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Thermo-chemotherapy of the advanced pancreas carcinoma
Abstract
The results of chemotherapy of pancreas carcinoma are still disappointing. In nearly all cases the disease progresses, response rates to cytotoxic therapy are low and the 5-year survival rate amounts to 1%. The purpose of the present study was to evaluate whether response rate, time to progression and survival time can be improved by the combination of cytostatic treatment and loco-regional hyperthermia (thermo-chemotherapy). Results: According to the standard criteria, 1 patient had a complete remission, 10 patients had a partial remission; 7 patients did not respond to the therapy and showed progressive disease. Thermo-chemotherapy as applied in this clinical study shows a remarkable clinical outcome in advanced pancreas cancer and is well tolerated. The results suggest further evaluation in randomized trials.
... 45,46 Several studies show advantages and curative effects of mEHT alone or in association with chemo-radiotherapy for advanced pancreas carcinoma. [47][48][49][50] In this study, the effect of mEHT is monitored in terms of tumor response, OS, and safety in locally advanced or metastatic pancreatic adenocarcinoma. ...
... [33][34][35]56,57 mEHT allows use of a lower power than conventional hyperthermia 41,58 and can be applied with good results for pancreatic cancer treatment. [47][48][49][50] The tumor response analysis showed a response rate (RR = PR + SD) of 94.1% for the mEHT group and 36.1% for the non-mEHT group. A recent review on hyperthermia efficacy in pancreatic cancer therapy reported the results of 14 studies including a total of 395 patients. ...
Background: Pancreatic adenocarcinoma has a poor prognosis, resulting in a <10% survival rate at 5 years. Modulated electro-hyperthermia (mEHT) has been increasingly used for pancreatic cancer palliative care and therapy. Objective: To monitor the efficacy and safety of mEHT for the treatment of advanced pancreatic cancer. Methods: We collected data retrospectively on 106 patients affected by stage III-IV pancreatic adenocarcinoma. They were divided into 2 groups: patients who did not receive mEHT (no-mEHT) and patients who were treated with mEHT. We performed mEHT applying a power of 60 to 150 W for 40 to 90 minutes. The mEHT treatment was associated with chemotherapy and/or radiotherapy for 33 (84.6%) patients, whereas 6 (15.4%) patients received mEHT alone. The patients of the no-mEHT group received chemotherapy and/or radiotherapy in 55.2% of cases. Results: Median age of the sample was 65.3 years (range = 31-80 years). After 3 months of therapy, the mEHT group had partial response in 22/34 patients (64.7%), stable disease in 10/34 patients (29.4%), and progressive disease in 2/34 patients (8.3%). The no-mEHT group had partial response in 3/36 patients (8.3%), stable disease in 10/36 patients (27.8%), and progressive disease in 23/36 patients (34.3%). The median overall survival of the mEHT group was 18.0 months (range = 1.5-68.0 months) and 10.9 months (range = 0.4-55.4 months) for the non-mEHT group. Conclusions: mEHT may improve tumor response and survival of pancreatic cancer patients.
... Clinical results prove that the improvement of the survival is induced by mEHT [47]. There are studies for multiple localizations, like pancreas carcinoma [48] [49] [50]; small-cell [51] and non-small-cell lung cancer [ ...
Simple Summary
Modulated electro-hyperthermia (mEHT) is a heating therapy that uses synergized thermal and nonthermal effects to heat and destroy malignant cells selectively without damaging healthy cells. This article presents the clinical validation of mEHT. The therapy is dominantly applied for such advanced malignancies when the conventional oncotherapies fail to apply. Survival results of mEHT were collected and compared with other methods. The results demonstrate the superiority of the mEHT method.
