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• Resting-state fMRI detected early radiation-induced brain functional abnormalities. • Brain nodal changes were dynamic, mainly manifesting an 'impairment-recovery' pattern. • D 20cc was an important prognostic determinant for nodal changes of STG.R. To investigate radiotherapy (RT)-related brain network changes in patients with nasopharyngeal carcinoma (NPC) over time and develop least absolute shrinkage and selection operator (LASSO)-based multivariable normal tissue complication probability (NTCP) models to predict RT-related brain network changes. 36 NPC patients were followed up at four timepoints: baseline, within 3 months (acute), 6 months (subacute), and 12 months (delayed) post-RT. 15 comparable healthy controls (HCs) were finally included and followed up in parallel. Functional neuroimaging data, dose–volume parameters of bilateral temporal lobes and Montreal Cognitive Assessment (MoCA) were acquired. Graph theoretical analysis and mixed-design analysis of variance were performed to investigate how the brain global and nodal changes were affected by RT. Multivariate logistic regression NTCP models were developed. LASSO with nested cross-validation strategy was used to select features. The relationships between network changes and MoCA changes were also examined. Significant changes were detected in nodal efficiency (NE) in NPC patients but not in HCs over time. Altered NE was distributed in the bilateral frontal, temporal lobes and the right insula, which showed a "decrease-increase/recovery" pattern over time. Among all models, the model for predicting NE changes of STG.R showed a relatively good performance (area under the receiver operating curve: 0.68), and D 20cc and V 20 to right temporal lobe outperformed in this model. Our findings indicate that RT-induced brain injury begin at the acute period and follow a recovery over time. Furthermore, our study presents prediction models for brain dysfunction based on the dosimetric and clinical parameters. [ABSTRACT FROM AUTHOR]

• PIF following C-ion RT for uterus carcinomas were retrospectively evaluated. • The 5-year cumulative PIF incidence in the whole pelvis was 42.4%. • The 5-year cumulative PIF incidence in the sacrum was 27.1%. • V10–40, D 50% , D mean , BMI, smoking, and port directions may affect sacral PIF. There is growing evidence on the role of carbon-ion radiotherapy (C-ion RT) for gynaecological tumours. Pelvic insufficiency fracture (PIF) decreases the quality of life after photon beam radiotherapy (RT). However, there is little information on PIF after C-ion RT. This study retrospectively assessed incidence of PIF after C-ion RT for uterine carcinomas (UCs) and the associations of clinical and dosimetric parameters with PIF incidence. We performed a pooled analysis of 102 patients with UCs who underwent definitive C-ion RT alone and were followed up for >6 months without any additional RT in the pelvic region. PIF occurrence was surveyed using magnetic resonance imaging and/or computed tomography. Associations of clinical and dosimetric parameters with PIF incidence were analysed. The 2- and 5-year actuarial incidences of ≥grade 1 PIF in all pelvic regions were 22.3% and 42.4%, respectively. The most frequent site of involvement was the sacrum. Log-rank tests showed that higher volumes receiving >10 Gy (relative biological effectiveness) (V10), V20, V30, and V40, body mass index (BMI) under 18.5, and current smoking were associated with increased incidence of ≥grade 1 PIF in the sacrum. We clarified the actuarial incidence of PIF after C-ion RT for UCs. Higher V10, V20, V30, V40, D 50% , D mean , current smoking, BMI <18.5, and using the anterior-posterior direction in whole pelvic irradiation were associated with higher incidences of PIF in the sacrum. The present results may lead to further improvement of C-ion RT for UCs. [ABSTRACT FROM AUTHOR]

• Incidence of ND obstruction was 46% (13/28) for Grade 1 and 7% (2/28) for Grade 2. • High ND volumes receiving 10–60 Gy(RBE) were associated with ND obstruction. • Cutoff values classified obstruction-positive patients with >96% accuracy. Little information is available on the risk factors for nasolacrimal duct obstruction after radiotherapy for head and neck tumors. We investigated the incidence and predictive dosimetric parameters for nasolacrimal duct obstruction following carbon-ion radiotherapy for head and neck tumors. Twenty-eight patients with head and neck non-squamous cell carcinoma were analyzed in this single-institution prospective study. More than half of the tumors were located in the nasal cavity and maxillary sinus. Carbon-ion radiotherapy consisting of 57.6 or 64.0 Gy(relative biological effectiveness; RBE) in 16 fractions was administered. Nasolacrimal duct obstruction was recorded according to Common Terminology Criteria for Adverse Events version 4.0. Cutoff values were determined using receiver operating characteristic (ROC) curve analysis. VX indicates the volume irradiated with X Gy(RBE). The median follow-up period was 60.3 months. Incidences of Grade 1 and 2 nasolacrimal duct obstructions were 46% (13/28) and 7% (2/28), respectively; no Grade 3 or greater toxicities were recorded. Throughout the dose range, the volumes of the irradiated nasolacrimal ducts were significantly higher in the obstruction-positive patients than in the obstruction-negative patients (p < 0.001 for V10, V20, V30, V40, V50, and V60). Cutoff values determined by the ROC curve analysis classified the obstruction-positive patients with an accuracy of >96% over the entire range of V10–V60. The incidence and predictive dosimetric parameters for nasolacrimal duct obstruction after carbon-ion radiotherapy were demonstrated in a prospective cohort. These data should help optimize carbon-ion radiotherapy treatments for patients with head and neck tumors. [ABSTRACT FROM AUTHOR]

