current status of oncothermia therapy for lung cancer

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Korean J Thorac Cardiovasc Surg 2014;47:77-93 □ Review □http://dx.doi.org/10.5090/kjtcs.2014.47.2.77 ISSN: 2233-601X (Print) ISSN: 2093-6516 (Online)− 77 −Department of Biotechnics, St. Istvan University, Godollo, HungaryReceived: February 28, 2014, Revised: March 24, 2014, Accepted: March 28, 2014Corresponding author: Andras Szasz, Department of Biotechnics, St. Istvan University, Godollo, Ibolya u. 2. 2071 Paty, Hungary(Tel) 36 (23) 555 510 (Fax) 36 (23) 555 515 (E-mail) Szasz.Andras@gek.szie.hu C The Korean Society for Thoracic and Cardiovascular Surgery. 2014. All right reserved.CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creative-commons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Current Status of Oncothermia Therapy for Lung CancerAndras Szasz, Ph.D.Lung cancer is one of the most common malignant tumors, and it has the highest death rate. Oncothermia is a feasible and successful treatment for lung cancer. Results show a remarkable survival benefit for patients, with a good quality of life. The treatment has no, or in some cases mild, side-effects and could decrease the adverse ef-fects of the complementary treatment. Applying oncothermia together with other treatment methods could increase the effects and result in better performance. A comparison of studies demonstrates a good correspondence in the data, which strengthens the reliability of the studies, and clearly shows the feasibility of the application of onco-thermia to treating all kinds of pulmonary malignancies including non-small-cell and small-cell primary tumors, and all of the metastatic diseases of the pulmonary system.Key words: 1. Lung neoplasms2. Fever3. Meta-analysis4. HyperthermiaINTRODUCTIONCancer morbidity worldwide is growing. However in the United States, the overall morbidity slightly decreased in 2013, (by > 0.6%/yr in men, but it was stable in women), while the mortality rates decreased by 1.8%/yr in men and by 1.5%/yr in women [1]. The lung was the site of the highest cancer mortality in both the sexes (28% and 26% in men and women, respectively, while the second highest mortality rates, prostate cancer in men and breast cancer in women (10% and 14%, respectively), were nearly half those of the lung cancer rates [1]. While the disease, when recognized in its localized state, has good five-year survival (52%), the regional or far distant stages have survival rates of only 25% and 4%, respectively. However, at the first diagnosis, 56% of cases al-ready show distant metastatic lesions, while only 22% are re-gional and 15% are local only [2]. This is why the overall survival data shows a sad picture: relative survival rates (male/female) are 29.4%/33%, 7.8%/9.3%, and 4.9%/5.9% for one-, five-, and ten-year-survival studied in 2005 to 2009 [3]. Due to the sad fact that lung cancer is one of the leading causes of mortality for humans, there have been numerous at-tempts to stop this trend [4]. Despite the well developing treatment modalities, the ratio of lung cancer mortality rate to the incidence (0.8) is more than double the average mortal-ity/incidence ratio (0.3) among the population < 65 years [5]. The incidence of lung cancer between the ≥ 65 years and < 65 years old patients differs in 14%. The Korean statistics are similar to the worldwide trends [6,7]. Furthermore, special circumstances were observed in the case of Korean patients: The profiles of EML4-ALK fu-sion gene variants of non-small-cell lung carcinoma (NSCLC)