Abstract
The mEHT method uses tissues’ thermal and bioelectromagnetic heterogeneity for the selective mechanisms. The success of the therapy for advanced, relapsed, and metastatic aggressive tumors can only be demonstrated by measuring survival time and quality of life (QoL). The complication is that mEHT-treated patients cannot be curatively treated any longer with “gold standards”, where the permanent progression of the disease, the refractory, relapsing situation, the organ failure, the worsening of blood counts, etc., block them. Collecting a cohort of these patients is frequently impossible. Only an intent-to-treat (ITT) patient group was available. Due to the above limitations, many studies have single-arm data collection. The Phase III trial of advanced cervix tumors subgrouping of HIV-negative and -positive patients showed the stable efficacy of mEHT in all patients’ subgroups. The single-arm represents lower-level evidence, which can be improved by comparing the survival data of various studies from different institutes. The Kaplan–Meier probability comparison had no significant differences, so pooled data were compared to other methods. Following this approach, we demonstrate the feasibility and superiority of mEHT in the cases of glioblastoma multiform, pancreas carcinomas, lung tumors, and colorectal tumors.
Hyperthermia is a generic term for different techniques using heat in cancer therapies. Temperatures of about 42° Celsius in combination with chemo- or radiotherapy may improve the effectiveness of those treatments. Clinical benefit is shown in “standard hyperthermia” with tumour temperatures assessed during treatment. This systematic review thoroughly assesses the state of evidence concerning the benefits and side effects of electro hyperthermia or whole-body hyperthermia (“alternative hyperthermia”) in oncology. From 26 April 2021 to 09 May 2021, a systematic search was conducted searching five electronic databases (Embase, Cochrane, PsycINFO, CINAHL and Medline) to find studies concerning the use, effectiveness and potential harm of alternative medical hyperthermia therapy on cancer patients. From all 47,388 search results, 53 publications concerning 53 studies with 2006 patients were included in this systematic review. The patients were diagnosed with different types of cancer. The hyperthermic methods included whole-body hyperthermia (WBH) with different methods and electro hyperthermia (EH). The majority of the included studies were single-arm studies, counting in total 32 studies. Six studies were randomized controlled trials (RCT). In addition, one systematic review (SR) was found. The most critical endpoints were tumour response, survival data, pain relief, myelosuppression and toxicities. Outcome was heterogeneous, and considering the methodological limitations, clinical evidence for the benefit of alternative hyperthermia in cancer patients is lacking. Neither for whole-body hyperthermia nor for electro hyperthermia there is any evidence with respect to improvement of survival or quality of life in cancer patients.
Our present oncological treatment arsenal has limited treatment options for pancreatic ductal adenocarcinoma (PDAC). Extended reviews have shown the benefits of hyperthermia for PDAC, supporting the perspectives with the improvements of the treatment possibilities.
Methods:
A retrospective single-center case-control study was conducted with the inclusion of 78 inoperable PDAC patients. Age-, sex-, chemotherapy-, stage-, and ascites formation-matched patients were assigned to two equal groups based on the application of modulated electro-hyperthermia (mEHT). The EHY2030 mEHT device was used.
Results:
A trend in favor of mEHT was found in overall survival (p = 0.1420). To further evaluate the potential beneficial effects of mEHT, the presence of distant metastasis or ascites in the patients' oncological history was investigated. Of note, mEHT treatment had a favorable effect on patients' overall survival in metastatic disease (p = 0.0154), while less abdominal fluid responded to the mEHT treatment in a more efficient way (p ≤ 0.0138).
Conclusion:
mEHT treatment was associated with improved overall survival in PDAC in our single-center retrospective case-control study. The outcome measures encourage us to design a randomized prospective clinical study to further confirm the efficiency of mEHT in this patient cohort.
Oncothermia is a method of hyperthermia in oncology, controlling the locally applied deep heat by selectively targeting the cellular membrane of the malignant cells. The selection of the method is based on various biophysical and biochemical achievements. There are various differences between the malignant and healthy cells, which could be used for their selection by heat targeting. The primary selection factor is a different metabolic activity which creates distinguishable environments of the malignant cells. The other factor is the clear difference of dielectric properties of the membrane and near-membrane extracellular electrolytes, marking off the malignancies. There is also a structural factor, which is clear in the different pathological patterns of the malignancy from their healthy counterparts. This last is described by fractal pattern evaluation technique, in which dynamic time-fractal transformation is used for further discernment of the malignancy. My objective is to show a new heating method, which makes oncological hyperthermia controllable and effective.
