Radiation Pneumonitis after Intensity-Modulated Radiotherapy for Esophageal Cancer: Institutional Data and a Systematic Review.

Radiation pneumonitis (RP) is a serious complication that can occur after thoracic radiotherapy. The goal of this study is to investigate the incidence of RP after radiochemotherapy with intensity modulated radiotherapy (IMRT) in patients with esophageal cancer and correlate this with dose volume histogram (DVH) related parameters. For this purpose, the clinical course of 73 patients was evaluated and irradiation doses to the lungs were extracted from radiotherapy treatment plans. Furthermore, a systematic review on this topic was conducted across PubMed. In our institutional cohort, Common Terminology Criteria for Adverse Events (CTCAE) grade II or higher RP occurred in four patients (5.5%). The systematic review identified 493 titles of which 19 studies reporting 874 patients qualified for the final analysis. No grade IV or V RP after radiochemotherapy with IMRT for esophageal cancer was reported in the screened literature. Grade II or higher RP is reported in 6.6% of the patients. A higher incidence can be seen with increasing values for lung V20. In conclusion, our institutional data and the literature consistently show a low incidence of symptomatic RP after radiochemotherapy in patients with esophageal cancer treated with IMRT. However, efforts should be made to keep the lung V20 below 23% and specific caution is warranted in patients with pre-existing lung conditions.

Unilateral cochlea sparing in locoregionally advanced head and neck cancer: a planning study.

BACKGROUND: Cochlea sparing can reduce late ototoxicity in head and neck cancer patients treated with cisplatin-based radiochemotherapy. In this situation, a mean cochlear dose (MCD) constraint of 10 Gy has been suggested by others based on the dose-effect relationship of clinical data. We aimed to investigate whether this is feasible for primary and postoperative radiochemotherapy in locoregionally advanced tumors without compromising target coverage. PATIENTS AND METHODS: Ten patients treated with definitive and ten patients treated with adjuvant intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy were investigated. The cochleae and a planning risk volume (PRV) with a 3 mm margin were newly delineated, whereas target volumes and other organs at risk were not changed. The initial plan was recalculated with a constraint of 10 Gy (MCD) on the low-risk side. The quality of the resulting plan was evaluated using the difference in the equivalent uniform dose (EUD). RESULTS: A unilateral MCD of below 10 Gy could be achieved in every patient. The mean MCD was 6.8 Gy in the adjuvant cohort and 7.6 Gy in the definitive cohort, while the non-spared side showed a mean MCD of 18.7 and 30.3 Gy, respectively. The mean PRV doses were 7.8 and 8.4 Gy for the spared side and 18.5 and 29.8 Gy for the non-spared side, respectively. The mean EUD values of the initial and recalculated plans were identical. Target volume was not compromised. CONCLUSION: Unilateral cochlea sparing with an MCD of less than 10 Gy is feasible without compromising the target volume or dose coverage in locoregionally advanced head and neck cancer patients treated with IMRT. A prospective evaluation of the clinical benefit of this approach as well as further investigation of the dose-response relationship for future treatment modification appears promising.

Automatic delineation of tumor volumes by co-segmentation of combined PET/MR data.

Combined PET/MRI may be highly beneficial for radiotherapy treatment planning in terms of tumor delineation and characterization. To standardize tumor volume delineation, an automatic algorithm for the co-segmentation of head and neck (HN) tumors based on PET/MR data was developed. Ten HN patient datasets acquired in a combined PET/MR system were available for this study. The proposed algorithm uses both the anatomical T2-weighted MR and FDG-PET data. For both imaging modalities tumor probability maps were derived, assigning each voxel a probability of being cancerous based on its signal intensity. A combination of these maps was subsequently segmented using a threshold level set algorithm. To validate the method, tumor delineations from three radiation oncologists were available. Inter-observer variabilities and variabilities between the algorithm and each observer were quantified by means of the Dice similarity index and a distance measure. Inter-observer variabilities and variabilities between observers and algorithm were found to be comparable, suggesting that the proposed algorithm is adequate for PET/MR co-segmentation. Moreover, taking into account combined PET/MR data resulted in more consistent tumor delineations compared to MR information only.

Feasibility of 6-month maintenance cetuximab after adjuvant concurrent chemoradiation plus cetuximab in squamous cell carcinoma of the head and neck.