Purpose To investigate three-dimensional cluster structure and its correlation to clinical endpoint in heterogeneous dose distributions from intensity modulated radiation therapy. Methods Twenty-five clinical plans from twenty-one head and neck (HN) patients were used for a phenomenological study of the cluster structure formed from the dose distributions of organs at risks (OARs) close to the planning target volumes (PTVs). Initially, OAR clusters were searched to examine the pattern consistence among ten HN patients and five clinically similar plans from another HN patient. Second, clusters of the esophagus from another ten HN patients were scrutinized to correlate their sizes to radiobiological parameters. Finally, an extensive Monte Carlo (MC) procedure was implemented to gain deeper insights into the behavioral properties of the cluster formation. Results Clinical studies showed that OAR clusters had drastic differences despite similar PTV coverage among different patients, and the radiobiological parameters failed to positively correlate with the cluster sizes. MC study demonstrated the inverse relationship between the cluster size and the cluster connectivity, and the nonlinear changes in cluster size with dose thresholds. In addition, the clusters were insensitive to the shape of OARs. Conclusion The results demonstrated that the cluster size could serve as an insightful index of normal tissue damage. The clinical outcome of the same dose–volume might be potentially different. [ABSTRACT FROM AUTHOR]

Background and purpose We aimed to evaluate the relationship between brainstem necrosis and dose–volume histograms in patients with head and neck tumors after carbon-ion radiotherapy. Material and methods We evaluated 85 patients with head and neck tumors who underwent carbon-ion radiotherapy and were followed-up for ≥12 months. Brainstem necrosis was evaluated using the Common Terminology Criteria for Adverse Events (version 4.0). Results The median follow-up was 24 months, and four patients developed grade 1 brainstem necrosis, with 2-year and 3-year cumulative rates of 2.8% and 6.5%, respectively. Receiver operating characteristic curve analysis revealed the following significant cut-off values: a maximum brainstem dose of 48 Gy (relative biological effectiveness [RBE]), D1 cm 3 of 27 Gy (RBE), V40 Gy (RBE) of 0.1 cm 3 , V30 Gy (RBE) of 0.7 cm 3 , and V20 Gy (RBE) of 1.4 cm 3 . Multivariate analysis revealed that V30 Gy (RBE) was most significantly associated with brainstem necrosis. The 2-year cumulative rates were 33% and 0% for V30 Gy (RBE) of ≥0.7 cm 3 and <0.7 cm 3 , respectively ( p < 0.001). Conclusions The present study indicated that the dose constraints might help minimize brainstem necrosis after carbon-ion radiotherapy. [ABSTRACT FROM AUTHOR]

Purpose To determine dosimetric parameters associated with osteoradionecrosis (ORN) in oropharyngeal cancer (OPC) patients in the IMRT era. Material and methods Subsequent to institutional review board approval, we identified ORN in OPC patients treated with IMRT from 2002 to 2013. 1:2 case-control matching was implemented. Mandibular dose-volume histograms (DVH) were extracted. Dosimetric parameters were compared using non-parametric stats. Recursive partitioning analysis (RPA) was done to identify DVH correlates of ORN. Results 68 ORN cases and 131 controls were matched. Median follow-up was 41 months and median time to development of ORN was 16 months. Mandibular mean dose was significantly higher in the ORN cohort (48.1 vs 43.6 Gy, p < 0.0001). However, the maximum dose was not statistically different . DVH bins from V35 to V73 were all significantly higher in the ORN cohort compared with controls ( p < 0.0006). Two DVH parameters were identified in RPA analysis, V43 and V58. The majority (81%) of ORN cases were observed with both V44 ≥ 42% and V58 ≥ 25%. Conclusions Our data demonstrate that a wide range of DVH parameters in the intermediate and high beam path were all significantly higher in ORN patients. Mandibular V44 < 42% and V58 < 25% represent reasonable DVH constraints for IMRT plan acceptability, when tumor coverage is not compromised. [ABSTRACT FROM AUTHOR]

Background and purpose To analyze the distribution of individually-determined radiation dose to the heart and its functional sub-structures after radiotherapy in breast cancer patients treated in Germany during 1998–2008. Material and methods We obtained electronic treatment planning records for 769 female breast cancer patients treated with megavoltage tangential field radiotherapy. All dose distributions were re-calculated using Eclipse with the anisotropic analytical algorithm (AAA) for photon fields, and the electron Monte Carlo algorithm for electron boost fields. Based on individual dose volume histograms for the complete heart and several functional sub-structures, we estimated various dose measures in patient groups. Results Mean heart dose spanned a range of 0.9–19.1 Gy for left-sided radiotherapy and 0.3–11.6 Gy for right-sided radiotherapy. Average (median) mean heart dose was 4.6 Gy (3.7 Gy) for left-sided radiotherapy, and 1.7 Gy (1.4 Gy) for right-sided RT. With left-sided radiotherapy, 66% of the patients had 2 cm 3 of the complete heart exposed to at least 40 Gy. Younger age, higher body mass index, tumor location in a medial quadrant, and presence of a parasternal field were also associated with higher heart dose. Conclusion Tumor location and treatment choices influence cardiac dose with complex interactions. There is considerable variability in heart dose, with dose metrics of different cardiac sub-structures showing different patterns in their dependency on external influences. Dose–response analysis of late cardiac effects after radiotherapy requires detailed individual dosimetry. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: This study aimed to determine the risk factors for radiation-induced brain injury (RIBI) after carbon ion radiotherapy (CIRT) for treating skull base tumors. Materials and methods: Between April 1997 and January 2009, CIRT at a total dose of 48.0–60.8Gy equivalent (GyE) was administered in 16 fractions to 47 patients with skull base tumors. Of these patients, 39 who were followed up with magnetic resonance imaging (MRI) for more than 24months were analyzed. RIBI was assessed according to the MRI findings based on the Late Effects of Normal Tissue-Subjective, Objective, Management, Analytic criteria; clinical symptoms were assessed according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer tables. The correlations of clinical and dosimetric parameters with incidence of ⩾grade 2 RIBI were retrospectively analyzed. Results: The median follow-up period was 67months. The 5-year actuarial likelihoods of ⩾grade 2 RIBI and ⩾grade 2 clinical symptoms were 24.5% and 7.0%, respectively. Multivariate analysis demonstrated that the brain volume receiving more than 50GyE (V50) was a significant risk factor for the development of ⩾grade 2 RIBI (p =0.004). Conclusion: V50 was a significant risk factor for ⩾grade 2 RIBI after CIRT using a 16-fraction regimen. [Copyright &y& Elsevier]

