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Hyperthermia was added to standard preoperative chemoradiation for rectal adenocarcinomas in a phase II study. Patients with T3-4 N0-2 M0 rectal cancer or local recurrences were included. Radiation dose was 54 Gy combined with capecitabine 825 mg/m2 × 2 daily and once weekly oxaliplatin 55 mg/m2. Regional hyperthermia aimed at 41.5–42.5 °C for 60 min combined with oxaliplatin infusion. Radical surgery with total or extended TME technique, was scheduled at 6–8 weeks after radiation. From April 2003 to April 2008, a total of 49 eligible patients were recruited. Median number of hyperthermia sessions were 5.4. A total of 47 out of 49 patients (96%) had the scheduled surgery, which was clinically radical in 44 patients. Complete tumour regression occurred in 29.8% of the patients who also exhibited statistically significantly better RFS and CSS. Rate of local recurrence alone at 10 years was 9.1%, distant metastases alone occurred in 25.6%, including local recurrences 40.4%. RFS for all patients was 54.8% after 5 years and CSS was 73.5%. Patients with T50 temperatures in tumours above median 39.9 °C had better RFS, 66.7% vs. 31.3%, p = 0.047, indicating a role of hyperthermia. Toxicity was acceptable.

Importance Patients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite optimal local treatment. Preoperative anthracycline plus ifosfamide chemotherapy improves outcome in common histological subtypes. Objective To analyze whether the previously reported improvement in local progression-free survival by adding regional hyperthermia to neoadjuvant chemotherapy translates into improved survival. Design, Setting, and Participants Open-label, phase 3 randomized clinical trial to evaluate the efficacy and toxic effects of neoadjuvant chemotherapy plus regional hyperthermia. Adult patients (age ≥18 years) with localized soft tissue sarcoma (tumor ≥5 cm, French Federation Nationale des Centers de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep) were accrued across 9 centers (6, Germany; 1, Norway; 1, Austria; 1, United States) from July 1997 to November 2006. Follow-up ended December 2014. Interventions After stratification for tumor presentation and site, patients were randomly assigned to either neoadjuvant chemotherapy consisting of doxorubicin, ifosfamide, and etoposide alone, or combined with regional hyperthermia. Main Outcomes and Measures The primary end point was local progression-free survival. Secondary end points included treatment safety and survival, with survival defined from date of randomization to death due to disease or treatment. Patients lost to follow-up were censored at the date of their last follow-up. Results A total of 341 patients were randomized, and 329 (median [range] age, 51 [18-70] years; 147 women, 182 men) were eligible for the intention-to-treat analysis. By December 2014, 220 patients (67%; 95% CI, 62%-72%) had experienced disease relapse, and 188 (57%; 95% CI, 52%-62%) had died. Median follow-up was 11.3 years. Compared with neoadjuvant chemotherapy alone, adding regional hyperthermia improved local progression-free survival (hazard ratio [HR], 0.65; 95% CI, 0.49-0.86;P = .002). Patients randomized to chemotherapy plus hyperthermia had prolonged survival rates compared with those randomized to neoadjuvant chemotherapy alone (HR, 0.73; 95% CI, 0.54-0.98;P = .04) with 5-year survival of 62.7% (95% CI, 55.2%-70.1%) vs 51.3% (95% CI, 43.7%-59.0%), respectively, and 10-year survival of 52.6% (95% CI, 44.7%-60.6%) vs 42.7% (95% CI, 35.0%-50.4%). Conclusions and Relevance Among patients with localized high-risk soft tissue sarcoma the addition of regional hyperthermia to neoadjuvant chemotherapy resulted in increased survival, as well as local progression-free survival. For patients who are candidates for neoadjuvant treatment, adding regional hyperthermia may be warranted. Trial Registration clinicaltrials.gov Identifier:NCT00003052

The role of consolidative radiotherapy (RT) in advanced diffuse large B-cell lymphoma (DLBCL) is not established.In a population-based retrospective analysis of patients with DLBCL in Western Norway during 2003 to 2008, 170 consecutive patients admitted to Haukeland University Hospital (HUS) and 94 to Stavanger University Hospital (SUS) were included. The mean age was 64 years (range, 17-95 years), 147 patients (56%) were male, 80 patients (30%) had stage I/II, 126 patients (48%) stage III/IV, and 57 patients (22%) had primary extranodal disease.There were no differences between hospitals in patient characteristics, use of rituximab, number of chemotherapy courses or cumulative doses, or in distribution of response categories after chemotherapy. The use of RT was significantly different: 17 patients (23%) received RT at SUS and 92 patients (65%) at HUS (P .001). For 219 patients with International Prognostic Index (IPI) score of 0 to 3, 5-year cancer-specific survival (CSS) was 67% at SUS and 81% at HUS (P = .012). For 73 patients with complete response after chemotherapy there were no differences in survival between patients with and without RT. For 138 patients with any residual mass after chemotherapy, there were highly significant differences in favor of receiving RT (n = 81) versus no RT (n = 57): 5-year CSS 89% versus 69% (P .001), and 5-year overall survival 82% versus 59% (P = .005). The effect of RT on residual mass was evident in most subgroups, mainly in low to intermediate risk, but not in high-risk (IPI 4-5) patients.With the limitations of a retrospective study, these data suggest that consolidative RT might improve survival in DLBCL patients with a residual mass after chemotherapy, also in advanced disease.

