Whole brain radiotherapy versus stereotactic radiosurgery for 4-10 brain metastases: a phase III randomised multicentre trial.

BACKGROUND: Maintenance of quality of life is the primary goal during treatment of brain metastases (BM). This is a protocol of an ongoing phase III randomised multicentre study. This study aims to determine the exact additional palliative value of stereotactic radiosurgery (SRS) over whole brain radiotherapy (WBRT) in patients with 4-10 BM. METHODS: The study will include patients with 4-10 BM from solid primary tumours diagnosed on a high-resolution contrast-enhanced MRI scan with a maximum lesional diameter of 2.5 cm in any direction and a maximum cumulative lesional volume of 30 cm3. Patients will be randomised between WBRT in five fractions of 4 Gy to a total dose of 20 Gy (standard arm) and single dose SRS to the BMs (study arm) in the range of 15-24 Gy. The largest BM or a localisation in the brainstem will determine the prescribed SRS dose. The primary endpoint is difference in quality of life (EQ5D EUROQOL score) at 3 months after radiotherapy with regard to baseline. Secondary endpoints are difference in quality of life (EQ5D EUROQOL questionnaire) at 6, 9 and 12 months after radiotherapy with regard to baseline. Other secondary endpoints are at 3, 6, 9 and 12 months after radiotherapy survival, Karnofsky ≥ 70, WHO performance status, steroid use (mg), toxicity according to CTCAE V4.0 including hair loss, fatigue, brain salvage during follow-up, type of salvage, time to salvage after randomisation and Barthel index. Facultative secondary endpoints are neurocognition with the Hopkins verbal learning test revised, quality of life EORTC QLQ-C30, quality of life EORTC BN20 brain module and fatigue scale EORTC QLQ-FA13. DISCUSSION: Worldwide, most patients with more than 4 BM will be treated with WBRT. Considering the potential advantages of SRS over WBRT, i.e. limiting radiation doses to uninvolved brain and a high rate of local tumour control by just a single treatment with fewer side effects, such as hair loss and fatigue, compared to WBRT, SRS might be a suitable alternative for patients with 4-10 BM. TRIAL REGISTRATION: Trial registration number: NCT02353000 , trial registration date 15th January 2015, open for accrual 1st July 2016, nine patients were enrolled in this trial on 14th April 2017.

Modern clinical research: How rapid learning health care and cohort multiple randomised clinical trials complement traditional evidence based medicine.

BACKGROUND: Trials are vital in informing routine clinical care; however, current designs have major deficiencies. An overview of the various challenges that face modern clinical research and the methods that can be exploited to solve these challenges, in the context of personalised cancer treatment in the 21st century is provided. AIM: The purpose of this manuscript, without intending to be comprehensive, is to spark thought whilst presenting and discussing two important and complementary alternatives to traditional evidence-based medicine, specifically rapid learning health care and cohort multiple randomised controlled trial design. Rapid learning health care is an approach that proposes to extract and apply knowledge from routine clinical care data rather than exclusively depending on clinical trial evidence, (please watch the animation: http://youtu.be/ZDJFOxpwqEA). The cohort multiple randomised controlled trial design is a pragmatic method which has been proposed to help overcome the weaknesses of conventional randomised trials, taking advantage of the standardised follow-up approaches more and more used in routine patient care. This approach is particularly useful when the new intervention is a priori attractive for the patient (i.e. proton therapy, patient decision aids or expensive medications), when the outcomes are easily collected, and when there is no need of a placebo arm. DISCUSSION: Truly personalised cancer treatment is the goal in modern radiotherapy. However, personalised cancer treatment is also an immense challenge. The vast variety of both cancer patients and treatment options makes it extremely difficult to determine which decisions are optimal for the individual patient. Nevertheless, rapid learning health care and cohort multiple randomised controlled trial design are two approaches (among others) that can help meet this challenge.

Combined use of hyperthermia and radiation therapy for treating locally advanced cervix carcinoma.