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Andras Szasz− 78 −may differ from those in other populations of other ethnicities [8]. The need to improve the rate of cure has remained of central importance in the field. The majority of cases (range, 75% to 85%) are of the non-small-cell histology, and half of these are adenocarcino-mas [9]. The intense challenge is that most of the NSCLCs are first diagnosed when they have already in advanced stage or have already become rapidly metastatic [10]. The majority of patients present with either locally advanced disease (stage III) or metastatic disease (stage IV). The standard first-line strategy for the treatment of advanced stage NSCLCs is a limited number of chemotherapy cycles to achieve tumor re-gression or at least stabilization [11]. Importantly, patients who undergo curative surgical resection for apparent localized disease have survival rates ranging between 50% and 80%, implying the need for better systemic treatment to cure occult micrometastatic disease. Therefore, the majority of patients ei-ther presents with advanced disease requiring chemotherapy or require chemotherapy at the time of relapse after surgical resection. While efforts to cut down on smoking are crucial to the eventual control of the disease, newer treatments for patients who currently have the disease are critical. As a class, NSCLC is relatively insensitive to chemo-therapy, compared to small cell carcinoma (SCLC). When possible, they are primarily treated by surgical resection with curative intent; however, chemotherapy is increasingly being used both preoperatively (neoadjuvant chemotherapy) and postoperatively (adjuvant chemotherapy). Modern lung-cancer treatment is based on platinum-con-taining doublets (carboplatin and cisplatin) and more recently on gemcitabine, paclitaxel (Taxol and Doxitaxel), vinorelbine (Navelbine). The analysis of 52 clinical studies shows the ad-vantages of cisplatin-based therapies (10% 1-year survival in-crease), which reduce the risk of exitus by 27% [12], com-pared to the applied supportive therapies. In general, the me-dian survival with such chemotherapy is 7 months. The gemcitabine-based triplets and doublets (paclitaxel/car-boplatin/gemcitabine; paclitaxel/carboplatin/vinorelbine; pacli-taxel/gemcitabine; gemcitabine/vinorelbine); had 37%, 29%, 40%, and 49% one-year survival and 9.6, 9.9, 8.7, and 10.7 months median survival, respectively [13]. The gemcita-bine-based doublets had a lower response rate (RR), but lon-ger survival and less adverse effects. In general, the median survival ranges between 6 and 12 months, with 7 months on average. The one year survival is 24% to 51%, and 25% to 30% on average. An extended large study including in total 1,207 patients [14] with advanced NSCLC was performed to compare the randomly assigned treatment to a reference regimen of cispla-tin and paclitaxel or to one of three protocols: cisplatin and docetaxel, cisplatin and gemcitabine, or carboplatin and paclitaxel. The result was somewhat disappointing: none of the four chemotherapy protocols showed significant advantage over the others in the treatment of advanced NSCLC. The RR was 19%, with a median survival of 7.9 months, the first-year survival rate was 33%, while the second-year sur-vival rate was 11%. Two other chemo-protocols were also compared, pemetrexed and docetaxel. The clinical efficacy was equivalent, but significantly fewer side effects were ob-served with the docetaxel regime in the second-line treatment of patients with advanced NSCLC [15]. Considering the side effects of the present treatment op-tions, including surgery, radiation, and platinum-based doublet chemotherapy, another promising drug family was developed connected to growth factor receptors (GFR) to treat NSCLC. To increase the efficacy of such growth factor receptor ty-rosine kinase inhibitors, the coinhibition of GFR signaling pathways and combination of inhibitors along with radiation or chemotherapy have been studied [16]. This is a clinically validated therapy targeting the signaling pathways of either the vascular endothelial GFR or epidermal GFR (e.g., gefiti-nib, cetuximab, erlotinib, bevacizumab), but the complex sig-naling system of solid tumors could adapt to the situation [17], so the targeting of multiple regulatory pathways makes sense [16]. The development of multitargeted tyrosine kinase inhibitors (TKIs) is thus a concern. Although there is increas-ing research interest in these kinds of drugs, their therapy-re-lated adverse effects and their safety remain controversial. As we discussed above, some clinical trials have been stopped early because of toxicity issues with multitargeted TKIs, and some other trials did not achieve primary improvement in overall survival; there is still a need for exploring more con-venient, newer pathways as well as to develop insight into the coinhibition of existing pathways. It is important that