BACKGROUND. The incidence of primary central nervous system lymphoma (PCNSL) appears to be increasing in some countries, whereas it is stable in others. Many reports the last decades have suggested that there have been improvements in the treatment of PCNSL. The objective of this study was to analyze time trends in the incidence, clinical features, histologic diagnosis, treatment, and outcome of nonacquired immunodeficiency syndrome (non-AIDS) PCNSL in Norway from 1989 to 2003. METHODS. Patients were identified by a chart review of all patients who had a recorded diagnosis of PCNSL from 1989 to 2003 in The Norwegian Cancer Registry. The histologic and cytologic material from each patient was re-examined by pathologists. Time trends were analyzed according to year of diagnosis grouped into 3 5-year periods: 1989–1993, 1994–1998, and 1999–2003. RESULTS. There were 98 patients who had confirmed, newly diagnosed non-AIDS PCNSL in Norway from 1989 to 2003. The incidence rate increased during the consecutive 5-year periods from 0.89 per million during 1989 to 1993, to 1.74 per million during 1994 to 1998, and to 1.82 per million during 1999 to 2003 (P = .013). Diagnostic delay and overall survival did not improve with time. Survival decreased from 1999 to 2003 compared with survival from 1994 to 1998, which was explained in part by reduced performance status and fewer patients receiving combined chemotherapy and radiotherapy during 1999 to 2003. In multivariate analysis, age ≤50 years, a good performance status, and active treatment (especially combined chemotherapy and radiotherapy) significantly improved survival. CONCLUSIONS. The incidence of PCNSL is increasing in Norway. Despite diagnostic and therapeutic advances over the last decades, neither a reduction in diagnostic delay nor any improvement in overall survival with time was observed. The search for improved understanding of etiology and treatment should be intensified. Cancer 2007. © 2007 American Cancer Society.

This study investigates delay in diagnosing primary central nervous system lymphoma (PCNSL), which has a variable clinical and radiological presentation. Early diagnosis and treatment may improve survival and cause less sequela in PCNSL. Medical records of all new cases of PCNSL morphologically verified while alive or by autopsy in Norway in 1989-1998 were reviewed (n = 74). The time from initial symptom to final morphological diagnosis of PCNSL had a median (mean, range) of 70 (106, 22-330) days in 16 AIDS patients and 75 (157, 8-1285) days in 58 non-AIDS patients. Among non-AIDS patients, the time to diagnosis was longer in patients with no tumour in the first neuroimaging report after initial symptom (p = 0.001). Median (mean, range) time from initial symptom to neuroimaging was 14 (25, 1-60) days in AIDS patients and 21 (88, 1-1095) days in non-AIDS patients. In the non-AIDS group, those presenting with personality change or visual disturbance had more delayed imaging than the others. The time from first neuroimaging examination to final diagnosis in non-AIDS patients had a median (mean, range) of 28 (69, 1-845) days, and was longer when no tumour was indicated in the imaging report (p = 0.005) and if first biopsy did not confirm the diagnosis (p = 0.02). All AIDS patients had their diagnosis of PCNSL first established by autopsy. The time from first neuroimaging to autopsy had a median (mean, range) of 48 (81, 10-270) days. There is a considerable delay in the diagnosis of PCNSL and strategies for earlier diagnosis are thus needed. Physicians should consider early neuroimaging in patients with personality changes or visual disturbance, early renewed imaging in patients with persistent neurological symptoms but no tumour on initial imaging, and early/repeated biopsy of focal brain lesions in both AIDS patients and non-AIDS patients.

BACKGROUND. Patients with advanced cervical carcinoma are treated routinely with radiotherapy and cisplatin-containing chemotherapy. It has been shown that hyperthermia can improve the results of both radiotherapy and cisplatin. In the current study, the feasibility and efficacy of the combination of all three modalities was studied in previously untreated patients with cervical carcinoma. METHODS. Patients with advanced cervical carcinoma were registered prospectively in the U.S., Norway, and the Netherlands. External-beam radiotherapy and brachytherapy were administered for a biologically effective dose ! 86.7 gray. At least 4 courses of weekly cisplatin (40 mg/m 2 ) and 4 sessions of weekly locoregional hyperthermia were added to radiotherapy. RESULTS. Sixty-eight patients with a median age of 45 years were enrolled. Fulldose radiotherapy was delivered to all patients according to plan. At least 4 courses of chemotherapy were received by 97% of patients, and at least 4 courses of hyperthermia treatment were received by 93% of patients. Toxicity was fully comparable to that described for chemoradiotherapy alone, and the median total treatment time was 45 days. Complete remission was achieved by 61 patients (90%). After a median follow-up of 538 days, 74% of patients remained alive without signs of recurrence, and the overall survival rate was 84%. CONCLUSIONS. The combination of full-dose radiotherapy, chemotherapy, and hyperthermia was feasible and effective in a multicenter international setting among patients with advanced cervical carcinoma. A Phase III study comparing this novel triplet with standard chemoradiation, designed to show at least a 15% improvement in overall survival, has been launched. Cancer 2005;104:763‐70. © 2005 American Cancer Society.

