[Metronidazole-induced encephalopathy: description of a case with radiological and anatomopathological findings]. / Encefalopatia inducida por metronidazol: descripcion de un caso con hallazgos radiologicos y anatomopatologicos.

INTRODUCTION: Metronidazole is a widely known and used antibiotic. In exceptional cases, an encephalopathy with characteristic lesions on magnetic resonance imaging (MRI), usually located in the cerebellum and splenium of the corpus callosum, may be an adverse effect. The incidence and pathogenesis are unknown. The suspension of the treatment usually resolves the symptoms and normalizes the MRI in a few weeks. Due to the usual good prognosis, the anatomopathological findings are exceptional. We present a clinical case with the radiological findings suggestive of metronidazole-induced encephalopathy and, exceptionally, we provide the anatomopathological findings. CASE REPORT: A 72 years-old woman with severe Crohn's disease who, months after starting treatment with metronidazole, presented a slowly progressing bradypsychia and difficulty walking until she came to coma. In MRI it showed hyperintense images in T2 in the corpus callosum, red and dentate nuclei. He improved by stopping metronidazole but later developed sepsis and died. At autopsy, softening of the red nucleus was observed and, microscopically, cell necrosis and demyelination. CONCLUSION: With the publication of the clinical, radiological and anatomopathological information of our case we intend to promote the knowledge of this infrequent treatable cause of subacute encephalopathy and provide data that help to clarify its pathogenesis.

TITLE: Encefalopatia inducida por metronidazol: descripcion de un caso con hallazgos radiologicos y anatomopatologicos.Introduccion. El metronidazol es un antibiotico ampliamente conocido y utilizado. En casos excepcionales puede producir como efecto adverso un cuadro de encefalopatia con unas lesiones caracteristicas en la resonancia magnetica, localizadas generalmente en el cerebelo y el esplenio del cuerpo calloso. La incidencia y la patogenia se desconocen. La suspension del tratamiento habitualmente resuelve los sintomas y normaliza la resonancia magnetica en pocas semanas. Debido al habitual buen pronostico, los hallazgos anatomopatologicos son excepcionales. Se presenta un caso clinico con los hallazgos radiologicos sugestivos de la encefalopatia inducida por metronidazol y, de forma excepcional, se aportan los hallazgos anatomopatologicos. Caso clinico. Mujer de 72 años, con enfermedad de Crohn grave, que meses mas tarde de iniciar tratamiento con metronidazol presento de forma lentamente progresiva bradipsiquia y dificultad para caminar hasta llegar al coma. En la resonancia magnetica mostraba caracteristicas imagenes hiperintensas en T2 en el cuerpo calloso, y los nucleos rojos y dentados. Mejoro al suspender el metronidazol, pero posteriormente desarrollo una sepsis y fallecio. En la autopsia se observo reblandecimiento del nucleo rojo y, microscopicamente, necrosis celular y desmielinizacion. Conclusion. Con la publicacion de la informacion clinica, radiologica y anatomopatologica de este caso se pretende fomentar el conocimiento de esta infrecuente causa tratable de encefalopatia subaguda y aportar datos que ayuden a aclarar su patogenia.

A feasibility study in oesophageal carcinoma using deep loco-regional hyperthermia combined with concurrent chemotherapy followed by surgery.

This phase I-II study investigated the feasibility of external deep loco-regional hyperthermia in localized primarily operable carcinoma of the thoracic oesophagus and gastro-oesophageal junction. Toxicity when combining neo-adjuvant hyperthermia with concurrent chemotherapy (CDDP and etoposide) was evaluated. Hyperthermia was given with a four antenna array, operating at 70 MHz arranged around the thorax. Temperatures were monitored rectally, intra-oesophageal at tumour level and intramuscular near the spine. In four steps, a thermal dose escalation was performed from 15-60 min of heating to 41 degrees C with two patients in each step. The combined treatment courses were repeated every 3 weeks for a maximum of four courses. From January 1999-February 2002, 31 patients were included. Pre-treatment tumour stage mainly consisted of T3N1 (stage III) tumours, with a mean length of 6 cm. The maximum tumour temperature failed to reach at least 41 degrees C in five patients during the test session of hyperthermia alone. Combined hyperthermia and chemotherapy was given 55 times in 26 patients. The amplitude was set at a ratio between top:bottom:left:right = 1:3:3:3, with a power range of 800-1000 W. Thermal data showed that is was technically feasible to heat the oesophagus; the median results were T(90) = 39.3 degrees C, T(50) = 40 degrees C, T(10) = 40.7 degrees C and a median T(max) = 41.9 degrees C. In more distally located tumours higher temperatures were reached. In one patient, a transient grade 2 sensory neuropathy was seen. Further toxicity was mainly of haematological origin. Blisters or fat necrosis were not observed. Twenty-two patients underwent oesophageal-cardia resection with gastric tube reconstruction. There was no report of complications in the post-operative phase, which could be contributed to either the prior chemotherapy or the hyperthermia.

