Effect of Hyperthermic Intraperitoneal Chemotherapy on Cytoreductive Surgery in Gastric Cancer With Synchronous Peritoneal Metastases: The Phase III GASTRIPEC-I Trial.

PURPOSE: In patients with peritoneal metastasis (PM) from gastric cancer (GC), chemotherapy is the treatment of choice. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are still being debated. This randomized, controlled, open-label, multicenter phase III trial (EudraCT 2006-006088-22; ClinicalTrials.gov identifier: NCT02158988) explored the impact on overall survival (OS) of HIPEC after CRS. PATIENTS AND METHODS: Adult patients with GC and histologically proven PM were randomly assigned (1:1) to perioperative chemotherapy and CRS alone (CRS-A) or CRS plus HIPEC (CRS + H). HIPEC comprised mitomycin C 15 mg/m2 and cisplatin 75 mg/m2 in 5 L of saline perfused for 60 minutes at 42°C. The primary end point was OS; secondary endpoints included progression-free survival (PFS), other distant metastasis-free survival (MFS), and safety. Analyses followed the intention-to-treat principle. RESULTS: Between March 2014 and June 2018, 105 patients were randomly assigned (53 patients to CRS-A and 52 patients to CRS + H). The trial stopped prematurely because of slow recruitment. In 55 patients, treatment stopped before CRS mainly due to disease progression/death. Median OS was the same for both groups (CRS + H, 14.9 [97.2% CI, 8.7 to 17.7] months v CRS-A, 14.9 [97.2% CI, 7.0 to 19.4] months; P = .1647). The PFS was 3.5 months (95% CI, 3.0 to 7.0) in the CRS-A group and 7.1 months (95% CI, 3.7 to 10.5; P = .047) in the CRS + H group. The CRS + H group showed better MFS (10.2 months [95% CI, 7.7 to 14.7] v CRS-A, 9.2 months [95% CI, 6.8 to 11.5]; P = .0286). The incidence of grade ≥3 adverse events (AEs) was similar between groups (CRS-A, 38.1% v CRS + H, 43.6%; P = .79). CONCLUSION: This study showed no OS difference between CRS + H and CRS-A. PFS and MFS were significantly better in the CRS + H group, which needs further exploration. HIPEC did not increase AEs.

European Groundshot-addressing Europe's cancer research challenges: a Lancet Oncology Commission.

Cancer research is a crucial pillar for countries to deliver more affordable, higher quality, and more equitable cancer care. Patients treated in research-active hospitals have better outcomes than patients who are not treated in these settings. However, cancer in Europe is at a crossroads. Cancer was already a leading cause of premature death before the COVID-19 pandemic, and the disastrous effects of the pandemic on early diagnosis and treatment will probably set back cancer outcomes in Europe by almost a decade. Recognising the pivotal importance of research not just to mitigate the pandemic today, but to build better European cancer services and systems for patients tomorrow, the Lancet Oncology European Groundshot Commission on cancer research brings together a wide range of experts, together with detailed new data on cancer research activity across Europe during the past 12 years. We have deployed this knowledge to help inform Europe's Beating Cancer Plan and the EU Cancer Mission, and to set out an evidence-driven, patient-centred cancer research roadmap for Europe. The high-resolution cancer research data we have generated show current activities, captured through different metrics, including by region, disease burden, research domain, and effect on outcomes. We have also included granular data on research collaboration, gender of researchers, and research funding. The inclusion of granular data has facilitated the identification of areas that are perhaps overemphasised in current cancer research in Europe, while also highlighting domains that are underserved. Our detailed data emphasise the need for more information-driven and data-driven cancer research strategies and planning going forward. A particular focus must be on central and eastern Europe, because our findings emphasise the widening gap in cancer research activity, and capacity and outcomes, compared with the rest of Europe. Citizens and patients, no matter where they are, must benefit from advances in cancer research. This Commission also highlights that the narrow focus on discovery science and biopharmaceutical research in Europe needs to be widened to include such areas as prevention and early diagnosis; treatment modalities such as radiotherapy and surgery; and a larger concentration on developing a research and innovation strategy for the 20 million Europeans living beyond a cancer diagnosis. Our data highlight the important role of comprehensive cancer centres in driving the European cancer research agenda. Crucial to a functioning cancer research strategy and its translation into patient benefit is the need for a greater emphasis on health policy and systems research, including implementation science, so that the innovative technological outputs from cancer research have a clear pathway to delivery. This European cancer research Commission has identified 12 key recommendations within a call to action to reimagine cancer research and its implementation in Europe. We hope this call to action will help to achieve our ambitious 70:35 target: 70% average 10-year survival for all European cancer patients by 2035.

