CONKO-006: A randomised double-blinded phase IIb-study of additive therapy with gemcitabine + sorafenib/placebo in patients with R1 resection of pancreatic cancer - Final results.

BACKGROUND: CONKO-006 was designed for patients with pancreatic adenocarcinoma with postsurgical R1 residual status to evaluate the efficacy and safety of the combination of gemcitabine and sorafenib (GemSorafenib) compared with those of gemcitabine + placebo (GemP) for 12 cycles. PATIENTS AND METHODS: This randomised, double-blind, placebo-controlled, multicenter study was planned to detect an improvement in recurrence-free survival (RFS) from 42% to 60% after 18 months. Secondary objectives were overall survival (OS), safety and duration of treatment. RESULTS: 122 patients were included between 02/2008 and 09/2013; 57 were randomised to GemSorafenib and 65 to GemP. Patient characteristics were wellbalanced (GemSorafenib/GemP) in terms of median age (63/63 years), tumour size (T3/T4: 97/97%), and nodal positivity (86/85%). Grade 3/4 toxicities comprised diarrhoea (GemSorafenib: 12%; GemP: 2%), elevated gamma-glutamyl transferase (GGT) (19%; 9%), fatigue (5%; 2%) and hypertension (5%; 2%), as well as neutropenia (18%; 25%) and thrombocytopenia (9%; 2%). By August 2017, 118 (97%) RFS event had occurred. There were no difference in RFS (median GemSorafenib: 8.5 versus GemP: 9.4 months; p = 0.730) nor OS (median GemSorafenib: 17.6 versus GemP: 17.5 months; p = 0.481). Landmark analyses suggest that patients who received more than six cycles of postoperative chemotherapy had significantly longer OS (p = 0.021). CONCLUSION: CONKO-006 is the first randomised clinical trial to include exclusively patients with PDAC with postsurgical R1 status thus far. Sorafenib added to gemcitabine did neither improve RFS nor OS. However, postoperative treatment exceeding six months seemed to prolong survival and should be further investigated in these high-risk patients. CLINICAL TRIAL INFORMATION: German Tumor Study Registry (Deutsches Krebsstudienregister), DRKS00000242.

Evaluation of patients with liver metastases from colorectal cancer for locally ablative treatment with laser induced thermotherapy. Impact of PET with 18F-fluorodeoxyglucose on therapeutic decisions.

PURPOSE: Before locally ablative treatment of colorectal liver metastases, patients have to be carefully evaluated to decide whether this is the adequate therapy. In this study we determined the value of FDG-PET in comparison to conventional staging procedures. PATIENTS, METHODS: In 68 consecutive patients referred for laser induced thermotherapy (LITT) of liver metastases from colorectal cancer, pretherapeutic staging with conventional imaging (thoracic and abdominal CT, liver MRI, chest X-ray) and FDG-PET was performed. The examinations were analysed separately and blinded. Based on the staging information, therapeutic decisions were made by an interdisciplinary review board according to a standardized algorithm. The results were compared between conventional imaging and FDG-PET, and were validated by clinical follow up data and histopathology, respectively. RESULTS: On FDG-PET 210 lesions were interpreted as tumour manifestations. 48 of these were not seen on conventional imaging (true positive, n = 46). In contrast, 24 lesions were visualized by conventional imaging only (true positive, n = 12). Compared to conventional imaging, discrepant findings on FDG-PET led to treatment modifications in 25 patients (37%); these were correct in 20/25 patients. According to the actual treatment course, the inadequate treatment modifications in the remaining 5 patients were avoided by further diagnostic procedures (i.e. biopsies). CONCLUSION: In the evaluation of patients with known liver metastases from colorectal cancer before LITT, FDG-PET depicts relevant findings subsidiary to conventional imaging and thus is of high value for therapeutic decision making.

Influence of neoadjuvant radiochemotherapy combined with hyperthermia on the quality of life in rectum cancer patients.