Abstract: Background and Purpose: To investigate possible relationships between the dose to the sub-segments of the lower urinary tract and lower urinary tract symptoms (LUTS) after brachytherapy of the prostate. Materials and Methods: This study involved 225 patients treated for prostate cancer with I-125 seeds. Post-implant dose-volume histograms of the prostate, urethra, bladder wall, bladder neck and external sphincter were determined. Endpoints were the mean and the maximum International Prostate Symptom Score (IPSS) during the first 3months after the treatment. For binary analysis the patients were stratified in a group with enhanced LUTS and a group with non-enhanced LUTS. Results: The dose to 0.5cm3 of the bladder neck ‘D 0.5cc-blne’ (p =0.002 and p =0.005), the prostate volume prior to treatment ‘V pr-0’ (p =0.005 and p =0.024) and the pre-treatment IPSS (both p <0.001) were independently correlated with mean and maximum IPSS, respectively. Of the patients with a D 0.5cc-blne⩾175Gy and a V pr-0⩾42cm3, 68% suffered from enhanced LUTS, against just 30% of the other patients (p <0.0001). Conclusions: Pre-treatment IPSS, prostate volume and dose to the bladder neck are correlated with post-implant IPSS. A combination of a large prostate and a high dose to the bladder neck is highly predictive for enhanced early LUTS. [Copyright &y& Elsevier]

Abstract: Background and purpose: To determine the dose constraints for rectal bleeding in brachytherapy (BRT) combined with external beam radiotherapy (EBRT). Materials and methods: Post-BRT, pelvic computed tomography images were used for subsequent EBRT planning and BRT postplans in 37 patients. The physical doses for each plan were converted to biologically effective doses, and corresponding voxel doses were integrated to plot the summed dose-volume histogram (sum-DVH). Between 5 patients with (bled-pts) and 32 without (spared-pts) grade 2 or 3 rectal bleeding, the differences in the mean minimal dose (rDn) covering the rectal volume of 0.5–10.0cc and the rectal volume (rVn) receiving the calculated dose of 20–150Gy were compared. Results: The differences in the summed-rDn were determined by BRT exposure, while those of the summed-rVn were determined in the low-dose range and superimposed in the high-dose range by EBRT exposure. Of the 13 patients with rV150 of >1.2cc, 4 were bled-pts (30.8%). Of the 24 patients with rV150 of 1.2cc, 1 was a bled-pts (4.2%) (p =0.024; odds ratio, 10.2; CI (95%), 1.0–104.3). Conclusions: The mono-scale DVH analysis is a promising method for exploring the threshold for rectal bleeding in combined radiotherapy. [Copyright &y& Elsevier]

Abstract: Background and purpose: For toxicities occurring during the course of radiotherapy, it is conceptually inaccurate to perform normal-tissue complication probability analyses using the complete dose–volume histogram. The goal of this study was to analyze acute rectal toxicity using a novel approach in which the fit of the Lyman–Kutcher–Burman (LKB) model is based on the fractional rectal dose–volume histogram (DVH). Materials and methods: Grade ⩾2 acute rectal toxicity was analyzed in 509 patients treated on Radiation Therapy Oncology Group (RTOG) protocol 94-06. These patients had no field reductions or treatment-plan revisions during therapy, allowing the fractional rectal DVH to be estimated from the complete rectal DVH based on the total number of dose fractions delivered. Results: The majority of patients experiencing Grade ⩾2 acute rectal toxicity did so before completion of radiotherapy (70/80=88%). Acute rectal toxicity depends on fractional mean rectal dose, with no significant improvement in the LKB model fit when the volume parameter differs from n =1. The incidence of toxicity was significantly lower for patients who received hormone therapy (P =0.024). Conclusions: Variations in fractional mean dose explain the differences in incidence of acute rectal toxicity, with no detectable effect seen here for differences in numbers of dose fractions delivered. [Copyright &y& Elsevier]

Abstract: Background and purpose: To assess the association between dosimetric/clinical parameters and gastrointestinal/urinary grade 2–4 side effects in cervix cancer patients treated with 3D pulse dose rate brachytherapy. Materials and methods: Three hundred and fifty-two patients received brachytherapy associated with external-beam radiotherapy (EBRT) for 266 of them; 236 patients underwent surgery. The doses for the most exposed 2, and 0.1cm3 (D 2cc and D 0.1cc) volumes of the rectum and bladder as well as bladder ICRU point dose (D ICRU) were converted into isoeffective doses in 2-Gy fractions. The clinical parameters analyzed were: age, smoking habits, arteritis, diabetes, previous pelvic surgery, FIGO stage, nodal status, pathology, pelvic surgery, EBRT and chemotherapy. Side effects were prospectively assessed using the CTCAEv3.0. Cutoff dose levels were defined separately for patients treated with EBRT and brachytherapy (Group 1) and with preoperative brachytherapy (Group 2). Results: The median follow-up was 23.4months. In Group 1 a significant predictive value of rectum D 0.1cc and D 2cc, bladder D 0.1cc and D ICRU for gastrointestinal and urinary toxicity was found using as cutoff 83, 68, 109 and 68Gy α / β 3. In Group 2 a significant predictive value of bladder D 0.1cc, D 2cc and D ICRU for urinary toxicity was found using as cutoff 141, 91 and 67Gy α / β 3, but not for the rectum D 0.1cc and D 2cc; smoking had a significant predictive value on urinary toxicity. Conclusions: For patients treated with brachytherapy and EBRT, rectum D 0.1cc and D 2cc and bladder D 0.1cc and D ICRU had a predictive value for toxicity. For patients treated with preoperative brachytherapy, bladder D 0.1cc, D 2cc and D ICRU and smoking had a predictive value for urinary toxicity. [Copyright &y& Elsevier]