The incidence of primary central nervous system lymphoma (PCNSL) has been reported to increase in some parts of the world, while being stable in other regions. In an attempt to characterize the incidence rate, clinical features, treatment, outcome, and prognostic factors of PCNSL in Norway, we report our experience in a large unselected series of patients. Clinical features, histological diagnosis, radiological findings, treatment, and outcome of all patients diagnosed with PCNSL in Norway in the years 1989 � /1998 were registered. During the 10-year period 58 new cases of histologically verified PCNSL were registered in Norway. The annual incidence rate of PCNSL was on average 1.34 cases per million people with a non-significant increasing trend (p� /0.069). For patients diagnosed before death (n� /45) the estimated survival following histological diagnosis was 55%, 47%, and 23% at 1, 2, and 5 years, respectively. In Cox-regression analysis age, WHO performance status and treatment had independent prognostic impact on survival. In the studied decade, there was a non-significant trend towards increased incidence of PCNSL, perhaps due to increased availability of diagnostic imaging, especially magnetic resonance imaging.

This study reports on oncology professionals' knowledge and attitude toward complementary and alternative medicines (CAM), classified according to their primary application as complementary or alternative methods. In June 2002, we conducted a national, multicentre survey of 828 Norwegian oncologists, nurses, clerks and therapeutic radiographers. A response rate of 61% was achieved. Only a few physicians (4%) described their reactions to alternative medicine as positive compared with nurses (33%), therapeutic radiographers (32%) and clerks (55%) (P

Estrogens administered in high doses were commonly used for therapy of advanced breast cancer before the introduction of contemporary endocrine therapy. While the mechanism of the antitumor effect is unknown, in vitro investigations have shown estrogens in high concentrations to be toxic to cell growth. Further, it has been shown that exposure of MCF-7 cells to estrogens in low concentrations may enhance the sensitivity and also lower the toxicity threshold to estrogens. This study was designed to evaluate treatment with diethylstilbestrol (DES) in postmenopausal women with advanced breast cancer becoming resistant to estrogen deprivation. Thirty-two patients with advanced breast cancer previously exposed to multiple endocrine treatment regimens (median 4, range 2-10) were enrolled. Their tumor should have revealed evidence of endocrine sensitivity (previous partial response or at least stable disease foror = 6 months to therapy). Each patient received DES 5 mg t.i.d. Four patients terminated therapy afteror = 2 weeks on therapy due to side effects; another two patients terminated therapy before progression for similar reasons (one patient after SD for 15 weeks and one with a PR after 39 weeks). Four patients obtained CR and six patients PR. In addition, two patients had SD foror = 6 months duration. Five patients had an objective response and one patient a SD lasting foror = 1 year. Our results reveal estrogens administered in high doses may have antitumor effects in breast cancer patients heavily pretreated with endocrine therapy. Such treatment represents a valuable alternative to chemotherapy in selected patients.

Purpose : To examine the effect of infusion of the vasodilator sodium nitroprusside (SNP) on the blood flow in normal tissues and BT 4 An tumors growing subcutaneously or intramusculary in BD IX rats. Methods and Materials : Sodium nitroprusside was given as a continuous intravenous infusion to keep the mean arterial pressure stable at 60 mmHg. The cardiac output, organ blood flow, and perfusion of the BT4An tumors were measured by injection of radiolabelled microspheres at control conditions and after 20 min SNP infusion in each animal. Two series of experiments were performed with two anesthetics with different mechanisms of action, Inactin and the midazolam-fentanyl-fluanisone combination (MFF), to secure reliable conclusions. Results : Cardiac output, heart rate, and blood flow to the skeletal muscles, heart, and liver increased during SNP infusion in either anesthetic group. In the kidneys and particularly in the skin, decreased blood flow by SNP was observed. When located subcutaneously on the foot, the blood flow in the tumor fell to 23.4% and 21.4% of the control values in the MFF- and Inactin-anesthetized animals, respectively. This was accompanied by a similar fall in the blood flow in the foot (tumor bed) itself. In the intramuscular tumor the blood flow fell to 24.8% of the control value in the MFF group, whereas the corresponding figure was 36.2% in the Inactin group. In the surrounding muscle (tumor bed) the blood flow increased significantly, most pronounced in the MFF experiment, where it was tripled. Conclusion : The fall in the tumor perfusion by SNP may be exploited therapeutically to increase the tumor temperature during hyperthermia. Predominant heating of the tumor compared to the tumor bed can be expected if the tumor is growing in or near skeletal muscles.

Purpose: Intraperitoneal hypertonic glucose has previously been shown to induce hyperglycemia, hemoconcentration, and to influence systemic and tumor circulation, and, thus, enhance the effect of thermochemotherapy with 1-(4-amino-2-methylpyrimidine-5-yl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). However, the optimal timing and the precise mechanisms responsible are not known. The effect of different time intervals between glucose load and thermochemotherapy with ACNU in the treatment of BT 4 An tumors, therefore, was investigated. Changes of serum glucose (Se-glucose), hemoglobin, systemic circulation parameters, tumor pH, and tumor temperature, induced by intraperitoneal glucose and/or hyperthermia, were measured to assess their effect on tumor growth. Methods and Materials: (a): Inbred BD IX rats with BT 4 An tumors on the hind leg were treated with ACNU 7 mg/kg intravenously just before waterbath hyperthermia, and intraperitoneal hypertonic glucose (6 g/kg) at different time intervals before (240-0 min) or immediately after thermochemotherapy. (b): Intratumoral pH and temperature were measured at different intervals after intraperitoneal glucose, and during hyperthermia with or without previous glucose. (c): Hemoglobin, hematocrit, and Se-glucose were measured at different times after intraperitoneal glucose. (d): Mean arterial pressure, pulse pressure, and heart rate were measured for 120 min after intraperitoneal glucose. Results: (a): The number of tumor controls and the growth delay was greatest with glucose 45 min before thermochemotherapy, and least with a time interval of 240 min. Glucose after thermochemotherapy delayed tumor growth. (b): After intraperitoneal glucose alone, intratumoral pH decreased gradually from 6.76 to 5.86 after 240 min. Hyperthermia 120 min after glucose induced a rapid further pH drop, while hyperthermia alone had no significant influence on pH. Intratumoral temperature was higher during hyperthermia in animals given glucose. (c): A substantial rise of Se-glucose and hemoglobin developed. The hemoconcentration was maintained also after reduction of Se-glucose towards normal values. (d): An initial tachycardia, and a reduction of the mean arterial pressure of about 10% 5–45 min after glucose was measured. Conclusions: The data indicate that a complex interaction between gradually reduced tumor pH, hyperglycemia, hemoconcentration, and reduced tumor blood flow, and not a breakdown of systemic circulation, is responsible for the effect of intraperitoneal glucose on thermochemotherapy with ACNU. Interestingly, enhancement of thermochemotherapy effect was also seen when intraperitoneal glucose was given after heat and ACNU.