[Peritoneal carcinomatosis of gastric cancer : Treatment options for peritoneal carcinomatosis of gastric cancer]. / Peritonealkarzinose des Magenkarzinoms : Therapeutische Möglichkeiten bei Peritonealkarzinose des Magenkarzinoms.

BACKGROUND: Gastric cancer is one of the most aggressive malignant diseases of the gastrointestinal tract with a high rate of metastasis. Peritoneal metastasis occurs in up to 60% of all patients and synchronously in up to 30% in locally advanced gastric cancer. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been an established treatment option in selected patients for several years, as the HIPEC serves as an alternative administration route. OBJECTIVE: This article presents a schematic display of the various treatment options depending on the extent of peritoneal carcinomatosis in a gastric cancer. METHODS: A literature search and analysis of the current literature on the treatment of gastric cancer with peritoneal metastases were carried out. A differentiation was made between limited and extensive peritoneal carcinomatosis together with the appropriate treatment strategy. RESULTS: Principally, individual systemic chemotherapy is the backbone of treatment of gastric cancer with peritoneal metastases. In selected patients and in cases of limited peritoneal carcinomatosis, CRS and HIPEC can be conducted and survival is improved; however, CRS is still contraindicated in cases of extensive peritoneal carcinomatosis and in exceptional cases pressurized intraperitoneal aerosol chemotherapy (PIPAC) can be carried out. CONCLUSION: In selected patients CRS and HIPEC can lead to an improvement with respect to overall and disease-free survival. In cases of extensive peritoneal carcinomatosis, individualized chemotherapy remains the major treatment option.

[Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in gastric cancer]. / Zytoreduktive Chirurgie und hypertherme intraperitoneale Chemotherapie beim Magenkarzinom.

BACKGROUND: Gastric cancer with peritoneal metastases is associated with an extremely poor prognosis. Developed multimodal treatment concepts, which include a combination of perioperative systemic treatment and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC), show promising results with respect to improvement of the long-term survival. METHODS: This article contains a review of the literature of published studies on the topic of gastric cancer and peritoneal metastasis. RESULTS: The prognosis of patients with gastric cancer peritoneal carcinomatosis shows an extremely limited median survival of 7 months under palliative second-line systemic treatment. The median survival time increased to 12 months with cytoreductive surgery and in combination with HIPEC showed a positive effect on survival in individual studies. EXPERT OPINION: Treatment recommendations for patients with peritoneal metastases of gastric cancer should be carried out by experts in surgical reference centers.

The efficacy of treatment options for patients with gastric cancer and peritoneal metastasis.