Abstract: Background and purpose: Radiation induced lung fibrosis (RILF) is a major complication after lung irradiation and is very important for long term quality of life and could result in fatal respiratory insufficiency. However, there has been little information on dosimetric parameters for radiotherapy planning in the aspect of RILF. The features of RILF related with dosimetric parameters were evaluated. Methods and materials: Forty-eight patients with non-small cell lung carcinoma who underwent post-operative radiation therapy (PORT) without adjuvant chemotherapy were analyzed. The degree of lung fibrosis was estimated by fibrosis volume and the dosimetric parameters were calculated from the plan of 3-dimensional conformal radiotherapy. Results: The fibrosis volume and V-dose as dosimetric parameters showed significant correlation and the correlation coefficient ranged from 0.602 to 0.683 (P <0.01). The degree of the correlation line was steeper as the dose increase and threshold dose was not found. Mean lung dose (MLD) showed strong correlation with fibrosis volume (correlation coefficient=0.726, P <0.01). Conclusions: The fibrosis volume is continuously increased with V-dose as the reference dose increases. MLD is useful as a single parameter for comparing rival plans in the aspect of RILF. [Copyright &y& Elsevier]

Abstract: Background and purpose: In ITV-based 3D-planning, the information of volume occupancy versus respiratory phase is not utilized. We propose a motion-weighted CTV (mwCTV) delineation method, which carries some 4D-information into planning. This method allows plan optimization based on occupancy-weighting and generation of motion-weighted DVH (mwDVH) that approximate the DVHs of full 4D-dose accumulation. Material and methods: Occupancy information from contours in 4D-CT is incorporated in the mwCTV generation. Higher-occupancy volumes receive higher dosimetric priority in planning. The temporally-weighted mwCTV is converted to a spatially-weighted mwCTV incorporating the temporal-weighting in mwDVH generation using the 3D-dose distribution. The mwDVHs were compared with DVHs of deformable-image-registration (DIR)-based 4D-dose accumulation and 3D-method for 10 cases. Results: For all the cases, the mwDVH curves are closer to the 4D-calculated DVH than the 3D-DVHs are, indicating a better approximation of the 4D-DVH. The 70Gy-covered percentage-CTV volume differed by −2.8%±0.8% between 3D and 4D, and 0.3%±0.7% between mwDVH and 4D-methods. The mean RMS values of the percentage-volume differences for the 4D–3D is 1.7±1.1, while for the 4D-mwDVH is 0.4±0.3. Conclusion: The mwCTV and mwDVH method, which is simple in implementation and does not require DIR, is a practical approximation of DIR-based 4D-planning and evaluation. [Copyright &y& Elsevier]

Abstract: Purpose: To assess the accuracy of the initial CT plan dose–volume histograms (DVH’s) for prostate, rectum and bladder by comparison to delivered doses determined from cone beam CT (CBCT) scans acquired during image-guided treatment. Materials and methods: Twelve prostate patients were treated using daily implanted fiducial guidance and following local protocol for bladder and rectal preparation. CBCT scans were acquired twice weekly and contoured for prostate, rectum and bladder. The planned beams were applied to all CBCT scans to determine the delivered doses. Prostate dose coverage was assessed by the proportion of the CTV fully encompassed by the 95% and 98% isodose lines. Rectal and bladder volumes receiving 40Gy, 60Gy and 70Gy at treatment were compared to the initial plan, with significance determined using the one-sample t-test. Results: Four patients showed marginally compromised CTV coverage by the 95% isodose at all CBCT plans. For nine patients the initial plan rectal DVH was significantly outside the range of the treatment DVH’s. Conclusions: Dose coverage of the prostate was not achieved for all patients. Observed rectal and bladder doses were higher than predicted. The initial treatment plan cannot be assumed to represent accurate normal tissue doses. [Copyright &y& Elsevier]

Abstract: Purpose: To investigate the association of high-dose preoperative chemoradiotherapy (CRT) and dose–volume histogram (DVH) parameters of lungs with incidence of postoperative pulmonary complications and to identify predictive clinical factors of pulmonary complications. Methods: Data of 65 patients were collected retrospectively. Thirty-five patients underwent transthoracic esophagectomy (TTE) alone and 30 received cisplatin and 5-fluorouracil, concomitant with radiotherapy, median dose 66Gy, and followed by TTE. From the DVH for each lung alone and for both lungs together as one organ we generated total lung volume, mean radiotherapy dose, relative and absolute volumes receiving more than a threshold dose, and relative and absolute volumes receiving less than a threshold dose. Postoperative pulmonary complications were defined as pneumonia or respiratory failure. Results: Sixty percent of the patients in the TTE alone group had postoperative pulmonary complications versus 63% in the CRT+TTE group. Postoperative mortality was 8.6% and 16.7% in the respective patient groups (p =NS). None of the DVH parameters was associated with postoperative pulmonary complications. Squamous cell carcinoma was an adverse factor related to increased postoperative pulmonary complications. Conclusion: High-dose preoperative CRT was not associated with increased postoperative pulmonary complications in this cohort of esophageal cancer patients. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To evaluate dose–volume histogram (DVH) parameters as predictors of radiation pneumonitis (RP) in esophageal cancer patients treated with definitive concurrent chemoradiotherapy. Patients and methods: Thirty-seven esophageal cancer patients treated with radiotherapy with concomitant chemotherapy consisting of 5-fluorouracil and cisplatin were reviewed. Radiotherapy was delivered at 2Gy per fraction to a total of 60Gy. For most of the patients, two weeks of interruption was scheduled after 30Gy. The percentage of lung volume receiving more than 5–50Gy in increments of 5Gy (V5–V50, respectively), and the mean lung dose (MLD) were analyzed. Results: Ten (27%) patients developed RP of grade 2; 2 (5%), grade 3; 0 (0%), grade 4; and 1 (3%), grade 5. By univariate analysis, all DVH parameters (i.e., V5–V50 and MLD) were significantly associated with grade ⩾2 RP (p <0.01). The incidences of grade ⩾2 RP were 13%, 33%, and 78% in patients with V20s of ⩽24%, 25–36%, and ⩾37%, respectively. The optimal V20 threshold to predict symptomatic RP was 30.5% according to the receiver operating characteristics curve analysis. Conclusion: DVH parameters were predictors of symptomatic RP and should be considered in the evaluation of treatment planning for esophageal cancer. [Copyright &y& Elsevier]