e17023Background: Standard treatment of locally advanced cervical carcinoma consists of concurrent radiotherapy (including brachytherapy) and chemotherapy (weekly cisplatin 40 mg/m2), or chemoradio...

Published version of an article in the journal: BMC Cancer. Also available from the publisher at: http://dx.doi.org/10.1186/1471-2407-13-9 Open access Background: Faced with a life-threatening illness, such as cancer, many patients develop stress symptoms, i.e. avoidance behaviour, intrusive thoughts and worry. Stress management interventions have proven to be effective; however, they are mostly performed in group settings and it is commonly breast cancer patients who are studied. We hereby present the design of a randomized controlled trial (RCT) evaluating the effectiveness and cost-effectiveness of an individual stress-management intervention with a stepped-care approach in several cancer diagnoses. Method: Patients (>= 18 years) with a recent diagnosis of breast cancer, colorectal cancer, lymphoma, prostate cancer or testicle cancer and scheduled for adjuvant/curative oncology treatment, will consecutively be included in the study. In this prospective longitudinal intervention study with a stepped-care approach, patients will be randomized to control, treatment as usual, or an individual stress-management intervention in two steps. The first step is a low-intensity stress-management intervention, given to all patients randomized to intervention. Patients who continue to report stress symptoms after the first step will thereafter be given more intensive treatment at the second step of the programme. In the intervention patients will also be motivated to be physically active. Avoidance and intrusion are the primary outcomes. According to the power analyses, 300 patients are planned to be included in the study and will be followed for two years. Other outcomes are physical activity level, sleep duration and quality recorded objectively, and anxiety, depression, quality of life, fatigue, stress in daily living, and patient satisfaction assessed using valid and standardized psychometric tested questionnaires. Utilization of hospital services will be derived from the computerized patient administration systems used by the hospital. The cost-effectiveness of the intervention will be evaluated through a cost-utility analysis. Discussion: This RCT will provide empirical evidence of whether an individually administered stress-management programme in two steps can decrease stress as well as maintain or enhance patients' physical activity level, quality of life and psychological well-being. Further, this RCT, with a stepped-care approach, will provide knowledge regarding the cost-effectiveness of an individually administered stress-management programme whose aim is to help and support individual patients at the right level of care.

Patients given preoperative radiotherapy (31.5 Gy in 18 fractions) in a prospective, randomized trial of presumably operable rectal adenocarcinoma, were examined for a possible relation between bowel toxicity manifested as diarrhoea, and tumour size in the operative specimen, in addition to recurrence rate. The group requiring drugs for diarrhoea had significantly smaller tumours at surgery (2.5 cm versus 3.5 cm, p > 0.05). Patients without significant radiation-induced diarrhoea had also more recurrences (37.5% against 14.3%, p = 0.01). The disease-specific survival rate was also significantly better (p = 0.02) at 1.5 and 10 years in patients with diarrhoea WHO grade 3 and 4; 89.5%, 75.9% and 65.1% compared to 83.5%, 49.3% and 44.4% in patients with no or minimal radiation-induced loose bowels. These results indicate that the reaction of the normal bowel to radiation may correlate to radiation sensitivity of tumours derived from the same tissue.

The effect of thermochemotherapy with cisplatin or carboplatin was compared in the BT 4 -cell line. In vitro . BT 4 C-cells were treated with different concentrations of cisplatin or carboplatin, with or without simultaneous hyperthermia. In vivo : Inbred BD IX rats with transplanted glioma-like BT 4 A or glioblastoma-like BT 4 An tumors on the hind leg were treated with cisplatin (4 mg/kg) or carboplatin (50 mg/kg), with or without local hyperthermia. In vitro the benefit of adding hyperthermia to chemotherapy was similar for cisplatin and carboplatin. For both cisplatin and carboplatin, the difference of treatment effect between thermochemotherapy and chemotherapy alone increased with higher drug concentrations. In vivo hyperthermia clearly enhanced the effect of carboplatin on BT 4 A tumors. When treating BT 4 An tumors, thermochemotherapy with cisplatin or carboplatin was equally effective. Both combinations were superior to treatment with hyperthermia alone. Local toxicity and weight loss following thermochemotherapy were comparable when substituting cisplatin with carboplatin.

