Clinical implementation and feasibility of long-course fractionated MR-guided chemoradiotherapy for patients with esophageal cancer: An R-IDEAL stage 1b/2a evaluation of technical innovation.

Purpose: This R-Ideal stage 1b/2a study describes the workflow and feasibility of long-course fractionated online adaptive MR-guided chemoradiotherapy with reduced CTV-to-PTV margins on the 1.5T MR-Linac for patients with esophageal cancer. Methods: Patients with esophageal cancer scheduled to undergo chemoradiation were treated on a 1.5T MR-Linac. Daily MR-images were acquired for online contour adaptation and replanning. Contours were manually adapted to match the daily anatomy and an isotropic CTV-to-PTV margin of 6 mm was applied. Time was recorded for all individual steps in the workflow. Feasibility and patient tolerability were defined as on-table time of ≤60 min and completion of >95% of the fractions on the MR-Linac, respectively. Positioning verification and post-treatment MRIs were retrospectively analyzed and dosimetric parameters were compared to standard non-adaptive conventional treatment plans. Results: Nine patients with esophageal cancer were treated with chemoradiation; eight patients received 41.4 Gy in 23 fractions and one received 50.4 Gy in 28 fractions. Four patients received all planned fractions on the MR-Linac, whereas for two patients >5% of fractions were rescheduled to a conventional linac for reasons of discomfort. A total of 183 (86%) of 212 scheduled fractions were successfully delivered on the MR-Linac. Three fractions ended prematurely due to technical issues and 26 fractions were rescheduled on a conventional linac due to MR-Linac downtime (n = 10), logistical reasons (n = 3) or discomfort (n = 13).The median time per fraction was 53 min (IQR = 3 min). Daily adapted MR-Linac plans had similar target coverage, whereas dose to the organs-at-risk was significantly reduced compared to conventional treatment (26% and 12% reduction in mean lung and heart dose, respectively). Conclusion: Daily online adaptive fractionated chemoradiotherapy with reduced PTV margins is moderately feasible for esophageal cancer and results in better sparing of heart and lungs. Future studies should focus on further optimization and acceleration of the current workflow.

Online adaptive MR-guided radiotherapy for rectal cancer; feasibility of the workflow on a 1.5T MR-linac: clinical implementation and initial experience.

BACKGROUND AND PURPOSE: Daily online adaptation of the clinical target volume (CTV) using MR-guided radiotherapy enables margin reduction of the planning target volume (PTV). This study describes the implementation and initial experience of MR-guided radiotherapy on the 1.5T MR-linac and evaluates treatment time, patient compliance, and target coverage, including an initial assessment of margin reduction. MATERIALS AND METHODS: Patients were treated on a 1.5T MR-linac (7MV, FFF). At each fraction a 3D T2 weighted (T2w) MR-sequence was acquired on which the CTV was adapted after a deformable registration of the contours from the pre-planning CT scan. Based on the new contours a full online replanning was done after which a new 3D T2w MR-sequence was acquired for position verification. A 5 field Intensity Modulated Radiotherapy (IMRT) plan was delivered. RESULTS: Forty-three patients with rectal cancer were treated with 25 Gy in 5 fractions of which 18 with reduced margins. In total, 204 of 215 fractions were delivered on the MR-linac all of which obtained a clinically acceptable treatment plan. Median in-room time per fraction was 48 min (interquartile range 8). No fractions were canceled or interrupted because of patient intolerance. CTV coverage after margin reduction was good on all post-treatment scans but one due to passing gas. CONCLUSION: MR-guided radiotherapy using daily full online recontouring and replanning on a 1.5T MR-linac for rectal cancer is feasible and currently takes about 48 min per fraction.

First patients treated with a 1.5 T MRI-Linac: clinical proof of concept of a high-precision, high-field MRI guided radiotherapy treatment.