Abstract: Background and purpose: To evaluate the usefulness of the dose–volume histogram (DVH) and dose–surface histogram (DSH) as clinically relevant and available parameters that helped to identify bone and soft tissue sarcoma patients at risk of developing late skin reactions, including ulceration, when treated with carbon ion radiotherapy. Materials and methods: Thirty-five patients with bone and soft tissue sarcoma treated with carbon ion beams were studied. The clinical skin reactions were evaluated. Some pretreatment variables were compared with the grade of late skin reactions. Results: Average DVH and DSH were established in accordance with the grading of the skin reactions. Prescribed dose, the difference in depths between the skin surface and the proximal extent of the tumor, and some DVH/DSH parameters were correlated with late skin reaction (grade 3) according to univariate analysis. Furthermore, the area irradiated with over 60GyE (S 60 >20cm2) on DSH was the most important factor by multivariate analysis. Conclusions: The area irradiated with over 60GyE (S 60 >20cm2) on DSH was found to be a parameter for use as a predictor of late skin reactions. [Copyright &y& Elsevier]

Abstract: Purpose: To identify clinical risk factors and dose–volume thresholds for treatment-related pneumonitis (TRP) in patients with non-small cell lung cancer (NSCLC). Methods and materials: Data were retrospectively collected from patients with inoperable NSCLC treated with radiotherapy with or without chemotherapy. TRP was graded according to Common Terminology Criteria for Adverse Events, version 3.0, with time to grade ⩾3 TRP calculated from start of radiotherapy. Clinical factors and dose–volume parameters were analyzed for their association with risk of TRP. Results: Data from 576 patients (75% with stage III NSCLC) were included in this study. The Kaplan–Meier estimate of the incidence of grade ⩾3 TRP at 12 months was 22%. An analysis of dose–volume parameters identified a threshold dose–volume histogram (DVH) curve defined by V 20 ⩽25%, V 25 ⩽20%, V 35 ⩽15%, and V 50 ⩽10%. Patients with lung DVHs satisfying these constraints had only 2% incidence of grade ⩾3 TRP. Smoking status was the only clinical factor that affected the risk of TRP independent of dosimetric factors. Conclusions: The risk of TRP varied significantly, depending on radiation dose–volume parameters and patient smoking status. Further studies are needed to identify biological basis of smoking effect and methods to reduce the incidence of TRP. [Copyright &y& Elsevier]

Abstract: Background and purpose: The aims of this study are to compare our three-dimensional conformal radiotherapy (3D-CRT) plan using a combination of conformal dynamic-arc and five-static field (DASF) technique with other 3D-CRT plans for prostate cancer, and to estimate whether dose escalation is possible with DASF radiotherapy (DASF-RT). Methods and materials: Twenty patients with prostate cancer were included in this study. For each patient, five different treatment plans including DASF-RT were created to entire prostate and seminal vesicles. Dose distribution and rectal dose–volume histogram (DVH) for each planning technique were compared. Results: In DASF-RT treatment plan, rectum V40, V50, V60, and V70 were 61.6%, 39.6%, 21.4%, and 0.6%, respectively. Compared with four 3D-CRT techniques, DASF-RT technique significantly reduce rectum V50 to V70 without increasing irradiated bladder and femoral head volumes. In addition, in the simulation of dose escalation to 76Gy, the increase of each rectal dose–volume parameter (V40 to V75) was small enough. However, in dose escalation to 78Gy, rectum V75 exceeded 5%. Conclusion: DASF-RT technique could significantly reduce rectal volumes receiving 50–70Gy compared with other 3D-CRT techniques. DASF-RT was safe and feasible for dose escalation to 76Gy in prostate radiotherapy. [Copyright &y& Elsevier]

Abstract: Purpose: To report on: [1.] Late radiotherapy-induced lower intestinal toxicity (RILIT) after intensity-modulated radiotherapy (IMRT) for prostate cancer. [2.] The correlation between late RILIT and volume parameters of the rectum, sigmoid colon and small bowel. Materials and methods: We included 241 patients with a follow-up of ⩾18 months for this analysis. Late RILIT consisted of 8 different symptoms, comprising the 5 symptoms from the RTOG toxicity score supplemented with urgency, fecal incontinence and anal pain. Late RILIT and late RTOG toxicity were scored prospectively and correlated with: [1.] Different rectum, sigmoid colon and small bowel volume parameters. [2.] Patient-related morbidity. We calculated the median, quartile and percentiles for the different volume parameters and correlated them with grade 1–3 late RILIT. Results: Median follow-up was 42 months. Three patients developed grade 3 red blood loss. We registered grade 2 RILIT and RTOG toxicity in 13% and 10%, respectively, the most frequent grade 1 symptom being fecal urgency. The intermediate rectal volume parameters were significantly correlated with late RILIT. We were able to calculate cut-off dose–volume histograms (DVHs) that predict for grade 0–2 RILIT. Conclusions: After IMRT for prostate cancer, the overall incidence of grade ⩾2 RILIT is low. Cut-off DVHs can be used for patient counseling. [Copyright &y& Elsevier]

