Effectiveness of transcranial direct current stimulation preceding cognitive behavioural management for chronic low back pain: sham controlled double blinded randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of transcranial direct current stimulation alone and in combination with cognitive behavioural management in patients with non-specific chronic low back pain. DESIGN: Double blind parallel group randomised controlled trial with six months' follow-up conducted May 2011-March 2013. Participants, physiotherapists, assessors, and analyses were blinded to group allocation. SETTING: Interdisciplinary chronic pain centre. PARTICIPANTS: 135 participants with non-specific chronic low back pain >12 weeks were recruited from 225 patients assessed for eligibility. INTERVENTION: Participants were randomised to receive anodal (20 minutes to motor cortex at 2 mA) or sham transcranial direct current stimulation (identical electrode position, stimulator switched off after 30 seconds) for five consecutive days immediately before cognitive behavioural management (four week multidisciplinary programme of 80 hours). MAIN OUTCOMES MEASURES: Two primary outcome measures of pain intensity (0-100 visual analogue scale) and disability (Oswestry disability index) were evaluated at two primary endpoints after stimulation and after cognitive behavioural management. RESULTS: Analyses of covariance with baseline values (pain or disability) as covariates showed that transcranial direct current stimulation was ineffective for the reduction of pain (difference between groups on visual analogue scale 1 mm (99% confidence interval -8.69 mm to 6.3 mm; P=0.68)) and disability (difference between groups 1 point (-1.73 to 1.98; P=0.86)) and did not influence the outcome of cognitive behavioural management (difference between group 3 mm (-10.32 mm to 6.73 mm); P=0.58; difference between groups on Oswestry disability index 0 point (-2.45 to 2.62); P=0.92). The stimulation was well tolerated with minimal transitory side effects. CONCLUSIONS: This results of this trial on the effectiveness of transcranial direct current stimulation for the reduction of pain and disability do not support its clinical use for managing non-specific chronic low back pain.Trial registration Current controlled trials ISRCTN89874874.

Effectiveness of anodal transcranial direct current stimulation in patients with chronic low back pain: design, method and protocol for a randomised controlled trial.

BACKGROUND: Electrical stimulation of central nervous system areas with surgically implanted stimulators has been shown to result in pain relief. To avoid the risks and side effects of surgery, transcranial direct current stimulation is an option to electrically stimulate the motor cortex through the skull. Previous research has shown that transcranial direct current stimulation relieves pain in patients with fibromyalgia, chronic neuropathic pain and chronic pelvic pain. Evidence indicates that the method is pain free, safe and inexpensive. METHODS/DESIGN: A randomised controlled trial has been designed to evaluate the effect of transcranial direct current stimulation over the motor cortex for pain reduction in patients with chronic low back pain. It will also investigate whether transcranial direct current stimulation as a prior treatment enhances the symptom reduction achieved by a cognitive-behavioural group intervention. Participants will be randomised to receive a series of 5 days of transcranial direct current stimulation (2 mA, 20 mins) or 20 mins of sham stimulation; followed by a cognitive-behavioural group programme. The primary outcome parameters will measure pain (Visual Analog Scale) and disability (Oswestry Disability Index). Secondary outcome parameters will include the Fear Avoidance Beliefs Questionnaire, the Funktionsfragebogen Hannover (perceived function), Hospital Anxiety Depression Scale, bothersomeness and Health Related Quality of Life (SF 36), as well as Patient-Perceived Satisfactory Improvement. Assessments will take place immediately prior to the first application of transcranial direct current stimulation or sham, after 5 consecutive days of stimulation, immediately after the cognitive-behavioural group programme and at 4 weeks, 12 weeks and 24 weeks follow-up. DISCUSSION: This trial will help to determine, whether transcranial direct current stimulation is an effective treatment for patients with chronic low back pain and whether it can further enhance the effects of a cognitive behavioural pain management programme.

Dose-response relationship for radiation-induced pneumonitis after pulmonary stereotactic body radiotherapy.

PURPOSE: To evaluate dosimetric factors predictive for radiation-induced pneumonitis (RP) after pulmonary stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: A retrospective analysis was performed based on 59 consecutive patients treated with cone-beam CT-based image-guided SBRT for primary NSCLC (n=21) or pulmonary metastases (n=54). The majority of patients were treated with radiosurgery of 26 Gy to 80% (n=29) or three fractions of 12.5 Gy to 65% (n=40). To correct for different single fraction doses, local doses were converted to 2 Gy equivalent normalized total doses (NTDs) using α/ß ratio of 3 Gy for RP. Dose-volume parameters and incidences of RP ≥ grade II SWOG were fitted using NTCP models. RESULTS: Eleven patients developed RP grade II. With an average MLD of 10.3±5.6 Gy to the ipsilateral lung, a significant dose-response relationship was observed: the MLD was 12.5±4.3 Gy and 9.9±5.8 Gy for patients with and without development of RP, respectively. Additionally, volumes of the lung exposed to minimum doses between 2.5 and 50 Gy (V(2.5)-V(50)) were correlated with incidences of RP with a continuous decrease of the goodness of fit for higher doses. CONCLUSIONS: The MLD and V(2.5)-V(50) of the ipsilateral lung were correlated with incidences of RP after pulmonary SBRT.

