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1.  Radiation Oncology reviewer acknowledgement 2014 
Contributing reviewers
The editorial team of Radiation Oncology would like to thank all our reviewers who have contributed to the journal in Volume 9 (2014).
PMCID: PMC4336510
2.  Association between genetic polymorphisms and carotid atherosclerosis in patients treated with radiotherapy for nasopharyngeal carcinoma 
Radiotherapy (RT) of the neck is commonly given to nasopharyngeal carcinoma (NPC) patients for preventing cervical lymph node metastasis. However, neck RT may induce the development of carotid atherosclerosis. The mechanisms of radiation-induced carotid atherosclerosis are still unclear and no previous study has investigated the genetic involvement of radiation-induced carotid atherosclerosis. The present study aims to determine the association between genetic polymorphisms and carotid atherosclerosis in patients treated with RT for nasopharyngeal carcinoma.
The present study recruited 128 post-RT NPC patients. Carotid plaque score was assessed using ultrasonography. Thirteen single nucleotide polymorphisms (SNPs) that affect the function of anti-atherosclerotic genes, including SOD2, SOD3, CAT, PON1, PPARG, ADIPOQ, IL10, TGFB1 and NOS3, were genotyped. Association between the 13 SNPs and carotid atherosclerosis was evaluated using multiple regression after adjustment for covariates (PLINK). Multiple testing was corrected using Benjamini-Hochberg step-up false discovery rate controlling procedure.
rs662 and rs705379 of PON1 were close to be significantly associated with carotid plaque score (Corrected P value, Pcor = 0.0528 and Pcor = 0.0842). When the two SNPs were combined together, TC haplotype in rs662-rs705379 of PON1 was significantly associated with higher carotid plaque score (Pcor < 0.05). None of the other SNPs showed significant association with carotid plaque score.
TC haplotype in rs662-rs705379 of PON1 is likely to be a genetic risk factor of carotid plaque score. Post-RT NPC patients with the TC haplotype may need earlier and more frequent carotid ultrasound examinations for early detection of carotid atherosclerosis.
PMCID: PMC4332433
Radiation; Nasopharyngeal carcinoma; Carotid atherosclerosis; Carotid plaque score; Single nucleotide polymorphisms; Paraoxonase
3.  Infections after fiducial marker implantation for prostate radiotherapy: are we underestimating the risks? 
The use of gold fiducial markers (FM) for prostate image-guided radiotherapy (IGRT) is standard practice. Published literature suggests low rates of serious infection following this procedure of 0-1.3%, but this may be an underestimate. We aim to report on the infection incidence and severity associated with the use of transrectally implanted intraprostatic gold FM.
Three hundred and fifty-nine patients who underwent transrectal FM insertion between January 2012 and December 2013 were assessed retrospectively via a self-reported questionnaire. All had standard oral fluoroquinolone antibiotic prophylaxis. The patients were asked about infective symptoms and the treatment received including antibiotics and/or related hospital admissions. Potential infective events were confirmed through medical records.
285 patients (79.4%) completed the questionnaire. 77 (27.0%) patients experienced increased urinary frequency and dysuria, and 33 patients (11.6%) reported episodes of chills and fevers after the procedure. 22 patients (7.7%) reported receiving antibiotics for urinary infection and eight patients (2.8%) reported hospital admission for urosepsis related to the procedure.
The overall rate of symptomatic infection with FM implantation in this study is 7.7%, with one third requiring hospital admission. This exceeds the reported rates in other FM implantation series, but is in keeping with the larger prostate biopsy literature. Given the higher than expected complication rate, a risk-adaptive approach may be helpful. Where higher accuracy is important such as stereotactic prostate radiotherapy, the benefits of FM may still outweigh the risks. For others, a non-invasive approach for prostate IGRT such as cone-beam CT could be considered.
Electronic supplementary material
The online version of this article (doi:10.1186/s13014-015-0347-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4333155
Gold fiducial markers; Image guided radiotherapy; Infective complications; Prostate radiotherapy; Transrectal ultrasound guided
4.  Distinct increased outliers among 136 rectal cancer patients assessed by γH2AX 
In recent years attention has focused on γH2AX as a very sensitive double strand break indicator. It has been suggested that γH2AX might be able to predict individual radiosensitivity. Our aim was to study the induction and repair of DNA double strand breaks labelled by γH2AX in a large cohort.
In a prospective study lymphocytes of 136 rectal cancer (RC) patients and 59 healthy individuals were ex vivo irradiated (IR) and initial DNA damage was compared to remaining DNA damage after 2 Gy and 24 hours repair time and preexisting DNA damage in unirradiated lymphocytes. Lymphocytes were immunostained with anti-γH2AX antibodies and microscopic images with an extended depth of field were acquired. γH2AX foci counting was performed using a semi-automatic image analysis software.
Distinct increased values of preexisting and remaining γH2AX foci in the group of RC patients were found compared to the healthy individuals. Additionally there are clear differences within the groups and there are outliers in about 12% of the RC patients after ex vivo IR.
The γH2AX assay has the capability to identify a group of outliers which are most probably patients with increased radiosensitivity having the highest risk of suffering radiotherapy-related late sequelae.
PMCID: PMC4330982
γH2AX; DNA double strand breaks; Rectal cancer; Radiotherapy; Individual radiosensitivity
5.  Impact of tumor attachment to the pleura measured by a pretreatment CT image on outcome of stage I NSCLC treated with stereotactic body radiotherapy 
Pleural invasion status is known to be a predictor of survival after pulmonary resection for non-small cell lung cancer. Our goal was to determine whether the length of tumor attachment to the pleura on a pretreatment CT image has prognostic value as an alternative to pleural invasion status for stage I non-small cell lung cancer treated with stereotactic body radiotherapy (SBRT).