Abstract: Purpose: To investigate the impact of rectum motion on dose–volume histograms of the rectum including filling and of the wall (DVH and DWH, respectively), during 3D-conformal radiotherapy (3DCRT) for localized prostate cancer. Materials and methods: Ten patients received a planning CT scan (CT0) and 11–14 CT during 3DCRT for prostate cancer (total CT scans=126). CT images were 3D matched using bony anatomy. A single observer drew the external contours of rectum and rectum wall and the CTV (prostate+seminal vesicles) on CT0. Patients were asked to empty their rectum before every CT, as generally performed at the Institute for Cancer Research and Treatment (IRCC) before treatment delivery. Bladder was kept full by drinking 500cm3 of water 60min before the scan, according to our protocol. A 4-field box 3DCRT technique was planned and dose statistics/dose–volume histograms of the rectum were calculated for each contour referred to CT0,CT1,…,CT n for each patient. Average DVHs during treatment were calculated along with their standard deviation (SDrand) and compared to the planned DVH. The analyses on the patient population included the assessment of systematic deviation (average difference and SD, named SDsys) as well as the average SDrand value expressing the random component of organ motion. Rectum shifts were also assessed by anterior and lateral BEV projections. Results: As to the rectum, 8/10 patients showed a “better” average DVH than DVH on CT0. Wilcoxon test showed a statistically significant reduction when correlating the difference Δ between the average DVH during therapy and planning DVH at CT0: for instance V 70 Δ =−3.6% and p =0.022, V 50 Δ =−5.5% and p =0.022, D med Δ =−3.2Gy and p =0.007. Average values of DVH systematic difference (average difference between planning scan and treatment), standard deviations (SDsys) and average standard deviations of the random fluctuation (SDrandom) were −4.0%, 4.7% and 6.6%, respectively. Whilst the fluctuation results were slightly smaller for DWH. Volume analysis showed a slight systematic variation of the rectal volume between planning and treatment BEV. The average rectal volume during therapy was larger than at the planning CT in 8/10 patients. The systematic shifts of the rectal wall between the planning phase and the treatment were rather small, both below and above the flexure. The larger random fluctuation of the rectum shape was found to be in the cranial half (1 SD=4.4mm). Conclusions: The practice of carefully emptying the rectum during simulation and therapy for prostate cancer, which is a safe and simple procedure, reduces the impact of organ motion on dose–volume parameters of the rectum. [Copyright &y& Elsevier]

Abstract: Background and purpose: To evaluate the benefit of using non-coplanar treatment plans for irradiation of two different clinical treatment volumes: prostate only (PO) and the prostate plus seminal vesicles (PSV). Material and methods: An inverse planning algorithm was used to produce three-field, four-field, five-field and six-field non-coplanar treatment plans without intensity-modulation in ten patients. These were compared against a three-field coplanar plan. A dose of 74Gy was prescribed to the isocentre. Plans were compared using the minimum dose to the planning target volume (PTV), maximum dose to the small bowel, and irradiated volumes of rectum, bladder and femoral head. Biological indices were also evaluated. Results: For the PO group, volume of rectum irradiated to 60Gy (V 60) was 22.5±3.7% for the coplanar plan, and 21.5±5.3% for the five-field non-coplanar plan, which was the most beneficial (p=0.3). For the PSV group, the five-field non-coplanar plan was again the most beneficial. Rectal V 60 was in this case reduced from 41.5±10.4% for the coplanar plan to 35.2±9.3% for the non-coplanar plan (p=0.02). Conclusions: The use of non-coplanar beams in conformal prostate radiotherapy provides a small increase in rectal sparing, more significantly with PSV volumes than for PO volumes. [Copyright &y& Elsevier]

Abstract: Background and purpose: To correlate acute esophageal toxicity with dosimetric and clinical parameters for non-small cell lung cancer (NSCLC) patients treated with radiotherapy (RT) alone or with chemo-radiotherapy (CRT). Patients and methods: We analyzed the data of 156 patients with medically inoperable or locally advanced NSCLC. Seventy-four patients were irradiated with high dose RT only, 45 patients with sequential CRT (Gemicitabine/Cisplatin) and 37 patients with concurrent CRT (Cisplatin daily 6mg/m2). The radiation dose delivered ranged from 49.5 to 94.5Gy (2.25–2.75Gy per fraction) with an overall treatment time of 5–6 weeks. For all patients the maximal acute esophageal toxicity (RTOG/EORTC criteria) was scored and related to dose–volume parameters, as well as to clinical and treatment-related parameters. All parameters were tested univariable and multivariable in a binary logistic regression model. The toxicity data of a homogeneous subgroup was fitted to the Lyman–Kutcher–Burman model. Results: Grade 2 acute esophageal toxicity or higher occurred in 27% (n=42) of the patient population of which nine patients developed grade 3 toxicity and one patient grade 4. All 10 patients with grade≥3 esophageal toxicity received concurrent CRT. At multivariable analysis, the most significant clinical parameter to predict acute esophageal toxicity was the concurrent use of CRT. The most significant dosimetric parameter was the esophagus volume that received at least 35Gy. The data of the patients who did not receive concurrent CRT were well described by the Lyman–Kutcher–Burman normal tissue complication probability model. The optimal fit of the data of non-concurrent treated patients to this model was obtained using the following values for the parameters: TD50=47Gy (41–60Gy), n=0.69 (0.18–6.3) and m=0.36 (0.25–0.55) where the numbers between brackets denote the 95% confidence interval. Acute esophageal toxicity was not significantly increased for patients treated with sequential CRT. Conclusion: Both concurrent CRT and the volume that receives at least 35Gy were predictors of acute esophageal toxicity. [Copyright &y& Elsevier]

: Background and purposeTo perform a systematic review of the predictive ability of various dose–volume histogram (DVH) parameters (Vdose, mean lung dose (MLD), and normal tissue complication probability (NTCP)) in the incidence of radiation pneumonitis (RP) caused by external-beam radiation therapy.: Methods and materialsStudies assessing the relationship between CT-based DVH reduction parameters and RP rate in radically treated lung cancer were eligible for the review. Synonyms for RP, lung cancer, DVH and its associated parameters (NTCP, V20, V30, MLD) were combined in a search strategy involving electronic databases, secondary reference searching, and consultation with experts. Individual or group data were abstracted from the various reports to calculate operating characteristics and odds ratios for the different DVH metrics.: ResultsA total of 12 published studies and two abstracts were identified. Eleven studies assessed Vdose, seven assessed MLD, and eight assessed NTCP. Nine studies exclusively analyzed the association between various DVH metrics and RP risk. Five studies also analyzed other patient, tumor, and treatment variables in conjunction with standard DVH metrics. A direct comparison between studies and the generation of summary statistics (i.e. meta-analysis) could not be achieved due to significant predictive and outcome variable heterogeneity. Most studies did show an association between DVH parameters and RP risk. However, overall accuracy, sensitivity, specificity, and positive predictive value were generally poor to fair for all three classes of DVH metrics.: ConclusionsAn association between DVH parameters and RP risk has been demonstrated in the literature. However, the ideal DVH metric with excellent operating characteristics, either alone or in a model with other predictive variables, for RP risk prediction has not yet been identified. Several recommendations for reporting and conduct of future research into the association between DVH metrics and RP risk are provided. [Copyright &y& Elsevier]

