Importance Active surveillance is noninferior to standard surgery for 2-year survival and improves short-term health-related quality of life among patients with a complete clinical response (CCR) after neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer. Although active surveillance reduces the upfront costs of surgery and hospital stay, it requires repeated diagnostic tests and, for some patients, delayed surgery and hospitalization during follow-up. Objective To assess the cost-effectiveness of active surveillance compared with standard surgery after nCRT. Design, Setting, and Participants This prespecified cost-effectiveness analysis from a health care perspective conducted at 12 hospitals in the Netherlands as a secondary analysis of the Surgery as Needed for Oesophageal Cancer (SANO) trial, a noninferiority, cluster randomized study, enrolled patients with esophageal cancer who achieved a CCR after nCRT between November 8, 2017, and January 17, 2021, with follow-up for up to 5 years. Data were analyzed on June 1, 2025. Interventions Active surveillance, consisting of repeated response evaluations at 6, 9, 12, 16, 20, 24, 30, 36, 48, and 60 months after nCRT, compared with standard surgery. Main Outcome and Measures Incremental cost-effectiveness of active surveillance vs standard surgery and quality-adjusted life-years (QALYs) with 95% CIs up to 5 years were derived with bootstrapping, with 80% of patients (247 of 309) having complete follow-up. Incremental net monetary benefit (iNMB) was calculated at varying willingness-to-pay thresholds. All analyses followed the modified intention-to-treat principle. Costs are given in Euros (currency exchange rate of €1 = US $1.16 as of June 11, 2026). Results Among 309 patients (198 in the active surveillance group; median age, 69 years [IQR, 63-74 years]; 156 men [79%]; and 111 in the standard surgery group; median age, 68 years [IQR, 61-73 years]; 86 men [77%]), those in the active surveillance group had a mean of 2.99 QALYs (95% CI, 2.73-3.26) at 5 years vs 2.88 QALYs (95% CI 2.69-3.06) in the standard surgery group. Mean health care costs per patient at 5 years were €36 733 (95% CI, €33 530-€40 009) in the active surveillance group vs €45 106 (95% CI, €39 449-€51 545) in the standard surgery group. The incremental QALY for active surveillance was 0.11 (95% CI, −0.10 to 0.33) and mean costs were €8374 lower (95% CI, €1792-€15 355) compared with standard surgery. At a willingness-to-pay threshold of €80 000 per QALY, the mean iNMB was €17 568 (95% CI, −€725 to €37 497), indicating that active surveillance is cost-effective. Bootstrap analysis showed that 97% of replications fell in the cost-effective region. Conclusions and Relevance In this secondary analysis of a randomized clinical trial of patients with esophageal cancer achieving a CCR after nCRT, active surveillance was cost-effective over a 5-year horizon compared with standard surgery. Broader implementation of this strategy among appropriately selected patients would most likely reduce health care costs without compromising health outcomes. Trial Registration The Dutch Trial Register: NTR 6803

Introduction: Due to the rarity of anal cancer, real-world data on treatment outcomes are scarce. However, its incidence is increasing in the Netherlands with > 300 new cases and 70 deaths yearly. Standard of care consists of chemoradiotherapy (CRT) or radiotherapy alone (RT). The primary objective of our nationwide study was twofold; to evaluate real-world outcomes after curatively intended CRT/RT for anal squamous cell carcinoma (ASCC), and to create a large, high-quality dataset as a national benchmark to guide future prospective research. Material and methods: Data were collected retrospectively from 16 Dutch institutions treating ASCC between 2015 and 2018. Primary endpoint was locoregional recurrence free survival (LRFS). Secondary endpoints were overall survival (OS), disease specific survival (DSS), colostomy free survival (CFS), complete response (CR) and toxicity. Results: A total of 462 patients were analysed. Most patients received CRT (85%), with mitomycin-capecitabine as a radiosensitizer in 86% of cases. After median follow-up of 5 years, LRFS for all patients was 80% at 3 years and 78% at 5 years. In total 82% of patients had reached CR, with a median interval to define CR of 3 months. At 3 years, OS, DSS and CFS were 78%, 86% and 88%, respectively. Conclusion: These real-world data demonstrate that curatively intended CRT/RT for ASCC results in LRFS of 80% at 3 years. Organ preservation outcomes were favourable with a CFS of 88% at 3 years. These findings support the current treatment approach as the reference standard for these patients and provide a national benchmark to guide future prospective research.