The integration of 1.5 T MRI functionality with a radiotherapy linear accelerator (linac) has been pursued since 1999 by the UMC Utrecht in close collaboration with Elekta and Philips. The idea behind this integrated device is to offer unrivalled, online and real-time, soft-tissue visualization of the tumour and the surroundings for more precise radiation delivery. The proof of concept of this device was given in 2009 by demonstrating simultaneous irradiation and MR imaging on phantoms, since then the device has been further developed and commercialized by Elekta. The aim of this work is to demonstrate the clinical feasibility of online, high-precision, high-field MRI guidance of radiotherapy using the first clinical prototype MRI-Linac. Four patients with lumbar spine bone metastases were treated with a 3 or 5 beam step-and-shoot IMRT plan. The IMRT plan was created while the patient was on the treatment table and based on the online 1.5 T MR images; pre-treatment CT was deformably registered to the online MRI to obtain Hounsfield values. Bone metastases were chosen as the first site as these tumors can be clearly visualized on MRI and the surrounding spine bone can be detected on the integrated portal imager. This way the portal images served as an independent verification of the MRI based guidance to quantify the geometric precision of radiation delivery. Dosimetric accuracy was assessed post-treatment from phantom measurements with an ionization chamber and film. Absolute doses were found to be highly accurate, with deviations ranging from 0.0% to 1.7% in the isocenter. The geometrical, MRI based targeting as confirmed using portal images was better than 0.5 mm, ranging from 0.2 mm to 0.4 mm. In conclusion, high precision, high-field, 1.5 T MRI guided radiotherapy is clinically feasible.

Salvage surgery in post-chemoradiation laryngeal and hypopharyngeal carcinoma: outcome and review.

Our objective was to evaluate recurrence patterns of hypopharyngeal and laryngeal carcinoma after chemoradiation and options for salvage surgery, with special emphasis on elderly patients. In a retrospective study all patients who underwent chemoradiation for hypopharyngeal and laryngeal carcinoma in a tertiary care academic center from 1990 through 2010 were evaluated. Primary outcome measures were the survival and complication rates of patients undergoing salvage surgery, especially in elderly patients. Secondary outcome measures were the predictors for salvage surgery for patients with locoregional recurrence after failed chemoradiotherapy. A review of the literature was performed. Of the 136 included patients, 60 patients had recurrent locoregional disease, of whom 22 underwent salvage surgery. Fifteen patients underwent a total laryngectomy with neck dissection(s) and 7 neck dissection without primary tumour surgery. Independent predictors for salvage surgery within the group of 60 patients with recurrent disease, were age under the median of 59 years (p = 0.036) and larynx vs. hypopharynx (p = 0.002) in multivariate analyses. The complication rate was 68% (14% major and 54% minor), with fistulas in 23% of the patients. Significantly more wound related complications occurred in patients with current excessive alcohol use (p = 0.04). Five-year disease free control rate of 35%, overall survival rate of 27% and disease specific survival rate of 35% were found. For the 38 patients who were not suitable for salvage surgery, median survival was 12 months. Patients in whom the tumour was controlled had a 5-year overall survival of 70%. In patients selected for salvage surgery age was not predictive for complications and survival. In conclusion, at two years follow-up after chemoradiation 40% of the patients were diagnosed with recurrent locoregional disease. One third underwent salvage surgery with 35% 5-year disease specific survival and 14% major complications. Older patients selected for salvage surgery had a similar complication rate and survival as younger patients.

Postoperative elective nodal irradiation for squamous cell carcinoma of the head and neck: outcome and prognostic factors for regional recurrence.

BACKGROUND: This study describes the results of elective irradiation in the N0 neck and tries to identify prognostic factors for regional recurrence. MATERIALS AND METHODS: Between 1985 and 2000, 785 cN0 or pN0 necks were treated with elective nodal irradiation in 619 head and neck squamous cell carcinoma patients. RESULTS: Regional control at 3 years was 94% in the cN0 (nondissected) neck compared with 97% in the pN0 (dissected) neck and 90% in the ipsilateral compared with 96% in the contralateral neck (P = 0.08 and P = 0.006, respectively). Regional control in the ipsilateral cN0 neck was 78% compared with 96% in the contralateral cN0 neck. Surgical margin of the primary tumor was an additional prognostic factor in all N0 and pN0 necks. CONCLUSIONS: Neck control rates in electively irradiated N0 necks were excellent. Regional control was worse in the cN0 neck compared with the pN0 neck and in the ipsilateral neck compared with the contralateral side. Additionally, in case of positive surgical margins of the primary tumor, elective nodal irradiation should be applied, even in case of a pN0 neck.

Paratracheal lymph node dissection during laryngectomy after previous (chemo)radiotherapy: a retrospective analysis of complications and histopathological results.