BACKGROUND: Close resection margins < 5 mm (CM) or extra capsular extent at the lymph nodes (ECE) impair the prognosis of patients with squamous cell cancer of the head and neck (SCCHN) scheduled for adjuvant radiochemotherapy. We conducted a multicenter phase II study to investigate toxicity and efficacy of additional cetuximab administered concomitantly and as maintenance for the duration of 6 months following adjuvant radiochemotherapy., Ppreliminary results on feasibility and acute toxicity on skin and mucosa are presented in this article. METHODS: Patients with SCCHN following CM resection or with ECE were eligible for the study. In all, 61.6 Gy (1.8/2.0/2.2 Gy, days 1-36) were administered using an integrated boost intensity-modulated radiotherapy (IMRT) technique. Cisplatin (20 mg/m(2), days 1-5 and days 29-33) and 5-fluorouracil (5-FU) as continuous infusion (600 mg/m(2), days 1-5 + days 29-33) were given concurrently. Cetuximab was started 7 days prior to radiochemotherapy at 400 mg/m(2) followed by weekly doses of 250 mg/m(2). Maintenance cetuximab began after radiochemotherapy at 500 mg/m(2) every 2 weeks for 6 months. RESULTS: Of the 55 patients (46 male, 9 female, mean age 55.6, range 29-70 years) who finished radiochemotherapy, 50 were evaluable for acute toxicity concerning grade III/IV toxicities of skin and mucosa. Grade 3-4 (CTC 3.0) mucositis, radiation dermatitis, and skin reactions outside the radiation portals were documented for 46, 28, and 14 % of patients, respectively. One toxic death occurred (peritonitis at day 57). Cetuximab was terminated in 5 patients due to allergic reactions after the first application. In addition, 22 % of patients discontinued cetuximab within the last 2 weeks or at the end of radiochemotherapy. Of patients embarking on maintenance treatment, 80 % were still on cetuximab at 3 months and 63 % at 5 months. Concurrent and maintenance treatment with cetuximab could be administered as scheduled in 48 % of patients. CONCLUSION: Adjuvant radiochemotherapy with concomitant and maintenance cetuximab is feasible and acute toxicities are within the expected range. Compliance within the first 3-5 months is moderate.

Combined treatment of colorectal tumours with agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and radiotherapy: enhanced effects in vitro and dose-dependent growth delay in vivo.

We and others have demonstrated already that TRAIL (TNF-related apoptosis-inducing ligand) is a very promising candidate for molecular targeted anticancer therapy, especially when combined with ionizing radiation or other DNA-damaging agents. Agonist monoclonal antibodies that activate and are specific for the death signaling TRAIL receptors are an alternative method to stimulate the programmed cell death pathway. Phase 1 clinical trials have subsequently been conducted and shown a very good tolerability of these antibodies. In order to assess the efficacy of TRAIL receptor stimulation to induce cell death by this alternate method, we studied the combination of the agonistic-TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 with radiation in vitro and in vivo. Induction of apoptosis after combined treatment with TRAIL receptor antibodies HGS-ETR1 and/or HGS-ETR2 (0.01, 0.1, 1.0 mg/ml) and irradiation with 2, 5 or 10 Gy was determined by fluorescence microscopy and Western blot analysis of caspase-8 and PARP. The colorectal tumour cell lines Colo 205, HCT 116 and HCT-15 were used for in vitro experiments. Growth delay experiments were performed with combined treatment with fractionated irradiation (days 1-5 and 3 Gy single dose/day) and the receptor antibodies (intraperitonially, three different concentrations, application on days 1, 4 and 8) on Colo 205 xenograft-bearing NMRI (nu/nu) nude mice. HGS-ETR1 and HGS-ETR2 induced apoptotic cell death in a dose-dependent fashion and significantly increased cell death in combination with irradiation in vitro when compared to either irradiation or antibody treatment alone. The efficacy of the combined treatment seems to be at least partially Bax-dependent. Similar to the results from cell culture experiments, in vivo experiments demonstrated a dose-dependent delay in tumour growth after combined treatment. In vivo, in the Colo205 xenograft model, HGS-ETR2 revealed a higher activity than HGS-ETR1. This is the first study to demonstrate significant efficacy of combined treatment with the monoclonal agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and ionising radiation in in vitro and in vivo models. We postulate that HGS-ETR1 and HGS-ETR2 will be very promising new agents in the field of molecular targeted multi-modality anticancer therapy.

Thermoradiotherapy of the chest wall in locally advanced or recurrent breast cancer with marginal resection.

BACKGROUND AND PURPOSE: Evaluation of the efficacy of combined hyperthermia and radiotherapy (TRT) in high-risk breast cancer patients with microscopic involved margins (R1) after mastectomy or with resected locoregional, early recurrence with close margins or R1-resection. Main endpoint was local tumour control (LC); secondary endpoints were overall survival (OS), disease free survival (DFS) and acute toxicity. MATERIAL AND METHODS: Between 1997-2001, 50 patients were treated with TRT. Thirteen patients (group 1) received a post-operative TRT in a high-risk situation (free margin <1 cm or R1, N+), 37 patients (group 2) received TRT after close/R1 resection of a locoregional recurrence. Thirteen out of 37 patients in group 2 already had had two-to-seven recurrences prior to TRT. Median radiation dose was 60 Gy (range: 44-66.4 Gy), the additional local hyperthermia (>41 degrees C, 60 min) was given twice a week. Median follow-up for patients at risk was 28 months. All statistical tests were done using Statistica software. RESULTS: Actuarial OS for all patients at 3 years accounted for 89%, DFS for 68% and LC for 80%. Actuarial OS was 90% for group 1 and 89% for group 2, with four patients having died so far. DFS at 3 years was 64% in group 1 and 69% in group 2, actuarial 3 year LC was 75% and 81%, respectively. For patients with recurrent chest wall disease, there was no difference concerning local control between patients who underwent TRT with or without prior radiation. No prognostic factors could be detected due to the small number of patients investigated. The combined modality treatment was well tolerated. Grade IV toxicity, according to the Common Toxicity Criteria, did not occur. CONCLUSION: The results concerning local tumour control and overall survival in these high-risk patients are promising, especially for TRT for the treatment of local recurrences. A longer follow-up is needed to estimate late toxicity.