BACKGROUND: Patients with peritoneal metastases of gastric cancer have a poor prognosis and median survival of 7 months. This study compared treatment options and outcomes based on the Peritoneal Cancer Index (PCI). METHODS: This retrospective analysis included patients with gastric cancer treated between August 2008 and December 2017 with synchronous peritoneal metastases only diagnosed by laparoscopy. The three treatments were as follows: (1) cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in combination with pre- and postoperative systemic chemotherapy (n = 58), (2) laparotomy/laparoscopy without CRS, but HIPEC in combination with pre- and postoperative systemic chemotherapy (n = 11), and (3) systemic chemotherapy only (n = 19). RESULTS: A total of 88 patients aged 54.6 ± 10.9 years with mean PCI of 14.3 ± 11.3 were included. The PCI was significantly lower in group 1 (8.3 ± 5.7) than in group 2 (23.9 ± 11.1, p < 0.001) and group 3 (27.3 ± 9.3, p < 0.001). Mean time from diagnosis to laparoscopy was 5.2 ± 2.9 months. The median overall survival was 9.8 ± 0.7 for group 1, 6.3 ± 3.0 for group 2 and 4.9 ± 1.9 months for group 3 (p < 0.001). Predictors for deteriorated overall patient survival included > 4 cycles of preoperative chemotherapy (HR 4.49, p < 0.001), lymph-node metastasis (HR 3.53, p = 0.005), PCI ≥ 12 (HR 2.11, p = 0.036), and incompleteness of cytoreduction (HR 4.30, p = 0.001) in patients treated with CRS and HIPEC. CONCLUSION: CRS and HIPEC showed convincing results in selected patients with PCI < 12 and complete cytoreduction. Prolonged duration (> 4 cycles) of preoperative intravenous chemotherapy reduced patient survival in patients suitable for CRS and HIPEC.

Pressurized intraperitoneal aerosol chemotherapy and its effect on gastric-cancer-derived peritoneal metastases: an overview.

This manuscript aspires to portray a review of the current literature focusing on manifest peritoneal metastasis (PM) derived from gastric cancer and its treatment options. Despite the development of chemotherapy and multimodal treatment options during the last decades, mortality remains high worldwide. After refreshing important epidemiological considerations, the molecular mechanisms currently accepted through which PM occurs are revised. Palliative chemotherapy is the only recommended treatment option for patients with PM of gastric cancer according to the National Comprehensive Cancer Network guidelines, although cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy demonstrated promising results in selected patients with regional PM and localized intraabdominal tumor spread. A novel treatment named pressurized intraperitoneal aerosol chemotherapy may have a promising future in improving overall survival with an acceptable postoperative complication rate and stabilizing quality of life during treatment. Additionally, the procedure has been proved to be safe for the patient and medical personnel and a feasible, repeatable method to deter metastatic proliferation. This overview comprehensively addresses this novel and promising treatment in the context of a scientifically and clinically challenging disease.

Morbidity and Mortality Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Data from the DGAV StuDoQ Registry with 2149 Consecutive Patients.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are performed for well-selected patients with peritoneal surface malignancies. This combined treatment is potentially associated with an increased rate of complications. OBJECTIVE: The aim of this paper was to analyze the morbidity and mortality of CRS and HIPEC in the German national registry. METHODS: We present a retrospective analysis of 2149 consecutive patients from 52 hospitals. The data were prospectively documented in the DGAV StuDoQ Registry between February 2011 and December 2016. RESULTS: Almost two-thirds of all patients had a colorectal malignancy; therefore, the most frequently performed resections were colectomies (54%) and rectal resections (30%). Only 36.2% of all patients had no anastomosis, and fewer than 20% of all patients were older than 70 years of age (16.4%). Enteric fistula and anastomotic leaks occurred in 10.5% of all cases. The reoperation rate was 14.6% (95% confidence interval [CI] 11.51-18.1). Major grade 3 and 4 complications (Clavien-Dindo classification) occurred in 19.3% of all patients, half of which were due to surgical complications. The overall 30-day postoperative hospital mortality was 2.3% (95% CI 1.02-3.85). Multivariate analysis showed an increased risk for morbidity associated with pancreatic resections (odds ratio [OR] 2.4), rectal resection (OR 1.5), or at least one anastomosis (OR 1.35), and mortality with reoperation (OR 8.7) or age > 70 years (OR 3.35). CONCLUSIONS: CRS and HIPEC are associated with acceptable morbidity and low mortality. These results show that CRS and HIPEC can be safely performed nationwide when close mentoring by experienced centers is provided.