Purpose: The late toxicity of fecal incontinence after pelvic radiotherapy is now frequently recognized but the etiology poorly understood. We therefore investigated associations between dose–volume histogram (DVH) parameters of the rectum and the anal canal with fecal continence as measured by an established 10-item questionnaire.Methods and materials: Forty-four patients treated for carcinoma of the prostate with 58–72 Gy of 3D conformal radiotherapy between 1995 and 1999 who completed the questionnaire formed the study population. Total continence scores of treated patients obtained 1.5 years (median) after radiotherapy were compared to a control group of 30 patients before radiotherapy. Median, mean, minimum and maximum doses as well as the volume (% and ml) treated to 40, 50, 60 and 70 Gy were determined separately for anal canal and rectum. DVH parameters were correlated with total continence score (Spearman rank test) and patients grouped according to observed continence were compared regarding DVH values (Mann–Whitney U-test).Results: Median fecal continence scores were significantly worse in the irradiated than in the control group (31 vs. 35 of a maximum 36 points). In treated patients, 59%/27%/14% were classified as fully continent, slightly incontinent and severely incontinent. Continence was similar in the 58-to-62-Gy, 66-Gy and 68-to-72-Gy dose groups. No DVH parameter was significantly correlated with total continence score, but severely incontinent patients had a significantly higher minimum dose to the anal canal than fully continent/slightly incontinent, accompanied by portals extending significantly further inferiorly with respect to the ischial tuberosities.Conclusions: Excluding the inferior part of the anal canal from the treated volume in 3D conformal therapy for carcinoma of the prostate appears to be a promising strategy to prevent radiation-induced fecal incontinence. [Copyright &y& Elsevier]

Purpose: The purpose of this comparative prospective study was to assess the effect of CT and MR based individualisation and adaptation on the dose distribution in the target volume and organs at risk compared to a radiography based procedure.Material and methods: In 15 patients MR scans, in 10 patients additional axial CT-scans with compatible tube-ring applicator in situ were performed and digitally transferred to the PLATO® planning system. Considering clinical examination and MR-scan before radiotherapy individual 3-D dose distribution was calculated and adapted based on (1) two orthogonal radiographs; (2) isodoses superimposed on the CT images; and (3) isodoses superimposed on the MR images. Adaptation was strictly limited by the dose level at 2 cm3 bladder or rectum volume (D2) to allow comparison of CT and MR plans. All three individualised dose distributions were superimposed on the MR images and cumulative dose–volume histograms were calculated for comparison.Results: 3-D individualisation based on sectional imaging enabled higher dose to the target volume (isodose enclosing 95% of the CTV=CTV95) compared to individualised treatment plans based on orthogonal radiographs by a mean factor of 1.2 (1–1.7). The dose to bladder and/or rectum wall was at the same time not increased beyond the prescribed tolerance level (71% of the prescribed target dose). In a subgroup of 10 patients MRI based treatment plans were superior to CT based treatment plans allowing for a higher dose (138% vs. 124%).Conclusion: Sectional imaging based treatment planning, in particular using MR, was superior to radiography allowing for a clinical meaningful dose escalation without increasing the dose to bladder and rectum beyond the tolerance level. [Copyright &y& Elsevier]

Purpose: To evaluate clinical and lung dose–volume histogram based factors as predictors of radiation pneumonitis (RP) in lung cancer patients (PTs) treated with thoracic irradiation.Methods and materials: Records of all lung cancer PTs irradiated at our Institution between 1994 and 2000 were retrospectively reviewed. Eighty-four PTs with small or non-small-cell lung cancer, irradiated at >40 Gy, with full 3D dosimetry data and a follow-up time of >6 months from start of treatment, were analysed for RP. Pneumonitis was scored on the basis of SWOG toxicity criteria and was considered a complication when grade≥II. The following clinical parameters were considered: gender, age, surgery, chemotherapy agents, presence of chronic obstructive pulmonary disease (COPD), performance status. Dosimetric factors including prescribed dose (Diso), presence of final conformal boost, mean lung dose (Dmean), % of lung receiving ≥20, 25, 30, 35, 40, and 45 Gy (respectively V20→V45), and normal tissue complication probability (NTCP) values were analysed. DVHs data and NTCP values were collected for both lungs considered as a paired organ. Median and quartile values were taken as cut-off for statistical analysis. Factors that influenced RP were assessed by univariate (log-rank) and multivariate analyses (Cox hazard model).Results: There were 14 PTs (16.6%) who had ≥grade II pulmonary toxicity. In the entire population, the univariate analysis revealed that many dosimetric parameters (Diso, V20, V30, V40, V45) were significantly associated with RP. No significant correlation was found between the incidence of RP and Dmean or NTCP values. Multivariate analysis revealed that the use of mitomycin (MMC) (P=0.005) and the presence of COPD (P=0.026) were the most important risk factor for RP. In the group without COPD (55 PTs, seven RP) a few dosimetric factors (Dmean, V20, V45) and NTCP values (all models) were associated with RP in the univariate analysis (P≤0.06). According to the multivariate analysis, the use of MMC was independently associated with RP (P=0.007), while Dmean approached statistical significance (P=0.082).Conclusions: In this study the use of mitomycin or the presence of COPD is associated with a higher risk of RP. In the entire population NTCP values were not significantly correlated with the incidence of RP. Mean lung dose shows a clear trend toward statistical significance in the patient group without COPD. [Copyright &y& Elsevier]