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Current Status of Oncothermia Therapy for Lung Cancer− 79 −Table 1. Response and survival rates in controlled double-arm studies for non-small cell lung cancer treated by capacitive hyperthermia (8 MHz)StudyResponse rate by arms, remission rate (%)First year survival ratio (%) Second year survival ratio (%)Hyperthermia Control Hyperthermia Control Hyperthermia ControlKarasawa et al. [27] (1994) 94.7 (n=19) 70 (n=30) 55 (n=19) 30 (n=30) 35 (n=19) 15 (n=30)Sukurai et al. [28] (2002) 76.9 (n=13) 53.8 (n=13) - - 44.4 (n=13) 15.4 (n=13)greater attention be drawn to the signaling pathways that are modified by the use of kinase inhibitors. Genomic landscapes for patient-specific evaluation should be provided to appropri-ately select patients who are most likely to benefit from RTK (receptor tyrosine kinase)-inhibition therapy. SCLC comprises about 15% of all primary lung cancer cases, and it is usually the consequence of smoking. SCLC is a major clinical problem, with an aggressive clinical appear-ance and short survival time. Its treatment protocol is differ-ent from that of NSCLC [18]. Currently, the optimal treat-ment is platinum-etoposide chemotherapy (four cycles) ap-plied with complementary thoracic irradiation in patients in early stages, but radiotherapy is not applied in the late stage. Many promising clinical approaches are available for lung cancer, but unfortunately, the breakthrough in this kind of malignancy has not been reached yet, and lung cancer treat-ments remain a high priority in clinical practice. Our present paper reviews the feasibility of oncothermia treatment for both NSCLC and SCLC. This study concen-trates on the significance of the survival time as one of the most important factors for measuring the success of a treat-ment in oncology.HYPERTHERMIA IN PULMONARY CANCERS Hyperthermia (HT), combined with radiotherapy and che-motherapy, seems to be a promising method for cancer treat-ment [19], although many of the underlying molecular mech-anisms of this combination treatment are still not clearly understood. Preliminary results with NSCLC recruiting a lim-ited number of patients (range, 5 to 80 patients) also seem encouraging where HT was combined with chemotherapy, ra-diotherapy, or both. The co-administration of HT was proven to be safe [20-22]. A great number of studies show that HT inhibits angiogenesis, enhances chemo- and radio-sensitivity, and induces a high concentration of drugs within a tumor [23-25]. However, there are some restrictions on HT, in general, that hamper its use in lung cancer treatment. Namely, it could aggravate preexisting pleural liquids, the intensive cool-ing by actual breathing is contra-effective for the overall tem-perature increase. Furthermore, the increasingly constrained blood flow supports the tumor by glucose, which is an im-portant contra-action, together with the increased risk of the dissemination. Focusing of the energy is limited by the in-tensive movement of the organ by breathing, and maintains the raised temperature on the place where the energy is focused. In fact, it has even more complications in a good heat-conducting environment than in thermal spreading in oth-er organs. However, some successful clinical trials have shown the feasibility of the HT method for lung cancer. Most of these are combined with radiotherapy, having a 14÷70 Gy dose in the given session. The measured RR was surprisingly high: RR=75% (n=12) [26] and RR=100% (n=13) [26]. In this last study, the mean survival time (MST) was 15 months, (mean-value, 17 months) on the tumors, which had a size on average of 22 cm 3 . The average total dose was 60 Gy, aver-age heating time was 52.3 minutes, and average total session in the cycle was 27. Others had a comparison to a con-trol-arm (not randomized), studying the RR (Table 1). Other trials had a comparison to a control-arm (not randomized), growing the RR from RR=70% (n=30) and RR=53.8% (n=13), to RR=94.7% (n=19) [27] and RR=76.9% (n=13) [28], respectively. The second year survival also in-creased remarkably: from 15% and 15.4%, to 35% and