Perioperative Systemic Chemotherapy, Cytoreductive Surgery, and Hyperthermic Intraperitoneal Chemotherapy in Patients With Colorectal Peritoneal Metastasis: Results of the Prospective Multicenter Phase 2 COMBATAC Trial.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) as parts of an interdisciplinary treatment concept including systemic chemotherapy can improve survival of selected patients with peritoneal metastatic colorectal cancer (pmCRC). Nevertheless, the sequence of the therapeutic options is still a matter of debate. Thus, the COMBATAC (COMBined Anticancer Treatment of Advanced Colorectal cancer) trial was conducted to evaluate a combined treatment regimen consisting of preoperative systemic polychemotherapy + cetuximab followed by CRS + HIPEC and postoperative systemic polychemotherapy + cetuximab. PATIENTS AND METHODS: The COMBATAC trial is a prospective, multicenter, open-label, single-arm, single-stage phase 2 trial. Twenty-six patients with synchronous or metachronous colorectal or appendiceal peritoneal carcinomatosis were included. Enrollment was terminated prematurely by the sponsor because of slow recruitment. Progression-free survival as primary end point and overall survival were estimated by the Kaplan-Meier method. Also evaluated were morbidity according to Common Terminology Criteria for Adverse Events v4.0 and feasibility of the combined treatment concept. RESULTS: Median progression-free survival for the intention-to-treat population (n = 25) was 14.9 months. Median overall survival was not reached during the study duration. Ninety-two adverse events were documented in 16 patients, including 14 serious adverse events in 9 patients. The overall morbidity rate was 64%, and the grade 3/4 morbidity rate was 44%. Of all grade 3/4 morbidity events, 36.4% were related to systemic chemotherapy and 22.7% to surgery, whereas 40.9% were not directly related. There was no treatment-related mortality. CONCLUSION: The results of the COMBATAC trial show that the multimodal treatment concept consisting of perioperative systemic chemotherapy and CRS + HIPEC is safe and feasible. Progression-free survival in selected patients with colorectal or appendiceal peritoneal metastasis might be improved.

Predictive value of peritoneal cancer index for survival in patients with mucinous peritoneal malignancies treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a single centre experience.

OBJECTIVES: This study investigated the correlation between the peritoneal carcinomatosis index (PCI) and patient outcome depending on the tumour type. BACKGROUND: Peritoneal surface malignancy (PSM) treatment depends on tumour type. Mucinous PSM (m-PSM) is associated with a better prognosis than non-mucinous PSM (nm-PSM). The PCI's predictive ability has not yet been evaluated. METHODS: We analysed 123 patients with PSM treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) between 2008 and 2015. The m-PSM group (n = 75) included patients with appendiceal cancer (n = 15), colorectal cancer (n = 21), or low-grade appendiceal mucinous neoplasm (n = 39); the nm-PSM group (n = 48) included patients with gastric (n = 18) or colorectal (n = 30) cancer. The PCI's predictive ability was evaluated by multiple Cox-proportional hazard regression analysis and Kaplan-Meier curves. RESULTS: The 5-year survival and PCI were higher in m-PSM patients (67.0%; 20.5 ± 12.1) than in nm-PSM patients (32.6%; p = 0.013; 8.9 ± 6.0; p < 0.001). Colorectal nm-PSM patients with PCI ≥16 had a worse 2-year survival (25.0%) vs. patients with PCI <16 (79.1%; log rank = 0.009), but no significant effect was observed in patients with m-PSM (66.7% vs. 68.1%; p = 0.935). Underlying disease (HR 5.666-16.240), BMI (HR 1.109), and PCI (HR 1.068) significantly influenced overall survival in all patients. CONCLUSIONS: PCI is prognostic in nm-PSM, but not in m-PSM. CRS and HIPEC may benefit not only patients with low PCI, but also those with high PCI and m-PSM.

Can hyperthermic intraperitoneal chemotherapy efficiency be improved by blocking the DNA repair factor COP9 signalosome?