PURPOSE: The present study compares quality of life (QoL) after neoadjuvant radiochemotherapy with or without hyperthermia in patients with advanced rectal cancer. METHODS: Between April 1994 and May 1999, 137 patients were treated by neoadjuvant radiochemotherapy with (69 patients (50.4%)) or without (68 patients (49.6%)) hyperthermia. Forty-six patients (33.6%) filled-out a 'Gastrointestinal Quality of Life Index' (GIQLI) questionnaire at four time points (before and after neoadjuvant therapy, early after surgery and after long-term follow-up) and were included in the present study. RESULTS: There were no statistically significant differences in the global GIQLI index between patients treated with neoadjuvant radiochemotherapy with and without hyperthermia at any time point. The longitudinal analysis of GIQLI values in both treatment groups showed specific profiles that were identical in both treatment groups. Occurrence of severe toxicity during the neoadjuvant therapy in both arms lead to a significant temporary reduction of QoL scores at TP2 without any detrimental long-term effects. Patients with sphincter preservation and patients with sphincter resection reported similar QoL scores during long-term follow-up. CONCLUSION: Neoadjuvant radiochemotherapy with and without hyperthermia has similar effects on the QoL of patients with locally advanced rectal cancer. The addition of hyperthermia during the neoadjuvant therapy with the potentially associated inconveniences has no negative effects on QoL.

Current status of radiant whole-body hyperthermia at temperatures >41.5 degrees C and practical guidelines for the treatment of adults. The German 'Interdisciplinary Working Group on Hyperthermia'.

The term 'extreme' whole-body hyperthermia (WBH) describes the procedure of raising a patients' body-core temperature to 41.5-42.0 degrees C for 60 min. WBH represents the only hyperthermia technique that enables systemic heat treatment in patients with disseminated malignancies and is, therefore, usually combined with systemic chemotherapy. Up to now, several WBH-approaches have proved to be safe and associated with acceptable toxicity rates when radiant heat devices are employed. Until the late 1990s, the use of radiant WBH was restricted to a few specialized treatment centres worldwide. During the last 5 years, a larger number of WBH-devices were put into operation particularly in Germany. As a result, a novel generation on phase II trials on chemotherapy and adjunctive WBH in patients with various malignancies has been completed. Based on the promising results observed herein, first multi-centric phase III-trials on chemotherapy +/- WBH have been initiated, with a considerable number of patients treated at German institutions. The authors are members of the 'Interdisciplinary Working Group for Hyperthermia' ('Interdisziplinäre Arbeitsgruppe Hyperthermie'), a sub-group of the German Cancer Society. They formulated these guidelines in order to standardize the WBH treatment procedure and supportive measures, to provide some uniformity in the selection of patients to be treated and to define criteria of a successful WBH-treatment. These recommendations may be helpful to ensure the quality of WBH performed at different institutions.

Treatment of locally recurrent rectal cancer with special focus on regional pelvic hyperthermia.

Progress in surgery and adjuvant therapy has markedly improved local control and survival rates in patients with primary, non-metastatic rectal cancer. However, the prognosis of patients with locally recurrent disease is still poor, and a realistic chance for repeated treatment with curative intent is still restricted to the minority of cases. Therefore, effective palliation of symptoms and preservation of a good quality of life are the major goals of therapy for most patients with local recurrence of rectal cancer. Here we give a short overview on the options available for the treatment of pelvic recurrence of rectal cancer, with special focus on adjunctive regional pelvic radiofrequency hyperthermia.

Regional pelvic hyperthermia as an adjunct to chemotherapy (oxaliplatin, folinic acid, 5-fluorouracil) in pre-irradiated patients with locally recurrent rectal cancer: a pilot study.