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Andras Szasz− 80 −Table 2. The results of radio-thermotherapy for advanced non-small cell lung cancer patients1-Year survival rate (%) Mean survival time (mo) Objective response Pain reliefIIIb IV IIIb IVComplete remission/responsePartial remission/responseNo response Complete Partial No-relief63.0 40.0 13.5 10.0 15.4 69.2 15.4 15.4 76.9 7.7IIIb and IV are the staging categories according to the World Health Organization.44.4%, respectively. The first year survival was measured as well, increasing from 30% to 55% [27]. A study on advanced NSCLC patients (n=13, capacitive coupling, f=8 MHz) to control local chest invasion [29] showed similar good results, and the pain relief was also sur-prisingly good (Table 2). The chemo-thermotherapy combination was also inves-tigated for NSCLC with success. In laboratory studies, cispla-tin was shown to be effective [30], so the clinical studies concentrated on this drug combination. A special case report has shown its feasibility [31], and has demonstrated a median survival gain (from 15 [n=20] to 25 [n=32] months) [32]. The median survival was measured in another study [33] as 19.2 months, with RR=73% and a 1 year-survival of 75%. The 13.5 months median survival of the historical control was increased to 17.5 months using postoperative (lobectomy or pneumonectomy) application of intrathoracic chemo-ther-motherapy by capacitive coupled HT [32,34]. Local control by capacitive HT in combination with radio-therapy was also successful for locally advanced non-small lung cancer [27]. The complete remission rates were 26% and 0% with and without HT, respectively, while the full RRs were 95% and 70%, respectively. Others have also achieved good results from complementary radiotherapy with capacitive HT [26]. The survivals for the treatment group (resection+post-operative intrathoracic chemo-thermotherapy [PICT], n=32) and the historical control groups: resection only (n=20) or ex-ploratory thoracotomy (n=11) had median survival rates of 25, 15, and 10 months, respectively [32,34]. The survival curve of the treatment group was significantly better than those of the control groups. Furthermore, the local relapse- free survival for the treatment group (resection+PICT, n=32) and for the historical control group (resection only n=20) was drastically and significantly increased, having more than dou-ble the relapsed-free survival in the HT treated group than in its historical counterpart after 48 months. The postoperative application was successful in other studies too [31,34]. The 5-year median survival was measured in another study [34], showing rather high numbers (24.5%, for patients with N0+N1 status [n=14]). The median survival with PICT was measured, and definite gain was found (from 15 [n=20] to 25 [n=32] months) (capacitive coupling, 8 MHz and 13.56 MHz). The MST was 10, 15, and 25 months for treatment group (resection+PICT) and the historical control groups (resection only and exploratory thoracotomy only), respec-tively. The survival curve of the treatment group was sig-nificantly better than those of the control groups. Measuring the local relapse-free survival for the treatment group (resection+PICT) and the historical control group (resection only) also revealed a significant benefit with HT treatment. Another chemo-thermotherapy study [35] showed fairly good results: an MST of 19.2 months, RR=73%, and a 1 year-sur-vival of 75%. The chemo-thermotherapy combination was also inves-tigated for NSCLC with success. In laboratory studies, the synergy between the gemcitabine and HT in NSCLC was shown in vitro, and in vivo in a nude mouse xenograft model [36]. The decrease in the tumor size and a significant in-hibitory effect of growth were shown, and HT supported gemcitabine-induced apoptosis. Locally advanced NSCLC was studied (n=32) with frac-tional radiation (180 – 300 cGy/fraction, 5 fractions/wk, median dose 5.58 Gy) [37] (Table 3). The results indicate differences, but they were not significant. To search for significant improvements in outcomes of

