Delayed TME Surgery in a Watch-and-Wait Strategy After Neoadjuvant Chemoradiotherapy for Rectal Cancer: An Analysis of Hospital Costs and Surgical and Oncological Outcomes.

BACKGROUND: A watch-and-wait strategy for patients with rectal cancer with a clinical complete response after neoadjuvant chemoradiotherapy is a valuable alternative for rectal resection. However, there are patients who will have residual tumor or regrowth during watch and wait. OBJECTIVE: The aim of this study was to investigate safety and costs for patients who underwent delayed surgery after neoadjuvant chemoradiotherapy. DESIGN: This is a retrospective cohort study with prospectively collected data. SETTINGS: The study was conducted at a large teaching hospital. PATIENTS: Between January 2015 and May 2020, 622 new rectal cancer patients were seen, of whom 200 received neoadjuvant chemoradiotherapy. Ninety-four patients were included, 65 of whom underwent immediate surgery and 29 of whom required delayed surgery after an initial watch-and-wait approach. MAIN OUTCOME MEASURES: Outcome measures included 30-day postoperative morbidity rate, hospital costs. 2-year overall and disease-free survival. RESULTS: There was no difference in length of stay (9 vs 8; p = 0.83), readmissions (27.6% vs 10.0%; p = 0.10), surgical re-interventions (15.0% vs 3.4%; p = 0.16), or stoma-free rate (52.6% vs 31.0%; p = 0.09) between immediate and delayed surgery groups. Hospital costs were similar in the delayed group (€11,913 vs €13,769; p = 0.89). Two-year overall survival (93% vs 100%; p = 0.23) and disease-free survival (78% vs 81%; p = 0.47) rates were comparable. LIMITATIONS: Limitations included small sample size, follow-up time and retrospective design. CONCLUSION: Delayed surgery for regrowth in a watch-and-wait program or for persistent residual disease after a repeated assessment is not associated with an increased risk of postoperative morbidity or a significant rise in costs compared to immediate total mesorectal excision. There also appears to be no evident compromise in oncological outcome. Repeated response assessment in patients with a near complete clinical response after neoadjuvant chemoradiotherapy is a useful approach to identify more patients who can benefit from a watch-and-wait strategy. See Video Abstract at http://links.lww.com/DCR/B836 . CIRUGA DE TME RETRASADA EN UNA ESTRATEGIA DE WATCH AND WAIT DESPUS DE LA QUIMIORRADIOTERAPIA NEOADYUVANTE PARA CNCER DE RECTO UN ANLISIS DE COSTOS HOSPITALARIOS, Y DE RESULTADOS QUIRRGICOS Y ONCOLGICOS: ANTECEDENTES: Una estrategia de Watch and Wait para pacientes con cáncer de recto con una respuesta clínica completa después de quimiorradioterapia neoadyuvante es una alternativa valiosa en vez de resección rectal. Sin embargo, hay pacientes que tendrán tumor residual o un recrecimiento durante el Watch and Wait .OBJETIVO: El objetivo fue investigar la seguridad y los costos para los pacientes que se sometieron a una cirugía diferida después de la quimiorradioterapia neoadyuvante.DISEÑO: Este es un estudio de cohorte retrospectivo con datos recolectados prospectivamente.AJUSTE: El estudio se llevó a cabo en un gran hospital universitario.PACIENTES: Entre enero de 2015 y mayo de 2020, se atendieron 622 nuevos pacientes con cáncer de recto, de los cuales 200 recibieron quimiorradioterapia neoadyuvante. Se incluyeron 94 pacientes, de los cuales 65 se sometieron a cirugía inmediata y 29 pacientes requirieron cirugía diferida después de un enfoque inicial de observación y espera.PRINCIPALES MEDIDAS DE RESULTADO: se incluyeron la tasa de morbilidad posoperatoria a 30 días, los costos hospitalarios y las sobrevidas general y libre de enfermedad a dos años.RESULTADOS: No hubo diferencia en la duración de la estancia (9 vs 8, p = 0,83), reingresos (27,6% vs 10,0%, p = 0,10), reintervenciones quirúrgicas (15,0% vs 3,4%, p = 0,16) y tasa libre de estoma (52,6% vs 31,0%, p = 0,09) entre los grupos de cirugía inmediata y tardía. Los costos hospitalarios fueron similares en el grupo retrasado (11913 € frente a 13769 €, p = 0,89). Las tasas de sobrevida general a dos años (93% frente a 100%, p = 0,23) y sobrevida libre de enfermedad (78% frente a 81%, p = 0,47) fueron comparables.LIMITACIONES: Tamaño de muestra pequeño, tiempo de seguimiento y diseño retrospectivo.CONCLUSIÓN: La cirugía tardía para el recrecimiento en un programa de Watch and Wait o para la enfermedad residual persistente después de una evaluación repetida no se asocia con un riesgo mayor de morbilidad posoperatoria ni con un aumento significativo en los costos, en comparación con la escisión total de mesorrecto inmediata. Tampoco parece haber un compromiso evidente en el resultado oncológico. La evaluación repetida de la respuesta en pacientes con una respuesta clínica casi completa después de la quimiorradioterapia neoadyuvante es un enfoque útil para identificar más pacientes que pueden beneficiarse de una estrategia de Watch and Wait . Consulte Video Resumen en http://links.lww.com/DCR/B836 . (Traducción-Dr. Juan Carlos Reyes ).