Stereotactic body radiotherapy for local boost irradiation in unfavourable locally recurrent gynaecological cancer.

PURPOSE: To evaluate outcome of radiotherapy for locally recurrent cervical and endometrial cancer. MATERIALS AND METHODS: Nineteen patients were treated for a locally recurrent cervical (n=12) or endometrial (n=7) cancer median 26 months after initial surgery (n=18) or radiotherapy (n=1). The whole pelvis was irradiated with 50Gy conventionally fractionated radiotherapy (n=16). Because of large size of the recurrent cancer (median 4.5 cm) and peripheral location (n=12), stereotactic body radiotherapy (SBRT; median 3 fractions of 5Gy to 65%) was used for local dose escalation instead of (n=16) or combined with (n=3) vaginal brachytherapy. RESULTS: After median follow-up of 22 months, 3-year overall survival was 34% with systemic progression the leading cause of death (7/10). Median time to systemic progression was 16 months. Three local recurrences resulted in a local control rate of 81% at 3 years. No correlation between survival, systemic or local control and any patient or treatment characteristic was observed. The rate of late toxicity>grade II was 25% at 3 years: two patients developed a grade IV intestino-vaginal fistula and one patient suffered from a grade IV small bowel ileus. CONCLUSION: Image-guided SBRT for local dose escalation resulted in high rates of local control but was associated with significant late toxicity.

Dose-response relationship for image-guided stereotactic body radiotherapy of pulmonary tumors: relevance of 4D dose calculation.

PURPOSE: To evaluate outcome after image-guided stereotactic body radiotherapy (SBRT) for early-stage non-small-cell lung cancer (NSCLC) and pulmonary metastases. METHODS AND MATERIALS: A total of 124 patients with 159 pulmonary lesions (metastases n = 118; NSCLC, n = 41; Stage IA, n = 13; Stage IB, n = 19; T3N0, n = 9) were treated with SBRT. Patients were treated with hypofractionated schemata (one to eight fractions of 6-26 Gy); biologic effective doses (BED) to the clinical target volume (CTV) were calculated based on four-dimensional (4D) dose calculation. The position of the pulmonary target was verified using volume imaging before all treatments. RESULTS: With mean/median follow-up of 18/14 months, actuarial local control was 83% at 36 months with no difference between NSCLC and metastases. The dose to the CTV based on 4D dose calculation was closely correlated with local control: local control rates were 89% and 62% at 36 months for >100 Gy and <100 Gy BED (p = 0.0001), respectively. Actuarial freedom from regional and systemic progression was 34% at 36 months for primary NSCLC group; crude rate of regional failure was 15%. Three-year overall survival was 37% for primary NSCLC and 16% for metastases; no dose-response relationship for survival was observed. Exacerbation of comorbidities was the most frequent cause of death for primary NSCLC. CONCLUSIONS: Doses of >100 Gy BED to the CTV based on 4D dose calculation resulted in excellent local control rates. This cutoff dose is not specific to the treatment technique and protocol of our study and may serve as a general recommendation.

Image-guided radiotherapy for liver cancer using respiratory-correlated computed tomography and cone-beam computed tomography.

PURPOSE: To evaluate a novel four-dimensional (4D) image-guided radiotherapy (IGRT) technique in stereotactic body RT for liver tumors. METHODS AND MATERIALS: For 11 patients with 13 intrahepatic tumors, a respiratory-correlated 4D computed tomography (CT) scan was acquired at treatment planning. The target was defined using CT series reconstructed at end-inhalation and end-exhalation. The liver was delineated on these two CT series and served as a reference for image guidance. A cone-beam CT scan was acquired after patient positioning; the blurred diaphragm dome was interpreted as a probability density function showing the motion range of the liver. Manual contour matching of the liver structures from the planning 4D CT scan with the cone-beam CT scan was performed. Inter- and intrafractional uncertainties of target position and motion range were evaluated, and interobserver variability of the 4D-IGRT technique was tested. RESULTS: The workflow of 4D-IGRT was successfully practiced in all patients. The absolute error in the liver position and error in relation to the bony anatomy was 8 +/- 4 mm and 5 +/- 2 mm (three-dimensional vector), respectively. Margins of 4-6 mm were calculated for compensation of the intrafractional drifts of the liver. The motion range of the diaphragm dome was reproducible within 5 mm for 11 of 13 lesions, and the interobserver variability of the 4D-IGRT technique was small (standard deviation, 1.5 mm). In 4 patients, the position of the intrahepatic lesion was directly verified using a mobile in-room CT scanner after application of intravenous contrast. CONCLUSION: The results of our study have shown that 4D image guidance using liver contour matching between respiratory-correlated CT and cone-beam CT scans increased the accuracy compared with stereotactic positioning and compared with IGRT without consideration of breathing motion.