[Cognitive behavioral therapy for depressed older outpatients--a controlled, randomized trial]. / Kognitive Verhaltenstherapie bei Depressionen im Alter. Ergebnisse einer kontrollierten Vergleichsstudie unter ambulanten Bedingungen an Depressionen mittleren Schweregrads.

OBJECTIVE: There is a lack of scientific evidence of psychotherapy with depressed elderly. In a controlled randomized trial we compare a cognitive behavioral group intervention with a waiting list control condition. It is expected that cognitive behavior therapy is more efficient in reducing depressive symptoms than the control group at post-treatment as well as at follow-up. METHOD: A total of 100 older adults presently fulfilling the diagnosis of a depressive disorder but not showing any signs of cognitive impairment were randomly assigned (ratio 2 : 1) to either cognitive behavior therapy (N=65) or to waiting list condition (N=35). Assessment took place at pre-treatment, after 3 months of treatment or waiting, and after 6 months follow-up. RESULTS: As expected, cognitive behavior group therapy was superior to waiting list control in all measures at post-treatment as well as at follow-up (intent-to-treat analysis). These effects are statistically and clinically relevant and not influenced by parallel treatment with antidepressant medication. After cognitive behavior therapy 36 patients were in complete remission but only 4 after three months of waiting. Six patients in the control group became even worse during the 3 months waiting while only 1 patient under cognitive behavior therapy has to be considered as treatment failure. DISCUSSION: Cognitive behavioral group treatment is a well accepted, successful intervention for older adults. Waiting for treatment is problematic. It does not only produce no changes in symptomatology but even leads to worsening of depression in a large number of subjects.

Mitomycin C in combination with radiotherapy as a potent inhibitor of tumour cell repopulation in a human squamous cell carcinoma.

The potential of Mitomycin C in combination with fractionated irradiation to inhibit tumour cell repopulation of a fast growing squamous cell carcinoma after fractionated radiotherapy was investigated in vivo. A rapidly growing human squamous cell carcinoma (FaDu(dd)) was used for the study. For experiments, NMRI (nu/nu) mice with subcutaneously growing tumours were randomly allocated to no treatment, Mitomycin C, fractionated irradiation (ambient: 11 x 4.5 Gy in 15 days), or fractionated irradiation combined with Mitomycin C. Graded top up doses (clamped blood flow: 0-57 Gy) were given at day 16, 23, 30 or 37. End point of the study was the time to local tumour progression. Data were examined by multiple regression analysis (Cox). Mitomycin C alone resulted in a median time to local tumour progression of 23 (95% confidence limits: 17-43) days, fractionated irradiation in 31 (25-35) days and combined Mitomycin C plus fractionated irradiation in 65 (58-73) days (P=0.02). Mitomycin C decreased the relative risk of local recurrence by 94% (P<<0.001) equivalent to 31.7 Gy top up dose. Repopulation accounted for 1.33 (0.95-1.72) Gy per day top up dose after fractionated irradiation alone and for 0.68 (0.13-1.22) Gy per day after fractionated irradiation+Mitomycin C (P=0.018). Mitomycin C significantly reduces the risk of local recurrence and inhibits tumour cell repopulation in combination with fractionated irradiation in vivo in the tested tumour model.

Conversion of silicon carbide to crystalline diamond-structured carbon at ambient pressure.

Synthetic diamond is formed commercially using high-pressure, chemical-vapour-deposition and shock-wave processes, but these approaches have serious limitations owing to low production volumes and high costs. Recently suggested alternative methods of diamond growth include plasma activation, high pressures, exotic precursors or explosive mixtures, but they suffer from very low yield and are intrinsically limited to small volumes or thin films. Here we report the synthesis of nano- and micro-crystalline diamond-structured carbon, with cubic and hexagonal structure, by extracting silicon from silicon carbide in chlorine-containing gases at ambient pressure and temperatures not exceeding 1,000 degrees C. The presence of hydrogen in the gas mixture leads to a stable conversion of silicon carbide to diamond-structured carbon with an average crystallite size ranging from 5 to 10 nanometres. The linear reaction kinetics allows transformation to any depth, so that the whole silicon carbide sample can be converted to carbon. Nanocrystalline coatings of diamond-structured carbon produced by this route show promising mechanical properties, with hardness values in excess of 50 GPa and Young's moduli up to 800 GPa. Our approach should be applicable to large-scale production of crystalline diamond-structured carbon.