MRI-based tumor inter-fraction motion statistics for rectal cancer boost radiotherapy.

BACKGROUND: In patients diagnosed with rectal cancer, dose escalation is currently being investigated in a large number of studies. Since there is little known on gross tumor volume (GTV) inter-fraction motion for rectal cancer, a wide variety in margins is used. Purpose of this study is to quantify GTV inter-fraction motion statistics on different timescales and to give estimates of planning target volume (PTV) margins. MATERIAL AND METHODS: Thirty-two patients, diagnosed with rectal cancer, were included. To investigate motion from week-to-week, 16 patients underwent a pretreatment and five weekly MRIs, prior to a radiotherapy (RT) fraction of the chemoradiotherapy treatment. To investigate motion from day-to-day, the remaining 16 patients underwent five daily MRIs before each fraction in one week of RT. GTV was delineated on all scans according to guidelines. Scans were aligned on bony anatomy with the first MRI. For both datasets separately, GTV inter-fraction motion was determined based on center-of-gravity displacement. Therefrom, systematic and random errors were determined in left/right (LR), anterior/posterior and cranial/caudal (CC) direction. PTV margin estimates were calculated and evaluated on GTV coverage. RESULTS: Systematic and random errors were found in the range of 2.3-4.8 mm and 1.5-3.3 mm from week-to-week, and 1.8-4.5 mm and 1.8-4.0 mm from day-to-day, respectively. On both timescales, similar motion patterns were found; the most motion was observed in CC whilst the least motion was observed in LR. On the week-to-week data more systematic and less random motion was observed compared to the day-to-day data. Overall, only slight differences in margin estimates were found. Derived PTV margin estimates were found to give adequate GTV coverage. CONCLUSION: GTV inter-fraction motion, on a week-to-week and day-to-day timescale, can be accounted for using motion statistics presented in this study.

Tumor volume regression during preoperative chemoradiotherapy for rectal cancer: a prospective observational study with weekly MRI.

PURPOSE: Few data is available on rectal tumor shrinkage during preoperative chemoradiotherapy (CRT). This regression pattern is interesting to optimize timing of dose escalation on the tumor. METHODS: Gross tumor volumes (GTV) were contoured by two observers on magnetic resonance imaging (MRI) obtained before, weekly during, 2-4 weeks after, and 7-8 weeks after a 5-week course of concomitant CRT for rectal cancer. RESULTS: Overall, 120 MRIs were acquired in 15 patients. A statistically significant tumor volume reduction is seen from the first week, and between any two time points (p < .007). At the end of CRT, 46.3% of the initial tumor volume remained, and 32.4% at time of surgery. PTV measured 61.2% at the end of treatment. Tumor shrinkage is the fastest in the beginning of treatment (26%/week), slows down to 7%/week in the last 2 weeks of CRT, and finally to 1.3%/week in the last 5 weeks before surgery. CONCLUSIONS: The main rectal tumor regression occurs during CRT course itself, and mostly in the first half, with shrinking speed decreasing over the course. This suggests that a sequential boost is preferably done after the elective fields, yielding an average PTV-reduction of 39%. A simultaneous integrated boost strategy could benefit from adaptive planning during the course.

Diffusion-weighted MRI for Early Prediction of Treatment Response on Preoperative Chemoradiotherapy for Patients With Locally Advanced Rectal Cancer: A Feasibility Study.

OBJECTIVE: This study investigates the predictive value of diffusion-weighted magnetic resonance imaging (DW-MRI) for good pathological response at different time points during and after preoperative chemoradiotherapy (CRT) in locally advanced rectal cancer. BACKGROUND: Preoperative CRT followed by total mesorectal excision (TME) is the standard of care for locally advanced rectal cancer. The use of standard radical surgery in good treatment responders after CRT is being questioned. METHODS: Patients with locally advanced rectal adenocarcinoma were treated with preoperative CRT followed by surgery. DW-MRI scans were performed before CRT, during the third week of CRT, 4 weeks post-CRT and presurgery. Tumor apparent diffusion coefficient (ADC) values were acquired from the DW-MRI scans. After surgery the pathological tumor regression grade was assessed according to the classification by Mandard et al [Cancer. 1994;73:2680-2686]. Patients with pathological complete or near-complete response (tumor regression grade 1-2) were classified as good responders (GRs). RESULTS: Twenty-two patients participated of which 9 were GRs (41%). Pre-CRT ADC values were lower in good versus moderate/poor responders (P = 0.04). ADC values during CRT and four weeks post-CRT were higher in GR. ADC values presurgery did not differ between response groups. For all time points the relative ADC increase (ΔADC) compared to the ADC pre-CRT was higher in GR (P < 0.001). The ΔADC during CRT and four weeks post-CRT were the best predictive parameters for pathological good response. CONCLUSIONS: This study shows that DW-MRI is feasible to select good treatment responders during preoperative CRT for locally advanced rectal cancer.