We analyzed heating profiles from 318 hyperthermic treatments of 39 patients with recurrent or inoperable cancers of the digestive organs whose deep-seated tumors were treated by radiofrequency (RF) capacitive heating of the abdominal region, and we investigated the heating efficiency and antitumor effect of such treatment. It was apparent that heating with a mean maximum RF output of 1,000 watts (700 watts at least), repeated four times or more, was necessary for a high rate of response by the tumor. Although it was difficult to heat tumors of the bile duct/pancreas to 42°C or more, there was a strong positive correlation between maximum output of RF energy and maximum temperature of tumors (r = 0.839, P < 0.001). The antitumor effect of RF hyperthermia was augmented with increasing output of RF energy. Therefore, the maximum level of RF output may be a useful index for expressing the heating efficiency with respect to intra-abdominal deep-seated tumors.
The cytotoxic effect of 5-FU (5-fluorouracil) was demonstrated to be enhanced by hyperthermia after treatment with 5-FU at even a comparatively low dose over fairly long periods. The cytotoxic effect of the combined treatment with 42 degrees C-hyperthermia and 1 microgram/ml 5-FU for 48 hrs, the cytotoxic effect of 42 degrees C-hyperthermia and 5 micrograms/ml 5-FU for 24 hrs, and the cytotoxic effect of 43 degrees C-hyperthermia and 1 and 5 micrograms/ml 5-FU for 8 hrs were studied. The maximally enhanced rate of 42 degrees C-hyperthermia after 5-FU treatment for 96 hrs was 48% after a 1 microgram/ml 5-FU treatment and 150% after 45 hrs with the 5 micrograms/ml 5-FU treatment. The maximally enhanced rate of 43 degrees C-hyperthermia after 5-FU treatment was 170% after 45 hrs with 1 microgram/ml 5-FU treatment and 180% after 24 hrs with 5 mg/ml 5-FU treatment. When V-79 cells were treated at the same temperature, the maximally enhanced rate with 1 microgram/ml 5-FU was almost equal to that of 5 micrograms/ml. Moreover, when each maximally enhanced rate was equalized, each concentration of FU (RNA)/RNA practically became equal, i.e., when the maximally enhanced rates were approximately 150 and 170-180%, FU (RNA)/RNA concentrations were about 40 and 15 ng/mg RNA, respectively. We thus concluded that FU (RNA)/RNA concentration might play an important role as an indicator of the effect of the combined treatment of 5-FU and hyperthermia.
Multi-institutional studies on clinical hyperthermia of deep-seated tumours were undertaken using 8 MHz radiofrequency capacitive heating devices (Thermotron RF-8) at seven institutions. Each institute was designated to treat specific organs. This paper contains the accumulations of the results obtained at different institutions charged for different tumours. Deep-seated tumours in the lung, stomach, pancreas, liver, urinary bladder and rectum were treated. A total of 177 cases examined from January 1985 to December 1988 included 96 cases (54%) treated with radiotherapy plus hyperthermia, among which 14 cases were pre-operative. Of 177 cases, 81 (46%) were treated with chemotherapy plus hyperthermia. Complete response (CR) and partial response (PR) were obtained in 80% of the cases with lung cancer, 39% with stomach cancer, 56% with liver cancer, 35% with pancreas cancer, 71% with urinary bladder cancer, 100% with primary rectal cancer, and 47% with recurrent rectal cancer. Thermometry was performed using two techniques; one is direct measurement of intratumour temperature in lung and liver cancers, the other is indirect measurement of intracavitary temperature for stomach, pancreas, urinary bladder and rectal cancers. Intratumour temperatures were measured in 30 of the 43 tumours of the lung and liver. The maximum tumour temperature was greater than 42 degrees C in 23 (77%) of the 30 tumours. Intracavitary temperatures were measured in 133 (99%) of the 134 tumours of stomach, pancreas, urinary bladder and rectum. An intracavitary temperature greater than 42 degrees C was obtained in 98 (73.7%) of the 133 tumours. The contribution of hyperthermia in improving the quality of life of patients under terminal care was also investigated. It was indicated that hyperthermia was one of the most effective treatment techniques for advanced or inoperable cases. In this study local control rate (LCR) was mainly discussed because the period of follow-up was only 3 years. Side-effects were observed in 37 cases (21%); main side-effects were fatty induration, pain during treatment and burn. However, no side-effects were severe enough to interrupt therapy.