A total of 90 tumors in 87 patients (males: 68, females: 19) who received SBRT between March 2005 and September 2011 in our institution were reviewed. The median age of the patients was 78 years (range, 48-90 years). The median tumor diameter was 2.2 cm (range, 0.9-4.2 cm). The prescribed dose was typically 48 Gy in 4 fractions, 60 Gy in 8 fractions or 60 Gy in 15 fractions to the isocenter with 6 MV X-ray using 4 non-coplanar and 3 coplanar static beams. The lengths of attachment were measured using pretreatment CT images at the lung window. Cumulative incidence rates were calculated using Kaplan-Meier curves, and univariate and multivariate analyses for in-field tumor control, locoregional control (LRC), freedom from distant metastasis and freedom from progression (FFP) were performed using a Cox proportional hazards model.
Of the 90 tumors, 42 tumors were attached to the pleura (median, 14.7 mm; range, 4.3-36.0 mm), 21 tumors had pleural indentation and 27 tumors had no attachment. The median follow-up period for survivors was 46.1 months. The 3-year in-field control, LRC, FFP and overall survival rates were 91.2%, 75.3%, 63.8% and 68.6%, respectively. SBRT dose and tumor diameter were independently significant predictors of in-field control (p = 0.02 and p = 0.04, respectively). Broad attachment to the pleura, the length being more than 14.7 mm, was a negative independent predictor of LRC and FFP (p = 0.02 and p = 0.01, respectively).
Pleural attachment status on a pretreatment CT image might be an important predictor of LRC and FFP.
PMCID: PMC4324854
Stereotactic radiotherapy; Lung cancer; Prognostic factor; Pleural invasion; Pleural attachment; Pleural contact
6.  Psychosocial encounters correlates with higher patient-reported functional quality of life in gynecological cancer patients receiving radiotherapy 
Our objective was to assess longitudinal health-related quality of life (HRQoL) in patients treated with radiotherapy for gynecologic malignancy and assess the relationship of psychosocial encounters on HRQoL.
Women with gynecologic malignancy were prospectively enrolled and HRQoL assessed before, during, and after radiotherapy treatment using validated measures. Treatment and demographic information were reviewed. Mixed-effects models were used to assess changes in quality of life (QoL) over time and association of psychologist and social worker encounters with overall QoL as well as subdomains of QoL.
Fifty-two women were enrolled and 41 completed at least one assessment. Fatigue (p = 0.008), nausea (p = 0.001), feeling ill (p = 0.007), and being bothered by side effects (p < 0.001) worsened on treatment with subsequent improvement. By follow-up, patients reported increased functional well-being (FWB) with significant decrease in worry (p = 0.003), increase in enjoyment of things usually done for fun (p = 0.003) and increase in contentment (p = 0.047). Twenty-three patients had at least one interaction with a social worker or psychologist during treatment. Each additional interaction was associated with a 2.12 increase in FWB score from before to after treatment (p = 0.002), and 1.74 increase from on to after treatment (p = 0.011). Additional interactions were not significantly associated with changes in overall FACT score (p = 0.056) or SWB (p = 0.305).
Patient-reported HRQoL significantly worsened during radiotherapy treatment with subsequent improvement, affirming transiency of treatment-induced toxicities. Our preliminary study suggests that clinically-recommended psychological and social work interventions have potential value with respect to improving patient QoL during radiotherapy. Larger studies are needed to validate our findings.
PMCID: PMC4332924  PMID: 25657054
Gynecologic cancer; Radiation therapy; Patient reported outcomes; FACT-G; MDASI; Psychological support
7.  The impact of induction chemotherapy on the dosimetric parameters of subsequent radiotherapy: an investigation of 30 consecutive patients with locally-advanced non-small cell lung cancer and modern radiation planning techniques 
To investigate the influence of induction chemotherapy (ICT) on dosimetric outcomes in patients with inoperable non-small cell lung cancer (NSCLC) treated with definitive chemoradiation (CRT).
Materials and methods
30 patients with inoperable stage II-III NSCLC treated with 2–4 cycles of ICT followed by definitive CRT to ≥ 60 Gy were selected. Tumor response to chemotherapy was scored by RECIST criteria. Treatment plans based on tumor extent prior to chemotherapy were generated based on equivalent planning constraints and techniques as the original post-chemotherapy plans. Dosimetric parameters predictive of toxicity for lung, esophagus, heart, and spinal cord were compared amongst the pre- and post-ICT plans.
The majority of patients (70%) experienced an overall reduction in GTV size between the pre-ICT imaging and the time of simulation. Comparing pre-and post-ICT diagnostic imaging, 5 patients met the RECIST criteria for response, 23 were classified as stable, and 2 experienced disease progression on diagnostic imaging. Despite a significantly reduced GTV size in the post-ICT group, no systematic improvements in normal tissue doses were seen amongst the entire cohort. This result persisted amongst the subgroup of patients with larger pre-ICT GTV tumor volumes (>100 cc3). Among patients with RECIST-defined response, a significant reduction in lung mean dose (1.9 Gy absolute, median 18.2 Gy to 16.4 Gy, p = 0.04) and V20, the percentage of lung receiving 20 Gy (3.1% absolute, median 29.3% to 26.3%, p = 0.04) was observed. In the non-responding group of patients, an increased esophageal V50 was found post-chemotherapy (median 28.9% vs 30.1%, p = 0.02).