BACKGROUND:Chemoradiotherapy (CRT) plays a key role in treating esophageal cancer (EC) but is associated with significant toxicity. Proton radiotherapy (PRT) may reduce this risk by limiting radiation dose to organs at risk. In the Netherlands, PRT is reimbursed only when eligibility criteria defined in a National Indication Protocol for Proton Therapy (NIPP) are met. This study describes the development and implementation of such a protocol for EC based on model-based selection. MATERIALS AND METHODS:A national multidisciplinary working group was formed aiming to develop the NIPP protocol through literature review, evaluation of prediction models, external model validation, and stakeholder engagement. RESULTS:Cardiac events and overall survival were identified as the most clinically relevant endpoints. As no existing models met the quality criteria for model-based selection, a validated 2-year mortality prediction model originally developed for lung cancer was externally validated in EC patients treated with definitive (dCRT) or neoadjuvant (nCRT) CRT. The model performed well after updates to the intercept (both cohorts) and slope (nCRT). Model-based selection was defined as a ≥ 5 % predicted absolute reduction in 2-year mortality with PRT versus photon radiotherapy, using Mean Heart Dose (MHD) and Gross Tumor Volume (GTV) as predictors. Additional selection criteria included WHO performance status 0-2 and exclusion of cT4, cN3, or cM1 status. The NIPP was approved by the Dutch Society of Radiation Oncology in June 2021 and by the Dutch Health Care Institute in October 2021. National implementation and prospective outcome evaluation are ongoing via the ProTRAIT registry. CONCLUSION:A national indication protocol enabling model-based selection for PRT in EC was successfully implemented in the Netherlands. The NIPP describes eligibility criteria for proton therapy reimbursement and enables reimbursement for individual patients who are expected to benefit from PRT.