Purpose: This study was performed to evaluate the efficacy and safety of dynamic arc conformal radiotherapy, a simple intensity modulated radiation therapy (IMRT), for the treatment of paraaortic lymph node metastases.Materials and methods: Twenty-nine patients with paraaortic lymph node metastases were enrolled in this study. The total planned dose was 55–60 Gy. A computed tomography (CT) simulator was used in the treatment planning.Results: The total radiation dose delivered was 50–63.4 Gy (median 60 Gy). Sixteen of 29 patients showed local tumor shrinkage on CT, and the 2 year in-field recurrence free survival rate was 58%. Acute Grade 1 and Grade 2 gastrointestinal disorders occurred in 31% and 17%, respectively, and acute Grade 2 liver dysfunction occurred in 7%. As a late complication, Grade 1 and Grade 2 liver dysfunction occurred in six patients (21%) and five patients (17%), respectively. There was no renal dysfunction or myelopathy detected.Conclusion: Dynamic arc conformal radiotherapy, a simple IMRT, is a safe and effective treatment method for paraaortic lymph node metastasis. [Copyright &y& Elsevier]

Background and purpose: Previous analyses of target reproducibility in extracranial stereotactic radiotherapy have revealed standard security margins for planning target volume (PTV) definition of 5 mm in axial and 5–10 mm in longitudinal direction. In this study the reproducibility of the clinical target volume (CTV) of lung and liver tumors within the PTV over the complete course of hypofractionated treatment is evaluated. The impact of target mobility on dose to the CTV is assessed by dose–volume histograms (DVH).Materials and methods: Twenty-two pulmonary and 21 hepatic targets were treated with three stereotactic fractions of 10 Gy to the PTV-enclosing 100%-isodose with normalization to 150% at the isocenter. A conformal dose distribution was related to the PTV, which was defined by margins of 5–10 mm added to the CTV. Prior to each fraction a computed tomography (CT)-simulation over the complete target volume was performed resulting in a total of 60 CT-simulations for lung and 58 CT-simulations for hepatic targets. The CTV from each CT-simulation was segmented and matched with the CT-study used for treatment planning. A DVH of the simulated CTV was calculated for each fraction. The target coverage (TC) of dose to the simulated CTV was defined as the proportion of the CTV receiving at least the reference dose (100%).Results: A decrease of TC to <95% was found in 3/60 simulations (5%) of pulmonary and 7/58 simulations (12%) of hepatic targets. In two of 22 pulmonary targets (9%) and in four of 21 hepatic targets (19%) a TC of <95% occurred in at least one fraction. At risk for a decreased TC <95% were pulmonary targets with increased breathing mobility and hepatic targets with a CTV exceeding 100 cm3.Conclusions: Target reproducibility was precise within the reference isodose in 91% of lung and 81% of liver tumors with a TC of the complete CTV ≥95% at each fraction of treatment. Pulmonary targets with increased breathing mobility and liver tumors >100 cm3 are at risk for target deviation exceeding the standard security margins for PTV-definition at least for one fraction and require individual evaluation of sufficient margins. [Copyright &y& Elsevier]

Background: Recent investigations showed some correlation between three-dimensional (3D) treatment planning dose–volume data (dose–volume histograms: DVH, dose statistics) and rectal toxicity for patients treated for prostate cancer. However, no data are available about the possible impact of inter-institute variability in contouring the rectum, so that the possibility of reliably using information from single-centre studies remains doubtful.Purpose: Within a retrospective three-institutes study on correlation between dose–volume treatment planning data and rectum bleeding in patients treated for prostate cancer, an investigation about the impact of inter- and intra-observer variability in contouring the rectum was performed.Materials and methods: Ten patients were considered for a dummy run exercise and three observers (one per Institute) contoured the rectum (including filling). An anatomically based definition of rectum extension was previously accepted by the three observers. Six of the ten patients were randomly chosen in the subgroup of patients (large spacing, LS) with a distance between computed tomography (CT) slices (outside the prostate region) equal to 10 mm; for the remaining four patients the distance between CT slices was 5 mm over the whole rectum volume (small spacing, SS). The original 3D treatment planning was recovered on the Cadplan treatment planning system for each patient and rectum dose statistics (mean, median and maximum rectum dose), volume, DVH and NTCP values were calculated for each observer. For DVH analysis, the values of V50, V55, V60, V65 and V70 (defined as the % of rectum volume receiving at least 50, 55, 60, 65, 70 Gy) were considered. Normal tissue complication probabilities (NTCPs) were calculated for the original ICRU dose and for a 75.6 Gy ICRU dose (NTCP and NTCP75.6, respectively). Intra-observer variability was investigated by asking the observers to redraw the same rectum contours 6 months later and comparing the two contouring sessions.Results: In general, a good agreement was found for most patients and, in particular, for all SS patients. The impact of inter-observer variability was quite significant on dose statistics and DVH in two of six LS patients. Looking at the patient population, some systematic deviations, even if quite small, were demonstrated between institute B and institute C (volume, P=0.02) and between institute A and institute B (mean/median dose, V50–V65, NTCP75.6; P<0.05). Four of six LS patients (0/4 in the SS group) presented a maximum difference among observers at the cranial and/or caudal limit of the rectum equal to 1 cm. For these patients, inter-observer variability was significantly higher than for the others (P<0.03). When inter-observer variability was expressed in terms of standard deviations (SD), values around 2–3 Gy and 0.5 Gy for LS and SS patients, respectively, were found for mean/median dose; values around 3–4% and 0.5–2% for LS and SS patients, respectively, were found for V50–V70. The average SD for NTCP and NTCP75.6 were 0.4 and 0.6%, respectively (0.5 and 0.9% for LS patients; 0.2 and 0.3% for SS patients). Intra-observer variability was found to be lower than inter-observer variability even if the impact on dose statistics and DVH was visible.Conclusions: Once a robust definition of rectum is assessed, inter- and intra-institute variability in contouring the rectum appear relatively modest. However, the results suggest that the number of LS patients in DVH correlation studies should be as low as possible; the low number of these patients in the multi-centric trial involving our institutions should not have significant impact on the results of the study. [Copyright &y& Elsevier]