PURPOSE: A frequently used chemotherapeutic agent in hyperthermic intraperitoneal chemotherapy (HIPEC) is mitomycin C (MMC) which induces DNA damage and apoptosis in tumor cells. In addition, MMC activates DNA damage response (DDR) leading to repair mechanisms counteracting the effect of chemotherapy. COP9 signalosome (CSN) positively influences the DDR pathway by its intrinsic deneddylating and associated kinase activities. In an in vitro HIPEC model, we studied the impact of curcumin, an inhibitor of CSN-associated kinases, and of the microRNA (miRNA) let-7a-1, an inhibitor of CSN subunit expression, on the MMC-induced apoptosis in human HT29 colon cancer cells. METHODS: Cells were incubated at 37 °C and indicated concentrations of MMC in a medium preheated to 42 °C as under HIPEC conditions for 1 or 4 h. HT29 cells were cotreated with 50 µM curcumin or transfected with let-7a-1 miRNA mimic. After incubation, cells were analyzed by Western blotting, densitometry, and caspase-3 ELISA. RESULTS: An increase of CSN subunits in response to MMC treatment was detected. Apoptosis was only measured after 4 h with 50 µM MMC. MMC-induced apoptosis was elevated by cotreatment with curcumin. Transfection of HT29 cells with let-7a-1 reduced the expression of tested CSN subunits associated with the accumulation of the pro-apoptotic factors p27 and p53. CONCLUSIONS: In response to MMC treatment, the CSN is elevated as a regulator of DDR retarding apoptosis in tumor cells. The therapeutic effect of HIPEC can be increased by inhibiting CSN-associated kinases via curcumin or by blocking CSN expression with let-7a-1 miRNA.

Quality of life in patients after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: is it worth the risk?

OBJECTIVE: To investigate the course of health-related quality of life (HQL) over time in patients with peritoneal carcinomatosis (PC) after complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: Prospective, single-center, nonrandomized cohort study using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. RESULTS: Ninety patients who underwent CRS and HIPEC for PC in our institution were enrolled in the study. Mean age was 56 years (range 27-77 years) (61% female). Primary tumor was colorectal in 21%, ovarian in 19%, pseudomyxoma peritonei in 16%, an appendix tumor in 16%, gastric cancer in 10%, and peritoneal mesothelioma in 13% of cases. Mean peritoneal carcinomatosis index was 22 (range 2-39). Mean global health status score was 69±25 preoperatively and 55±20, 66±22, 66±23, 71±23, and 78±21 at months 1, 6, 12, 24, and 36, respectively. Physical and role function recovered significantly at 6 months and were close to baseline at the 24-month measurement. Emotional function starting from a low baseline recovered to baseline by month 12. Cognitive and social function had slow recovery on follow-up. Fatigue, diarrhea, dyspnea, and sleep disturbance were symptoms persistent at 6-month follow-up, improving later on in survivors. CONCLUSIONS: Survivors after CRS and HIPEC have postoperative quality of life similar to preoperatively, with most of the reduced elements recovering after 6-12 months. We conclude that reduced quality of life of patients after CRS and HIPEC should not be used as an argument to deny surgical therapy to these patients.

Genetic dissection of apoptosis and cell cycle control in response of colorectal cancer treated with preoperative radiochemotherapy.