The aim of this study was to evaluate the feasibility and toxicity of a novel hyperthermic chemotherapy approach for patients with locally recurrent adenocarcinoma of the rectum. All patients were pre-irradiated (> or = 45 Gy) and had histologically proven pelvic recurrence. Hyperthermic chemotherapy was applied according to a modified 'OFF'-schedule with weekly infusions of 43 mg/m2 of oxaliplatin (i.v., 120 min), 500 mg/m2 of folinic acid (i.v., 120 min) and 2.6 g/m2 of continuous infusional 5-fluorouracil (24 h) for 6 consecutive weeks. Oxaliplatin was started in parallel to pelvic radiofrequency hyperthermia that was provided by the BSD 2000-system. A total of 67 applications were administered to nine patients and were well tolerated. A total of 55/67 (82%) chemotherapy courses were applied without dose-reduction. In 62/67 (93%) hyperthermia sessions, a treatment time of > 60 min was maintained. Tolerated power levels were on average 600 W and, thus, slightly lower than those described in curative pelvic hyperthermia schedules. Eight out of 10 episodes of severe (WHO III degrees) toxicity represented typical side-effects of the chemotherapy given (nausea n = 4, diarrhoea n = 3, neuropathy n = 1). Two severe adverse events were firstly attributable to hyperthermia (haematuria, n = 1; deterioration of a decubital ulcer, n = 1). No patient suffered WHO-disease progression during the treatment period. Two patients achieved a partial remission. It is concluded that hyperthermic chemotherapy with oxaliplatin, folinic acid and 5-FU is feasible on an outpatient basis. Overall toxicity was moderate, although hyperthermia may add side-effects to this approach. Results, moreover, suggest a relevant palliative effect in patients with pre-irradiated pelvic recurrence of rectal cancer.

Whole-body hyperthermia in the scope of von Ardenne's systemic cancer multistep therapy (sCMT) combined with chemotherapy in patients with metastatic colorectal cancer: a phase I/II study.

This phase I/II study evaluated the feasibility, toxicity and response rates of von Ardenne's systemic cancer multistep therapy (sCMT) when applied as an adjunct to cytostatic therapy in patients with metastatic colorectal cancer. sCMT consists of whole-body hyperthermia (WBH) at 41.8-42.1 degrees C, hyperglycaemia and hyperoxaemia. All patients who entered the trial first received three monthly courses of chemotherapy (folinic acid, 50 mg, days 1-5; 5-fluorouracil, 425 mg/m2, days 1-5; mitomycin 8 mg/m2, day 1), followed by response evaluation according World Health Organization (WHO) criteria. Responders (partial/complete remission) were assigned to three further courses of chemotherapy, whereas non-responders (stable/progressive disease) were allocated to additional sCMT on day 1 of every subsequent chemotherapy course. The WBH procedure was administered under general anaesthesia employing the Iratherm-2000 radiant heat device. Of 28 patients enrolled, 19 received more than three treatment courses. Eight of these 19 patients had responded to chemotherapy (PR) and thus obtained three further courses of chemotherapy alone. In 10 of 19 patients who had not responded (SD, PD), three additional courses of chemotherapy were combined with sCMT (with 25 sCMT applications). One patient who did not respond to initial treatment declined sCMT and was continued with chemotherapy alone. It was found that sCMT was feasible, but associated with a specific spectrum of grade III/IV toxicity (skin 20%, pain 16%, peripheral nerves 8% of treatment courses). The fact that three patients who did not respond to initial chemotherapy achieved a PR after additional sCMT suggests that sCMT may enhance the effect of chemotherapy in patients with colorectal cancer.

Anaesthesiological experiences with whole body hyperthermia.