Purpose To elucidate changes in gene expression after treatment with regional thermochemoradiotherapy in locally advanced squamous cell cervical cancer. Methods and Materials Tru-Cut biopsy specimens were serially collected from 16 patients. Microarray gene expression levels before and 24 h after the first and second trimodality treatment sessions were compared. Pathway and network analyses were conducted by use of Ingenuity Pathways Analysis (IPA; Ingenuity Systems, Redwood City, CA). Single gene expressions were analyzed by quantitative real-time reverse transcription–polymerase chain reaction. Results We detected 53 annotated genes that were differentially expressed after trimodality treatment. Central in the three top networks detected by IPA were interferon alfa, interferon beta, and interferon gamma receptor; nuclear factor κB; and tumor necrosis factor, respectively. These genes encode proteins that are important in regulation cell signaling, proliferation, gene expression, and immune stimulation. Biological processes over-represented among the 53 genes were fibrosis, tumorigenesis, and immune response. Conclusions Microarrays showed minor changes in gene expression after thermochemoradiotherapy in locally advanced cervical cancer. We detected 53 differentially expressed genes, mainly involved in fibrosis, tumorigenesis, and immune response. A limitation with the use of serial biopsy specimens was low quality of ribonucleic acid from tumors that respond to highly effective therapy. Another “key limitation” is timing of the post-treatment biopsy, because 24 h may be too late to adequately assess the impact of hyperthermia on gene expression.

Background Primary central nervous system lymphoma (PCNSL) is a frequent complication in acquired immunodeficiency syndrome (AIDS). The objective of this survey was to investigate incidence, clinical features, radiological findings, histologic diagnosis, treatment and outcome for all patients with histologically verified AIDS-related PCNSL diagnosed in Norway in 1989–2003. Methods We identified the patients by chart review of all cases recorded as PCNSL in The Norwegian Cancer Registry (by law recording all cases of cancer in Norway) and all cases recorded as AIDS-related PCNSL in the autopsy registry at a hospital having 67% autopsy rate and treating 59% of AIDS patients in Norway, from 1989 to 2003. Histologic material and radiological images were reviewed. We used person-time techniques to calculate incidence rates of PCNSL among AIDS patients based on recordings on AIDS at the Norwegian Surveillance System for Communicable Diseases (by law recording all cases of AIDS in Norway). Results Twenty-nine patients had histologically confirmed, newly diagnosed AIDS-related PCNSL in Norway from 1989–2003. Only 2 patients had this diagnosis established while alive. AIDS patients had 5.5% lifetime risk of PCNSL. Their absolute incidence rate of PCNSL per 100 person-years was 1.7 (95%CI: 1.1–2.4) and decreased during the consecutive 5-year periods from 3.6, to 2.5, and to 0.4 (p < 0.001). Median survival from initial symptom of PCNSL was 2.3 months, but one patient was still alive 4 years after completed radiotherapy. Conclusion This is the first national survey to confirm decreasing incidence of AIDS-related PCNSL. Despite dismal survival in most patients, the possibility of long term survival should prompt more aggressive diagnostics in suspected PCNSL.

As low-dose metronomic cyclophosphamide (CTX) and hyperthermia (HT) both exert antitumour effects in part through antiangiogenic mechanisms, interactive effects of the two modalities were explored.Subcutaneously implanted rat tumours (BT4An) were treated with CTX 35 mg/kg i.p. three doses a week for two weeks, local water-bath HT yielding mean tumour temperature of 43 degrees C for one hour at day 0, both modalities combined (CTX-HT(0)), or saline. TUNEL assays, immunohistochemical staining of thrombospondin 1 (TSP-1) and real time RT-PCR of TSP-1 mRNA were analysed the first three hours after completed treatment day 0.Metronomic dosed CTX (p=0.006) and HT (p0.001) both delayed tumour growth. The combined regimen was superior to either modality alone (p0.001). Complete tumour regressions were observed in CTX (6%), HT (12%), and CTX-HT(0) (41%) treated rats. TSP-1 protein was specifically upregulated in the vascular matrix of tumours receiving CTX (weak), HT (moderate) and CTX-HT(0) (strong). In contrast, reduced expression of TSP-1 protein was observed in tumour cells after HT alone and CTX-HT(0). TUNEL assays indicated induction of apoptosis by HT and CTX-HT(0) 90 minutes after end of the first treatment.A single session of local HT enhances the effects of low-dose metronomic CTX, possibly in part mediated through a differential effect on TSP-1 protein levels in tumour cells and tumour vasculature.