BACKGROUND: In previous analyses we identified therapy-induced upregulation of the CDK inhibitor p21CIP/WAF-1 and consequently decreased tumor cell proliferation or loss of Bax as adverse factors for survival in rectal cancer treated with radiochemotherapy. Here, we address the individual role of p53 and its transcriptional targets, p21CIP/WAF-1 and Bax, on apoptosis induced by individual components of multimodal anticancer therapy, i.e. 5-fluorouracil (5-FU), ionising gamma-radiation (IR) and heat shock/hyperthermia. METHODS: We analysed tumor samples 66 patients with rectal carcinoma treated by a neoadjuvant approach with radiochemotherapy +/- heat shock/hyperthermia for the expression and mutation of p53 and the expression of p21CIP/WAF-1 and Bax. These data were correlated with the tumor response. The functional relevance of p53, p21CIP/WAF-1 and Bax was investigated in isogeneic HCT116 cell mutants treated with 5-FU, IR and heat shock. RESULTS: Rectal carcinoma patients who received an optimal heat shock treatment showed a response that correlated well with Bax expression (p = 0.018). Local tumor response in the whole cohort was linked to expression of p21CIP/WAF-1 (p < 0.05), but not p53 expression or mutation. This dichotomy of p53 pathway components regulating response to therapy was confirmed in vitro. In isogeneic HCT116 cell mutants, loss of Bax but not p53 or p21CIP/WAF-1 resulted in resistance against heat shock. In contrast, loss of p21CIP/WAF-1 or, to a lesser extent, p53 sensitized predominantly for 5-FU and IR. CONCLUSION: These data establish a different impact of p53 pathway components on treatment responses. While chemotherapy and IR depend primarily on cell cycle control and p21, heat shock depends primarily on Bax. In contrast, p53 status poorly correlates with response. These analyses therefore provide a rational approach for dissecting the mode of action of single treatment modalities that may be employed to circumvent clinically relevant resistance mechanisms in rectal cancer.

Adjuvant chemotherapy with folinic acid and 5-fluorouracil in patients with locally advanced rectal cancer previously treated by preoperative radiochemotherapy and curative tumor resection.

BACKGROUND AND AIMS: The role of postoperative adjuvant chemotherapy in patients with rectal cancer pretreated by preoperative radiochemotherapy (RCT) and curative surgery is still poorly investigated. PATIENTS AND METHODS: We pooled data from both arms of a phase III trial in which patients with locally advanced (T3/4) rectal cancer were randomized to preoperative RCT alone or combined with pelvic radio-frequency hyperthermia. After surgery, R0-resected patients were scheduled to adjuvant chemotherapy with four monthly courses of 50 mg folinic acid (FA) and gradually escalated 5-fluorouracil (5-FU, 350-500 mg/m2, days 1-5). Reasons preventing initiation of chemotherapy and treatment-related toxicities were evaluated. Patients' characteristics and survival parameters were compared between the treated and untreated patient groups. RESULTS: Out of 93 patients, 73 (79%) started adjuvant chemotherapy, whereas 19 (21%) did not, mostly due to perioperative complications and refusal. Chemotherapy-related toxicities were mild to moderate in most cases, but--together with protracted postoperative complications--prevented the intended dose escalation of 5-FU in 71% of patients. Distant-failure-free (p=0.03) and overall survival (p=0.03) were improved in the chemotherapy group, although there was a negative selection of patients with unfavourable characteristics into the untreated patient group. INTERPRETATION/CONCLUSION: Adjuvant chemotherapy using FA and 5-FU can be safely applied to the majority of patients with rectal cancer pretreated by RCT and surgery. Survival data are not suitable to allow far-reaching conclusions, but are in line with suggestions of a favourable effect of adjuvant chemotherapy in these patients.

Noninvasive magnetic resonance thermography of recurrent rectal carcinoma in a 1.5 Tesla hybrid system.

To implement noninvasive thermometry, we installed a hybrid system consisting of a radiofrequency multiantenna applicator (SIGMA-Eye) for deep hyperthermia (BSD-2000/3D) integrated into the gantry of a 1.5 Tesla magnetic resonance (MR) tomograph Symphony. This system can record MR data during radiofrequency heating and is suitable for application and evaluation of methods for MR thermography. In 15 patients with preirradiated pelvic rectal recurrences, we acquired phase data sets (25 slices) every 10 to 15 minutes over the treatment time (60-90 minutes) using gradient echo sequences (echo time = 20 ms), transformed the phase differences to MR temperatures, and fused the color-coded MR-temperature distributions with anatomic T1-weighted MR data sets. We could generate one complete series of MR data sets per patient with satisfactory quality for further analysis. In fat, muscle, water bolus, prostate, bladder, and tumor, we delineated regions of interest (ROI), used the fat ROI for drift correction by transforming these regions to a phase shift zero, and evaluated the MR-temperature frequency distributions. Mean MR temperatures (T(MR)), maximum T(MR), full width half maximum (FWHM), and other descriptors of tumors and normal tissues were noninvasively derived and their dependencies outlined. In 8 of 15 patients, direct temperature measurements in reference points were available. We correlated the tumor MR temperatures with direct measurements, clinical response, and tumor features (volume and location), and found reasonable trends and correlations. Therefore, the mean T(MR) of the tumor might be useful as a variable to evaluate the quality and effectivity of heat treatments, and consequently as optimization variable. Feasibility of noninvasive MR thermography for regional hyperthermia has been shown and should be further investigated.