For patients classified as having a response by RECIST to ICT, modest improvements in V20 and mean lung dose were found. However, these benefits were not realized for the cohort as a whole or for patients with larger tumors upfront. Given the variability of tumor response to ICT, the a priori impact of induction chemotherapy to reduce RT dose to normal tissue in these patients is minimal in the setting of modern treatment planning.
PMCID: PMC4316728  PMID: 25636372
8.  The effectiveness of endoscopic submucosal dissection followed by chemoradiotherapy for superficial esophageal cancer 
To evaluate the risks and benefits of endoscopic submucosal dissection (ESD) in addition to chemoradiotherapy (CRT) for the treatment of superficial esophageal squamous cell carcinoma (SESCC).
Methods and materials
We retrospectively reviewed the treatment outcomes of 47 patients with SESCC treated between October 2000 and December 2011. Sixteen patients with invasion into the submucosal layer (T1b) or the muscularis mucosa (m3) with positive vascular invasion were treated with CRT after ESD (ESD-CRT group). The lymph node area was irradiated to a total dose of 40–44 Gy and a boost radiation was administered if PET-positive lymph nodes or positive margins were observed. The remaining 31 patients received definitive CRT only (dCRT group).
The radiation field was significantly larger in the ESD-CRT group; the “long T” was used in 11 patients (35.4%) in the dCRT group and 15 (93.7%) in the ESD-CRT group (p = 0.0001). The total radiation dose was smaller in the ESD-CRT group; 40 Gy was used in 10 patients (62.5%) in the ESD-CRT group and all but one patient in the dCRT group received ≥60 Gy (p = 0.00001). The 3-year overall survival rates in the dCRT and ESD-CRT groups were 63.2% and 90.0% respectively (p = 0.118). Recurrence developed in nine patients (29.0%) in the dCRT group and one (6.3%) in the ESD-CRT group. Local recurrence was observed in six patients (19%) in the dCRT group and none in the ESD-CRT-group (p = 0.029). Pericardial effusion (≥Grade 3) occurred in three patients (9.7%) in the dCRT group and none in the ESD-CRT group.
ESD followed by CRT is an effective and safe approach for SESCC at m3 or T1b. This combination of ESD and CRT improves the local control rate, and it could decrease the number of cardiac toxicities due to a radiation-dose reduction relative to CRT alone.
PMCID: PMC4316795  PMID: 25636830
Superficial esophageal cancer; Endoscopic submucosal dissection; Chemoradiotherapy; Combination; Pericardial effusion
9.  Acute small-bowel toxicity during neoadjuvant combined radiochemotherapy in locally advanced rectal cancer: determination of optimal dose-volume cut-off value predicting grade 2–3 diarrhoea 
Current therapeutic standard for locally advanced rectal cancer is the neoadjuvant radiochemotherapy with total mesorectal excision. Diarrhoea is the main acute side effect, induced by the dose to the small-bowel, frequently leading to a treatment modification. Aim of this study was to analyse the differences between the irradiated small-bowel volumes and the occurrence of acute diarrhea during combined radiochemotherapy for rectal cancer.
45 patients treated with a neoadjuvant radiochemotherapy (three-field box 50.4 Gy; Cetuximab, Capecitabine, Irinotecan) for locally advanced rectal cancer within a prospective phase I/II study were evaluated. Based on the dose-volume histograms, the small-bowel volumes receiving doses of 5, 10 … 45 Gy (V5, V10 …V45) were calculated and compared with the prospectively documented small- bowel toxicities.
There was a statistically significant difference between irradiated small-bowel volumes and the severity of therapy related diarrhoea. The strongest validity concerning the risk of developing a grade 2–3 diarrhoea was seen at a dose level of 5 Gy (V 5) with a small-bowel volume of 291.94 cc. Patients with V 5 > 291.94 cc had significantly more often grade 2–3 diarrhoea, than patients with V5 below this cut-off value (82% vs. 29%; p < 0.0001).
In the inverse treatment planning of rectal caner patients the small-bowel volume receiving 5 Gy should be limited to about 300 cc.
PMCID: PMC4324657  PMID: 25636703
Locally advanced rectal cancer; Radiation enteritis; Dose-volume histogram; Dose-volume constraints; Neoadjuvant radiochemotherapy
10.  Perilesional edema in radiation necrosis reflects axonal degeneration 
Recently, we characterized a Gamma Knife® radiation necrosis mouse model with various magnetic resonance imaging (MRI) protocols to identify biomarkers useful in differentiation from tumors. Though the irradiation was focal to one hemisphere, a contralateral injury was observed that appeared to be localized in the white matter only. Interestingly, this injury was identifiable in T2-weighted images, apparent diffusion coefficient (ADC), and magnetization transfer ratio (MTR) maps, but not on post-contrast T1-weighted images. This observation of edema independent of vascular changes is akin to the perilesional edema seen in clinical radiation necrosis.
The pathology underlying the observed white-matter MRI changes was explored by performing immunohistochemistry for healthy axons and myelin. The presence of both healthy axons and myelin was reduced in the contralateral white-matter lesion.
Based on our immunohistochemical findings, the contralateral white-matter injury is most likely due to axonal degeneration.