BACKGROUND: Hyperthermia is a type of cancer treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells. It was introduced into clinical oncology practice several decades ago. Positive clinical results, mostly obtained in single institutions, resulted in clinical implementation albeit in a limited number of cancer centres worldwide. Because large scale randomised clinical trials (RCTs) are lacking, firm conclusions cannot be drawn regarding its definitive role as an adjunct to radiotherapy in the treatment of locally advanced cervix carcinoma (LACC). OBJECTIVES: To assess whether adding hyperthermia to standard radiotherapy for LACC has an impact on (1) local tumour control, (2) survival and (3) treatment related morbidity. SEARCH STRATEGY: The electronic databases of the Cochrane Central Register of Controlled Trials (CENTRAL), (Issue 1, 2009) and Cochrane Gynaecological Cancer Groups Specialised Register, MEDLINE, EMBASE, online databases for trial registration, handsearching of journals and conference abstracts, reviews, reference lists, and contacts with experts were used to identify potentially eligible trials, published and unpublished until January 2009. SELECTION CRITERIA: RCTs comparing radiotherapy alone (RT) versus combined hyperthermia and radiotherapy (RHT) in patients with LACC. DATA COLLECTION AND ANALYSIS: Between 1987 and 2009 the results of six RCTs were published, these were used for the current analysis. MAIN RESULTS: 74% of patients had FIGO stage IIIB LACC. Treatment outcome was significantly better for patients receiving the combined treatment (Figures 4 to 6). The pooled data analysis yielded a significantly higher complete response rate (relative risk (RR) 0.56; 95% confidence interval (CI) 0.39 to 0.79; p < 0.001), a significantly reduced local recurrence rate (hazard ratio (HR) 0.48; 95% CI 0.37 to 0.63; p < 0.001) and a significantly better overall survival (OS) following the combined treatment with RHT(HR 0.67; 95% CI 0.45 to 0.99; p = 0.05). No significant difference was observed in treatment related acute (RR 0.99; 95% CI 0.30 to 3.31; p = 0.99) or late grade 3 to 4 toxicity (RR 1.01; CI 95% 0.44 to 2.30; p = 0.96) between both treatments. AUTHORS' CONCLUSIONS: The limited number of patients available for analysis, methodological flaws and a significant over-representation of patients with FIGO stage IIIB prohibit drawing definite conclusions regarding the impact of adding hyperthermia to standard radiotherapy. However, available data do suggest that the addition of hyperthermia improves local tumour control and overall survival in patients with locally advanced cervix carcinoma without affecting treatment related grade 3 to 4 acute or late toxicity.

Evaluation of early metabolic responses in rectal cancer during combined radiochemotherapy or radiotherapy alone: sequential FDG-PET-CT findings.

BACKGROUND AND PURPOSE: The purpose of this study was to prospectively investigate metabolic changes of rectal tumors after 1 week of treatment of either radiochemotherapy (28 x 1.8 Gy+Capecitabine) (RCT) or hypofractionated radiotherapy (5 x 5 Gy) alone (RT). MATERIALS AND METHODS: Fourty-six rectal cancer patients, 25 RCT- and 21 RT-patients, were included in this study. Sequential FDG-PET-CT scans were performed for each of the included patients both prior to treatment and after the first week of treatment. Consecutively, the metabolic treatment response of the tumor was evaluated. RESULTS: For the patients referred for pre-operative RCT, significant reductions of SUV(mean) (p<0.001) and SUV(max) (p<0.001) within the tumor were found already after the first week of treatment (8 Gy biological equivalent dose (BED). In contrast, 1 week of treatment with RT alone did not result in significant changes in the metabolic activity of the tumor (p=0.767, p=0.434), despite the higher applied RT dose of 38.7 Gy BED. CONCLUSIONS: Radiochemotherapy of rectal cancer leads to significant early changes in the metabolic activity of the tumor, which was not the case early after hypofractionated radiotherapy alone, despite the higher radiotherapy dose given. Thus, the chemotherapeutic agent Capecitabine might be responsible for the early metabolic treatment responses during radiochemotherapy in rectal cancer.

Dose recalculation in megavoltage cone-beam CT for treatment evaluation: removal of cupping and truncation artefacts in scans of the thorax and abdomen.