R.D. Issels, L.H. Lindner, P. Ghadjar, P. Reichardt, P. Hohenberger, J. Verweij, S. Abdel-Rahman, S. Daugaard, C. Salat, Z. Vujaskovic, R. Wessalowski, H.R. Duerr, F. Ploner, O. Mella, M. Schmidt, U. Mansmann, K.W. Jauch, C. Belka, W. Hiddemann, A. Gronchi. Klinikum der Univers. Munchen-Groshadern Klinikum Grosshadern, Medical Clinic III, Munchen, Germany; Klinikum der Universitat Munchen, Medizinische Klinik III, Munich, Germany; Charite Universitatsmedizin Berlin, Klinik fur Radio-Onkologie und Strahlentherapie, Berlin, Germany; Helios Klinikum Berlin-Buch, Interdisziplinare Onkologie, Berlin, Germany; Universitatsklinikum Mannheim, Spezielle chirurgische Onkologie, Mannheim, Germany; Erasmus Medical Center, Medical Oncology, Rotterdam, Netherlands; Rigshospitalet, Pathology, Copenhague, Denmark; University of Maryland, Translational Radiation Sciences, Baltimore, USA; Universitatsklinikum Duesseldorf, Klinik fur Kinder-Onkologie − Hamatologie und Immunologie, Duesseldorf, Germany; Klinikum der Universitat Munchen, Tumororthopadie, Munich, Germany; Universitatsklinikum Graz, Klinische Onkologie, Graz, Austria; Haukeland University Hospital, Medical Oncology, Bergen, Norway; Ludwig Maximilians Universitat Munchen, Institut fur Medizinische Informatik − Biostatistik und Epidemiologie, Munich, Germany; Klinikum der Universitat Munchen, Klinik fur Chirurgie, Munich, Germany; Klinikum der Universitat Munchen, Klinik fur Strahlentherapie, Munich, Germany; 16 Istituto Nazionale dei Tumori, Chirurgia dei Sarcoma, Milano, Italy

AIthough intensity-modulated radiotherapy (IMRT) may increase the therapeutic ratio of radiotherapy for a range of malignancies, only a few IMRT treatments have yet been performed in the Nordic countries. The scores derived from a national survey to assess Norwegian oncologists' expectations of IMRT are presented. A questionnaire was distributed to all consultants in oncology at Norwegian radiotherapy clinics. Summary scores of daily general radiotherapy workload (DGRTW), acquaintance with IMRT (AI) and expectations of IMRT (EI) were derived. Thirty-nine questionnaires (67%) were returned from a total of 58 oncologists. The oncologists' scores on the AI scale (mean score: 7.5 out of 21) were rather low. Their AI scores were found to be positively correlated with their DGRTW. Higher scores on the EI scale were documented (mean score: 6.2 out of 14): 15 oncologists (39%) rated IMRT as one of the three major contributors to potentially increased cancer survival. Oncologists treating patients with prostate, head and neck, gastrointestinal and CNS tumours had higher EI scores than the other oncologists (7.7 vs. 5.1; p = 0.01). The Norwegian radiation oncologists' expectations of IMRT are high in terms of both the potential clinical benefit and the rate of implementation. This should encourage the radiotherapy communities to continue (or rapidly initiate) their efforts in providing the routines required for safe implementation of IMRT.

There are two evidence based therapeutic options for locally advanced cervical cancer: Radiotherapy and concurrent chemotherapy (cisplatin alone or combined with other drugs) or radiation and hyperthermia, documented in randomised trials. The weight of evidence is less for the most advanced stages. Combination of all three options are currently tested in several centres with good clinical response and acceptable toxicity. Based on a pragmatic approach we propose to proceed with a trial selecting cisplatin concurrent with radiation therapy as the standard arm to be compared with the same regimen with the addition of hyperthermia once a week.

Background and purpose: Combretastatin A-4 disodium phosphate (CA-4) enhances thermal damage in s.c. BT4An rat gliomas. We currently investigated how CA-4 and hyperthermia affect the tumor microenvironment and neovasculature to disclose how the two treatment modalities interact to produce tumor response. Methods: By confocal microscopy and immunostaining for von Willebrand factor, we examined the extent of vascular damage subsequent to CA-4 (50 mg/kg) and hyperthermia (waterbath 44°C, 60 min). The influence on tumor oxygenation was assessed using interstitial pO2-probes (Licox system) and by immunostaining for pimonidazole. We examined the direct effect of CA-4 on the tumor cell population by flow cytometry (cell cycle distribution) and immunostaining for β-tubulin (cytoskeletal damage). Results: Whereas slight vascular damage was produced by CA-4 in the BT4An tumors, local hyperthermia exhibited moderate anti-vascular activity. In tumors exposed to CA-4 3 h before hyperthermia, massive vascular damage ensued. CA-4 reduced the pO2 from 36.1 to 17.6 mmHg (P=0.01) in the tumor base, and tumor hypoxia increased slightly in the tumor center (pimonidazole staining). Extensive tumor hypoxia developed subsequent to hyperthermia or combination therapy. Despite a profound influence on β-tubulin organization in vitro, CA-4 had no significant effect on the cell cycle distribution in vivo. Conclusion: Our results indicate that the anti-vascular activity exhibited by local hyperthermia can be augmented by previous exposure to CA-4.

Attacking tumor vasculature is a promising approach for the treatment of solid tumors. The tubulin inhibitor combretastatin A-4 disodium phosphate (CA-4) is a new vascular targeting drug which displays a low toxicity profile. We wanted to investigate how CA-4 influences tumor perfusion in the BT4An rat glioma and how the vascular targeting properties of CA-4 could be exploited to augment hyperthermic damage towards tumor vasculature.We used the (86)RbCl extraction technique to assess how CA-4 influences tumor perfusion, and the tumor endothelium was examined for morphological changes induced by the drug. We combined CA-4 (50 mg/kg i.p.) with hyperthermia (44 degrees C, 60 min) at different time intervals to evaluate how therapy should be designed to affect tumor growth, and we studied the tumors histologically to assess tissue viability.We found that CA-4 induced a profound, but transient reduction in tumor perfusion 3-6 h postinjection. If hyperthermia was administered 3-6 h after injecting CA-4, massive hemorrhagic necrosis developed, and tumor response was significantly enhanced compared to simultaneous administration of the two treatment modalities (P0.005). CA-4 alone had no influence on tumor growth and failed to disrupt the vasculature of the BT4An solid tumors. Interestingly though, a mild endothelial edema was observed in some tumor areas 3 h after injecting CA-4.We conclude that the combination of CA-4 and hyperthermia is a potent therapeutic option for BT4An tumors, but the selection of adequate time intervals between CA-4 and hyperthermia are imperative to obtain tumor response.