Dynamic contrast enhanced MR imaging for rectal cancer response assessment after neo-adjuvant chemoradiation.

BACKGROUND: Patient selection for organ sparing treatment after good response to neo-adjuvant chemoradiation (CRT) for locally advanced rectal cancer is challenging as no optimal restaging modality is available after CRT. In this study, we assessed the value of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for rectal cancer pathological response prediction. METHODS: In 51 patients with locally advanced rectal cancer, the tumor volume and volume transfer constant (Ktrans) were obtained at 3 Tesla before CRT and surgery. The predictive potential for pathological complete response (pCR) and good response (GR) was assessed. GR was defined as pCR and near-pCR based on the tumor regression grade. RESULTS: The GR group consisted of 10 patients (19.6%) with six pCR (11.8%). Both the post-CRT tumor volume and post-CRT Ktrans values and the relative change in volume (ΔVolume) and Ktrans (ΔKtrans) were predictive for pathological response. ΔKtrans showed the best predictive potential with a positive predictive value (PPV) of 100% for GR using a cutoff value of 32% reduction in Ktrans. For pCR the best PPV was 80% with a multiparameter model containing ΔVolume and ΔKtrans. CONCLUSION: DCE-MRI has predictive potential for pathological response after CRT in rectal cancer with the relative ΔKtrans being the most predictive parameter.

Combined T2w volumetry, DW-MRI and DCE-MRI for response assessment after neo-adjuvant chemoradiation in locally advanced rectal cancer.

BACKGROUND: To assess the value of combined T2-weighted magnetic resonance imaging (MRI) (T2w) volumetry, diffusion-weighted (DW)-MRI and dynamic contrast enhanced (DCE)-MRI for pathological response prediction after neo-adjuvant chemoradiation (CRT) in locally advanced rectal cancer (LARC). MATERIAL AND METHODS: MRI with DW-MRI and DCE-MRI sequences was performed before start of CRT and before surgery. After surgery, the tumor regression grade (TRG) was obtained based on the score by Mandard et al. Pathological complete responders (pCR, TRG 1), and pathological good responders (GR, TRG 1 + 2) were compared to non-pCR and non-GR patients, respectively. RESULTS: In total 55 patients were analyzed, six had a pCR (10.9%) and 10 a GR (18.2%). Favorable responders had a larger decrease in tumor volume and Ktrans and a larger increase in apparent diffusion coefficient (ADC) values compared to non-responders. ADC change showed the best diagnostic accuracy for pCR. For GR, the model including ADC change and volume change showed the best diagnostic performance. However, this performance was not statistically better compared to the model with ADC change alone. Inclusion of Ktrans change did not increase the diagnostic accuracy for pathological favorable response. CONCLUSIONS: This explorative study showed that ADC change is a promising diagnostic tool for pCR and GR. Volume decrease showed potential limited additional diagnostic value for GR while Ktrans change showed no additional diagnostic value for pCR and GR.

Adding preoperative radiotherapy plus cetuximab to perioperative chemotherapy for resectable esophageal adenocarcinoma: a single-center prospective phase II trial.

BACKGROUND: Local and systemic recurrence are important sources of treatment failure following surgical resection of esophageal adenocarcinoma. We hypothesized that adding preoperative cetuximab and radiotherapy (cetux-RT) to perioperative chemotherapy would increase treatment efficacy with acceptable toxicity. METHODS: In this prospective phase II trial, patients were treated with three cycles of epirubicin, cisplatin, and capecitabine (ECX), followed by cetux-RT. After surgery with curative intent, patients received three more cycles of ECX. Primary endpoints were efficacy, determined by histopathological complete response (pCR) rate, and safety, which was assessed with resectability rate. RESULTS: Of the 12 patients enrolled in this trial, six received at least one dose of cetux-RT. In five patients, cetux-RT was not started because of adverse events (AEs) related to preoperative chemotherapy; one patient had progressive disease. Addition of cetux-RT was well tolerated and did not interfere with the resectability rate (100%). However, the pCR rate was 0, and 50% of patients experienced serious adverse events (SAEs) postoperatively. CONCLUSION: With 12 patients enrolled, the lack of initial signs of efficacy and a high incidence of postoperative SAEs prompted us to end this study prematurely. Perioperative ECX was associated with considerable toxicity, and further treatment intensification is problematic.

Repeatability of diffusion-weighted imaging in rectal cancer.