Background Light chain amyloidosis (AL) is a rare, systemic disease characterized by amyloid fibril deposition in various organs due to overproduction of light chains from plasma cell dyscrasia (PCD). Current treatment strategies target PCD rather than clearing amyloid deposits directly from organs. CAEL-101 is a chimeric monoclonal IgG1 antibody that targets these amyloid fibrils. It binds to a cryptic epitope at the N-terminus of both kappa (κ) and lambda (λ) light chain misfolded proteins. In this study we tested the role of CAEL-101 in mediating the phagocytosis of synthetic fibrils and their intermediates by macrophages and neutrophils, as a way of elucidating its mechanism of action. Methods Two human VL proteins, named LEN and AL09, were recombinantly expressed in mammalian cell systems. Synthetic LEN and AL09 fibrils were generated using purified recombinant VL protein. Fibril formation was assessed by Thioflavin T (ThT) fluorescence emission fold change over time, change in radius of protein sample via Dynamic Light Scattering (DLS), and Transmission Electron Microscopy (TEM). The binding of CAEL-101 to fibrils was determined using an immunoassay performed on an MSD® platform and SPR (Biacore™ T200). To generate fibril intermediates (light chain aggregates), recombinant AL09 VL protein was processed per a fibril formation protocol. Samples were taken at 48- and 72-hour timepoints wherein the ThT signal had not yet achieved saturation. DLS readings showed these samples to be smaller in size than samples acquired with fully formed synthetic fibrils. TEM revealed samples to be aggregated and lacking a beta-pleated fibrillar structure. Phagocytosis of synthetic fibrils and intermediates were demonstrated using PMA differentiated THP1 macrophages and neutrophils isolated from healthy donors. Synthetic fibrils and intermediates were labeled with pHrodo™ iFL Red STP Ester dye and incubated with various dilutions of CAEL-101, IgGk1 isotype control, and 10% normal human serum (NHS). Fucoidan, a macrophage scavenger receptor A inhibitor, was included in assays using THP-1 cells. An Fc blocking reagent was included to evaluate whether the observed phagocytosis is FcγR dependent. Phagocytosis assays were also done with complement depleted human serum to evaluate the impact of complement activation on CAEL-101 mediated amyloid clearance. Phagocytosis at 3hr timepoint was assessed using an Incucyte® S3 system, as indicated by presence of pHrodo signal emitted from cells. Results CAEL-101 bound to synthetic fibrils dehydrated onto an MSD plate with an EC 50 of 6.346E-010 M for LEN fibrils and 9.21E-07 M for AL09 fibrils. CAEL-101 bound to LEN fibrils via SPR with an affinity of 2.66E-11 KD (M) and to AL09 fibrils with 3.62E-07 KD (M) at pH 7.4. Phagocytosis assays demonstrated that incubation of synthetic fibrils with CAEL-101 led to statistically significant enhancement of phagocytosis in both the differentiated THP-1 cells and neutrophils, as compared to phagocytosis observed with IgGk1 isotype control antibody or fibril alone. Phagocytosis was enhanced in the presence of 10% normal human serum compared to complement depleted serum. At 3hr timepoint, CAEL-101 significantly enhanced LEN fibril phagocytosis (p<0.05, two-way ANOVA) at antibody concentrations of 0.41 nM and above, with no phagocytosis observed above background in the presence of Fc block. CAEL-101 significantly enhanced the phagocytosis of intermediate AL09 light chain aggregates (48- and 72- hour timepoint collections), as compared with IgGk1 isotype control antibody or fibril alone. Conclusions The current in-vitro study demonstrated that CAEL-101 binds to light chain amyloid fibrils and upon binding causes the phagocytosis of fibrils via macrophages and neutrophils in a FcγR dependent manner. The phagocytotic activity is further enhanced in the presence of complement. In addition, for the first time we demonstrated that CAEL-101 was able to phagocytose intermediate soluble light chain aggregates, known precursors of amyloid fibril formation.

Purpose: Involved internal iliac and obturator lateral lymph nodes (LLNs) are a known risk factor for the occurrence of ipsilateral local recurrences (LLR) in rectal cancer. This study examined coverage of LLNs with routine radiation therapy practice in the Netherlands and associated LLR rates. Methods and Materials: Patients with a primary tumor <= 8 cm of the anorectal junction, cT3-4 stage, and at least 1 internal iliac or obturator LLN with short axis >5 mm who received neoadjuvant (chemo)radiation therapy, were selected from a national, cross-sectional study of patients with rectal cancer treated in the Netherlands in 2016. Magnetic resonance images and radiation therapy treatment plans were reviewed regarding segmented LLNs as gross tumor volume (GTV), location of LLNs within clinical target volume (CTV), and received proportion of the planned radiation therapy dose. Results: A total of 223 out of 3057 patients with at least 1 LLN 95% versus 95% of the planned radiation therapy dose (7.1% vs 11.3%, P = .843), respectively. Two of 7 patients who received a dose escalation of 60 Gy developed an LLR (4-year LLR rate of 28.6%). Conclusions: This evaluation of routine radiation therapy practice showed that adequate coverage of LLNs was still associated with considerable 4-year LLR rates. Techniques resulting in better local control for patients with involved LLNs need to be explored further. (c) 2023 Elsevier Inc. All rights reserved.

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.