OBJECTIVES: To evaluate complications and histopathological results of paratracheal lymph node dissection (PTLND) at laryngectomy after (chemo)radiotherapy. DESIGN, SETTING AND PARTICIPANTS: In a retrospective analysis, complications and histopathological results of paratracheal lymph node dissections were analysed in 191 patients with a recurrent or second primary laryngeal or hypopharyngeal carcinoma following radiotherapy with or without chemotherapy. MAIN OUTCOME MEASURES: The percentage of complications in patients with bilateral, unilateral or without PTLND. RESULTS: Forty-seven patients underwent laryngectomy with bilateral paratracheal lymph node dissection, 52 with unilateral and 92 without paratracheal lymph node dissection. Although the difference in total complications was not significant, significantly more fistulae developed in patients with bilateral paratracheal lymph node dissection (40%versus 22%; P =0.016). In multivariate analysis, this difference maintained significant (P = 0.038). Pathological examination of the lymph node dissection specimen showed tumour in 3 of the 96 ipsilateral dissections (3%) and in 1 of the 50 contralateral dissections (2%). This suggests that if unilateral instead of a bilateral paratracheal lymph node dissection had been performed, 17% less fistulae would have occurred in this group of patients, while paratracheal lymph node (PTLN) metastases would have been missed in one patient. Three of four patients with paratracheal lymph nodeparatracheal lymph node metastases had glottic carcinoma, all with subglottic extension. CONCLUSION: Because of the low incidence of lymph node metastases and the increased risk of fistulae, there is a need for a strict selection of patients who need a bilateral paratracheal lymph node dissection at laryngectomy after previous (chemo)radiotherapy.

Indications and extent of elective neck dissection in patients with early stage oral and oropharyngeal carcinoma: nationwide survey in The Netherlands.

BACKGROUND: Different strategies are available for the management of patients with early (i.e. tumour stage one or two) oral or oropharyngeal carcinoma and a clinically negative neck. MATERIAL AND METHODS: In 2006, a questionnaire was sent to the eight head and neck cancer centres of the Dutch Head and Neck Oncology Cooperative Group. This questionnaire covered: the factors influencing the decision to perform an elective neck dissection; the neck staging procedure; and the types of neck dissection undertaken. RESULTS: All eight questionnaires were returned completed. Respondents indicated that the site (n = 6), size (n = 7) and thickness (n = 6) of the primary tumour were important in decisions regarding elective neck dissection. Ultrasound-guided fine needle aspiration cytology was the most frequently used diagnostic technique (n = 7). Depending on the site and stage of the primary tumour presented, in the different cases 3-7 of the centres would perform an elective neck dissection. Selective neck dissections (i.e. levels I to III/IV) were more frequently performed than modified radical neck dissections. CONCLUSION: There was no uniformity regarding management of the clinically negative neck in patients with early stage oral and oropharyngeal carcinoma, within The Netherlands.

Risk-group definition by recursive partitioning analysis of patients with squamous cell head and neck carcinoma treated with surgery and postoperative radiotherapy.

BACKGROUND: The objective of this study was to define different prognostic groups with regard to locoregional control (LRC) derived from recursive partitioning analysis (RPA). METHODS: Eight hundred one patients with squamous cell head and neck carcinoma underwent with primary surgery and received postoperative radiotherapy. For the definition of prognostic groups, the method of classification and regression trees was performed, including a large number of well known prognostic factors. RESULTS: The final model was composed of six prognostic factors for LRC, resulting in seven terminal nodes. RPA Class I (intermediate risk) consisted of 381 patients who had no N3 lymph nodes, free surgical margins (> 5 mm), and no extranodal spread (ENS). RPA Class II (high risk) consisted of 189 patients who had 1 positive lymph node with ENS or had T1, T2, or T4 tumors with close or positive surgical margins. RPA Class III (very high risk) consisted of 231 patients who had a N3 neck, > or = 2 positive lymph nodes with ENS, or a T3 tumor with close or positive surgical margins. The 5-year LRC rate was 88%, 73% and 58%, in RPA Class I, II, and III, respectively (P < 0.0001). The hazard ratio (HR) relative to RPA Class I was 2.3 (95% confidence interval [95%CI], 1.5-3.6) for RPA Class II and 4.2 (95%CI, 2.8-6.1) for RPA Class III. CONCLUSIONS: The RPA classification scheme studied allowed for the clear definition of three prognostic groups with regard to LRC and OS. These groups may be useful in the design of future prospective, randomized studies investigating new treatment modalities.