Pulmonary injury and tumor response after stereotactic body radiotherapy (SBRT): results of a serial follow-up CT study.

PURPOSE: To evaluate the CT morphological pattern of tumor response and pulmonary injury after stereotactic body radiotherapy (SBRT) for early stage non-small lung cancer (NSCLC) and pulmonary metastases. MATERIALS AND METHODS: Seventy patients (lesions n=86) with pulmonary metastases (n=48) or primary early stage NSCLC (n=38) were analyzed. Patients were treated with hypofractionated SBRT (three to eight fractions with a single dose between 6 and 12.5 Gy; n=56) or with radiosurgery (26 Gy; n=30). The pattern and sequence of pulmonary injury and of tumor response was evaluated in 346 follow-up CT studies, 4.9 on average. RESULTS: Symptomatic pneumonitis was observed in 10% after a median interval of 5 months. No pulmonary reaction was observed in most patients 6 weeks after treatment; spotted-streaky condensations were characteristic between 3 months and 6 months. Dense consolidation and retraction started after 9 months and the fibrotic remodelling process continued for years. Ten targets relapsed after a median of 7 months. At 12 months complete response was seen in 43% and the differentiation of residual tumor from pulmonary reaction was not possible in 33%. CONCLUSIONS: A typical sequence of pulmonary reactions was observed without differences between hypofractionated treatment and radiosurgery. Onset of pneumonitis was later compared to conventionally fractionated radiotherapy.

Intra-fractional uncertainties in cone-beam CT based image-guided radiotherapy (IGRT) of pulmonary tumors.

PURPOSE: Intra-fractional variability of tumor position and breathing motion was evaluated in cone-beam CT (CB-CT) based image-guided radiotherapy (IGRT) of pulmonary tumors. MATERIALS AND METHODS: Twenty-four patients (27 lesions: prim. NSCLC n=6; metastases n=21) were treated with stereotactic body radiotherapy (SBRT) (one to eight fractions). Prior to every treatment fraction (n=66) and immediately after treatment a CB-CT was acquired. Patient motion, absolute drift and drift of the tumor relative to the bony anatomy were measured. Tumor motion was investigated based on the density distribution in the CB-CT. RESULTS: Absolute intra-fractional drift (3D vector) of the tumor position was 2.8 mm+/-1.6 mm (mean +/- SD), maximum 7.2 mm. Poor correlation between patient motion and absolute tumor drift was observed. Changes of the tumor position due to patient motion and due to drifts independently from the bony anatomy were of similar magnitude with 2.1 mm +/- 1.4 mm and 2.3 mm +/- 1.6 mm, respectively. No systematic increase or decrease of breathing motion was seen. The intra-fractional change of breathing motion was more than 2 mm and 3 mm in 39% and 16%, respectively. CONCLUSION: Intra-fractional tumor position and breathing motion were stable. In IGRT of pulmonary tumors we suggest an ITV-to-PTV margin of 5 mm to compensate intra-fractional changes.

Stereotactic radiotherapy of primary liver cancer and hepatic metastases.

The purpose was to evaluate the clinical results of stereotactic radiotherapy in primary liver tumors and hepatic metastases. Five patients with primary liver cancer and 39 patients with 51 hepatic metastases were treated by stereotactic radiotherapy since 1997. Twenty-eight targets were treated in a "low-dose"-group with 3 x 10 Gy (n = 27) or 4 x 7 Gy (n = 1) prescribed to the PTV-encl. 65%-isodose. In a "high-dose"-group patients were treated with 3 x 12 - 12.5 Gy (n = 19; same dose prescription) or 1 x 26 Gy/PTV-enclosing 80%-isodose (n = 9). Median follow-up was 15 months (2-48 months) for primary liver cancer and 15 months (2-85 months) for hepatic metastases. While all primary liver cancers were controlled, nine local failures (3-19 months) of 51 metastases were observed resulting in an actuarial local control rate of 92% after 12 months and 66% after 24 months and later. A borderline significant correlation between dose and local control was observed (p = 0.077): the actuarial local control rate after 12 and 24 months was 86% and 58% in the low-dose-group versus 100% and 82% in the high-dose-group. In multivariate analysis high versus low-dose was the only significant factor predicting local control (p = 0.0089). Overall survival after 1 and 2 years was 72% and 32% for all patients and was impaired due to systemic progression of disease. No severe acute or late toxicity exceeding RTOG/EORTC-score 2 were observed. Stereotactic irradiation of primary liver cancer and hepatic metastases offers a locally effective treatment without significant complications in patients, who are not amenable for surgery. Patient selection is important, because those with low risk for systemic progression are more likely to benefit from this approach.