A feasibility study of interstitial hyperthermia plus external beam radiotherapy in glioblastoma multiforme using the Multi ELectrode Current Source (MECS) system.

PURPOSE: Thermoradiotherapy has been shown in several randomized trials to increase local control compared to radiotherapy alone. The first randomized study of interstitial hyperthermia in glioblastoma multiforme showed a survival benefit for hyperthermia, though small. Improvement of the heating technique could lead to improved results. The purpose of this feasibility study is to present the clinical and thermal data of application of an improved interstitial hyperthermia system. METHODS AND MATERIALS: Six patients with a glioblastoma multiforme were treated with interstitial hyperthermia using the Multi Electrode Current Source Interstitial Hyperthermia (MECS-IHT) system. The MECS-IHT system has the capability of spatial monitoring of temperature and individually steering of heating electrodes. Three sessions were given aiming at a steady state temperature of 42 degrees C for 1 h, with an interval of 3-4 days, during an external irradiation scheme of 60 Gy in 6 weeks. Hyperthermia was delivered with a mean of 10 catheters, 18 heating electrodes and 38 thermal probes per patient. RESULTS: Sub-optimal temperatures were encountered in the first two patients leading to adjustments in technique thereafter with subsequent improvement of thermal data. With a catheter spacing of 11-12 mm, measurements yielded a mean T(90), T(50) and T(10) of 39.9, 43.7 and 45.2 degrees C, respectively, over three sessions in the last patient. The power per electrode to reach this temperature distribution varied from 25-100% of full power in each of the last four patients. Thermal data were reproducible over the three sessions. Acute toxicity was minimal. CONCLUSIONS: Despite the spatial steering capabilities of the MECS-IHT system, a large temperature heterogeneity was encountered. The heterogeneity was the reason to limit the catheter spacing to 11-12 mm, thus making only small tumour volumes feasible for interstitial heating.

[Clinical effects and pharmacokinetics of ropivacaine and bupivacaine for epidural analgesia during labor]. / Efectos clínicos y farmacocinética de ropivacaína y bupivacaína en la analgesia epidural durante el trabajo de parto.

OBJECTIVE: To compare the analgesic efficacy, pharmacokinetics and histamine release of ropivacaine and bupivacaine with fentanyl in continuous epidural perfusion during labor and childbirth. MATERIAL AND METHODS: Prospective study of 40 women at full-term pregnancy who requested epidural analgesia. The patients were randomly assigned to 2 groups of 20: group R received an initial bolus dose of 10 mL of 0.25% ropivacaine and group B received 0.25% bupivacaine, followed in both groups by epidural infusion of the assigned drugs at a concentration of 0.125% plus 0.30 mg of fentanyl at a rate of 5 mL/h through a patient-controlled analgesia device that allowed additional bolus doses. The studied variables were age, weight, height, sensory and motor block, mean blood pressure and maternal-fetal heart rates, number of bolus doses, total local anesthetic administered, duration and type of delivery, oxytocin increase, Apgar at 1 and 5 minutes, plasma levels of local anesthetic (30 minutes after the initial dose, at the end of dilation, in the umbilical vein, and 30 minutes after switching off the perfusion pump), time to clearance, elimination half-life, and a test of histamine release by radioimmunoassay. RESULTS: No significant differences were observed in the course of labor or in Apgar scores. The plasma concentrations of ropivacaine were higher than those of bupivacaine (p<0.03). Clearance of both drugs was similar. The elimination half-life of ropivacaine was significantly less than that of bupivacaine (5.2 +/- 0.7 h vs. 10.8 +/- 1.06 h). CONCLUSIONS: Analgesia was equally effective in both groups, without adverse maternal-fetal effects, with spontaneous micturition and absence of motor blockade in both groups. The plasma concentrations were higher with ropivacaine but were not toxic.