PMCID: PMC4331301  PMID: 25636531
Radiation necrosis; White matter injury; Axonal degeneration
11.  Radiation myelitis after hypofractionated radiotherapy with concomitant gefitinib 
We describe the case of a 71-year-old Caucasian female with primary disseminated non-small cell cancer of the lung, presented for palliative radiotherapy of metastatic spread to the 9th and 11th thoracic vertebrae without intramedullary growth. Palliative radiotherapy with daily fractions of 3 Gy and a cumulative dose of 36 Gy to thoracic vertebrae 8-12 was performed. The patient received concomitantly 250 mg gefitinib daily. After a latent period of 16 months, the patient developed symptoms of myelitis. Magnetic resonance imaging (MRI) did not reveal any bony or intraspinal tumor progression, but spinal cord signal alteration. No response to steroids was achieved. The neurological symptoms were progressive in August 2013 with the right leg being completely plegic. The left leg was incompletely paralyzed. Deep and superficial sensitivity was also diminished bilaterally. The patient was completely urinary and anally incontinent. Contrary to the clinical findings, a follow-up MRI (July 2013) showed amelioration of the former signal alterations in the spinal cord. The diagnosis of paraneoplastic myelopathy was refuted by a negative test for autologous antibodies. At the last clinical visit in May 2014, the neurological symptoms were stable. The last tumor-specific treatment the patient is receiving is erlotinib 125 mg/d.
We reviewed the literature and found no reported cases of radiation myelopathy after the treatment in such a setting. The calculated probability of such complication after radiotherapy alone is statistically measurable at the level of 0.02%. We suppose that gefitinib could also play a role in the development of this rare complication.
PMCID: PMC4313465  PMID: 25631068
Radiation myelitis; Concomitant radiotherapy; Gefitinib
12.  Dosimetric comparison between jaw tracking and static jaw techniques in intensity-modulated radiotherapy 
To compare the dosimetric differences between jaw tracking technique (JTT) and static jaw technique (SJT) in dynamic intensity-modulated radiotherapy (d-IMRT) and assess the potential advantages of jaw tracking technique.
Two techniques, jaw tracking and static jaw, were used respectively to develop the d-IMRT plans for 28 cancer patients with various lesion sites: head and neck, lungs, esophageal, abdominal, prostate, rectal and cervical. The dose volume histograms (DVH) and selected dosimetric indexes for the whole body and for organs at risk (OARs) were compared. A two dimensional ionization chamber Array Seven29 (PTW, Freiburg, Germany) and OCTAVIUS Octagonal phantom (PTW, Freiburg, Germany) were used to verify all the plans.
For all patients, the treatment plans using both techniques met the clinical requirements. The V5, V10, V20, V30, V40 (volumes receiving 5, 10, 20, 30 and 40 Gy at least, respectively), mean dose (Dmean) for the whole body and V5, V10, V20, Dmean for lungs in the JTT d-IMRT plans were significantly less than the corresponding values of the SJT d-IMRT plans (p < 0.001). The JTT d-IMRT plans deposited lower maximum dose (Dmax) to the lens, eyes, brainstem, spinal cord, and right optic nerve, the doses reductions for these OARs ranged from 2.2% to 28.6%. The JTT d-IMRT plans deposited significantly lower Dmean to various OARs (all p values < 0.05), the mean doses reductions for these OARs ranged from 1.1% to 31.0%, and the value reductions depend on the volume and the location of the OARs. The γ evaluation method showed an excellent agreement between calculation and measurement for all techniques with criteria of 3%/3 mm.
Both jaw tracking and static jaw d-IMRT plans can achieve comparable target dose coverage. JTT displays superior OARs sparing than SJT plans. These results are of clinical importance, especially for the patients with large and complex targets but close to some highly radio-sensitive organs to spare, and for patients with local recurrent or secondary primary malignant lesion within a previously irradiated area.
PMCID: PMC4326511  PMID: 25623899
Jaw tracking; IMRT; Dosimetry; OARs sparing
13.  A phase I dose escalation study of oxaliplatin plus oral S-1 and pelvic radiation in patients with locally advanced rectal cancer (SHOGUN trial) 
The objective of this phase I study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of preoperative chemoradiotherapy (CRT) with S-1 plus oxaliplatin in patients with locally advanced rectal cancer.
Patients received radiotherapy in a total dose of 50.4 Gy in 28 fractions. Concurrent chemotherapy consisted of a fixed oral dose of S-1 (80 mg/m2/day) on days 1–5, 8–12, 22–27, and 29–33, plus escalated doses of oxaliplatin as an intravenous infusion on days 1, 8, 22, and 29. Oxaliplatin was initially given in a dose of 40 mg/m2/week to three patients. The dose was then increased in a stepwise fashion to 50 mg/m2/week and the highest dose level of 60 mg/m2/week until the MTD was attained.
Thirteen patients were enrolled, and 12 received CRT. Dose-limiting toxicity (DLT) occurred in two of six patients (persistent grade 2 neutropenia, delaying oxaliplatin treatment by more than 3 days) at dose level 3; there were no grade 3 or 4 adverse events defined as DLT. The RD was 60 mg/m2/week of oxaliplatin on days 1, 8, 22, and 29. Twelve patients underwent histologically confirmed R0 resections, and two out of six patients (33%) given dose level 3 had pathological complete responses.
The RD for further studies is 80 mg/m2 of S-1 5 days per week plus 60 mg/m2 of oxaliplatin on days 1, 8, 22, and 29 and concurrent radiotherapy. Although our results are preliminary, this new regimen for neoadjuvant chemoradiotherapy is considered safe and active.
Trial registration
This trial was registered with (identifier: NCT01227239).
PMCID: PMC4312451  PMID: 25612635
Rectal cancer; Chemoradiotherapy; Phase I study; Oxaliplatin; S-1
14.  Pneumomediastinum as a complication of SABR for lung metastases 
Stereotactic ablative body radiation (SABR) is a novel and sophisticated radiation modality that involves the irradiation of extracranial tumors through precise and very high doses in patients with oligometastatic lung disease and primary lung tumors.