OBJECTIVE: In order to investigate the safety of whole body hyperthermia (WBH) within the context of systemic Cancer Multistep Therapy (sCMT) in patients with disseminated malignancies, cardiopulmonary changes and various organ functions were examined. METHODS AND PROCEDURES: Fifty-seven sCMT treatments were performed in 22 patients. WBH with a plateau phase of 1 h at 41.8 degrees C was induced by an IRATHERM 2000 device. Cardiopulmonary parameters were measured at 37, 40, 41.8 and 39 degrees C by use of a pulmonary artery catheter, femoral oxymetry and a radial artery catheter. Organ functions of the liver, kidney, cardiovascular and central nervous system were evaluated before and after treatment. RESULTS: Compared with the initial values, significant alterations were found of most cardiopulmonary parameters in the sense of hypercirculation at 41.8 degrees C. With the exception of extra vascular lung water index, all parameters showed a clear tendency towards the pre-treatment levels at 39 degrees C. In eight out of 57 sCMT treatments, reversible organ dysfunctions were observed. Comparison of radial and femoral arterial blood pressure showed significantly different values at 40 and 41.8 degrees C. CONCLUSIONS: WBH induces cardiovascular stress, but by careful selection of patients and appropriate anaesthesiological monitoring it can be performed safely using general anaesthesia. This enables further evaluation of WBH in multimodal treatment concepts.

Hyperthermia in combined treatment of cancer.

Hyperthermia, the procedure of raising the temperature of tumour-loaded tissue to 40-43 degrees C, is applied as an adjunctive therapy with various established cancer treatments such as radiotherapy and chemotherapy. The potential to control power distributions in vivo has been significantly improved lately by the development of planning systems and other modelling tools. This increased understanding has led to the design of multiantenna applicators (including their transforming networks) and implementation of systems for monitoring of E-fields (eg, electro-optical sensors) and temperature (particularly, on-line magnetic resonance tomography). Several phase III trials comparing radiotherapy alone or with hyperthermia have shown a beneficial effect of hyperthermia (with existing standard equipment) in terms of local control (eg, recurrent breast cancer and malignant melanoma) and survival (eg, head and neck lymph-node metastases, glioblastoma, cervical carcinoma). Therefore, further development of existing technology and elucidation of molecular mechanisms are justified. In recent molecular and biological investigations there have been novel applications such as gene therapy or immunotherapy (vaccination) with temperature acting as an enhancer, to trigger or to switch mechanisms on and off. However, for every particular temperature-dependent interaction exploited for clinical purposes, sophisticated control of temperature, spatially as well as temporally, in deep body regions will further improve the potential.

Monitoring arterial blood pressure during whole body hyperthermia.

BACKGROUND: For monitoring of arterial blood pressure (ABP) during whole body hyperthermia (WBH) different methods have been recommended. This investigation was performed to evaluate the agreement of invasive measurements at various sites, and to compare invasive and non-invasive methods of ABP monitoring under conditions of a heat-induced extreme vasodilation. METHODS: In 19 patients, 48 treatments with WBH were performed. Measurements of ABP in the radial and femoral artery by oscillometry and by sphygmomanometry were taken at four temperature levels during WBH (37, 40, 41.8 and 39 degrees C). RESULTS: Significant differences were observed between invasive and non-invasive methods for systolic ABP, with higher values for non-invasive measurements. When compared with both invasive measurements for diastolic blood pressures, sphygmomanometry gave higher values and oscillometry gave lower values. Sphygmomanometry also showed higher values for mean ABP compared with all other techniques, while measurements in radial and femoral artery and by oscillometry only differed by approximately 5 mmHg. CONCLUSION: The mean arterial pressure and not the systolic and/or diastolic pressure should guide hemodynamic management during WBH. The sphygmomanometric technique is not recommended for use during hyperthermia.

[T4 rectal carcinoma. Surgical and multimodal therapy]. / T4-Rektumkarzinom. Operative und multimodale Therapie.