Eficacia analgésica de la asociación ketamina+morfina epidural: experiencia en 75 casos / Analgesic effectiveness of combined epidural ketamine+morphine: experience in 75 cases

Objetivo: El objetivo de este estudio fue comprobar la eficacia analgésica de la combinación de morfina y ketamina por vía epidural, y determinar la dosis óptima de ketamina que incrementa la capacidad analgésica de los opiáceos peridurales, en pacientes sometidos a artroplastia total de cadera y rodilla. Material y métodos: Se realizó un estudio prospectivo, de 75 pacientes, a lo largo de un año. La técnica locorregional anestésica realizada fue combinada intradural-epidural, con colocación de catéter epidural para analgesia. Todos los pacientes recibieron 30 mg de ketamina epidural 30 min antes de la intervención. La anestesia intradural se realizó con bupivacaína 0,5 por ciento hiperbara, 2-3 cc, según el paciente tuviera una estatura <170 cm o 170 cm, respectivamente .Los pacientes fueron divididos e 5 grupos: Grupo A: recibieron analgesia i.v. con metamizol (2 g i.v. . 6 h- 1) y tramado l (100 mg i.v./6 h). Grupo B: 10 mg de ketamina epidural, diluidos en 10 ml de suero salino fisiológico (SSF), al llegar al despertar y 12 h después. Grupo C: 2 mg de morfina epidural, diluidos en 10 ml de SSF, a la llegada al despertar y 12 h después. Grupo D: 10 mg de ketamina + 0,5 mg de cloruro mófico epidural, diluidos en 10 ml de SSF, a la llegada al despertar y 12 h después.Grupo E: 5 mg de Ketamina + 0,5 mg de morfina epidural, diluidos en 10 ml de SSF, a la llegada al despertar y 12 h después. Se valoraron la eficacia analgésica (utilizando la Escala Analógica Visual: EVA), la necesidad de analgesia suplementaria y los efectos indeseables (despertar, salida, 12, 24, 48 y 72 h postcirugía).Resultados: Se observó una eficacia analgésica significativamente superior en los grupos C, D y E, respecto a los grupos A y B (p<0,05). La analgesia obtenida en los grupos en los que se administró la asociación ketamina+cloruro mórfico (D,E), fue superior a la del grupo en que se administró sólo cloruro mórfico, pero sin diferencias significativas. El consumo de analgésicos fue significativamente superior (p<0,02) para los grupos A y B, con respecto al resto. Los efectos secundarios fueron significativamente superiores (p<0,03) en el grupo C. Discusión: La administración epidural de ketamina, no se comportó como analgésico eficaz, sin embargo la asociación ketamina+morfina permitió una analgesia eficaz y prolongada, con bajas dosis de ambos fármacos, reduciéndose de forma significativa los efectos secundarios. Ambas dosis de ketamina fueron consideradas como eficaces para la analgesia preventiva (AU)

The Dutch Deep Hyperthermia Trial: results in cervical cancer.

BACKGROUND: Radiotherapy plus hyperthermia was compared to radiotherapy alone in the Dutch Deep Hyperthermia Trial, in patients with advanced bladder, cervical, and rectal tumours. The overall results, published elsewhere, demonstrate that addition of hyperthermia to radiotherapy improves both pelvic control and overall survival rates. The therapeutic gain appeared especially worthwhile in locally advanced cervical tumours. Here, the results in patients with cervical cancer are summarized and discussed, and further details provided. METHODS: From 1990-1996, 114 patients with cervical cancer were entered into this prospective randomized trial. RT was applied to a median total dose of 68 Gy. HT was given once weekly. The median follow-up time was 43 months. All randomized patients were included in the statistical analysis, which was done by intention to treat. The primary end points of the trial were complete response (CR) and duration of pelvic control (PC), secondary end points were overall survival (OS) and toxicity. Besides, an economic evaluation was performed. RESULTS: CR rates were 57% following RT and 83% following RT + HT(p = 0.003). The difference in PC was maintained during follow-up, with 3-year LC rates of 41% following RT and 61% following RT + HT. The 3-year OS rates were 27% and 51% following RT and RT + HT, respectively (p = 0.009). When the patients were divided into two subgroups by whether or not the planned RT was completed, a beneficial effect of hyperthermia was observed in both subgroups. Radiation toxicity was not enhanced by HT. Additional hyperthermia proved to be cost-effective, with maximum discounted cost-per-life-year gained of about Euro 4000. CONCLUSION: Hyperthermia in addition to standard radiotherapy of locally advanced cervical tumours results in therapeutic gain and is cost-effective.