The interaction of hyperthermia and mitomycin C (MMC) was studied in wild-type Chinese hamster ovary cells and in Chinese hamster ovary cells selected for resistance to MMC. Hyperthermic potentiation of MMC activity was maximal if heating was done simultaneously, or up to 3 h following MMC exposure. Heat enhanced the effect of MMC in both drug-sensitive and -resistant cells. Dose enhancement ratios increased from 1.3-2.0 at 42 degrees C to 2.6-3.8 at 43.5 degrees C and were similar for all cell lines. Cellular uptake of MMC was determined by high pressure liquid chromatography. MMC uptake was similar in the drug-sensitive and -resistant cell lines at 37 degrees C. Hyperthermia (43.5 degrees C) increased cellular uptake of MMC by 78 and 27% in MMC-sensitive and -resistant cell lines. MMC-resistant cells were more sensitive to heat alone at 42, 43, and 44 degrees C. The results suggest that tumor cells that have developed resistance to MMC might be treated effectively with MMC combined with heat to augment the response to MMC. Resistance to MMC may also render tumor cells more sensitive to hyperthermia.
Microregional distributions of glucose, lactate and ATP concentrations as well as tissue pH values were determined in subcutaneous rat tumours during normothermia and normoglycaemia, and upon local hyperthermia (HT) and/or hyperglycaemia (HG). Experiments were performed in order to investigate whether, and to what extent, these adjuvant therapeutic measures applied alone or in combination can modify the bioenergetic and metabolic status, parameters that are known to markedly influence the therapeutic response of tumours to heat. Local HT was performed in a saline bath (44 degrees C/2 h) and HG was induced by i.v. infusion of glucose for 2.5 h (blood glucose levels during heating: 35-40 mM). Immediately after treatment, the microregional distributions of glucose, lactate and ATP concentrations were assessed using quantitative bioluminescence and single-photon counting. In corresponding histological sections the fraction of tumour tissue with changes indicating cellular damage was determined. For comparison, global levels of glucose, lactate, ATP, ADP and AMP were measured using enzymatic assays or HPLC. Tumour tissue pH values were recorded immediately after treatment with miniaturised needle glass pH electrodes. Upon HT alone, the microregional glucose distribution remained unchanged. Lactate concentrations significantly increased, resulting in a pH drop of about 0.20 pH units. Mean ATP concentrations decreased without an obvious change in the shape of the distribution curve. The fraction of tumour tissue showing cellular damage increased from 18% (in control tumours) to 27%. Upon HG alone, mean glucose and lactate levels in the tumours increased. Glucose, lactate and pH distributions became broader. Lactate accumulation results in a severe tumour acidosis (mean pH = 6.22). Mean ATP concentrations marginally decreased despite a higher glucose availability, probably because of poorer ATP yield resulting from changes in metabolic channelling (Crabtree effect). The fraction of tumour tissue exhibiting cellular damage was 23%. Following the combined treatment (HT/HG), glucose and lactate levels, and tissue pH were similar to those seen upon HG alone. However, ATP concentrations were lowest under this condition. The variation of tumour ATP concentrations is substantially reduced with only a few tumour areas remaining with ATP levels of at least 0.6 mumol/g. The ATP depletion upon HT/HG is accompanied by a drastic increase in the fraction of tissue areas exhibiting cellular damage to 61%. It may therefore be concluded that only the combined treatment can deplete ATP to such an extent that a pronounced cytotoxic effect is achieved.