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Current Status of Oncothermia Therapy for Lung Cancer− 81 −Table 3. The measured data in locally advanced non-small cell lung cancer patientsArmNo. of patientsClinical response (%) 2 Year-survival (%) Survival mean (mo)Complete remission/responsePartial remission/responseNo responseAll TRT# < 10 TRT# > 10 All TRT# < 10 TRT# > 10Radiotherapy 18 11.1 55.6 33.3 0 - - 8.1 - -TRT 14 0 85.7 14.3 7.1 7.4 40 10.5 18.2 40TRT#, number of thermoradiotherapy treatments.thermotherapy, a large study involving two randomized, con-trolled, multicenter phase III studies was sponsored by a non- medical international organization, the International Atomic Energy Organization to avoid any bias in medical sponsoring: for uterine cervix (n=110) [38] and for NSCLC (n=80) [39]. Both studies were performed in combination with radio-therapy and with or without HT. The results of both studies were disappointing. The differences in the complete clinical response (complete remission) as well as overall survival rates in combined and single radiotherapy arms were statistically insignificant (p=0.49 and p=0.868, respectively), while the local pro-gression-free survival was significantly better in the combined arm (p=0.036). The authors concluded that there was no sub-stantial benefit in treating locally advanced NSCLC by adding HT to radiotherapy, although there was some improvement in local progression-free survival. Other kinds of HT (whole-body heating and very local ablative heating) have also been attempted. Whole-body HT was also applied to treating advanced lung cancer [40]. A benefit of HT was found (n=49), which was more substantial in elderly ( > 60 years) patients. The remission rate was 50%, and the MST was 7 months (mean is 12.7 months) in pri-mary and 5.5 months for metastatic diseases. Percutaneous ablation by radiofrequency (RF) [41,42] and by laser-induced interstitial thermotherapy [43] are also used for pulmonary tumors. In addition, intrapleural HT by perfu-sion is being used in clinical practice [44]. The breathable perfluorochemical liquid used in convective HT also appears to be a feasible alternative for lung cancer treatment [45].ONCOTHERMIA METHOD There is a serious need for a stable HT method that is free from controversy and adverse effects, not only because of the high incidence of pulmonary malignancies, but also because of the variety of primary tumors that frequently metastasize to the lungs. The most common types include breast cancer, colon cancer, prostate cancer, and bladder cancer. A primary lung lesion can also quickly develop metastatic lung malignancies in other lobes. This causes the patient to progress quickly to advanced disease and requires a high stage of care (frequently stage IV). Furthermore, due to the lack of multiple effective therapies for high-line treatment (third-line or over), no real treatment options are available in such cases, which is another cause of the high mortality rate. Good supportive and sensitizing com-plementary therapies are missing from the application spectra. Another important factor demands new therapies: the qual-ity of life. Patients with lung malignancies rapidly lose their Karnowski Performance Score (KPS), so any new therapy should have minimal adverse effects and improve the quality of life of the patient. One of the most advanced HT modalities devoted to oncol-ogy is oncothermia [46,47]. This method aims to preserve all positive effects of conventional HT while improving on the imperfections and answering the challenges posed by conven-tional approaches. The key is nano-range energy liberation in-stead of overall heating of the mass of the target [48]. This review will not explain the method of oncothermia in detail, which has already been done elsewhere [46,49], or describe its technical realization [50]. However, this paper will note some important factors of the method that are closely related

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Andras Szasz− 82 −Fig. 1. Comparison of the local control in the two arms. CR, complete remission/response, PR, partial remission/response; SD, stable disease; PD, progress disease.Fig. 2. The Kaplan-Meyer plot of survival showing a clear sig-nificant benefit of the oncothermia-treated arm.to pulmonology applications. Oncothermia is a highly sophisticated method that ad-dresses some of the limitations of HT [51] and makes it pos-sible to reintroduce HT by new standards [52]. It is based on a strong synergy between the temperature and the electric field [53]. The RF current is chosen with a proper ampli-tude-modulated RF (13.56 MHz) [54], which is absorbed in the nanoscopic range by the malignant cells [55]. The physio-logical differences of the malignant cells from their healthy counterparts [51] distinguish the malignancy, which is self-se-lected by additional time-fractal modulation [56], which means that this is a highly customized treatment method [57]. The malignant cell is destroyed by apoptosis [58]. The apop-totic process uses an outer pathway [59] (not the mitochon-drial internal pathway that is used in normal HT [60]), form-ing a damage-associated molecular pattern [61] and inducing immunogenic cell death [62], which could be the basis of the directed abscopal effect too [63]. These effects start to emerge in lung cancer management [64,65], and could be the basis of a long-awaited feature of oncology: personalized care [66]. The treatment technique is simple and very user-friendly. It is safe and rarely has any side effects; patients are relaxed during the treatment thanks to the comfortable waterbed be-low containing the lower electrode. The upper electrode is a thermally and electrically balanced water bolus, which con-forms to any body shape. The RF current flows through the patient self-selectively, irrespective of the movements of the tumor. The current flows along the best path for conduction, which is also the best pathway for treatment.CLINICAL RESULTS Given that oncothermia is usually applied in very advanced cases, mostly third-line therapy and beyond, it is rather com-plicated to assemble an appropriate cohort for a prospective study. The present clinical results are dominated by case re-ports and few more extensive studies.SOME CASE REPORTS Several reports on cases of oncothermia application world-wide have been informative (Figs. 1 – 4). Some important messages from these cases are: 1) Do not evaluate too early by imaging, due to the slow apoptotic process [46]. 2) It is better to measure the actual change of the tumor marker from serum [67]. Their clinical effectiveness is rela-tively good [68], and corresponds well with the genetic ab-normalities of the cancer [69]. Tumor markers may be used to monitor any response to the treatment and determine whether the cancer has recurred after treatment, but in gen-eral, tumor markers alone cannot be used to diagnose cancer; they must be combined with other tests. The guidelines of the National Academy of Clinical Biochemistry USA are best followed [70].