Prognostic value of plasma transforming growth factor-beta in patients with glioblastoma multiforme.

We investigated whether the postoperative concentration of circulating transforming growth factor beta (TGF-beta) yields prognostic value in patients with glioblastoma multiforme (gbm). Blood was collected from 20 healthy volunteers and in 28 patients with mainly glioblastoma multiforme (gbm), both before radiotherapy, during and after 4 weeks of irradiation. Both latent and active TGF-beta were quantified directly in the blood plasma using a bioassay with mink lung epithelial cells transfected with a plasminogen activator inhibitor-1 promotor luciferase construct. The average plasma concentration of TGF-beta before radiotherapy for gbm patients was 26.2 ng/ml, which was significant higher than in normal controls (16.2 ng/ml, p=0.02). No correlation was found between TGF-beta and survival, nor between plasma TGF-beta and the diameter of the postoperative contrast-enhancing lesion. The pattern of plasma TGF-beta during radiotherapy did not correlate with the clinical course of patients, nor with the fractionation scheme. Plasma TGF-beta did not reveal a clinical useful prognostic value for gbm patients, which is partly due to the large variation in TGF-beta plasma levels between individual patients.

Prognostic factors in glioblastoma multiforme. 10 years experience of a single institution.

BACKGROUND: To analyze prognostic factors in patients with a glioblastoma multiforme treated in an academic institute over the last 10 years. PATIENTS AND METHOD: From 1988 to 1998, 198 patients with pathologically confirmed glioblastoma multiforme were analyzed. Five radiation schedules were used mainly based on pretreatment selection criteria: 1. 60 Gy in 30 fractions followed by an interstitial iridium-192 (Ir-192) boost for selected patients with a good performance and a small circumscribed tumor, 2. 66 Gy in 33 fractions for good performance patients, 3. 40 Gy in eight fractions or 4. 28 Gy in four fractions for poor prognostic patients and 5. no irradiation. RESULTS: Median survival was 16 months, 7 months, 5.6 months, 6.6 months and 1.8 months for the groups treated with Ir-192, 66 Gy, 40 Gy, 28 Gy and the group without treatment, respectively. No significant improvement in survival was encountered over the last 10 years. At multivariate analysis patients treated with a hypofractionated scheme showed a similar survival probability and duration of palliative effect compared to the conventionally fractionated group. The poor prognostic groups receiving radiotherapy had a highly significant better survival compared to the no-treatment group. Patients treated with an Ir-192 boost had a better median survival compared to a historical group matched on selection criteria but without boost treatment (16 vs 9.7 months, n.s.). However, survival at 2 years was similar. Analysis on pretreatment characteristics at multivariate analysis revealed age, neurological performance, addition of radiotherapy, total resection, tumor size post surgery and deterioration before start of radiotherapy (borderline) as significant prognostic factors for survival. CONCLUSION: Despite technical developments in surgery and radiotherapy over the last 10 years, survival of patients with a glioblastoma multiforme has not improved in our institution. The analysis of prognostic factors corresponded well with data from the literature. A short hypofractionated scheme seems to be a more appropriate treatment for patients with intermediate or poor prognosis as compared to a conventional scheme. The benefit in median survival for patients treated with an interstitial boost is partly explained by patient selection. Since there were no long-term survivors with this boost treatment, its clinical value, if there is one, is still limited.

Palliative treatment in patients with unresectable hilar cholangiocarcinoma: results of endoscopic drainage in patients with type III and IV hilar cholangiocarcinoma.

OBJECTIVE: To find out how patients fared after palliative endoscopic biliary drainage for inoperable hilar cholangiocarcinoma. DESIGN: Retrospective study. SETTING: University hospital, the Netherlands. SUBJECTS: Between 1992 and 1999, 41 patients who were referred for resection had tumours that were considered unresectable after additional investigations, including an exploratory laparotomy in 16 patients. In all patients, biliary drainage was established by endoscopic retrograde cholangiography (ERCP) and insertion of endoprostheses. Twelve patients also had percutaneous transhepatic biliary drainage (PTBD). RESULTS: The patients who did not have an exploratory laparotomy had fewer complications (1/25) than those who had explorations (4/16). All patients in both groups had one or more long-term complications during follow-up, of which cholangitis, jaundice, and abdominal pain were the most often recorded. In 32 patients, endoprostheses had to be replaced, a mean of 4 times. Median survival was 9 months, with no significant difference between the groups (8 and 11 months). Adjuvant radiotherapy had no influence on survival. CONCLUSION: The patients in this series had relatively long survival times, during which they had a substantial number of complications predominantly related to biliary drainage. Because biliary-enteric bypass operations result in effective relief of symptoms and excellent palliation, we suggest that when an exploration is done for patients with type III and IV tumours, a bypass should be made.