Case presentation
A 52-year-old female with subclinical idiopathic interstitial lung disease (ILD) and oligometastatic lung disease from squamous urethral cancer who was treated with SABR for a metastatic lesion located in the right lower pulmonary lobe. The patient received a hypo-fractionated course of SABR. A 3D-conformal multifield technique was used with six coplanar and one non-coplanar statics beams. A 48 Gy total dose in three fractions over six days was prescribed to the 95% of the PTV. The presence of idiopathic ILD and other identifiable underlying lung conditions were not taken into account as a constraint to prescribe a different than standard total dose or fractionation schedule. Six months after the SABR treatment, a CT-scan showed the presence of a pneumomediastinum with air outside the bronchial tree and within the subcutaneous tissue without co-existing pneumothorax. To our knowledge, this is the first case of pneumomediastinum appearing 6 months after SABR treatment for a lung metastasis located in the perihiliar/central tumors region as defined by the RTOG protocols as the proximal bronchial tree.
Radiation oncologist should be aware of the potential risk of severe lung toxicity caused by SABR in patients with ILD, especially when chemotherapy-induced pulmonary toxicity is administered in a short time interval.
PMCID: PMC4313462  PMID: 25612575
Oligometastatic lung disease; Pneumomediastinum; SABR (stereotactic ablative body radiation); SBRT (stereotactic beam radiation therapy)
15.  Safety of high-dose-rate stereotactic body radiotherapy 
Background and purpose
Flattening filter free (FFF) beams with high dose rate are increasingly used for stereotactic body radiotherapy (SBRT), because they substantially shorten beam-on time. The physical properties of these beams together with potentially unknown radiobiological effects might affect patient safety. Therefore here we analyzed the clinical outcome of our patients.
Material and methods
Between 3/2010 and 2/2014 84 patients with 100 lesions (lung 75, liver 10, adrenal 6, lymph nodes 5, others 4) were treated with SBRT using 6 MV FFF or 10 MV FFF beams at our institution. Clinical efficacy endpoints and toxicity were assessed by Kaplan-Meier analysis and CTCAE criteria version 4.0.
Median follow-up was 11 months (range: 3–41). No severe acute toxicity was observed. There has been one case of severe late toxicity (1%), a grade 3 bile duct stricture that was possibly related to SBRT. For all patients, the 1-year local control rate, progression free survival and overall survival were 94%, 38% and 80% respectively, and for patients with lung lesions 94%, 48% and 83%, respectively.
No unexpected toxicity occurred. Toxicity and treatment efficacy are perfectly in range with studies investigating SBRT with flattened beams. The use of FFF beams at maximum dose rate for SBRT is time efficient and appears to be safe.
PMCID: PMC4313468  PMID: 25614416
Flattening filter free; Stereotactic body radiotherapy (SBRT); Stereotactic ablative radiotherapy (SABR); Dose rate; Toxicity
16.  GTV delineation in supraglottic laryngeal carcinoma: interobserver agreement of CT versus CT-MR delineation 
GTV delineation is the first crucial step in radiotherapy and requires high accuracy, especially with the growing use of highly conformal and adaptive radiotherapy techniques. If GTV delineations of observers concord, they are considered to be of high accuracy.
The aim of the study is to determine the interobserver agreement for GTV delineations of supraglottic laryngeal carcinoma on CT and on CT combined with MR-images and to determine the effect of adding MR images to CT-based delineation on the delineated volume and the interobserver agreement.
Twenty patients with biopsy proven T1-T4 supraglottic laryngeal cancer, treated with curative intent were included. For all patients a contrast enhanced planning CT and a 1.5-T MRI with gadolinium were acquired in the same head-and-shoulder mask for fixation as used during treatment. For MRI, a two element surface coil was used as a receiver coil. Three dedicated observers independently delineated the GTV on CT. After an interval of 2 weeks, a set of co-registered CT and MR-images was provided to delineate the GTV on CT. Common volumes (C) and encompassing volumes (E) were calculated and C/E ratios were determined for each pair of observers. The conformity index general (CIgen) was used to quantify the interobserver agreement. Results: In general, a large variation in interobserver agreement was found for CT (range: 0.29-0.77) as well as for CT-MR delineations (range: 0.17-0.80). The mean CIgen for CT (0.61) was larger compared to CT-MR (0.57) (p = 0.032). Mean GTV volume delineated on CT-MR (6.6 cm3) was larger compared to CT (5.6 cm3) (p = 0.002).
Delineation on CT with co-registered MR-images resulted in a larger mean GTV volume and in a decrease in interobserver agreement compared to CT only delineation for supraglottic laryngeal carcinoma.
Electronic supplementary material
The online version of this article (doi:10.1186/s13014-014-0321-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4327804  PMID: 25612508
Interobserver agreement; Supraglottic laryngeal carcinoma; Head-and-neck cancer; GTV; MRI
17.  Visualization of data in radiotherapy using web services for optimization of workflow 
Every day a large amount of data is produced within a radiotherapy department. Although this data is available in one form or other within the centralised systems, it is often not in the form which is of interest to the departmental staff. This work presents a flexible browser based reporting and visualization system for clinical and scientific use, not currently found in commercially available software such as MOSAIQTM or ARIATM. Moreover, the majority of user merely wish to retrieve data and not record and/or modify data. Thus the idea was conceived, to present the user with all relevant information in a simple and effective manner in the form of web-services. Due to the widespread availability of the internet, most people can master the use of a web-browser. Ultimately the aim is to optimize clinical procedures, enhance transparency and improve revenue.