INTRODUCTION:Short-course external beam radiotherapy (EBRT) and intraluminal brachytherapy are both accepted treatments for the palliation of dysphagia in patients with incurable esophageal cancer. We compared the effects of both treatments from two prospective studies. METHODS:We performed a multicenter prospective cohort study of patients with metastasized or otherwise incurable esophageal cancer requiring palliation of dysphagia from September 2016 to March 2019. Patients were treated with EBRT in five fractions of 4 Gy. Data were compared with all patients treated with a single brachytherapy dose of 12 Gy in the SIREC (Stent or Intraluminal Radiotherapy for inoperable Esophageal Cancer) trial, both between the original cohorts and between 1:1 propensity score-matched cohorts. The primary end point was an improvement of dysphagia at 3 months without reintervention. The secondary end points included toxicity and time-to-effect. RESULTS:A total of 115 patients treated with EBRT and 93 patients who underwent brachytherapy were eligible for analysis. In the original cohorts, dysphagia improved after EBRT in 79% of patients compared with 64% after brachytherapy (p = 0.058). Propensity score matching resulted in 69 patients in each cohort well-balanced at baseline. Improvement of dysphagia was observed in 83% after EBRT versus 64% after brachytherapy (p = 0.048). In responding patients, improvement of dysphagia at 2 weeks was observed in 67% after EBRT compared with 35% after brachytherapy, and the maximum effect was reached after 4 weeks in 55% and 33%, respectively. Severe toxicity occurred in 3% of patients after EBRT compared with 13% after brachytherapy. CONCLUSIONS:Short-course EBRT appears at least as effective as brachytherapy in the palliation of dysphagia in patients with esophageal cancer.

Background and Purpose: Small cell carcinoma of the esophagus (SCEC) is a rare subtype of esophageal cancer for which optimal treatment is unknown. We analyzed the impact of treatment factors on outcome in patients with nonmetastasized SCEC. Methods: Patients with a histologically confirmed SCEC without distant metastases were analyzed in a nationwide multicenter retrospective cohort. All patients received radiotherapy as part of curative treatment between January 2000 and December 2014. Details on treatment and outcome were retrieved from individual charts. Cox regression analysis was used to determine prognostic factors for survival. Results: Fifty-eight patients were analyzed. Median survival was 16 months (95% confidence interval, 11-21 mo). Infield recurrences occurred in 25%, distant metastases in 45%, and brain metastases in 12%. In total, 63% of patients developed a recurrence. Most recurrences (67%) occurred within 1 year. In univariable analyses an increased number of chemotherapy cycles (> 3) and lower radiotherapy doses (< 45 Gy) were associated with improved survival. T-stage, N-stage, treatment period, type of chemotherapy, prophylactic cranial irradiation, and age were not associated with survival. In multivariable analyses, only the number of chemotherapy cycles was associated with better survival (hazard ratio, 0.78; P= 0.006). Conclusions: SCEC recurs frequently at distant sites after definitive chemoradiotherapy and usually within 1 year after curative treatment. With a dose of 45 to 50 Gy, infield recurrence rate was low. We found a relationship between number of received chemotherapy cycles and survival with best results obtained after at least 4 cycles of chemotherapy.

Introduction: Patient preferences are often not discussed in treatment decisions in oncology. We introduced an online values clarification method (VCM) to help newly diagnosed rectal cancer patients participate in shared decision making about short-course preoperative radiotherapy. Material and Methods: We offered a link to the VCM to a subset of consecutive patients before the pretreatment consultation with the radiation oncologist. Consultations were audiotaped and coded for expressions of patient preferences. Patients were asked to complete pre- and post-consultation questionnaires. Questionnaires assessed values clarity, decision regret and presence and impact of fecal incontinence and sexual problems. Results: Of 135 patients who had their consultation audiotaped and completed questionnaires, 35 received and accessed the VCM-link. Patients in the VCM-group slightly more often expressed preferences during consultations. Questionnaire data showed that patients in the VCM-group did not differ in how clear their values were, but experienced lower regret and less impact of treatment harms at 6 months follow-up; differences were non-significant but in the same direction at 12 months. Discussion: This is the first study to assess the effect of an adaptive conjoint analysis-based VCM on actual patient-clinician communication, and long-term decision regret and impact of treatment harms. Being explicitly invited to think about treatment benefits and harms seems to help patients to live with treatment consequences.