PURPOSE: Serial diffusion-weighted MRI (DW-MRI) measurements of the apparent diffusion coefficient (ADC) of rectal tumors are used for rectal cancer response evaluation after neo-adjuvant treatment. In this study, we determined the repeatability of DW-MRI to distinguish therapy-related response from measurement variations. MATERIALS AND METHODS: In 18 patients with rectal cancer on five consecutive days, 1.5 Tesla (T) MR imaging was performed including two identical DW-MRI sequences. The repeatability of the tumor ADC measurements and the intraobserver ADC variation were depicted in a Bland-Altman plot. The repeatability coefficient was calculated as the range of ADC values of two identical DWI measurements for 95% of subjects. It was expressed as percentage of the mean ADC value. RESULTS: Three females and 15 males were included. The mean tumor ADC value was 1.15 × 10(-3) mm(2)/s (SD 0.07 × 10(-3) mm(2)). The repeatability coefficient of the ADC value was 9.8% and for the intraobserver repeatability 4.7%. CONCLUSION: In serial DW-MRI for rectal cancer treatment response evaluation, a repeatability coefficient of 9.8% has to be considered to account for measurement variations in rectal tumor ADC. These variations represent observer judgement and patient and MR spectrometer induced variations.

Combination of biodegradable stent placement and single-dose brachytherapy is associated with an unacceptably high complication rate in the treatment of dysphagia from esophageal cancer.

BACKGROUND: For the palliative treatment of dysphagia, esophageal stent placement provides immediate improvement, whereas brachytherapy offers better long-term relief. OBJECTIVE: To evaluate safety and efficacy of concurrent brachytherapy and biodegradable stent placement. DESIGN: Prospective, single-arm study. SETTING: Two tertiary-care referral centers. PATIENTS: Nineteen consecutive patients with significant dysphagia resulting from unresectable esophageal cancer, with a life expectancy of more than 3 months. INTERVENTION: Single-dose brachytherapy (12 Gy) on day 1 followed by biodegradable stent placement on day 2. MAIN OUTCOME MEASUREMENTS: Intervention-related major complications (determined by an expert panel) and dysphagia. RESULTS: Nineteen patients (13 men, median age 66 years [interquartile range (IQR) 59-71] years) were included; 7 patients (37%) also received palliative chemotherapy. After inclusion of 19 patients, the study was ended prematurely because the safety threshold was exceeded. In total, 28 major complications occurred in 17 patients (89%). In 9 patients (47%), major complications were determined intervention-related (severe retrosternal pain with or without vomiting [n = 6], hematemesis [n = 1], recurrent dysphagia [n = 2]. Dysphagia scores decreased significantly from a median of 3 (IQR 3-4) to a median of 1 (IQR 0-3) after 1 month (P < .001). Despite adequate luminal patency in 17 patients (89%), normal diet could not be tolerated in 7 patients (37%) because of retrosternal pain and vomiting. LIMITATIONS: Lack of routine endoscopy or contrast esophagram to evaluate recurrent dysphagia during follow-up. CONCLUSION: Despite restoration of luminal patency, a combined treatment of brachytherapy and biodegradable stent placement cannot be recommended for the palliative treatment of esophageal cancer because of an unacceptably high intervention-related major complication rate.

High Yield of Chest X-ray in the Follow-Up of Colorectal Cancer.

PURPOSE: Worldwide, colorectal carcinoma (CRC) has a high incidence and a substantial cancer-related mortality. The recurrence risk is 30-50% and lung metastases are common. Treatment of lung metastases with stereotactic ablative radiotherapy (SABR) or metastasectomy may increase survival. The best modality for thoracic screening in the follow-up, however, remains controversial. In this study, we aimed to unravel the additional value of routine chest X-ray (CXR) for detecting lung metastases during the follow-up of CRC patients treated with curative surgery. METHODS: Between 2013 and 2017, 668 CRC patients were treated with curative intent, of whom 633 patients were included in follow-up, which consisted of CXR, serum Carcino-Embryonic Antigen (CEA) and ultrasound of the liver. Patients who developed lung metastases, diagnosed with CXR and characterised by a normal concomitant serum CEA level, were identified. Number, size and treatment of lung metastases were described. RESULTS: Thirty-four (5.4%) patients developed lung metastases. Seventeen (50%) were detected by CXR without pathological CEA levels. Eleven (65%) of these patients were treated with curative intent, whereas 21% of patients with lung metastases and elevated CEA levels were treated with curative intent (p = 0.049). Higher numbers of lung metastases were associated with a lower chance of curative treatment. CONCLUSIONS: More than 50% of patients with lung metastases on CXR in the follow-up would not have been detected with CEA-triggered imaging only. In addition, patients with colorectal lung metastases without elevated CEA levels were often suitable for curative treatment and, therefore, CXR seems to have additional value within the follow-up of CRC.