The effects of hyperthermia (38-42 degrees C) on the metabolism of 5-fluorouracil (5-FU) were examined using Ehrlich tumour cells (E-cells) and Sarcoma-180 cells (S-180 cells) in vitro. A temperature-dependent elevation of the intracellular concentration of 5-FU was observed in both types of tumour cell after incubation with 5-FU. The levels of 5-fluorouridine (FUR) and 5-fluoro-2'-deoxyuridine (FdUR), which are active metabolites of 5-FU, increased significantly after treatment of cells with 5-FU and hyperthermia. The highest concentrations of these active metabolites were found when the cells were incubated at 39 degrees C. The levels of alpha-fluoro-beta-ureido-propionic acid (FUPA) and F-beta-alanine, which are inactive catabolic metabolites of 5-FU, also increased when the cells were incubated at 39 degrees C. The percentage inhibition of thymidilate synthetase (TS) activity remained high (about 60-70%) at 39 degrees C for 240 min. These results suggest that the optimal temperature for potentiating the intracellular metabolism of 5-FU, in terms of both activation and inactivation, is 39 degrees C in vitro.
Following non-lethal heat stress (41.8 degrees C) and a recovery period at 37 degrees C, the inducible 72kDa HSP (HSP72) is detectable selectively on the cell surface of human Ewing's Sarcoma (ES) and of leukemic K562 cells but not on EBV transformed B cells (B-LCL) which were generated from PBL of healthy human volunteers. The HSP72 expression was measured by flowcytometric analysis using a monoclonal antibody (moAb) that specifically recognizes HSP72, the inducible form of the HSP70 group. The major histocompatibility complex (MHC) class I expression, detected with moAb W5/32 was not affected by non-lethal heat exposure and a recovery period at 37 degrees C for 12 h: ES cells express MHC class I molecules on about 80% of the cells; K562 cells exhibited no MHC class I expression neither before nor after heat shock. Inhibition of RNA-(actinomycin D) of protein-synthesis (cycloheximide) prior to heat treatment completely inhibits the expression of HSP72 on the cell surface of both tumour cells, thus indicating that de novo protein synthesis is required for HSP72 cell surface expression. Since, apart from HSP72, protein synthesis in general is down-modulated by heat shock we speculate that HSP72 molecules that are expressed on the cell surface of tumour cells might be recruited from newly synthesized proteins. The heat-inducible HSP72 cell surface expression on tumour cells could be correlated with an increased sensitivity of leukemic and sarcoma cells to lysis mediated by NK effector cells. The results of cold target inhibition assays revealed that histologically different tumour cells (sarcoma and leukemic cells) that were exposed to non-lethal temperatures have to share a similar if not identical HSP72 immunogenic determinant.
Patients at advanced stage of colorectal cancer with liver metastases have been treated with deep hyperthermia alone or in combination with chemotherapy (5-FU + FA + MMC). Hyperthermia was achieved by arrangements of capacitive electrodes with a radiofrequency field of 13.56 MHz (RF-DHT). This prospective open single-arm clinical study with 80 patients suffering from liver metastases from colorectal cancer gives some first hints, that deep RF-hyperthermia alone may have a substantial beneficial effect on overall survival time of patients with liver metastases from colorectal cancer. Long lasting no-change, partial and even some complete remissions could be observed. The overall median survival time from progression of metastases or relapse was 24.5 months and survival rates at 1, 2 or 3 years from first diagnosis of metastases or progression were twice as high as expected from patients treated with chemotherapy. The combination of hyperthermia with delayed chemotherapy did not change overall survival time. These encouraging results deserve to be confirmed in randomized clinical studies.
Whole Body Hyperthermia (WBH) enhancement of chemotherapy and/or radiation without a concomitant increase in myelosuppression has been documented in clinical trials. We propose that the biological basis for this phenomena relates in part to the previously reported induction of peripheral cytokines by WBH, that is, granulocyte colony stimulating factor (G-CSF), interleukin (IL)-1 beta, IL-6, IL-8, tumor necrosis factor-alpha (TNF-alpha), and the regulatory cytokine IL-10. To further explain this myeloprotection and the additional clinical observation that WBH promotes early engraftment of bone marrow (when used as part of an allogenic bone marrow transplant preconditioning regimen) we developed a hypothesis: WBH increases peripheral IL-1 beta, IL-6, and TNF-alpha resulting in a secondary induction of IL-3 and granulocyte macrophage colony stimulating factor (GM-CSF) in the bone marrow, for which supportive data also exists. Taken collectively, these data provide an increased understanding of the biological sequelae of fever, as well as a testable unifying hypothesis, for future antineoplastic treatment strategies.