Office hours pulsed brachytherapy boost in breast cancer.

BACKGROUND AND PURPOSE: Radiobiological studies suggest equivalent biological effects between continuous low dose rate brachytherapy (CLDR) and pulsed brachytherapy (PB) when pulses are applied without interruption every hour. However, radiation protection and institute-specific demands requested the design of a practical PB protocol substituting the CLDR boost in breast cancer patients. An office hours scheme was designed, considering the CLDR dose rate, the overall treatment time, pulse frequency and tissue repair characteristics. Radiobiological details are presented as well as the logistics and technical feasibility of the scheme after treatment of the first 100 patients. MATERIALS AND METHODS: Biologically effective doses (BEDs) were calculated according to the linear quadratic model for incomplete repair. Radiobiological parameters included an alpha/beta value of 3 Gy for normal tissue late effects and 10 Gy for early normal tissue or tumour effects. Tissue repair half-time ranged from 0.1 to 6 h. The reference CLDR dose rate of 0.80 Gy/h was obtained retrospectively from analysis of patients' data. The treatment procedure was evaluated with regard to variations in implant characteristics after treatment of 100 patients. RESULTS: A PB protocol was designed consisting of two treatment blocks separated by a night break. Dose delivery in PB was 20 Gy in two 10 Gy blocks and, for application of the 15 Gy boost, one 10 Gy block plus one 5 Gy block. The dose per pulse was 1.67 Gy, applied with a period time of approximately 1.5 h. An inter-patient variation of 30% (1 SD) was observed in the instantaneous source strength. Taking also the spread in implant size into account, the net variation in pulse duration amounted to 38%. CONCLUSION: An office hours PB boost regimen was designed for substitution of the CLDR boost in breast-conserving therapy on the basis of the BED. First treatment experience shows the office hour regimen to be convenient to the patients and no technical perturbations were encountered.

Surgery, radiotherapy, and chemotherapy for esophageal carcinoma.

Over the last year, several interesting studies have been published on the treatment of esophageal carcinoma. Surprisingly, none of them was a randomized phase III trial. The debate on the necessary extent of a potentially curative surgical resection is ongoing. After initially disappointing results, the innovative technique of minimally invasive surgery draws new attention, but clear advantages for the endoscopic approach are yet to emerge. An updated meta-analysis on the value of preoperative radiotherapy showed negative results. There is a clear tendency toward combined-modality treatment, especially in patients with more advanced disease. Some new chemotherapeutic agents showed promising preliminary results (especially paclitaxel), whereas others were clearly disappointing (eg, gemcitabine, topotecan). Concurrent chemoradiation as primary treatment for proximal (cervical) tumors was remarkably effective.

Brachytherapy with transperineal (125)Iodine seeds for localized prostate cancer.

BACKGROUND AND PURPOSE: To analyze the treatment results of transperineal (125)Iodine seeds in localized prostate cancer. PATIENTS AND METHODS: Between 1985 and 1996, 102 patients with T1-T2 N0 prostate cancer were treated with transperineal (125)Iodine seed implants at the Academic Medical Centre in Amsterdam. Tumours were classified as T1c in four patients, T2a in 73 patients and T2b in 25 patients. The mean pre-treatment PSA was 17 ng/ml. The (125)Iodine seeds were implanted transperineally under transrectal ultrasound guidance. The mean prostate volume was 31 ml (range 15-48 ml). An average of 49 seeds (range 29-74) was implanted. The dose to the periphery of the prostate was 160 Gy. Until 1988, 27 patients had additional external pelvic irradiation to a dose of 40 Gy in 20 daily fractions of 2 Gy. RESULTS: The 5- and 7-year actuarial survival rates were 77 and 63%, respectively (median 102 months). Ten patients (9.5%) died from prostate cancer. The 5- and 7-year clinical progression rates were 12 and 17%, respectively. Biochemical failure rates at 5 and 7 years were 39 and 44%, respectively. Age, alkaline phosphatase, creatinine, differentiation grade, additional treatment, staging procedure, number of seeds, prostate volume, treatment period and PSA were analyzed as prognostic factors. Only pre-treatment PSA was a prognosticator of clinical and biochemical outcome but not of survival. Biochemical control at 6 years varied from 30% for pre-treatment PSA values higher than 20 ng/ml to 95% for values < or =8 ng/ml. Forty-one out of 49 patients who were sexually active before brachytherapy maintained sexual function during the follow-up. Complete urinary incontinence occurred in one patient. No rectal complications were seen in patients receiving brachytherapy alone. CONCLUSIONS: Transperineal (125)Iodine seeds brachytherapy in localized prostate cancer achieves a good clinical control and overall survival with acceptable late toxicity. Biochemical failure was strongly correlated to the pre-treatment PSA value.

Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group.

BACKGROUND: Local-control rates after radiotherapy for locally advanced tumours of the bladder, cervix, and rectum are disappointing. We investigated the effect of adding hyperthermia to standard radiotherapy. METHODS: The study was a prospective, randomised, multicentre trial. 358 patients were enrolled from 1990 to 1996, in cancer centres in the Netherlands, who had bladder cancer stages T2, T3, or T4, NO, MO, cervical cancer stages IIB, IIIB, or IV, or rectal cancer stage M0-1 were assessed. Patients were randomly assigned radiotherapy (median total dose 65 Gy) alone (n=176) or radiotherapy plus hyperthermia (n=182). Our primary endpoints were complete response and duration of local control. We did the analysis by intention to treat. FINDINGS: Complete-response rates were 39% after radiotherapy and 55% after radiotherapy plus hyperthermia (p<0.001). The duration of local control was significantly longer with radiotherapy plus hyperthermia than with radiotherapy alone (p=0.04). Treatment effect did not differ significantly by tumour site, but the addition of hyperthermia seemed to be most important for cervical cancer, for which the complete-response rate with radiotherapy plus hyperthermia was 83% compared with 57% after radiotherapy alone (p=0.003). 3-year overall survival was 27% in the radiotherapy group and 51% in the radiotherapy plus hyperthermia group. For bladder cancer, an initial difference in local control disappeared during follow-up. INTERPRETATION: Hyperthermia in addition to standard radiotherapy may be especially useful in locally advanced cervical tumours. Studies of larger numbers of patients are needed for other pelvic tumour sites before practical recommendations can be made.

Toxicity of high-dose radiotherapy combined with daily cisplatin in non-small cell lung cancer: results of the EORTC 08912 phase I/II study. European Organization for Research and Treatment of Cancer.

The purpose of this work was to study the feasibility of concurrent chemoradiation in patients with inoperable non-small cell lung cancer (NSCLC). 40 patients with inoperable NSCLC were treated with escalating doses of radiotherapy and cisplatin (cDDP). The radiation dose was increased step by step from 60.5 to 66 Gy in daily fractions of 2.75 Gy. Chemotherapy was also increased step by step from 20 to 24 daily doses of cDDP 6 mg/m(2) and given concurrently with radiotherapy. A dose of 40 Gy/2 Gy/20 fractions (fx) was given to the EPTV (elective planning target volume) which included the gross tumour volume with a margin of 2 cm and part of or the entire mediastinum. During each session a boost dose of 0.75 Gy was given simultaneously to the BPTV (boost planning target volume), which encompassed the GTV (gross tumour volume) with a margin of 1 cm, for the first 20 fx, so the total dose to the tumour was 55 Gy. Cisplatin 6 mg/m(2) was given 1 h prior to radiotherapy at each fraction. From then on the dose of radiation to the BPTV and the dose of cDDP were increased step by step. In group I the BPTV was irradiated with two extra fractions of 2.75 Gy to a total dose of 60. 5 Gy without cDDP. In group II the same total dose of 60.5 Gy was given but the last two fractions were combined with cDDP. In group III four extra fractions of 2.75 Gy were given to the BPTV to a total dose of 66 Gy, only two of these fractions combined with cDDP. Finally, in group IV a total dose of 66 Gy was given in 24 fractions, all fractions combined with cDDP. All patients were planned by means of a CT-based conformal treatment planning. The maximal length of the oesophagus receiving >/=60.5 Gy was 11 cm. 40 patients were evaluable for acute and late toxicity and for survival. Acute toxicity grade >/=3 (common toxicity criteria, CTC) was rarely observed; nausea/vomiting in 3 patients (8%), leucopenia in 2 patients (5%), thrombocytopenia in 2 patients (5%), whilst 2 patients (5%) suffered from severe weight loss. Late side-effects (European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group, EORTC/RTOG) were: oesophageal toxicity >/=grade 3 in 2 patients (5%) and radiation pneumonitis grades 1 (3%) and 2 (3%) in 1 patient each. Overall actuarial 1- and 2-year survival was 53% and 40%, respectively. The 1- and 2-year local disease-free interval was 65% and 58% respectively. Radiotherapy at a dose of 66 Gy/2.75 Gy/24 fx combined with daily cDDP 6 mg/m(2) given over 5 weeks is feasible and results in a good local disease-free interval and a good survival rate. This treatment schedule is at present being tested as one of the two treatment arms of EORTC phase III study protocol 08972/22973.