Impact of Dose-Escalated Chemoradiation on Quality of Life in Patients With Locally Advanced Rectal Cancer: 2-Year Follow-Up of the Randomized RECTAL-BOOST Trial.

PURPOSE: Dose-escalated chemoradiation (CRT) for locally advanced rectal cancer did not result in higher complete response rates but initiated more tumor regression in the randomized RECTAL-BOOST trial (Clinicaltrials.gov NCT01951521). This study compared patient reported outcomes between patients who received dose-escalated CRT (5 × 3 gray boost + CRT) or standard CRT for 2 years after randomization. METHODS AND MATERIALS: Patients with locally advanced rectal cancer who were participating in the RECTAL-BOOST trial filled out European Organisation for Research and Treatment of Cancer QLQ-C30 and CR29 questionnaires on quality of life (QoL) and symptoms at baseline, 3, 6, 12, 18, and 24 months after start of treatment. Between-group differences in functional QoL domains were estimated using a linear mixed-effects model and expressed as effect size (ES). Symptom scores were compared using Mann-Whitney U test. RESULTS: Patients treated with dose-escalated CRT (boost group, n = 51) experienced a significantly stronger decline in global health at 3 and 6 months (ES -0.4 and ES -0.4), physical functioning at 6 months (ES -1.1), role functioning at 3 and 6 months (ES -0.8 and ES -0.6), and social functioning at 6 months (ES -0.6), compared with patients treated with standard CRT (control group, n = 64). The boost group reported significantly more fatigue at 3 and 6 months (83% vs 66% respectively 89% vs 76%), pain at 3 and 6 months (67% vs 36% respectively 80% vs 44%), and diarrhea at 3 months (45% vs 29%) compared with the control group. From 12 months onwards, QoL and symptoms were similar between groups, apart from more blood/mucus in stool in the boost group. CONCLUSIONS: In patients with locally advanced rectal cancer, dose-escalated CRT resulted in a transient deterioration in global health, physical, role, and social functioning and more pain, fatigue and diarrhea at 3 and 6 months after start of treatment compared with standard CRT. From 12 months onwards, the effect of dose-escalated CRT on QoL largely resolved.

The Dutch-Belgian Registry of Stereotactic Body Radiation Therapy for Liver Metastases: Clinical Outcomes of 515 Patients and 668 Metastases.

PURPOSE: Although various studies have reported that stereotactic body radiation therapy (SBRT) for liver metastases has high local control rates and relatively low toxicity, most series included a small number of patients. We aimed to validate these outcomes in a large multi-institution patient cohort treated in accordance with a common protocol. METHODS AND MATERIALS: A shared web-based registry of patients with liver metastases treated with SBRT was developed by 13 centers (12 in the Netherlands and 1 in Belgium). All the centers had previously agreed on the items to be collected, the fractionation schemes, and the organs-at-risk constraints to be applied. Follow-up was performed at the discretion of the centers. Patient, tumor, and treatment characteristics were entered in the registry. Only liver metastases treated individually as independent targets and with at least 1 radiologic follow-up examination were considered for local control analysis. Toxicity of grade 3 or greater was scored according to the Common Terminology Criteria of Adverse Events (v4.03). RESULTS: Between January 1, 2013, and July 31, 2019, a total of 515 patients were entered in the web-based registry. The median age was 71 years. In total, 668 liver metastases were registered, and 447 were included for local control analysis. The most common primary tumor origin was colorectal cancer (80.3%), followed by lung cancer (8.9%) and breast cancer (4%). The most-used fractionation scheme was 3x18-20 Gy (36.0%), followed by 8x7.5 Gy (31.8%), 5x11-12 Gy (25.5%), and 12x5 Gy (6.7%). The median follow-up time was 1.1 years for local control and 2.3 years for survival. Actuarial 1-year local control was 87%; 1-year overall survival was 84%. Toxicity of grade 3 or greater was found in 3.9% of the patients. CONCLUSIONS: This multi-institutional study confirms the high rates of local control and limited toxicity in a large patient cohort. Stereotactic body radiation therapy should be considered a valuable part of the multidisciplinary approach to treating liver metastases.

Efficacy of Dose-Escalated Chemoradiation on Complete Tumor Response in Patients with Locally Advanced Rectal Cancer (RECTAL-BOOST): A Phase 2 Randomized Controlled Trial.