Our working group (BAS) examined many internal procedures, to find out whether relevant information suitable for our purposes lay therein. After the results were collated, it was necessary to select an effective software platform. After a more detailed analysis of all data, it became clear that the implementation of web-services was appropriate. In our institute several such web-based information services had already been developed over the last few years, with which we gained invaluable experience. Moreover, we strived for high acceptance amongst staff members.
By employing web-services, we attained high effectiveness, transparency and efficient information processing for the user. Furthermore, we achieved an almost maintenance-free and low support system. The aim of the project, making web-based information available to the user from the departmental system MOSAIQ, physician letter system MEDATECR and the central finding server MiraPlus (laboratory, pathology and radiology) were implemented without restrictions.
Due to widespread use of web-based technology the training effort was effectively nil, since practically every member of staff can master the use of a web-browser. Moreover, we have achieved high acceptance amongst staff members and have improved our effectiveness resulting in a considerable time saving.
The many MOSAIQ-specific parts of the system can be readily used by departments which use MOSAIQ as the departmental system.
PMCID: PMC4307130  PMID: 25601225
Clinic management; Web-services; Information management; Workflow; Quality management; Radiotherapy
18.  Parotid gland shrinkage during IMRT predicts the time to Xerostomia resolution 
To assess the impact of mid-treatment parotid gland shrinkage on long term xerostomia during IMRT for oropharyngeal SCC.
Methods and materials
All patients treated with IMRT at a single Institution from November 2007 to June 2010 and undergoing weekly CT scans were selected. Parotid glands were contoured retrospectively on the mid treatment CT scan. For each parotid gland, the percent change relative to the planning volume was calculated and combined as weighted average. Patients were considered to be xerostomic if developed GR2+ dry mouth according to CTCAE v3.0. Predictors of the time to xerostomia resolution or downgrade to 1 were investigated at both uni- and multivariate analysis.
85 patients were selected. With a median follow up of 35.8 months (range: 2.4-62.6 months), the actuarial rate of xerostomia is 26.2% (SD: 5.3%) and 15.9% (SD: 5.3%) at 2 and 3 yrs, respectively. At multivariate analysis, mid-treatment shrink along with weighted average mean parotid dose at planning and body mass index are independent predictors of the time to xerostomia resolution. Patients were pooled in 4 groups based on median values of both mid-treatment shrink (cut-off: 19.6%) and mean WA parotid pl-D (cut-off: 35.7 Gy). Patients with a higher than median parotid dose at planning and who showed poor shrinkage at mid treatment are the ones with the outcome significantly worse (3-yr rate of xerostomia ≈ 50%) than the other three subgroups (3-yr rate of xerostomia ≈ 10%).
For a given planned dose, patients whose parotids significantly shrink during IMRT are less likely to be long-term supplemental fluids dependent.
PMCID: PMC4307228  PMID: 25595326
Parotid gland; IMRT; Shrinkage
19.  Definitive intensity modulated radiotherapy in locally advanced hypopharygeal and laryngeal squamous cell carcinoma: mature treatment results and patterns of locoregional failure 
To assess clinical outcomes and patterns of loco-regional failure (LRF) in relation to clinical target volumes (CTV) in patients with locally advanced hypopharyngeal and laryngeal squamous cell carcinoma (HL-SCC) treated with definitive intensity modulated radiotherapy (IMRT) and concurrent systemic therapy.
Data from HL-SCC patients treated from 2007 to 2010 were retrospectively evaluated. Primary endpoint was loco-regional control (LRC). Secondary endpoints included local (LC) and regional (RC) controls, distant metastasis free survival (DMFS), laryngectomy free survival (LFS), overall survival (OS), and acute and late toxicities. Time-to-event endpoints were estimated using Kaplan-Meier method, and univariate and multivariate analyses were performed using Cox proportional hazards models. Recurrent gross tumor volume (RTV) on post-treatment diagnostic imaging was analyzed in relation to corresponding CTV (in-volume, > 95% of RTV inside CTV; marginal, 20–95% inside CTV; out-volume, < 20% inside CTV).
Fifty patients (stage III: 14, IVa: 33, IVb: 3) completed treatment and were included in the analysis (median follow-up of 4.2 years). Three-year LRC, DMFS and overall survival (OS) were 77%, 96% and 63%, respectively. Grade 2 and 3 acute toxicity were 38% and 62%, respectively; grade 2 and 3 late toxicity were 23% and 15%, respectively. We identified 10 patients with LRF (8 local, 1 regional, 1 local + regional). Six out of 10 RTVs were fully included in both elective and high-dose CTVs, and 4 RTVs were marginal to the high-dose CTVs.
The treatment of locally advanced HL-SCC with definitive IMRT and concurrent systemic therapy provides good LRC rates with acceptable toxicity profile. Nevertheless, the analysis of LRFs in relation to CTVs showed in-volume relapses to be the major mode of recurrence indicating that novel strategies to overcome radioresistance are required.
PMCID: PMC4308085  PMID: 25595218
Hypoharyngeal cancer; Laryngeal cancer; IMRT; Patterns of failure; Radiotherapy
20.  Impact of weight loss on survival after chemoradiation for locally advanced head and neck Cancer: secondary results of a randomized phase III trial (SAKK 10/94) 
To analyze the impact of weight loss before and during chemoradiation on survival outcomes in patients with locally advanced head and neck cancer.
From 07/1994-07/2000 a total of 224 patients with squamous cell carcinoma of the head and neck were randomized to either hyperfractionated radiation therapy alone or the same radiation therapy combined with two cycles of concomitant cisplatin. The primary endpoint was time to any treatment failure (TTF); secondary endpoints were locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS). Patient weight was measured 6 months before treatment, at treatment start and treatment end.