PURPOSE: To correct megavoltage cone-beam CT (MVCBCT) images of the thorax and abdomen for cupping and truncation artefacts to reconstruct the 3D-delivered dose distribution for treatment evaluation. MATERIALS AND METHODS: MVCBCT scans of three phantoms, three lung and two rectal cancer patients were acquired. The cone-beam projection images were iteratively corrected for cupping and truncation artefacts and the resulting primary transmission was used for cone-beam reconstruction. The reconstructed scans were merged into the planning CT scan (MVCBCT+). Dose distributions of clinical IMRT, stereotactic and conformal treatment plans were recalculated on the uncorrected and corrected MVCBCT+ scans using the treatment planning system and compared to the planned dose distribution. RESULTS: The dose distributions on the corrected MVCBCT+ of the phantoms were accurate for 99% of the voxels within 2% or 2mm. Using this method the errors in mean GTV dose reduced from about 10% to 1% for the patients. CONCLUSIONS: The method corrects cupping and truncation artefacts in cone-beam scans of the thorax and abdomen in addition to head-and-neck (demonstrated previously). The corrected scans can be used to calculate the influence of anatomical changes on the 3D-delivered dose distribution.

Combined use of hyperthermia and radiation therapy for treating locally advanced cervical carcinoma.

BACKGROUND: Hyperthermia is a type of cancer treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells. It was introduced into clinical oncology practice several decades ago. Positive clinical results, mostly obtained in single institutions, resulted in clinical implementation albeit in a limited number of cancer centres worldwide. Because large scale randomised clinical trials (RCTs) are lacking, firm conclusions cannot be drawn regarding its definitive role as an adjunct to radiotherapy in the treatment of locally advanced cervical carcinoma (LACC). OBJECTIVES: To assess whether adding hyperthermia to standard radiotherapy for LACC has an impact on (1) local tumour control, (2) survival and (3) treatment related morbidity. SEARCH STRATEGY: The electronic databases of the Cochrane Central Register of Controlled Trials (CENTRAL), (Issue 1, 2009) and Cochrane Gynaecological Cancer Groups Specialised Register, MEDLINE, EMBASE, online databases for trial registration, handsearching of journals and conference abstracts, reviews, reference lists, and contacts with experts were used to identify potentially eligible trials, published and unpublished until January 2009. SELECTION CRITERIA: RCTs comparing radiotherapy alone (RT) versus combined hyperthermia and radiotherapy (RHT) in patients with LACC. DATA COLLECTION AND ANALYSIS: Between 1987 and 2009 the results of six RCTs were published, these were used for the current analysis. MAIN RESULTS: 74% of patients had FIGO stage IIIB LACC. Treatment outcome was significantly better for patients receiving the combined treatment (Figures 1 to 3). The pooled data analysis yielded a significantly higher complete response rate (relative risk (RR) 0.56; 95% confidence interval (CI) 0.39 to 0.79; p < 0.001), a significantly reduced local recurrence rate at 3 years (hazard ratio (HR) 0.48; 95% CI 0.37 to 0.63; p < 0.001) and a significanly better overall survival (OS) at three years following the combined treatment with RHT(HR 0.67; 95% CI 0.45 to 0.99; p = 0.05). No significant difference was observed in treatment related acute (RR 0.99; 95% CI 0.30 to 3.31; p = 0.99) or late grade 3 to 4 toxicity (RR 1.01; CI 95% 0.44 to 2.30; p = 0.96) between both treatments. AUTHORS' CONCLUSIONS: The limited number of patients available for analysis, methodological flaws and a significant over-representation of patients with FIGO stage IIIB prohibit drawing definite conclusions regarding the impact of adding hyperthermia to standard radiotherapy. However, available data do suggest that the addition of hyperthermia improves local tumour control and overall survival in patients with locally advanced cervical carcinoma without affecting treatment related grade 3 to 4 acute or late toxicity.

Erythropoietin as an adjuvant treatment with (chemo) radiation therapy for head and neck cancer.