PURPOSE: Pathologic complete tumor response after chemoradiation in patients with locally advanced rectal cancer (LARC) is associated with a favorable prognosis and allows organ-sparing treatment strategies. In the RECTAL-BOOST trial, we aimed to investigate the effect of an external radiation boost to the tumor before chemoradiation on pathologic or sustained clinical complete tumor response in LARC. METHODS AND MATERIALS: This multicenter, nonblinded, phase 2 randomized controlled trial followed the trials-within-cohorts design, which is a pragmatic trial design allowing cohort participants to be randomized for an experimental intervention. Patients in the intervention group are offered the intervention (and can either accept or refuse this), whereas patients in the control group are not notified about the randomization. Participants of a colorectal cancer cohort referred for chemoradiation of LARC to either of 2 radiation therapy centers were eligible. Patients were randomized to no boost or an external radiation boost (5 × 3 Gy) without concurrent chemotherapy, directly followed by standard pelvic chemoradiation (25 × 2 Gy with concurrent capecitabine). The primary outcome was pathologic complete response (ie, ypT0N0) in patients with planned surgery at 12 weeks, or, as surrogate for pathologic complete response, a 2-year sustained clinical complete response for patients treated with an organ preservation strategy. Analyses were intention to treat. The study was registered with ClinicalTrials.gov, number NCT01951521. RESULTS: Between September 2014 and July 2018, 128 patients were randomized. Fifty-one of the 64 (79.7%) patients in the intervention group accepted and received a boost. Compared with the control group, fewer patients in the intervention group had a cT4 stage and a low rectal tumor (31.3% vs 17.2% and 56.3% vs 45.3%, respectively), and more patients had a cN2 stage (59.4% vs 70.3%, respectively). Rate of pathologic or sustained clinical complete tumor response was similar between the groups: 23 of 64 (35.9%; 95% confidence interval [CI], 24.3-48.9) in the intervention group versus 24 of 64 (37.5%; 95% CI, 25.7-50.5) in the control group (odds ratio [OR] = 0.94; 95% CI, 0.46-1.92). Near-complete or complete tumor regression was more common in the intervention group (34 of 49; 69.4%) than in the control group (24 of 53; 45.3%; (OR = 2.74, 95% CI 1.21-6.18). Grade ≥3 acute toxicity was comparable: 6 of 64 (9.4%) in the intervention group versus 5 of 64 (7.8%) in the control group (OR = 1.22; 95% CI, 0.35-4.22). CONCLUSIONS: Dose escalation with an external radiation therapy boost to the tumor before neoadjuvant chemoradiation did not increase the pathologic or sustained clinical complete tumor response rate in LARC.

MRI guided stereotactic radiotherapy for locally advanced pancreatic cancer.

OBJECTIVE:: We want to explore the safety and technical feasibility of MRI-guided stereotactic radiotherapy for locally advanced pancreatic cancer. METHODS:: A custom-made abdominal corset was manufactured to reduce breathing induced tumour motion. Delineation of the tumour and organs at risk (OARs) was performed on CT and multiparametric MRI. Tumour motion was quantified with cine MRI. After treatment planning, the static dose distribution was convolved with the cine MRI-based motion trajectory to simulate the delivered dose to the tumour and OARs. Stereotactic body radiation therapy (SBRT) was carried out up to a dose of 24 G in three fractions in 1 week. RESULTS:: From July 2013 to January 2016, 20 patients were included. Tumours and OARs were clearly visible with contrast-enhanced CT and MRI. After simulation of the delivered dose taking the motion into account, an adequate target coverage was achieved with acceptable dose in the OARs. No Grade3 or higher treatment related toxicity was observed. CONCLUSION:: MRI-guided SBRT for pancreatic cancer is technical feasible and safe, with no treatment related grade ≥3 toxicity. New strategies are applied, including an individual corset to reduce breathing motion, MRI-based delineation and simulation of motion-integrated dose distributions. ADVANCES IN KNOWLEDGE:: This article is the first to describe an MRI-integrated workflow in SBRT for locally advanced pancreatic cancer. In addition, it demonstrated that SBRT with an abdominal corset to reduce tumour motion is feasible and safe. TRIAL REGISTRATION:: This trial was registered at www.clinicaltrials.gov (NCT01898741) on July 9, 2013.

The TRENDY multi-center randomized trial on hepatocellular carcinoma - Trial QA including automated treatment planning and benchmark-case results.

BACKGROUND AND PURPOSE: The TRENDY trial is an international multi-center phase-II study, randomizing hepatocellular carcinoma (HCC) patients between transarterial chemoembolization (TACE) and stereotactic body radiation therapy (SBRT) with a target dose of 48-54 Gy in six fractions. The radiotherapy quality assurance (QA) program, including prospective plan feedback based on automated treatment planning, is described and results are reported. MATERIALS AND METHODS: Scans of a single patient were used as a benchmark case. Contours submitted by nine participating centers were compared with reference contours. The subsequent planning round was based on a single set of contours. A total of 20 plans from participating centers, including 12 from the benchmark case, 5 from a clinical pilot and 3 from the first study patients, were compared to automatically generated VMAT plans. RESULTS: For the submitted liver contours, Dice Similarity Coefficients (DSC) with the reference delineation ranged from 0.925 to 0.954. For the GTV, the DSC varied between 0.721 and 0.876. For the 12 plans on the benchmark case, healthy liver normal-tissue complication probabilities (NTCPs) ranged from 0.2% to 22.2% with little correlation between NCTP and PTV-D95% (R2 < 0.3). Four protocol deviations were detected in the set of 20 treatment plans. Comparison with co-planar autoVMAT QA plans revealed these were due to too high target dose and suboptimal planning. Overall, autoVMAT resulted in an average liver NTCP reduction of 2.2 percent point (range: 16.2 percent point to -1.8 percent point, p = 0.03), and lower doses to the healthy liver (p < 0.01) and gastrointestinal organs at risk (p < 0.001). CONCLUSIONS: Delineation variation resulted in feedback to participating centers. Automated treatment planning can play an important role in clinical trials for prospective plan QA as suboptimal plans were detected.

