder set might depend on the tumor type. Stawarz et al. have shown an increase of the CD4/CD8 ratio by local In the multimodality treatment of cancer, a local HT in patients with advanced adenocarcinoma of the HT has been demonstrated to potentiate radiothera- prostate (10). In contrast, we found a decrease in the py, some chemotherapies, and immunotherapy (15- CD4/CD8 ratio, which was mainly due to the increase 17). Employment of HT in combination with other in the fraction of CD8+ cells. Taking into account modalities used in mild regimens has also been report- other data for ovarian cancer patients, where a ed. In treatment of HCC, the combination of HT with decrease of CD8+ lymphocytes was shown to correlate TAE and PEIT was found to be effective (18,19).
with the progression of the disease (26), we consider Moreover, HT alone has also been reported to effec- the changes observed by us as favorable ones. Inter- estingly, HT-induced changes in CD4+, CD8+ subsets It has been well established that immunocompe- were found in both groups, demonstrating some simi- tent cells, including macrophages, T-lymphocytes and larity in early and late effects of HT. Therefore, there natural killer (NK) cells, in vitro, are among the most was probably both a direct activation of immunocom- sensitive cells to temperature elevation (22,23). There- petent cells by elevated temperature, and an indirect fore, both whole-body and local HT may cause favor- one, mediated by HT-induced heat-shock proteins, as able immune changes when employed in cancer clinic.
follows from recent knowledge of the mechanisms of HT-related immune effects were found to depend on a heating regimen. For instance, temperature ranging A significant increase of NK cytolytic activity was from 39 to 41°C (fever range) was shown to confer an noted following transrectal HT of prostate, with the immunoregulatory advantage by enhancing the secre- peak effect at 2 months and a subsequent decrease tion of immunoglobulins, whereas elevation of tem- (27). In our series, there was a selective increase of NK perature to tumoricidal level (>42°C) led to inhibition activation in patients whose pretreatment values were of host competence (24,25). Therefore, a whole-body lower or within normal range. These data fit the state- HT, if used at tumoricidal temperature, may probably ment of Rosberger et al., who noticed not only cause unfavorable immune response. In the case of immunostimulation but also an immunomodulatory local HT, even if temperature in the tumor exceeds effect of local HT in patients with choroidal 42°C, the surrounding normal tissue usually remain melanoma. They showed that local HT inverted at fever-range temperatures. This selectivity of heat- CD4/CD8 resulting in a normalization of T-cell subset Hyperthermia and Immunity in Liver Cancer ratios (28). In our investigation, where the affects of whom quality of life was demonstrated to improve by HT on a group of patients were studied during one 60- HT had also demonstrated remarkable activation of min HT session (second group), we found that NK NK cells in the course of one HT session. In contrast, cells responded first to the local heating of the liver those who failed to recover QOL had little change in and showed a significant increase in activation already NK activity (data not shown). We have a special inter- at 20 min after the beginning of the treatment.
est to continue research in this field having being It was demonstrated previously that HT-related encouraged by previous finding by others that NK effects may also be an important step in anticancer activity in patients with anxiety about cancer was sig- defense as augmented immune cell traffic and its nificantly lower than that in those with no such anxi- enhanced responsiveness and stimulatory activity, shown in healthy volunteer study where skin was In conclusion, local HT stimulates cell-mediated heated in a water bath of 44°C for 3 h (6). As shown in host immunity, involving both innate responses such vivo for murine melanoma, local HT (43°C, 15 min) as NK cell activation, and adopted responses, such as induced infiltration of NK cells into the tumor (29). In change in CD4+, CD8+ subsets. These effects take patients with esophageal cancer, infiltration of lym- place as early as during the HT treatment and remain phocytes (IL) appeared to be a prognostic predictor through the 7-session treatment schedule, lasting up after preoperative chemoradiotherapy, while in addi- to 2 months. NK cells respond first to the elevation of tion, simultaneous HT significantly stimulated IL temperature of the lower abdomen, including the liver. However, a larger study is warranted in order to In addition to the above-mentioned properties of exclude the influence of such parameters as age, sex, NK cells, we have noticed that its activity may be asso- drug administration, and psycho-emotional condi- ciated with quality of life. Thus, those patients in REFERENCES
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