The proportion of patients with >5% weight loss was 32% before, and 51% during treatment, and the proportion of patients with >10% weight loss was 12% before, and 17% during treatment. After a median follow-up of 9.5 years (range, 0.1 – 15.4 years) weight loss before treatment was associated with decreased TTF, LRRFS, DMFS, cancer specific survival and OS in a multivariable analysis. However, weight loss during treatment was not associated with survival outcomes.
Weight loss before and during chemoradiation was commonly observed. Weight loss before but not during treatment was associated with worse survival.
PMCID: PMC4324674
Weight loss; Chemotherapy; Cisplatin; Head and neck cancer; Hyperfractionated radiation therapy; Survival; Malnutrition
21.  Analysis of late toxicity in nasopharyngeal carcinoma patients treated with intensity modulated radiation therapy 
To observe the late toxicities in nasopharyngeal carcinoma (NPC) patients who achieved long-term survival after intensity modulated radiation therapy (IMRT).
208 untreated NPC patients who received IMRT and survived more than five years with locoregional disease control and no metastasis were evaluated in this study. The prescription dose to the gross target volume of nasopharynx (GTVnx), positive neck lymph nodes (GTVnd), clinical target volume 1 (CTV1) and 2 (CTV2) was 68Gy/30f, 60-66Gy/30f, 60 Gy/30f and 54Gy/30f, respectively. The nasopharynx and upper neck targets were irradiated using IMRT, and the lower neck and supraclavicular fossae targets were irradiated using the half-beam technique with conventional irradiation. The late toxicities were evaluated according to the LENT/SOMA criteria of 1995.
The median follow-up time was 78 months (60–96 months). The occurrence rates of cervical subcutaneous fibrosis, hearing loss, skin dystrophy, xerostomia, trismus, temporal lobe injury, cranial nerve damage, cataract, and brain stem injury induced by radiotherapy were 89.9%, 67.8%, 47.6%, 40.9%, 7.21%, 4.33%, 2.88%, 1.44%, and 0.48%, respectively. No spinal cord injury and mandible damage were found. Grade 3–4 late injuries were observed as follows: 1 (0.48%) skin dystrophy, 4 (1.92%) cervical subcutaneous fibrosis, 2 (0.96%) hearing loss, 2 (0.96%) cranial nerve palsy, and 1 (0.48%) temporal lobe necrosis. No grade 3–4 late injuries occurred in parotid, temporomandibular joints and eyes. Xerostomia decreased gradually over time and then showed only slight changes after 4 years. The change in the incisor distance stabilised by 1 year after RT, however, the incidence of hearing loss, skin dystrophy, subcutaneous fibrosis and nervous system injuries increased over time after RT.
The late injuries in most NPC patients who had long-term survivals after IMRT are alleviated. Within the 5 years of follow-up, we found xerostomia decreased gradually; The change in the incisor distance stabilised by 1 year after RT; while hearing loss, nervous system injuries increased over time after RT.
PMCID: PMC4302701  PMID: 25582731
Nasopharyngeal neoplasm/radiotherapy; Intensity-modulated radiotherapy; Radiation injury; Late toxicity
22.  Treatment outcomes of extended-field radiation therapy and the effect of concurrent chemotherapy on uterine cervical cancer with para-aortic lymph node metastasis 
To review the clinical outcomes of extended-field radiation therapy (EFRT) and to analyze prognostic factors significant for survival in patients receiving EFRT for uterine cervical carcinoma with para-aortic node (PAN) metastasis.
Patients and methods
We retrospectively reviewed 90 patients with stage IB-IVA cervical cancer and PAN metastasis between 1987 and 2012. Median age was 50 (range, 24–77). Patients received median 70.2 Gy (range, 56–93) to point A and median 50.4 Gy (range, 45–60.4) to PAN over median 69 elapsed days (range, 43–182). Forty-six patients (51.1%) received concurrent chemotherapy. Survival was calculated using the Kaplan–Meier method. We analyzed prognostic factors for overall actuarial survival (OS) and progression-free survival (PFS) using a Cox regression method.
The median follow-up period for surviving patients was 55 months (range, 3–252). Seventy patients (77.8%) had complete remission. Forty-six patients experienced treatment failure as follows: 11 patients (12.2%) as local recurrence, 19 (21%) as regional recurrence and 33 (36.7%) as distant metastasis. The 5-yr OS and PFS were 62.6% and 43.9%, respectively. Treatment response was the only statistically independent prognostic factors for OS (p= 0.04) and PFS (p< 0.001) on multivariate analysis. Grade 3 or 4 hematologic gastrointestinal and urogenital toxicities were observed in about 10% of patients.
Our institutional experiences showed that EFRT was an effective treatment for cervical cancer patients with PAN metastasis. The addition of chemotherapy to EFRT seems to have uncertain survival benefit with higher hematologic toxicity.
Electronic supplementary material
The online version of this article (doi:10.1186/s13014-014-0320-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4311470  PMID: 25582425
Cervical cancer; Treatment outcome; Chemotherapy; Para-aortic lymph node; Extended-field radiation therapy
23.  Radiation therapy at the end of life: a population-based study examining palliative treatment intensity 
To examine factors associated with the use of radiation therapy (RT) at the end of life in patients with breast, prostate, or colorectal cancer.