Postoperative radiotherapy in squamous cell carcinoma of the oral cavity: the importance of the overall treatment time.

PURPOSE: To test the hypothesis that (1) the distinction between intermediate- and high-risk patients by clustering different prognostic factors results in a significant difference in treatment outcome and (2) a shorter interval between surgery and radiotherapy and shorter overall treatment times of radiation (OTTRT) result in higher rates of locoregional control (LRC). METHODS AND MATERIALS: Included were patients (n = 217) with previously untreated squamous cell carcinoma of the oral cavity treated with radical surgery and postoperative radiotherapy. Patients with extranodal spread or microscopic residual disease and patients with two or more other risk factors (i.e., N2b-N3, >1 nodal level involved, perineural growth, or stage T3-T4) were classified as high-risk patients. Patients with only one other risk factor were classified as intermediate risk. RESULTS: In the intermediate-risk group, the 3-year LRC was 87% as compared with 66% in the high-risk group (p = 0.0005). No association was found between interval and LRC. However, the OTTRT was significantly associated with LRC. The 3-year LRC was 87%, 75%, 69%, and 51% when the OTT was <6 weeks, 6-7 weeks, 7-8 weeks, and >8 weeks, respectively (p = 0.0004). The 3-year overall survival (OS) in the intermediate risk patients was 74% compared with 50% in the high-risk group (p = 0.0014). A significant association was also found between the OS and OTTRT. The OS increased from 50% when the OTTRT was >8 weeks to 74% when the OTT was <6 weeks (p = 0.006). Similar results were found with regard to the disease-free survival (DFS). In the multivariate analysis, both risk group and OTT were significantly associated with LRC, DFS, and OS. No significant interaction term was present between these two factors, which means that the OTT was of importance both for the high-risk and the intermediate-risk patients. CONCLUSION: In the subset of patients with carcinoma of the oral cavity, the classification of high- and intermediate-risk patients by clustering a number of prognostic factors provides important prognostic information regarding LRC, DFS, and OS. The OTT was the most important prognostic factor both in the high-risk and intermediate-risk patients. Reducing the OTT to 6 weeks or less is a rather simple measure to achieve a considerable improvement of the outcome of treatment in this category of patients.

Predicting the local outcome of glottic squamous cell carcinoma after definitive radiation therapy: value of computed tomography-determined tumour parameters.

BACKGROUND AND PURPOSE: The T-classification has shortcomings in the prediction of local outcome of glottic squamous cell carcinoma (SCC) treated by definitive radiation therapy. In this regard, the value of several CT-derived tumour parameters as predictors of local outcome was investigated. MATERIALS AND METHODS: The pretreatment CT studies of 119 patients with glottic SCC (T1, n=61; T2, n=40; T3, n=14; T4, n=4) treated with curative intent by radiation therapy were reviewed for tumoral involvement of specific laryngeal anatomic subsites (including laryngeal cartilages). Tumour volume was calculated with the summation-of-areas technique. Actuarial (life-table) statistical analysis was done for each of the covariates; multivariate analysis was performed using the Cox proportional hazards model. RESULTS: In the actuarial analysis tumour volume was significantly correlated with local recurrence rate (P=0.0062). Involvement of the cricoid cartilage (P=0.0052), anterior commissure (P=0.0203), subglottis (P=0.0481) and preepiglottic space (P=0.0134) and degree of involvement of the true vocal cord (P=0.0441) and paraglottic space at the level of the true vocal cord (P=0.0002) were also significantly correlated with local recurrence rate. In the multivariate analysis, only degree of involvement of the paraglottic space (at the level of the true vocal cord) (P=0.0001) and preepiglottic space (P=0.02) were found to be independent predictors of local recurrence. The T-category was significantly correlated with local outcome in the actuarial analysis (P=0.0001), but not in the multivariate analysis (P=0.5915). CONCLUSIONS: Several CT-derived parameters are powerful predictors of local outcome in glottic cancer treated with radiation therapy; some of these parameters are stronger linked to the local control rate than the T-classification.