Evolution of motion uncertainty in rectal cancer: implications for adaptive radiotherapy.

Reduction of motion uncertainty by applying adaptive radiotherapy strategies depends largely on the temporal behavior of this motion. To fully optimize adaptive strategies, insight into target motion is needed. The purpose of this study was to analyze stability and evolution in time of motion uncertainty of both the gross tumor volume (GTV) and clinical target volume (CTV) for patients with rectal cancer. We scanned 16 patients daily during one week, on a 1.5 T MRI scanner in treatment position, prior to each radiotherapy fraction. Single slice sagittal cine MRIs were made at the beginning, middle, and end of each scan session, for one minute at 2 Hz temporal resolution. GTV and CTV motion were determined by registering a delineated reference frame to time-points later in time. The 95th percentile of observed motion (dist95%) was taken as a measure of motion. The stability of motion in time was evaluated within each cine-MRI separately. The evolution of motion was investigated between the reference frame and the cine-MRIs of a single scan session and between the reference frame and the cine-MRIs of several days later in the course of treatment. This observed motion was then converted into a PTV-margin estimate. Within a one minute cine-MRI scan, motion was found to be stable and small. Independent of the time-point within the scan session, the average dist95% remains below 3.6 mm and 2.3 mm for CTV and GTV, respectively 90% of the time. We found similar motion over time intervals from 18 min to 4 days. When reducing the time interval from 18 min to 1 min, a large reduction in motion uncertainty is observed. A reduction in motion uncertainty, and thus the PTV-margin estimate, of 71% and 75% for CTV and tumor was observed, respectively. Time intervals of 15 and 30 s yield no further reduction in motion uncertainty compared to a 1 min time interval.

Inter-observer agreement of MRI-based tumor delineation for preoperative radiotherapy boost in locally advanced rectal cancer.

BACKGROUND: While surgery remains the cornerstone of rectal cancer treatment, organ-preservation is upcoming. Therefore, neo-adjuvant treatment should be optimized. By escalating doses, response can be increased. To limit toxicity of boost, accurate gross tumor volume (GTV) definition is required. MRI, especially undeformed fast spin echo diffusion-weighted MRI (DWI), looks promising for delineation. However, inconsistencies between observers should be quantified before clinical implementation. We aim to find which MRI sequence (T2w, DWI or combination) is optimal and clinically useful for GTV definition by evaluating inter-observer agreement. METHODS: Locally advanced rectal cancer patients (tumors <10 cm from anal verge) were scanned on 3T MRI transverse T2w and DWI (b=800 s/mm(2)). Three independent observers delineated T2w, DWI and combination (Combi) after training-set. Volumes, conformity index (CI), and maximum Hausdorff distance (HD) were calculated between any observer-pair per patient per modality. RESULTS: Twenty-four consecutive patients were included. One patient had cT2 (4.2%), 19 cT3 (79.1%) and 4 cT4 (16.7%), with 2 clinical node negative (8.3%), 4 cN1 (16.7%), and 18 cN2 (75.0%) on MRI. From 24 patients, 70 sequences were available (24x T2, 23x DWI, and 23x Combi). Between observers, no significant volume differences were observed per modality. T2 showed significantly largest volumes compared to DWI (mean difference 19.85 ml, SD 17.42, p<0.0001) and Combi (mean difference 7.16 ml, SD 11.58, p<0.0001). Mean CI was 0.70, 0.71 and 0.69 for T2, DWI and Combi respectively (p>0.61). Average HD was largest on T2 (18.60mm, max 31.40 mm, min 9.20mm). DISCUSSION: Delineation on DWI resulted in delineation of the smallest volumes with similar consistency and mean distances, but with slightly lower Hausdorff distances compared to T2 and Combi. However, with lack of a gold standard it remains difficult to establish if delineations also represent true tumor. Study strengths were DWI adaptation to exclude geometrical distortions and training-set. DWI shows great potential for delineation purposes as long as sufficient experience exists and geometrical distortions are eliminated.

Dynamic contrast-enhanced MRI for treatment response assessment in patients with oesophageal cancer receiving neoadjuvant chemoradiotherapy.