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Current Status of Oncothermia Therapy for Lung Cancer− 83 −Fig. 4. (A) Overall and (B) oncothermia treatment time survivals by Kaplan-Meier plot of the patients in PFY (Peterfy Hospital, Budapest, Hungary) study.Fig. 3. The Kaplan-Meyer plot shows a statistically significant benefit for the oncothermia group. 3) The optimization of the actual treatment has to be personalized. The trimodal therapies (oncothermia and two jointly applied ‘gold standards’ like radio- and chemo-therapies) have good outcomes, but bimodal application is al-so suitable in most cases. In the cases when the gold stand-ards are inapplicable, monotherapy with oncothermia also has good results, but in these cases, the number of sessions in a cycle is approximately doubled [71]. 4) In chemotherapy applications, old ‘simple’ drugs like mitomycin-C could be reapplied [46]. 5) The new chemo-categories (like the addition of bev-acizumab to conventional platinum derivatives) are also appli-cable to oncothermia [72]. Independently of oncothermia, we expect various chemo-agents from the literature to be syner-gistic; for example, the addition of bevacizumab to cispla-tin-based chemotherapy significantly prolonged progression free survival and overall survival in phase III [73,74] and phase IV trials [75], proved to be safe in treating over 5,000 patients [76-78], and in the maintenance setting, also demon-strated a beneficial effect on progression free survival [79,80], but the addition of oncothermia to this combination was re-cently approved for the first time [72]. 6) Even in the cases where the local control is not so ef-fective (poor partial remission/response or no response), the quality of life improved, which is a great advantage of oncothermia. 7) The method is safe and apparently free of adverse ef-fects in any combined or monotherapy applications. 8) In the mild trimodal application (low-dose radiotherapy, an immune activator, and oncothermia), the abscopal effect is clearly observable [81], which was also seen in laboratory model experiments without the addition of ionizing radiation [63]. 9) Oncothermia can be applied as concurrent therapy even in a fifth-line chemo-companion [82] in highly advanced dis-seminated cases. 10) The strategies of advanced cases have multiple vices [83], but oncothermia could be successfully applied in far ad-vanced cases too [84,85].

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Andras Szasz− 84 −Table 4. Distribution of the patients in the studyControl Treatment