BACKGROUND: In locally advanced rectal cancer with infiltration of neighbouring organs (uT4), resectability and local control are difficult to achieve. Combined preoperative radiochemotherapy may result in increased resectability and reduced local recurrence rates. PATIENTS AND METHODS: Thirty-four patients with biopsy-proven locally advanced rectal cancer were treated by preoperative radiochemotherapy. All tumours had been staged as uT4 lesions by endorectal ultrasound or computed tomography. Radiotherapy was applied in standard blocks, 5 x 1.8 Gy up to 45 Gy. Chemotherapy consisted of two cycles of 5-fluorouracil (300-350 mg/m2/day) and leucovorin (50 mg). In 20 patients, additional thermotherapy was carried out using the Sigma 60 applicator BSD 2000 once a week prior to radiotherapy. Surgery was performed 4-6 weeks after radiochemotherapy. Postoperatively, all patients received four cycles of 5-fluorouracil and leucovorin. RESULTS: Treatment-induced toxicity occurred in 26% of the patients (WHO grade III (n = 6) and IV (n = 3)). The resectability rate was 76% (26/34 patients) (R0 resectability n = 21; 62%). The pathological complete response rate was 6% (n = 2) and the partial response rate was 47% (n = 16). A local failure was observed in six patients after median time of 16 months (range 7-36 months). Patients with R0 resection achieved a 5-year disease-free survival rate of 55% and a survival rate of 71%. The overall 5-year survival rate for all patients with advanced uT4 rectal cancer was 49%. CONCLUSIONS: Our data on preoperative combined treatment in locally advanced T4 rectal cancer revealed encouraging downstaging, local control, and survival rates.

[Radiochemotherapy plus hyperthermia in rectal carcinoma]. / Radiochemotherapie plus Hyperthermie beim Rektumkarzinom.

In locally advanced rectal cancer (uT3/uT4) resectability as well as local control is reduced. In the patients combined preoperative radiochemotherapy demonstrated an increase of resectability and a reduction of local recurrence. Radiotherapy was applied in standard blocks, 5 x 1.8 Gy up to 45 Gy. Chemotherapy consisted out of two cycles of 5-Fluorouracil (300-350 mg/m2/d) and Leucovorin (50 mg). Prior to radiotherapy additionally thermotherapy was carried out using the SIGMA 60 applicator BSD 2000 once a week. The hyperthermia method is based on heating up affected tissue compartments to temperature above 42 degrees Celsius without damaging surrounding tissue compartments. In regional hyperthermia tumors in the abdominal region are treated by emitting radio waves into the patient. 4-6 weeks after radiochemotherapy, surgery was performed. The therapeutic toxicity was acceptable and the resectability rate was up to 90%. Response rate to treatment was 60%. Our data with preoperative combined treatment in locally advanced rectal cancer revealed encouraging downstaging, local control, and survival rates.

Preoperative radiochemotherapy in locally advanced or recurrent rectal cancer: regional radiofrequency hyperthermia correlates with clinical parameters.