Purpose: To investigate the toxicity of combretastatin A-4 disodium phosphate (CA-4) and its vascular effects in the subcutaneous (s.c.) BT 4 An rat glioma, and additionally, to determine the tumor response of CA-4 combined with hyperthermia. Methods and Materials: For assessment of drug toxicity, rats were given 50, 75, or 100 mg/kg CA-4 and followed by daily registration of weight and side effects. Interstitial tumor blood flow was determined by laser Doppler flowmetry in rats injected with 50 mg/kg CA-4. In the tumor response study we administered CA-4 50 mg/kg alone or combined with hyperthermia (waterbath 44°C for 60 min) 0 or 3 h later. Results: We found that CA-4, at a well-tolerated dose of 50 mg/kg, induced a considerable time-dependent decrease in the tumor blood flow. Tumor blood flow was reduced by 47–55% during the first 110 min after injecting CA-4, and thereafter remained decreased until the measurements were terminated. Administering CA-4 3 h before hyperthermia yielded the best tumor response and increased tumor growth time significantly compared with simultaneous administration of CA-4 and hyperthermia ( p = 0.03). Interestingly, CA-4 alone did not influence tumor growth. Conclusion: CA-4 induces a gradual reduction in tumor blood flow which can be exploited to sensitize the BT 4 An tumor for hyperthermia.

Purpose The effect of a decrease in the mean arterial blood pressure (MAP) induced by sodium nitroprusside (SNP) on the tumor temperature during hyperthermia (HT), and on the cytotoxic effect of HT, was studied in the BT4An tumor transplanted to the hind limb of BD IX rats. Experiments with two different anesthetics, pentobarbital and the midazolam/fentanyl/fluanisone combination (MFF), were performed to secure reliable conclusions. Methods and materials In the tumor response experiments local waterbath HT at 44.0 degrees C was given for 60 min. Sodium nitroprusside was administered as a continuous intravenous infusion to lower the MAP to 60 or 80 mmHg during HT. In two other experiments the temperature at the base of the tumor during HT was measured before and during SNP infusion. In animals without tumor the temperature was measured subcutaneously on the foot during HT with or without SNP-induced hypotension. Results When SNP was given to lower the MAP to 60 mmHg during HT in MFF anesthetized animals, the median tumor growth time (TGT) was 70 days, compared to 14.5 days in the HT alone group. The corresponding figures were 127 and 12.1 days with pentobarbital anesthesia. In the HT + SNP group, more than 40% cure was observed in both experiments. No cures were seen in any of the other groups. Hyperthermia alone prolonged the TGT slightly, whereas SNP given alone had no effect, compared to controls. When the MAP was lowered to 80 mmHg by SNP infusion during HT (MFF anesthesia), the median TGT was 19.9 days, which was significantly longer than that in the HT alone group (10.9 days). In the MAP range from 60 to 120 mmHg, a nearly linear relationship between the MAP and the tumor temperature was found during HT in MFF anesthetized animals. With both anesthetics, the median temperature at the base of the tumor was about 0.8 degrees C higher during HT when the MAP was lowered to 60 mmHg by SNP. In animals without tumors, the temperature subcutaneously on the foot was 0.3 and 0.4 degrees C higher during SNP infusion in the MFF and pentobarbital group, respectively. Conclusion We have developed a small animal model in inbred rats feasible for exploring the influence of a stable blood pressure reduction induced by SNP, on the effect of HT given alone or in combination with other treatment modalities to a transplantable tumor. The greatly increased cytotoxic effect of local waterbath HT in the present tumor response experiments is probably a consequence of increased tumor temperature during SNP infusion.

The cerebral BT4An glioma model in BD IX rats was used to study the effect of hyperthermia given in combination with radiotherapy (thermoradiotherapy) in the treatment of brain tumours. A single treatment with high dose rate radiation was given to a local brain field. Local brain hyperthermia was given at 42.4 degrees C for 45 min by externally applied microwaves (700 MHz), immediately before radiotherapy (10 Gy). In a pilot study, thermoradiotherapy increased the median life span with 20 days compared to controls, which was significantly better than that observed after radiotherapy alone (7 days). In an extended experiment the corresponding figures for thermoradiotherapy, hyperthermia alone and radiotherapy alone were 12.5, 3.5, and 3.5 days, respectively. Thermoradiotherapy was significantly better than radiotherapy and hyperthermia alone. There was no acute mortality in these experiments. Neurological side-effects were infrequent, of slight degree and reversible. The present study shows that a survival benefit of adding hyperthermia to radiotherapy can be achieved without unacceptable neurological side-effects in an animal glioma model.