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Variablegroup (n=40) group (n=75)Mean age (yr) 69.8 (54 – 86) 68 (53 – 81)Gender Female 13 (32.5) 27 (34.9) Male 27 (67.5) 48 (65.1)Pathology Squamous cell carcinoma 12 (30.0) 18 (24.0) Adenocarcinoma 23 (57.5) 4 (53.3) Adeno-squamous carcinoma 1 (2.5) 4 (53.0) Small cell lung cancer 4 (10.0) 13 (17.3)Stage (Union for International Cancer Control 2003) T4 27 (67.5) 52 (69.3) N3 11 (27.5) 12 (16.0) III 15 (37.5) 22 (29.3) IV 25 (62.5) 53 (70.6)Values are presented as mean (range) or number (%). 11) Oncothermia can be applied not only in primary lung malignancies, but also for metastatic cases as well [86,87].STUDIES Advanced lung cancer was studied in a double-arm pro-spective study [88] with real endpoints of survival time and quality of life. In the active arm (n=75), stage IIIb and IV lung cancer patients were included, while a same patient characteristics cohort (n=40) was on control arm (Table 4). These patients were inoperable. Oncothermia was applied in 20 sessions, every other day, 60 min/each. The treatment effi-cacy, survival rate, and life of quality were assessed before the treatment, after the treatment, and every sixth month. The local control (remission rate) (Fig. 1), as well as the overall survival (Fig. 2), was significantly superior in the on-cothermia combined (active) arm of the study in comparison with the control. In addition, the treatment group showed statistically significant differences in quality of life functions, emotions, general conditions, pain, shortness of breath, loss of appetite, cough, hemoptysis, and chest pain. Another study examined SCLC [89]. The double-armed study included treatment with (n=23) and without (n=8) onco-thermia complementary to chemotherapy for SCLC. Chemo-therapy was the first-line treatment: irinotecan (60 mg/m 2 ), and cisplatin (60 mg/m 2 ) three times. The status was eval-uated by chest computed tomography. When the progression of the tumor or metastases was detected, the chemotherapy was changed to etoposide (110 mg/m 2 ) and cisplatin (70 mg/m 2 ) in the second line. Oncothermia was performed from the first chemotherapy treatment period up to 150 W, 1,490.5 kJ energy for 60 minutes, every second day, with a rise in temperature to 38.5 o C to 42.5 o C. In this study, we used an electrode with a 30-cm diameter applied to the thorax, with at least 12 sessions in 1 cycle. The results showed promising improvement of the survival compared to chemotherapy alone. The overall survival showed a significant benefit for the oncothermia treated group (Fig. 3). An extended clinical investigation is in progress [87]. Presently, 10 NSCLC patients and 3 metastatic lung malig-nancies are included to study the safety (phase I) and the ef-ficacy (phase II) in a well-controlled study. The work is in progress. A retrospective clinical study of NSCLC patients was per-formed by two hospitals in Budapest [90-92], clearly demon-strating the feasibility and efficacy of oncothermia for ad-vanced cases [93]. The first study was obtained from an open-label, single-arm, monocentric study (n=61) carried out in Peterfy Hospital, Budapest, Hungary (referred to as ‘PFY’) [91,92]. The patients included were analyzed according to an intention-to-treat schedule. The primary endpoints of the study were the overall survival time and the survival time from the first oncothermia treatment. The dates of exitus were checked by the National Death Register, so that accu-rate data were collected. Inclusion criteria were: 1) Inoperable or sub-totally resected, or recurrent primary pancreas tumor, 2) progression after radio- and/or chemo-therapy, and 3) KPS ≥ 30%, and the inclusion was irrespective of the localization of the lesion in the lung. Patients started the oncothermia process in their late/advanced stages, where most of them had failed to respond to any of the applied conventional therapies. The exclusion criteria were only the well-known contra-indications of the oncothermia method (metallic implants or replacements in the treated area, missing heat sensitivity in the treated area, or a pacemaker or other field-sensitive im-plant in the patient). The age distribution of n=61 patients was near normal

说到暖心的事,记得之前玩排位,我玩李白准备冲王者,就遇到一个很懂事的虞姬。真的很懂事,不需要多说什么,她懂你相信你。开始选英雄的时候她在前面先选英雄,我叫她帮我抢李白,顺利抢到了,然后我帮她拿虞姬,最后交换英雄。详细看下面的截图。游戏过程,虞姬全程没动过我的野怪,甚至大部分红Buff都让给了我。说实话我当时觉得有点压力的,就像有人把她所有都托付给我那样,这份信任不可以辜负,这局我将尽全力一战。我决定关掉歌专心玩。我发信号进攻的时候她绝不后退,懂得配合我的节奏。有次差点被对面杨戬放狗咬死还是虞姬舍身相救,让我得以一次没死结束这场游戏。当然我也没有让她失望,最后我们顺利赢了。详细战绩看下图!最后,防抓取,突袭网提供内容,请查看原文。