BACKGROUND: Tumour hypoxia increases tumour invasiveness and has a negative impact on response to therapy. Hypoxic tumours are also associated with severely anaemic individuals. It has therefore been hypothesised that correcting anaemia, by increasing haemoglobin levels using erythropoietin, improves tumour oxygenation and consequently the patient's prognosis. OBJECTIVES: To assess whether combined treatment with radiotherapy and erythropoietin (RT plus EPO) is better than standard radiotherapy (RT alone) for the treatment of head and neck cancer patients. SEARCH STRATEGY: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; mRCT and additional sources for published and unpublished trials. The date of the most recent search was 24 February 2009. SELECTION CRITERIA: Two independent authors assessed identified studies according to the eligibility criteria: RCTs which delivered radiotherapy combined with or without erythropoietin, in patients of any age with head and neck cancer of any stage or type. In addition, trials administering concomitant iron therapy among one or both arms were also eligible. DATA COLLECTION AND ANALYSIS: For statistical analysis of survival data, we computed a weighted estimate of the typical treatment effect across studies. We used Chi(2) heterogeneity tests to test for statistical heterogeneity among trials and performed the statistical analyses using Review Manager 5.0. MAIN RESULTS: Five RCTs with a total of 1397 patients were included. Pooled data yielded a significantly worse overall survival (OS) for RT plus EPO as compared to RT alone (Peto odds ratio 0.73; 95% confidence interval (CI) 0.58 to 0.91; P = 0.005, five trials). For local regional tumour control (LRTC) analyses resulted in a small but non-significant difference between the RT alone group and the RT plus EPO group (RR 0.92; 95% CI 0.81 to 1.03; P = 0.15, four trials). In addition, the local regional progression free survival (LRPFS) measured in four studies was significantly different between groups (Peto odds ratio 0.63; 95% CI 0.49 to 0.80; P = 0.0002, four trials), in favour of the RT alone group. Two studies used supplemental iron in the RT plus EPO group and not in the RT alone group. When excluding these studies from the analyses, the statistically (non-) significant differences in OS, LRTC and LRPFS are maintained. AUTHORS' CONCLUSIONS: There are strong suggestions that RT plus EPO has a negative influence on outcome as opposed to RT alone. However, the target haemoglobin concentration, which was higher than recommended in four of the five included RCTs, may have had a significant role. Nevertheless, based on these findings EPO should not be administered as an addition to RT outside the experimental setting for patients with head and neck cancer.

Concomitant hyperthermia and radiation therapy for treating locally advanced rectal cancer.

BACKGROUND: Surgery has been the treatment of choice for patients with rectal cancer. For locally advanced cancer results were poor, with high rates of locoregional recurrences and poor overall survival data. Adding (chemo)radiotherapy upfront improved results mainly in locoregional control. Adding hyperthermia to radiotherapy preoperatively might have an equivalent beneficial effect. OBJECTIVES: To quantify the potential beneficial effect of thermo radiation compared to chemo-radiation with respect to pathological complete responses, overall survival and toxicity in rectal cancer therapy. SEARCH STRATEGY: We identified the relevant phase II and III randomised controlled trials in any language trough electronic searches May 2007 of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2007), the Cochrane Colorectal Cancer Groups Specialised Register, MEDLINE (from 1966), EMBASE (from 1974), CINAHL (from 1982). Furthermore, various trial databases were searched for the identification of recent completed and ongoing trials (metaRegister of Controlled Trials, Cancer Research UK, Cancer.gov, The Eastern Cooperative Oncology Group Trials Database). All studies identified until May 2007 were considered for inclusion in the present study. SELECTION CRITERIA: Only phase II and III randomised controlled clinical trials were included in the analysis. DATA COLLECTION AND ANALYSIS: All identified studies were assessed by two independent reviewers. A weighted estimate of the treatment effect was computed for 2, 3, 4 and 5-year survival, for local tumour recurrence, severe acute and late toxicity and complete tumour response (CR). CR was defined either clinically by disappearance of all pretreatment signs of local tumour or pathologically by microscopically free margins. The risk ratio (RR) and hazard ratio (HR) were used. Analyses were performed with the Reference Manager (RevMan). MAIN RESULTS: Six RCTs published between 1990 and 2007 were identified. A total number of 520 patients was treated, 258 in the radiotherapy only arm (RT) and 262 in the radiotherapy-hyperthermia arm (RHT). Four studies (424 patients) reported overall survival (OS) rates. After 2 years, OS was significantly better in the RHT group (HR 2.06; 95% CI 1.33-3.17; p=.001), but this difference disappeared after a longer period (3, 4 and 5 year OS). All but one studies reported CR rates. A significant higher CR rate was observed in the RHT group (RR 2.81; 95% CI 1.22-6.45; p=.01). Only 2 studies reported on acute toxicity. In these 2 studies no significant differences were observed between the RT and the RHT group. Late toxicity data were not reported. AUTHORS' CONCLUSIONS: Further studies are needed to compare chemoradiation versus thermoradiation versus chemoradiation plus hyperthermia in well selected/conducted and quality controlled randomised trials.