PURPOSE: Preoperative radiochemotherapy (RCT) is a widely used means of treatment for patients suffering from primary, locally advanced, or recurrent rectal cancer. We evaluated the efficacy of treatment due to additional application of regional hyperthermia (HRCT) to this conventional therapy regime in a Phase II study, employing the annular phased-array system BSD-2000 (SIGMA-60 applicator). The clinical results of the trial were encouraging. We investigated the relationship between a variety of thermal and clinical parameters in order to assess the adequacy of thermometry, the effectiveness of hyperthermia therapy, and its potential contribution to clinical endpoints. METHODS AND MATERIALS: A preoperative combination of radiotherapy (1.8 Gy for 5 days a week, total dose 45 Gy applied over 5 weeks) and chemotherapy (low-dose 5-fluorouracil [5-FU] plus leucovorin in the first and fourth week) was administered to 37 patients with primary rectal cancer (PRC) and 18 patients with recurrent rectal cancer (RRC). Regional hyperthermia (RHT) was applied once a week prior to the daily irradiation fraction of 1.8 Gy. Temperatures were registered along rectal catheters using Bowman thermistors. Measurement points related to the tumor were specified after estimating the section of the catheter in near contact with the tumor. Three patients with local recurrence after abdominoperineal resection, had their catheters positioned transgluteally under CT guidance, where the section of the catheter related to the tumor was estimated from the CT scans. Index temperatures (especially T(max), T(90)) averaged over time, cumulative minutes (cum min) (here for T(90) > reference temperature 40.5 degrees C), and equivalent minutes (equ min) (with respect to 43 degrees C) were derived from repetitive temperature-position scans (5- to 10-min intervals) utilizing software specially developed for this purpose on a PC platform. Using the statistical software package SPSS a careful analysis was performed, not only of the variance of thermal parameters with respect to clinical criteria such as toxicity, response, and survival but also its dependency on tumor characteristics. RESULTS: The rate of resectability (89%) and response (59%) were high for the PRC group, and a clear positive correlation existed between index temperatures (T(90)) and thermal doses (cum min T(90) >/= 40.5 degrees C). Even though the overall 5-year survival was encouraging (60%) and significantly associated with response, there was no statistically significant relationship between temperature parameters and long-term survival for this limited number of patients. However, nonresectable tumors with higher thermal parameters (especially cum min T(90) >/= 40.5 degrees C) had a tendency for better overall survival. We found even higher temperatures in patients with recurrences (T(90) = 40.7 degrees C versus T(90) = 40.2 degrees C). However, these conditions for easier heating did not involve a favorable clinical outcome, since surgical resectability (22%) and response rate (28%) for the RRC group were low. We did not notice any other dependency of thermal parameters to a specific tumor or patient characteristics. Finally, neither acute toxicity (hot spots) induced by hyperthermia or RCT nor perioperative morbidity were correlated with temperature-derived parameters. Only a higher probability for the occurrence of hot spots was found during treatment with elevated power levels. CONCLUSION: In this study with two subgroups, i.e., patients with PRC (n = 37) and RRC (n = 18), there exists a positive interrelationship between thermal parameters (such as T(90), cum min T(90) >/= 40,5 degrees C) and clinical parameters concerning effectiveness. Additional hyperthermia treatment does not seem to enhance toxicity or subacute morbidity. Procedures to measure temperatures and to derive thermal parameters, as well as the hyperthermia technique itself appear adequate enough to classify heat treatments in

Feasibility and analysis of thermal parameters for the whole-body-hyperthermia system IRATHERM-2000.

The infrared system IRATHERM-2000, with water-filtered infrared A wavelength underwent 20 treatments of whole body hyperthermia in conjunction with chemotherapy. In all the sessions, the aimed systemic temperature (41.8 degrees C, maximum 42.0 degrees C) could be achieved and maintained for 60 min. Due to increasing clinical experience, the unnegligible local toxicity, exhibited as heat-induced superficial lesions, and neurotoxicity, could be reduced during the course of the study. Data from three other series accomplished at the von Ardenne Clinic, totalling 120 heat sessions, were available and included for a comparative analysis. Analysis of the toxicity shows that a correlation exists between thermal side-effects and heat-up periods (until steady-state), maximum temperatures, and superficial thermal doses. The time needed to reach the plateau seems to correlate with fluid loss, which, thus, indirectly influences toxicity, and most importantly the initial power level. The typical heat-up time in such a standard set-up amounts to 100-150 min, for a temperature rise from 37.5 to 42.0 degrees C. Evaluation of the energy balance reveals a highly patient-specific range for the reactive evaporation in the IRATHERM system, resulting in a power (heat) loss of up to 1400 W via sweat production of approximately 2 l/h. In order to counterbalance this effect, an accordingly high infrared power, ranging from 1200-1500 W, needs to be delivered, resulting in a significant thermal skin exposition. Concepts used to reduce the heat loss by reactive evaporation include prevention of convection by appropriate sealing of the heating chamber and increasing the humidity by a nebulizer. For the more trained user, the heat-up time can be considerably shortened, particularly, in the introductory phase of the heating process, by employing higher, but still tolerable, patient-specific power levels. However, such a strategy requires, due to higher risks, close monitoring of skin temperatures together with a considerable amount of clinical experience. The results of the IRATHERM pilot study were compared, not only with previous groups where the IRATHERM was applied, but also with results of various other investigators where the Enthermics Radiant Heat Device was employed. In the authors' opinion, improved understanding of the mechanisms and crucial parameters underlying whole body hyperthermia, will enable a controllable and tolerable therapy through proficient contribution to equipment and methods.