Current Status of Oncothermia Therapy for Lung Cancer− 85 −(p=0.82); no outlier was present. The median age was 58 years (range, 38 to 77 years), the mean-age was 58.97 years (standard error [SE]=1.17). The gender distribution was 21/40 female/male (34.4%/65.6%). The proportion of the elderly ( > 68 years) patients was 21.3%. Oncothermia was performed in 2 to 3 sessions per week. The treatment time per session was 60 minutes. The power was gradually and linearly raised depending on the patient’s tolerance from 40 – 80 W to 100 –150 W. The applied average energy was 300 kJ/treatment (range, 250 to 450). The applicators used were 3.1 dm 2 and 7.1 dm 2 , depending on the tumor volume. Most of the patients (n=49, 80.3%) had distant metastases. They were heavily pre-treated; all of the patients had received at least one line of chemotherapy and had undergone other treatments (surgery, radio- or second-line chemo-therapy). The actual staging was made at the first diagnosis (44% was in advanced [World Health Organization IIIb or IV] stages) and at the first oncothermia treatment (75% was in an advanced stage). The median of the elapsed time from the first diagnosis to the first oncothermia treatment was 8 months (range, 0.4 to 172 months), while its mean was 16.3 months (SE=3.1). The elapsed time ratio to the overall sur-vival was more than 50% (median, 59.9% [6.5 – 99.1]; mean, 59.4 [SE=3.5]); the patients received their first oncothermia in the second half of their survival time. The oncothermia treat-ment was provided twice a week; the treatment number aver-aged 8.1 (SE=0.55) sessions with a median of 8 (range, 2 to 23). The Kaplan-Meier plots of the overall survival (median, 16.4 months [1.7 – 181.9]; mean, 25.6 months [SE=3.8]) and the survival from the first oncothermia treatment (median, 5.7 months [0.1 – 44.9]; mean, 9.2 months, [SE=1.3]) are shown in Fig. 4. For the elderly patients, neither the overall survival nor the oncothermia survival differed between the groups (p=0.68). The elapsed time to the first oncothermia treatment repre-sents an important parameter. Namely, this is of course smaller (p=0.0019) for the patients with advanced disease at their first diagnosis (n=3...

产后松弛的肚皮如何变平坦小腹呢?1??一定保证充分睡眠睡眠能帮助控制脂肪细胞体积,促进血液循环并促进真皮纤维增生,以增加肌肤的弹性。如果是产后有失眠症状的新妈妈们,可以每天做30~60分钟的有氧运动;一天3次,每次10分钟的散步对睡眠也很有帮助。2??一定少吃高脂肪高热量的食物产后的新妈妈们需要注意,在饮食上应少吃多脂肪高热量的食物,本身腹部就很容易会松弛,如果再吃多脂肪的食物,那么,会增加腹部的脂肪堆积,从而令松弛的赘肉感更加明显,也不利于收紧腹部。所以,在饮食上也是需要多多注意的,可以多吃一些低热量少脂肪的水果蔬菜,在为身体增加营养的同时,也能够减少腹部的赘肉堆积,从而恢复苗条的好身段。在防抓取,突袭网提供内容,请查看原文。

其实文玩里面我觉得也是有黑幕的,价格绝对人为操控,就拿金刚菩提和落地红来说,都是植物的种子吧?又不是多贵重的东西,产量也都很高,为什么大家都喜欢金刚,而很贬低落地红呢?这里面是有主流的流派诱导大家,还防抓取,突袭网提供内容,请查看原文。

thecurretrepairoperationcannotbecancelled是什么...答:Thecurrentrepairoperationcannotbecancelled.意思是:当前的修复操作不能被取消。西语一句话翻译nosoloocurreconelidioma.问:nosoloocurreconelidioma.请问这句话什么意思,solo中o上面有重...答:原型ocurrir主要是“发生”的意思,但也有“突然想起”的意思。原句应该是不仅仅是突然想起了这门语言的意思吧。重音符号可以这么打:换到西语输入法后按【号加需要加重音的字母。电脑开机显示curretrunningmode1.1.2问:电脑开机显示curretrunningmode1.1.2答:只是提示当前的运行模式是1.1.2。需要了解全部内容。

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