Using data from the Surveillance, Epidemiology, and End Results (SEER) – Medicare database, patients were over age 65 and diagnosed between January 1, 2004 and December 31, 2011 with any stage of cancer when the cause of death, as defined by SEER, was cancer; or with stage 4 cancer, who died of any cause. We employed multiple logistic regression models to identify patient and health systems factors associated with palliative radiation use.
50% of patients received RT in the last 6 months of life. RT was used less frequently in older patients and in non-Hispanic white patients. Similar patterns were observed in the last 14 days of life. Chemotherapy use in the last 6 months of life was strongly correlated with receiving RT in the last 6 months (OR 2.72, 95% CI: 2.59-2.88) and last 14 days of life (OR 1.55, 95% CI: 1.40-1.66). Patients receiving RT accrued more emergency department visits, radiographic exams and physician visits (all comparisons p < 0.0001).
Among patients with breast, colorectal, and prostate cancer, palliative RT use was common. End-of-life RT correlated with end-of-life chemotherapy use, including in the last 14 days of life, when treatment may cause increased treatment burden without improved quality of life. Research is needed optimize the role and timing of RT in palliative care.
Electronic supplementary material
The online version of this article (doi:10.1186/s13014-014-0305-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4314753  PMID: 25582217
Palliative care; SEER-Medicare; Radiation therapy; Radiotherapy; Radiation oncology; End-of-life care
24.  Effects on heart function of neoadjuvant chemotherapy and chemoradiotherapy in patients with cancer in the esophagus or gastroesophageal junction – a prospective cohort pilot study within a randomized clinical trial 
Neoadjuvant therapy for cancer of the esophagus or gastroesophageal (GE)-junction is well established. The pros and cons of chemoradiotherapy and chemotherapy are debated. Chemoradiotherapy might impair cardiac function eliciting postoperative morbidity. The aim of this pilot study was to describe acute changes in left ventricular function following chemoradiotherapy or chemotherapy.
Patients with esophageal and (GE)-junction cancer enrolled at our center into a multicenter trial comparing neoadjuvant chemoradiotherapy and chemotherapy were eligible. Patients were randomized to receive cisplatin and 5-fluorouracil with or without the addition of 40 Gy radiotherapy prior to surgery. Left ventricular function was evaluated using echocardiography and plasma N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) before and after neoadjuvant treatment. The primary outcome measure was left ventricular global strain (GS). Clinical effects were assessed using repeated exercise tests. Linear mixed models were used to analyze the effects of treatment group, and the interaction between groups.
40 patients participated (chemoradiotherapy, n = 17; chemotherapy, n = 23). In the chemoradiotherapy group there was no change in left ventricular global strain but mitral annular plane systolic excursion (MAPSE) of the ventricular septum, early diastolic filling velocity (E-velocity), and the ratio of early to late ventricular filling velocities (E/A ratio) decreased significantly (p = 0.02, p = 0.01, and p = 0.03, respectively). No changes were observed in the chemotherapy group. There was a trend towards an interaction effect for MAPSE sept and E (p = 0.09 and p = 0.09). NT-proBNP increased following chemoradiotherapy (p = 0.05) but not after chemotherapy (p > 0.99), and there was a trend towards an interaction effect (p = 0.07). Working capacity decreased following neoadjuvant treatment (chemoradiotherapy p = 0.001, chemotherapy p = 0.03) and was more pronounced after chemoradiotherapy with a trend towards an interaction effect (p = 0.10).
Neoadjuvant chemoradiotherapy but not chemotherapy before surgery for cancer of the esophagus or GE-junction seems to induce an acute negative effect on both systolic and diastolic left ventricular function. Future studies on neoadjuvant treatment for esophageal cancer are suggested to add measurements of cardiac function.
Trial registration
Clinical NCT01362127.
Electronic supplementary material
The online version of this article (doi:10.1186/s13014-014-0310-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4331444  PMID: 25582305
Esophageal neoplasms; Neoadjuvant therapy; Chemoradiotherapy; Echocardiography; Radiation effects; Cardiotoxicity
25.  Role of in vivo dosimetry with radiochromic films for dose verification during cutaneous radiation therapy 
To evaluate the role of in vivo dosimetry with radiochromic films for dose verification in cutaneous radiation therapy (RT).
Five patients with 8 cutaneous or sub-cutaneous malignancies of the face, neck, trunk and extremity receiving RT were included. Orthovoltage, megavoltage photon therapies were applied based on anatomic location. The delivered dose for each target was measured with GAFCHROMIC EBT3TM film. The differences between the prescribed and measured doses in each target were analyzed based on the RT characteristics, target location and custom patient set up. The accuracy of EBT3TM film measurement was verified by measurements in a solid water phantom.
The mean measured dose was -3.2% (-9.6% to +2.3%, P=0.86) lower than prescribed over 23 measurements. A wide range of under dose was detected in orthovoltage therapy when a gap existed between skin and a closed-ended applicator surface. The magnitude of the under dosage was correlated with the degree of the gap (P=0.01). The phantom study confirmed the accuracy of GAFCHROMIC EBT3TM film measurement and found that the low measured dose in orthovoltage therapy was caused by the deviation from the inverse square law (ISL) of the beam output at extended source surface distance (SSD) for closed-ended applicators.
A significantly low delivered dose for extended SSD orthovoltage therapy was demonstrated during cutaneous RT. The dose fall-off with distance is not completely compensated by the ISL standoff correction for orthovoltage therapy. GAFCHROMIC EBT3™ film is a useful and accurate tool for quality assurance of patients receiving a curative intended cutaneous RT.
PMCID: PMC4300174  PMID: 25582565
GAFCHROMIC EBT3™ film; Extended source surface distance; Orthovoltage; Inverse square law; Quality assurance

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