The purpose of the study was to evaluate and compare the efficacy and tolerability of two cytostatic regimens-chlorambucil, vinblastine, procarbazine and prednisone (ChlVPP) vs. ChlVPP alternating with doxorubicin, bleomycin, vincristine and dacarbazine (ABOD). One hundred eligible patients with stage IIIA-IVB Hodgkin's disease were randomized to either ChlVPP or ChlVPP alternating with ABOD. The complete response rate (CR) was 80% in both treatment groups. After a median follow-up time of 59 months, 42 (84%) of the patients in the ChlVPP-treated group were in CR compared with 39 (78%) treated with ChlVPP/ABOD. The estimated five-year overall and relapse-free survival rates were 87% and 74%, respectively, for the ChlVPP-treated patients and 76% and 73% for the ChlVPP/ABOD-treated patients. The ChlVPP regimen showed a slightly better subjective tolerance than the ChlVPP/ABOD regimen. The given dose intensity was very close to optimal, and equal for the two regimens.

An in vivo glioma model was developed in syngeneic BD IX rats. The BT4An tumor was derived from serial in vivo passages of the BT4A tumor, originally induced from transformed fetal rat brain cells after transplacental exposure to ethylnitrosourea. The cell line was characterized for the presence of neuroglial differentiation markers, chromosome content and cell cycle distribution as determined by flowcytometry. A standardized method for i.c. tumor induction was developed, and the tumors were investigated by light and electron microscopy and for evidence of blood-brain barrier disruption. Tumor cell ability for phagocytosis was studied, as this property may be important for the invasion pattern of the tumors. We conclude that the model seems suitable for both in vivo therapy and invasion studies. The tumor had 100% tumor take, yielded a predictable symptom-free life span after inoculation, had a characteristic histological picture of an aggressive glioma, and the blood-brain barrier within the tumor was in part disrupted. Compared to the parent cell line, there was loss of neuroglial differentiation markers, the chromosomal distribution was changed, and the ability for phagocytosis was practically lost.

A prospective and randomized trial has been performed in order to evaluate combined modality therapy in patients with astrocytomas grade 3 and 4. Follow-up information is available on 244 patients. One half of the series received radiation therapy twice a week (40.00 Gy/5 weeks), the other half five times a week (50.00 Gy/5 weeks). Misonidazole 1.2 g/m2 was given orally to one half of the patients in the first radiation treatment group 3 1/2 to 4 hours before the treatment. The other half received placebo. The second radiation treatment group was also divided in two halves, one receiving 0.48 g/m2 misonidazole and the other placebo 3 1/2 to 4 hours before radiation. The randomization also included a subdivision of the material into eight groups of which four were given CCNU and four no chemotherapy, beginning 3 months after operation. The dose of CCNU was 120 mg/m2 body surface every 6 weeks. All eight treatment groups showed practically identical periods of median survival, and no statistically significant differences were observed with regard to performance status, side effects, or complications. Another dosage and timing of misonidazole administration in relation to the irradiation schedule, and a consideration of effects of concomitant drugs like dexamethasone and phenytoin are discussed.

The interaction of hyperthermia (HT) 1 hour at 44.0"C and cyclophosphamide (CP) 200 mg/kg was studied in vivo in a solid transplantable neurogenic rat tumor (BT4A) in the foot of BD IX rats. HT was given by water bath heating. When both modalities were close in time (CP immediately before HT or 1 hour before HT), an enhanced effect with complete regression and cure of tumors was seen. This could not be obtained with either modality alone. Extending the interval between treatments within 24 hours, an effect equal to the sum of each modality was obtained when HT was given before CP, while HT after CP was less effective. Timing and sequence may be critical factors for the optimal combination of HT and cytotoxic drugs. Cancer 52:983-987, 1983.

We report three patients with advanced breast cancer who received hyperthermia (43 degrees C over 1 h, weekly x 4) and radiotherapy as palliative treatment for chest-wall recurrence. The case reports demonstrate situations where hyperthermia may be beneficial. These include tumours where radiotherapy alone is not expected to achieve control, such as large fungating tumours, and in previously irradiated areas. In these patients, hyperthermia with radiation achieves better local control of the tumour and delays the need for systemic chemotherapy. This may improve the quality of palliation.

To investigate the previously observed increased morbidity and mortality of combined cis-diamminedichloroplatinum (cis-DDP) and hyperthermia, BD IX rats were given 4 mg/kg cis-DDP i.p., waterbath hind leg heating (44 degrees C, 60 min) with resultant whole body hyperthermia, or combined treatment with or without systemic cooling. Cardiac blood and histopathologic sections of kidney, small intestine and liver were examined in rats sacrificed 2, 3 and 5 days after and femur bone marrow 5 days after treatment. In a separate experiment, the effect of systemic hyperthermia on renal function was tested. The most significant finding was a marked increase in cis-DDP induced renal damage by systemic hyperthermia, expressed as elevated creatinine levels and quantitatively enhanced proximal tubular necrosis. As both systemic hyperthermia and cis-DDP can result in primarily altered renal haemodynamics, it is postulated that relative tubular epithelial hypoxia and increased tubular exposure time to cis-DDP due to reduced tubular filtrate flow rate are likely mechanisms for the increased toxicity.

A 13-year-old girl was treated surgically for a giant-cell tumor of bone originating in the talus and for a recurrence in the distal tibia. She later developed liver and lung metastases and was treated for two years, five months with a combination of vincristine, doxorubicin, cyclophosphamide and actinomycin-D, and thereafter with high-dose methotrexate/vincristine with citrovorum factor rescue. A good response was obtained and the patient is without evidence of disease 12 months after a salvage thoracotomy for residual disease in the left lung. Aspects of this singular case are discussed.