Description and characterization of the novel hyperthermia- and thermoablation-system MFH 300F for clinical magnetic fluid hyperthermia.

Magnetic fluid hyperthermia (MFH) is a new approach to deposit heat power in deep tissues by overcoming limitations of conventional heat treatments. After infiltration of the target tissue with nanosized magnetic particles, the power of an alternating magnetic field is transformed into heat. The combination of the 100 kHz magnetic field applicator MFH 300F and the magnetofluid (MF), which both are designed for medical use, is investigated with respect to its dosage recommendations and clinical applicability. We found a magnetic field strength of up to 18 kA/m in a cylindrical treatment area of 20 cm diameter and aperture height up to 300 mm. The specific absorption rate (SAR) can be controlled directly by the magnetic field strength during the treatment. The relationship between magnetic field strength and the iron normalized SAR (SAR(Fe)) is only slightly depending on the concentration of the MF and can be used for planning the target SAR. The achievable energy absorption rates of the MF distributed in the tissue is sufficient for either hyperthermia or thermoablation. The fluid has a visible contrast in therapeutic concentrations on a CT scanner and can be detected down to 0.01 g/l Fe in the MRI. The system has proved its capability and practicability for heat treatment in deep regions of the human body.

[Standards and perspectives in locoregional hyperthermia]. / Lokoregionäre Hyperthermie: Standards und neue Entwicklungen.

The term "hyperthermia" summarises different procedures of raising the temperature of a tumour-loaded tissue to a temperature of 40-43 degrees C. In this context, locoregional procedures (radiative/capacitive local, interstitial and regional hyperthermia; endoluminal hyperthermia), hyperthermic perfusion techniques (hyperthermic peritoneal and isolated limb perfusion), and whole-body hyperthermia differ with regard to their indication, expenditure of application, and evidence of efficacy. All hyperthermia techniques have in common that they have no sufficient antineoplastic activity alone in the temperature range below 43-45 degrees C, but act in a synergistic way with radiotherapy and certain cytotoxic drugs. 14 out of 18 published randomised trials on hyperthermia as an adjunct to standard radio- or chemotherapy refer to locoregional approaches. Particular progress has been made in regional radiofrequency hyperthermia, where novel multiantenna-applicators and their integration into MR-applicators ("hybrid-systems") have recently been introduced into clinical practice. In addition, combinations of hyperthermia with novel technologies (magnetic fluid hyperthermia, thermosensitive liposomes, immunotherapy, gene targeting) are imminent. We here give a critical update on the proven indications of the different locoregional hyperthermia approaches and on the current clinical and technological progress in this field.

[Influence of preoperative (hyperthermic) radiochemotherapy on manometric anal sphincter function in locally advanced rectal cancer]. / Einfluss einer präoperativen (hyperthermen) Radiochemotherapie auf die manometrisch erfasste Analsphinkterfunktion beim lokal fortgeschrittenen Rektumkarzinom.