Cone-beam CT based image-guidance for extracranial stereotactic radiotherapy of intrapulmonary tumors.

Cone-beam CT (CB-CT) based image-guidance was evaluated for extracranial stereotactic radiotherapy of intrapulmonary tumors. A total of 21 patients (25 lesions: prim. NSCLC n = 6; pulmonary metastases n = 19) were treated with stereotactic radiotherapy (1 to 8 fractions). Prior to every fraction a CB-CT was acquired in treatment position, errors between planned and actual tumor position were measured and corrected. Intra- and inter-observer variability of manual evaluation of tumor position error was investigated and this manual method was compared with automatic image registration. Based on CB-CTs from 66 fractions the discrepancy (3-D vector) between planned and actual tumor position was 7.7 mm +/-1.3 mm. Tumor position error relative to the bony anatomy was 5.3 mm +/-1.2 mm, the correlation between bony anatomy and tumor position was poor. Intra-observer and inter-observer variability of manual evaluation of tumor position error was 0.9 mm +/-0.8 mm and 2.3 mm +/-1.1 mm, respectively. Automatic image registration showed highly reproducible results (<1 mm). However, compared with manual registration a systematic error was found in direction of predominant tumor breathing motion (2.5 mm vs 1.4 mm). Image-guidance using CB-CT was validated for high precision radiotherapy of intrapulmonary tumors. It was shown that both the planning reference and the verification image study have to consider tumor breathing motion.

Dose-response in stereotactic irradiation of lung tumors.

The dose-response for local tumor control after stereotactic radiotherapy of 92 pulmonary tumors (36 NSCLC and 56 metastases) was evaluated. Short course irradiation of 1-8 fractions with different fraction doses was used. After a median follow-up of 14 months (2-85 months) 11 local recurrences were observed with significant advantage for higher doses. When normalization to a biologically effective dose (BED) is used a dose of 94Gy at the isocenter and 50Gy at the PTV-margin are demonstrated to give 50% probability of tumor control (TCD50). Multivariate analysis revealed the dose at the PTV-margin as the only significant factor for local control.

Stereotactic radiotherapy for primary lung cancer and pulmonary metastases: a noninvasive treatment approach in medically inoperable patients.

PURPOSE: The clinical results of dose escalation using stereotactic radiotherapy to increase local tumor control in medically inoperable patients with Stage I-II non-small-cell lung cancer or pulmonary metastases were evaluated. METHODS AND MATERIALS: Twenty patients with Stage I-II non-small-cell lung cancer and 41 patients with 51 pulmonary metastases not amenable to surgery were treated with stereotactic radiotherapy at 3 x 10 Gy (n = 19), 3 x 12-12.5 Gy to the planning target volume enclosing 100%-isodose, with normalization to 150% at the isocenter; n = 26) or 1 x 26 Gy to the planning target volume enclosing 80%-isodose (n = 26). The median follow-up was 11 months (range, 2-61 months) for primary lung cancer patients and 9 months (range, 2-37 months) for patients with metastases. RESULTS: The actuarial local control rate was 92% for lung cancer patients and 80% for metastasis patients > or =1 year after treatment and was significantly improved by increasing the dose from 3 x 10 Gy to 3 x 12-12.5 Gy or 1 x 26 Gy (p = 0.038). The overall survival rate after 1 and 2 years was 52% and 32%, respectively, for lung cancer patients and 85% and 33%, respectively, for metastasis patients, impaired because of systemic disease progression. After 12 months, 60% of patients with primary lung cancer and 35% of patients with pulmonary metastases were without systemic progression. No severe acute or late toxicity was observed, and only 2 patients (3%) developed symptomatic Grade 2 pneumonitis, which was successfully treated with oral steroids. CONCLUSION: Stereotactic radiotherapy for lung tumors offers a very effective treatment option locally without significant complications in medically impaired patients who are not amenable to surgery. Patient selection is important, because those with a low risk of systemic progression are more likely to benefit from this approach.