[Adjuvant therapy of pancreatic carcinoma]. / Aspekte in der adjuvanten Therapie des Pankreaskarzinoms.

The poor prognosis in pancreatic carcinoma has been increased especially by improved diagnostic procedures and decreasing perioperative mortality. Median survival after complete resection is commonly less than 20 months and the 5 years survival is in the range of about 20%. Postoperative radiochemotherapy reduces the local recurrence rate but not the overall survival however. Pancreatic carcinoma is characterized by a low chemosensitivity of the drugs commonly used like 5-FU. More aggressive chemotherapy protocols are limited by the reduced status of the patient. Multimodal and prolonged adjuvant schedules did not show a prognostic benefit. The current ESPAC--study investigates the role of simultaneous radiotherapy and 5-FU alone or in combination with neoadjuvant 5-FU and folic acid for 6 months. New protocols will investigate the value of regional adjuvant chemotherapy ESPAC 2) [44] and of gemcitabine, 5-FU or control in a three arm study.--In a multicenter German trial the benefit of gemcitabene as weekly monotherapy for 6 months is investigated. The treatment starts soon after resection due to low toxicity and good patient compliance.

Whole body hyperthermia: a secure procedure for patients with various malignancies?

OBJECTIVE: To establish the safety of systemic Cancer Multistep Therapy (sCMT) including whole body hyperthermia, by means of hemodynamic, laboratory and clinical investigations. DESIGN: Prospective study. SETTING: University clinic. PATIENTS: 12 patients with various cancers (with sCMT), a second group of 20 patients with colorectal carcinoma treated with chemotherapy (without sCMT). INTERVENTIONS: 25 treatments with sCMT for 60 min at 41.8 degrees C (including chemotherapy) were given in addition to induced hyperoxemia and hyperglycemia under general anesthesia. MEASUREMENTS AND RESULTS: Invasive monitoring of systemic and pulmonary hemodynamics as well as pulmonary gas exchange was used at 37 degrees C, 40 degrees C, 41.8 degrees C and 39 degrees C. In addition, laboratory parameters were measured before and within 4 days of therapy. At 41.8 degrees C, invasive monitoring showed characteristic signs of hyperdynamic circulation. In addition, right-to-left shunt, oxygen consumption, oxygen delivery and lactate levels were significantly different from pretreatment values. At the end of therapy, lactate levels and the extravascular lung water index increased, whereas all other parameters showed a clear tendency to return to initial values. Within the first day after sCMT, we measured a slight but significant reversible increase in serum creatinine compared to pretreatment values, but found no significant alterations of other chemical parameters. Between the sCMT group and controls, there was only a temporary significant difference in aspartate aminotransferase levels 2 days after therapy. CONCLUSIONS: sCMT, including whole body hyperthermia, accompanied by suitable anesthesiological management and monitoring, does not lead to any serious or sustained organ dysfunction and can therefore be regarded as a safe therapy.

[Phase II study on preoperative radio-chemo-thermotherapy in locally advanced rectal carcinoma]. / Phase-II-Studie zur präoperativen Radio-Chemo-Thermo-Therapie beim lokal fortgeschrittenen Rektum-Karzinom.