In vivo dosimetry using a linear Mosfet-array dosimeter to determine the urethra dose in 125I permanent prostate implants.

PURPOSE: In vivo dosimetry during brachytherapy of the prostate with (125)I seeds is challenging because of the high dose gradients and low photon energies involved. We present the results of a study using metal-oxide-semiconductor field-effect transistor (MOSFET) dosimeters to evaluate the dose in the urethra after a permanent prostate implantation procedure. METHODS AND MATERIALS: Phantom measurements were made to validate the measurement technique, determine the measurement accuracy, and define action levels for clinical measurements. Patient measurements were performed with a MOSFET array in the urinary catheter immediately after the implantation procedure. A CT scan was performed, and dose values, calculated by the treatment planning system, were compared to in vivo dose values measured with MOSFET dosimeters. RESULTS: Corrections for temperature dependence of the MOSFET array response and photon attenuation in the catheter on the in vivo dose values are necessary. The overall uncertainty in the measurement procedure, determined in a simulation experiment, is 8.0% (1 SD). In vivo dose values were obtained for 17 patients. In the high-dose region (> 100 Gy), calculated and measured dose values agreed within 1.7% +/- 10.7% (1 SD). In the low-dose region outside the prostate (< 100 Gy), larger deviations occurred. CONCLUSIONS: MOSFET detectors are suitable for in vivo dosimetry during (125)I brachytherapy of prostate cancer. An action level of +/- 16% (2 SD) for detection of errors in the implantation procedure is achievable after validation of the detector system and measurement conditions.

Calibration of megavoltage cone-beam CT for radiotherapy dose calculations: correction of cupping artifacts and conversion of CT numbers to electron density.

Megavoltage cone-beam CT (MV CBCT) is used for three-dimensional imaging of the patient anatomy on the treatment table prior to or just after radiotherapy treatment. To use MV CBCT images for radiotherapy dose calculation purposes, reliable electron density (ED) distributions are needed. Patient scatter, beam hardening and softening effects result in cupping artifacts in MV CBCT images and distort the CT number to ED conversion. A method based on transmission images is presented to correct for these effects without using prior knowledge of the object's geometry. The scatter distribution originating from the patient is calculated with pencil beam scatter kernels that are fitted based on transmission measurements. The radiological thickness is extracted from the scatter subtracted transmission images and is then converted to the primary transmission used in the cone-beam reconstruction. These corrections are performed in an iterative manner, without using prior knowledge regarding the geometry and composition of the object. The method was tested using various homogeneous and inhomogeneous phantoms with varying shapes and compositions, including a phantom with different electron density inserts, phantoms with large density variations, and an anthropomorphic head phantom. For all phantoms, the cupping artifact was substantially removed from the images and a linear relation between the CT number and electron density was found. After correction the deviations in reconstructed ED from the true values were reduced from up to 0.30 ED units to 0.03 for the majority of the phantoms; the residual difference is equal to the amount of noise in the images. The ED distributions were evaluated in terms of absolute dose calculation accuracy for homogeneous cylinders of different size; errors decreased from 7% to below 1% in the center of the objects for the uncorrected and corrected images, respectively, and maximum differences were reduced from 17% to 2%, respectively. The presented method corrects the MV CBCT images for cupping artifacts and extracts reliable ED information of objects with varying geometries and composition, making these corrected MV CBCT images suitable for accurate dose calculation purposes.