Many biological attributes of tumors (including regional blood flow and microcirculation) can deteriorate the homogeneity of heat distribution and temperature elevation during hyperthermia. We analyzed the connection between the microcirculation status of osteogenic sarcomas and the posttreatment histology after neoadjuvant chemotherapy, irradiation and local hyperthermia.
62 patients with histologically verified osteosarcoma (35 men, 27 women, age 9-53, average 21 years) were enrolled in the retrospective pathohistological study. 61 patients were evaluable. In 72.6% of cases the tumor was localized in bones forming knee joints. All patients received neoadjuvant treatment [6 hyperthermias (60 min, 42-45 degrees C), daunorubicin 30-50 mg/m(2), 6 infusions, adriamycin or cisplatin 30 mg/m(2) for 3 days or once 90 mg/m(2) monochemotherapy before the hyperthermic procedure; subsequently gamma-therapy, 20-36 Gy] followed by surgery. From archives, a control group was formed of 20 therapy-naive tumors. Resected tumors were histologically examined for assessment of spontaneous and therapeutically induced alterations. For analysis of the functionality status of microcirculation on histological cuts, 40 tumors (without selection) were investigated: 10 controls and 10 cases each with minimal, subtotal and total posttreatment alterations.
Chemotherapy and radiotherapy in combination with local hyperthermia induced a distinct damage to osteosarcoma. In 39.3 and 35.7% of cases there was subtotal and total devitalization of tumor parenchyma, respectively. Thrombosis of magistral and middle vessels, stasis in the microcirculation tree (collapse), damage to intimal vessels and endothelial cells, and necrotic alterations of the vessel walls appeared predominantly in central areas of tumors. Tumors with minimal devitalization of the parenchyma had a share of nonfunctional vessels ranging from 10.6 to 61.7%, mean 29.7%. In tumors with subtotal necrosis, between 34.5 and 72.0% (mean 49.46%) of vessels were nonfunctional (stasis, thrombosis). In 10 cases with 100% necrosis of the osteosarcoma parenchyma, a mean of 56.05% of nonfunctional vessels was registered (12.3-83.0%). In the control group, between 2.85 and 73.4% (mean 21.69%) of vessels showed damage to the microcirculation.
There is a direct correlation between deterioration of the microcirculation in osteosarcoma and thermo-radiochemotherapy- induced tissue alteration; the devitalization grade is directly proportional to the number of nonfunctional vessels in the tumor.
Patients with advanced ovarian cancer have an enormous risk of relapse after primary therapy, and the prognosis for these patients remains bleak. Primary and acquired resistance of tumor cells to antineoplastic drugs is a major cause of the limited effectiveness of chemotherapy. The effect of whole-body hyperthermia (WBH) combined with platinum-containing chemotherapy in the treatment of recurrent ovarian cancer was examined in this study.
Methods
Patients studied were those with pathologically verified epithelial ovarian cancer after operation who had had first-line chemotherapy with cisplatin or carboplatin, and relapsed. All 21 patients were treated with WBH and platinum-based chemotherapy. During the WBH, a core temperature of 41.5°C–42°C was attained in the rectum. We combined the WBH with 300–400 mg/dl artificial hyperglycemia. The plateau temperature was held over a period of, on average, 90 ± 30 min, and the artificial hyperglycemia, on average, 240 ± 30 min. WBH was repeated at the beginning of each new chemotherapy cycle.
Results
One patient (4.8%) had a complete remission, 7 patients (33.3%) had a partial remission, stable disease was noted in 10 patients (47.6%), and 3 (14.3%) patients did not respond and had progressive disease. Median time to progression was 6.5 months, and median survival time, 16.5 months.
Conclusion
Our results validate the efficacy of WBH in the treatment of patients with recurrent platinum-resistant ovarian cancer. The overall tolerance of this treatment was good. The priority for all patients was an improvement in life quality; this was seen 3–4 days after WBH. The encouraging results should be confirmed in randomized studies.