Hypofractionation in glioblastoma multiforme.

PURPOSE: To compare conventional fractionation with hypofractionation in patients with a glioblastoma multiforme. Endpoints of the analysis are overall survival and palliative effect. MATERIALS AND METHODS: From 1988 to 1998, 155 patients with pathologically confirmed glioblastoma multiforme were prospectively analysed. Patients without irradiation and patients receiving an interstitial boost were excluded from this analysis. Three different radiation schemes were used in subsequent periods; 33x2, 8x5 and 4x7 Gy. In the last 5 years a scheme of 4x7 Gy conformal irradiation was given to poor prognosis patients. The more favourable group received the conventionally fractionated scheme up to 66 Gy. RESULTS: Median survival was 7, 5.6 and 6.6 months for the 33x2, 8x5 and 4x7 Gy, respectively. In general, patients in the hypofractionation group had far worse prognostic factors compared with patients treated with the conventional scheme. The period of neurological improvement or stabilisation was similar between the 4x7 and 33x2 Gy group. CONCLUSION: An extreme hypofractionation scheme of 4x7 Gy conformal irradiation in poor prognostic glioblastoma patients is well tolerated, convenient for the patient and provides equal palliation without negative effects on survival compared with conventional fractionation.

Feasibility and efficacy of high dose conformal radiotherapy for patients with locally advanced pancreatic carcinoma.

BACKGROUND: The feasibility and efficacy of high dose conformal radiotherapy were examined in the treatment of patients with locally advanced, unresectable pancreatic carcinoma. METHODS: Forty-four patients with pathologically confirmed, unresectable pancreatic adenocarcinoma without distant metastases were treated in a Phase II study. The patients received three-dimensional, planned, high dose conformal radiotherapy (70-72 grays). Toxicity was scored according to the World Health Organization criteria. Follow-up time ranged from 7 months to 25 months (median, 9 months). RESULTS: The treatment was feasible. Forty-one patients received the intended total dose. Treatment was never stopped because of toxicity. Acute toxicity was mainly Grade 1 and Grade 2 (in 70% and 57% of patients, respectively), whereas Grade 3 toxicity was seen in 9% of patients. One fatal event occurred that was not treatment related. Late Grade 3 and Grade 4 gastrointestinal toxicity was seen in 3 patients and 2 patients, respectively. Late (Grade 5) gastrointestinal bleeding was observed in 3 patients, 2 of whom had local tumor progression. At 3 months, reduction in tumor size was seen in 27% of patients, stable disease was seen in 20% of patients, and local disease progression was seen in 40% of patients. Ultimately, local disease progression was observed in 44% of patients. No true partial or complete responses were documented. The median survival from the time of diagnosis was 11 months (10 months from the start of radiotherapy). Seventeen of 25 patients (68%) experienced pain relief. CONCLUSIONS: High dose conformal radiotherapy for the treatment of patients with locally advanced pancreatic carcinoma is feasible with acceptable toxicity. In case of pain, it can offer palliation. The efficacy of the treatment in terms of prolongation of life is not proven. Distant metastases remain the major problem.

[Brachytherapy for urinary bladder cancer]. / Braquiterapia en el cáncer de vejiga urinaria.