PURPOSE: To explore and evaluate the potential value of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for the prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in oesophageal cancer. MATERIAL AND METHODS: Twenty-six patients underwent DCE-MRI before, during (week 2-3) and after nCRT, but before surgery (pre/per/post, respectively). Histopathologic tumour regression grade (TRG) was assessed after oesophagectomy. Tumour area-under-the-concentration time curve (AUC), time-to-peak (TTP) and slope were calculated. The ability of these DCE-parameters to distinguish good responders (GR, TRG 1-2) from poor responders (noGR, TRG⩾3), and pathologic complete responders (pCR) from no-pCR was assessed. RESULTS: Twelve patients (48%) showed GR of which 8 patients (32%) pCR. Analysis of AUC change throughout treatment, AUCper-pre, was most predictive for GR, at a threshold of 22.7% resulting in a sensitivity of 92%, specificity of 77%, PPV of 79%, and a NPV of 91%. AUCpost-pre was most predictive for pCR, at a threshold of -24.6% resulting in a sensitivity of 83%, specificity of 88%, PPV of 71%, and a NPV of 93%. TTP and slope were not associated with pathologic response. CONCLUSIONS: This study demonstrates that changes in AUC throughout treatment are promising for prediction of histopathologic response to nCRT for oesophageal cancer.

Addition of oxaliplatin to neo-adjuvant radiochemotherapy for irresectable rectal cancer, a phase I study.

BACKGROUND: The aim was to determine the maximum tolerable dose of oxaliplatin added to (oral) 5FU in irresectable rectal cancer. PATIENTS AND METHODS: Nineteen patients were treated; 13 patients received 5FU/LV and 6 patients capecitabine. Oxaliplatin was administered on days 1 and 29 at dose levels 85 and 130 mg/m2. Four to seven weeks thereafter, surgery was performed. RESULTS: In 6 patients treated with 85 mg/m2, one grade 3 elevation of liver transaminases occurred. Of 7 patients who received 130 mg/m2, 1 patient experienced a grade III thrombocytopenia and 1 patient died of neutropenic fever, probably due to an urosepsis. Six patients were treated with capecitabine, of whom 3 developed a grade III gastrointestinal toxicity. An R0 resection could be performed in 93%, a pT0-2N0 in 39%, with 2 pCR's. CONCLUSION: The addition of oxaliplatin at 85 mg/m2 on days 1 and 29 to radiotherapy and 5FU/LV or capecitabine in irresectable rectal cancer is feasible.

RandomizEd controlled trial for pre-operAtive dose-escaLation BOOST in locally advanced rectal cancer (RECTAL BOOST study): study protocol for a randomized controlled trial.

BACKGROUND: Treatment for locally advanced rectal cancer (LARC) consists of chemoradiation therapy (CRT) and surgery. Approximately 15% of patients show a pathological complete response (pCR). Increased pCR-rates can be achieved through dose escalation, thereby increasing the number patients eligible for organ-preservation to improve quality of life (QoL). A randomized comparison of 65 versus 50Gy with external-beam radiation alone has not yet been performed. This trial investigates pCR rate, clinical response, toxicity, QoL and (disease-free) survival in LARC patients treated with 65Gy (boost + chemoradiation) compared with 50Gy standard chemoradiation (sCRT). METHODS/DESIGN: This study follows the 'cohort multiple randomized controlled trial' (cmRCT) design: rectal cancer patients are included in a prospective cohort that registers clinical baseline, follow-up, survival and QoL data. At enrollment, patients are asked consent to offer them experimental interventions in the future. Eligible patients-histologically confirmed LARC (T3NxM0 <1 mm from mesorectal fascia, T4NxM0 or TxN2M0) located ≤10 cm from the anorectal transition who provided consent for experimental intervention offers-form a subcohort (n = 120). From this subcohort, a random sample is offered the boost prior to sCRT (n = 60), which they may accept or refuse. Informed consent is signed only after acceptance of the boost. Non-selected patients in the subcohort (n = 60) undergo sCRT alone and are not notified that they participate in the control arm until the trial is completed. sCRT consists of 50Gy (25 × 2Gy) with concomitant capecitabine. The boost (without chemotherapy) is given prior to sCRT and consists of 15 Gy (5 × 3Gy) delivered to the gross tumor volume (GTV). The primary endpoint is pCR (TRG 1). Secondary endpoints include acute grade 3-4 toxicity, good pathologic response (TRG 1-2), clinical response, surgical complications, QoL and (disease-free) survival. Data is analyzed by intention to treat. DISCUSSION: The boost is delivered prior to sCRT so that GTV adjustment for tumor shrinkage during sCRT is not necessary. Small margins also aim to limit irradiation of healthy tissue. The cmRCT design provides opportunity to overcome common shortcomings of classic RCTs, such as slow recruitment, disappointment-bias in control arm patients and poor generalizability. TRIAL REGISTRATION: The Netherlands Trials Register NL46051.041.13. Registered 22 August 2013. ClinicalTrials.gov NCT01951521 . Registered 18 September 2013.