BACKGROUND: Recent studies show that preoperative radio-chemotherapy can increase resectability and local control of locally advanced rectal carcinomas. Additional regional hyperthermia might increase remission rates and tumor response. We therefore tested regional hyperthermia together with radio-chemotherapy in a phase-II study on locally advanced rectal carcinomas. PATIENTS AND METHODS: Thirty-seven patients with primary advanced stage uT3/T4 rectal carcinomas were treated with preoperative radio-chemo-thermo-therapy. The initial tumor depth was determined using endosonography, CT, and MRI. Radiotherapy was carried out in prone position (on a belly board) using standard techniques, with 5 x 1.8 Gy per week up to 45 Gy at the reference point. 5-Fluorouracil (300 to 500 mg/m2) was administered with low doses of leucovorin (50 mg) on days 1 to 5 and 22 to 28. The patients were treated with regional hyperthermia each week prior to radiotherapy and simultaneously with chemotherapy, using the Sigma 60 ring from the BSD-2000 system. Temperature/position curves and temperature/time curves were recorded in endocavitary (endorectal) catheters in tumor contact and as well in bladder and vagina. Following endosonographic restaging, the operation was carried out 4 to 6 weeks after the end of preoperative therapy and adjuvant chemotherapy continued in four cycles. In cases where tumors were non-resectable, a boost up to 64 Gy was aimed. RESULTS: Thirty-one of the 37 patients (84%) with primary carcinoma proved locally R0-resectable. In addition we had 1 R1-resection (3%) and 5 non-resectable tumors (13%). Among the resected tumors, 53% experienced a reduction of depth infiltration from the initial endosonographic stage during preoperative therapy. The actuarial survival rate after 4 years is 65% (free of progression 57%). The actuarial 4-year survival rate was particularly favorable for the group of responders. Overall, the preoperative multimodal therapy was well tolerated, and premature termination was only necessary in 1 case (3%). Grade III/IV toxicities in the intestine and skin were reduced as far as possible by field blockings and cooling of the perineal region. They occurred only in 5/37 patients (13%) at the intestine and in 6/37 patients (16%) at the skin. The thermal data were subjected to a statistical analysis. The quality of temperature distribution (T90, cum min T90 > or = 40.5 degrees C) depends on the power level and relative power density. The response (reduction of tumor size or depth infiltration) correlated significantly with quality parameters of the temperature distributions. This dependency is found as a trend for progression-free survival, too. CONCLUSIONS: Preoperative radio-chemo-thermo-therapy proved to be practical and effective, with encouraging remission rates and excellent local control rates. For this reason, a phase-III study to test regional hyperthermia has been initiated. At the same time, certain technical improvements are still under development for regional hyperthermia.

Radiochemotherapy and hyperthermia in the treatment of rectal cancer.

We evaluated the use of regional hyperthermia with radio-chemotherapy in a phase I/II study on locally advanced rectal carcinomas. Thirty-four patients with primary advanced (stage T3/T4) rectal carcinomas (24 patients) or recurring rectal carcinomas (6 patients) were treated using preoperative radiochemo-thermotherapy. Initial tumour staging was carried out clinically (degree of fixation) and using endorectal ultrasonography and CT. Radiotherapy was carried out with the patient prone (on a belly board) at 5 x 1.8 Gy per week up to 45 Gy at the reference point. 5-Fluorouracil (300-500 mg/m2) was administered with low-dose leucovorin (50 mg) on days 1-5 and 22-26. Patients were treated with regional hyperthermia each week prior to radiotherapy, using the Sigma-60 ring of the BSD-2000 system. Temperature/position curves and temperature/time curves were recorded via endocavitary catheters (tumour contact, bladder, vagina). Following endosonographic and clinical restaging, the operation was carried out 4-6 weeks after the end of preoperative therapy. In cases where tumours were unresectable, a boost of up to 60 Gy was given. Twenty-three of the 34 patients (68%) proved to be curatively resectable. Of these patients, 70% were downstaged endosonographically during preoperative therapy. The actuarial survival rates among these patients were 85% (primary rectal cancer) and 60% (recurrences) at 30 months. All in all, the preoperative multimodal therapy was well tolerated, and premature termination was necessary in only two cases. The quality of temperature distribution (T90, cum min T90 > 40.5 degrees C) depends on the power level and relative power density. The response (particularly downstaging) correlates significantly with the quality parameters of the temperature distributions. This regimen proved practical and effective, with encouraging downstaging rates and local control rates.