OBJECTIVE: To present the results achieved by brachytherapy in the treatment of bladder cancer and to review the literature on this subject. METHODS: 120 patients with bladder cancer were treated with brachytherapy at two Dutch Centres. Selection criteria were good general condition allowing anesthesia, good bladder function (capacity of 300 ml), solitary tumor maximum 5 cm diameter, T1G3, T2, T3a. Before the implant an extensive transurethral resection was performed. The urologist carried out a cystostomy and the radiation oncologist did the implant using iridium-192 wires. The administered tumor dose was 60 Gy at a dose rate of 60-90 cGy/hour. RESULTS: The 5-year overall survival and disease-free survival was 67% and 73%, respectively. By stage, the 5-year disease-free survival was 100% in T1, 80% in T2 and 67% in T3. Local failure was observed in 15 patients (13%). Six of these relapses were salvaged by cystectomy. Ten patients had a superficial tumor Ta-T1 in bladder sites other than the original tumor site. Acute and late complications were unusual. The results compare quite well with those of other series published in the literature. CONCLUSION: Brachytherapy achieves excellent results in selected patients with solitary bladder cancer maintaining a fully functional bladder. Acute and late complications of this treatment modality are relatively infrequent.

Role of radiotherapy, in particular intraluminal brachytherapy, in the treatment of proximal bile duct carcinoma.

PURPOSE: To perform an analysis of the results obtained with radiotherapy in patients with either resectable or unresectable cholangiocarcinoma of the proximal bile ducts. Emphasis will be paid to analyse the role of radiotherapy, particularly brachytherapy. PATIENTS AND METHODS: Between 1985 and 1997, 109 patients received radiotherapy. In 71 patients (group I) tumor resection was combined with postoperative irradiation in 52 patients and pre- plus post-operative irradiation in 19 patients. Among this group, 41 patients had a boost of 10 Gy to the biliodigestive anastomosis using intraluminal brachytherapy. Median total dose was between 50-55 Gy. The other 38 patients (group II) had an unresectable tumor at laparotomy (16 patients) or were considered primary unresectable because locoregional tumor extension (22 patients). Brachytherapy boost through a nasobiliary approach was given to 19 patients (22-25 Gy). The median total dose varied between 60 to 68 Gy. Mean follow-up was 25 +/- 23 months. RESULTS: In group I, the survival rates at 1, 3, and 5 year were 84%, 37%, and 24%, respectively. Median survival was 24 months. Sixteen patients did live longer than 4 years. Analysis of prognostic factors among resected patients showed the tumor differentiation grade, microscopically involved margins other than the upper (hepatic) and lower (choledocus) resection parameters analysed, only the total dose had influence on margins, and elevated alkaline phosphatase as factors which significantly influence survival. From the different radiotherapy prognosis, patients receiving a total dose above 55 Gy had a shorter survival. It is important to note that patients receiving brachytherapy boost did not have a better survival than patients treated with external beam irradiation alone. Preoperative radiotherapy did not have impact on survival but recurrences in the surgical scars were not observed as compared to 15% recurrences if preoperative radiotherapy was not given. In group II the median survival was 10.4 months. Survival rates at 1 and 2 year were 43% and 10%, respectively. The only significant prognostic factor found was if unresectability was defined primarily or during laparotomy. As it was the case in group I, brachytherapy boost did not have influence on prognosis as compared to external beam irradiation alone. Observed late complications consisted of duodenal stenosis, upper digestive tract bleeding and cholangitis. Probably these complications were not only attributable to radiotherapy, as tumor relapse was also present in the majority of the cases. CONCLUSIONS: The role of radiotherapy either as adjuvant or as primary treatment remains to be demonstrated in prospective randomised studies. From our results, it seems that high radiation doses could be dangerous and could detriment prognosis. Brachytherapy boost was not superior to treatment with external beam irradiation alone.

[Hyperthermia in combination with radiotherapy]. / Hyperthermie in combinatie met radiotherapie.

The clinical application of hyperthermia in the treatment of oncological patients is based on a strong biological rationale: hyperthermia is an effective cell-killing agent, the effects of which can be induced selectively in tumour tissue. The mechanism of action of hyperthermia is complementary to that of radiotherapy (and chemotherapy). Furthermore, hyperthermia enhances the effects of radiotherapy (and of chemotherapy). In the approximately 20 years that hyperthermia was clinically investigated, much progress was made in the techniques of application. The clinical results achieved so far show that the therapeutic gain by adding hyperthermia can indeed be substantial.