BACKGROUND AND PURPOSE: Preoperative radiochemotherapy (RCT) followed by curative surgery is a well-accepted therapeutic option in the treatment of advanced rectal cancer. Usually, the anal sphincter is located in the irradiation area of a preoperative RCT regime. The aim of this study is to evaluate the influence of preoperative RCT on anal sphincter function. PATIENTS AND METHODS: Between 1994 and 2000, 102 patients with rectal cancer stage uT3/uT4 were analyzed. All patients underwent radiotherapy with 45 Gy (5 x 1.8 Gy) including two cycles of 5-fluorouracil (5-FU)/leucovorin (folinic acid) chemotherapy. 46 patients were treated additionally with up to five sessions of locoregional hyperthermia. The sphincter function was analyzed by perfusion manometry before preoperative therapy and 4 weeks after pretreatment had been finished. For statistics, the Wilcoxon signed rank test and Mann-Whitney U-test were used (SPSS 9.0 for Windows((R))). RESULTS: The mean value of all 102 patients showed a significant reduction of the mean maximum resting pressure from 97 to 89 mmHg (p = 0.02). For the mean maximal squeeze pressure no significant difference could be shown (178 vs. 176 mmHg). For patients with distal (

Response prediction by FDG-PET after neoadjuvant radiochemotherapy and combined regional hyperthermia of rectal cancer: correlation with endorectal ultrasound and histopathology.

Accurate response assessment after neoadjuvant therapy is essential in patients with rectal cancer. The aim of this study was to assess the value of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) in predicting response of locally advanced rectal cancer to preoperative multimodal treatment. Twenty-two consecutive patients with locally advanced (uT3/4) primary rectal cancer were entered in this prospective pilot study. FDG-PET was performed before and after neoadjuvant radiochemotherapy (RCT) with combined regional hyperthermia (RHT). Treatment consisted of external-beam radiotherapy (45 Gy), chemotherapy (folinic acid and 5-fluorouracil) and regional pelvic hyperthermia followed by curative tumour resection 6-8 weeks later. Semi-quantitative measurements (SUV) of tumour FDG uptake were made before and 2-4 weeks after completion of neoadjuvant treatment. Two patients who did not receive post-therapeutic restaging by FDG-PET were excluded from the analysis. Results were correlated with findings on endorectal ultrasound (EUS, n=17 patients) and histopathology. Histopathological evaluation of the resected tumour revealed complete response in one patient, partial response in 12 and stable disease in seven. SUV reduction in tumours was significantly greater in responders than in non-responders [60% (+/-15%) vs 30% (+/-18%), P=0.003, CI=95%). Using a minimum post-therapeutic SUV reduction of 36% to define response, FDG-PET revealed a sensitivity of 100% (EUS: 33%) and a specificity of 86% (EUS: 80%) in response prediction; the corresponding positive and negative predictive values were 93% (EUS: 80%) and 100% (EUS: 33%), respectively. FDG-PET results were statistically significant (P<0.001, CI=95%). FDG-PET has great potential in the assessment of tumour response to neoadjuvant RCT in combination with RHT and is superior to EUS for this purpose.

Development and evaluation of a three-dimensional hyperthermia applicator with Water-COated Antennas (WACOA).

A novel twelve-channel three-dimensional (3-D) hyperthermia applicator has been developed and evaluated, which consists of twelve separate WAter COated Antenna (WACOA) modules. The modules are arranged in three transversal antenna rings (sub-arrays) and are placed into an acrylic applicator frame as cartridge-like elements in a staggered arrangement. The operating frequency is 100 MHz. For the design of the applicator, the finite-difference time-domain (FDTD) method was used. The applicator's dimensions allow its placement into the gantry of a magnetic resonance (MR) tomograph. The WACOA modules are designed as MR-compatible specially shaped metallic cylindrical dipole structures that are placed into hermetically closed water-filled cassettes. Due to the design of the dipole structures, only a conventional coaxial feed circuitry is needed, and no external impedance matching networks are necessary. Instead, fine on-line impedance matching is realized using adjustable tuning rods and matching rings, both elements being parts of the radiating antenna structure. Experimental and numerical evaluations demonstrate a good stability of impedance matching, a low inter-channel coupling of less than -20 dB, and a good ability of field pattern steering.