Citation for published version (APA): Jeene, P. M., Geijsen, E. D., Muijs, C. T., Rozema, T., Aleman, B. M. P., Muller, K., ... Hulshof, M. C. C. M. (2019). Small Cell Carcinoma of the Esophagus A Nationwide Analysis of Treatment and Outcome at Patient Level in Locoregional Disease. American journal of clinical oncology-Cancer clinical trials, 42(6), 534-538. https://doi.org/10.1097/COC.0000000000000546

To report the quality of life and visual functioning in uveal melanoma patients treated with enucleation or fractionated stereotactic radiation therapy (fSRT).

Background The shared decision making (SDM) model states that patients' values and preferences should be clarified to choose a strategy that best fits the patient. This study aimed to assess whether values and preferences of rectal cancer patients are voiced and considered in deciding about preoperative radiotherapy (PRT), and whether this makes patients feel more involved in treatment decision making. Methods Pre-treatment consultations of radiation oncologists and patients eligible for PRT were audiotaped (N = 90). Tapes were transcribed and coded to identify patients' values and treatment preferences. Patients filled in a post-consultation questionnaire on their perceived involvement in decision making (N = 60). Results Patients' values were voiced for 62/611 of benefits/harms addressed (10%), in 38/90 consultations (42%; maximum 4 values per consultation), and most often related to major long-term treatment outcomes. Patients' treatment preferences were discussed in 20/90 consultations (22%). In 16/90 consultations (18%), the oncologists explicitly indicated to consider patients' values or preferences. Patients perceived a significantly more active role in decision making if their values or preferences had been voiced or considered. Conclusions Patients' values and treatment preferences are voiced or considered in a minority of consultations. If they are, this increases patients' perceived involvement in the decision making process.

PURPOSE:To evaluate risk factors for secondary enucleation after fractionated stereotactic radiotherapy (fSRT) in uveal melanoma.METHODS:In this retrospective study, clinical data of 118 consecutive patients who had initially been treated with fSRT between 1999 and 2009 were collected and analysed. The patients who had undergone secondary enucleation were identified and examined for clinical, histopathological and cytogenetical (fluorescence in situ hybridization determined) data. Also, the reasons for secondary enucleation, such as treatment failure (progressive tumour growth or tumour recurrence) or complications following fSRT (painful blind eye), were recorded and examined.RESULTS:The secondary enucleation rate was 16% after a median follow-up of 4.7 years, with 5% due to treatment failure and 11% due to complications. In the univariate analysis, large tumour diameter (p = 0.019) and large tumour height (p = 0.001) were associated with secondary enucleation, tumour involvement of the optic disc showed borderline significance (p = 0.068). Cox regression multivariate analysis displayed large tumour height as independent prognostic factor (HR 1.42, 95% CI 1.12-1.81, p = 0.004). Following secondary enucleation, mitotic figures were present in five of 18 tumours, and gain of chromosome 8q was also present in five tumours. Within the subgroup of patients who required secondary enucleation due to failed tumour control by fSRT (N = 6), mitotic figures were present in four of six tumours while gain of 8q was present in three of six tumours.CONCLUSION:Secondary enucleation after previous fSRT was associated with large tumour height. High mitotic counts and gain of chromosome 8q were frequently found in secondary enucleations and possibly indicate a more aggressive or radiation-resistant tumour.

Definitive (chemo)radiotherapy is employed in esophageal cancer patients as an alternative for patients considered medically unfit for surgery or having unresectable tumors. We evaluated a population-based cohort to improve the selection for intensified nonsurgical strategies and to identify prognostic factors.

83 Background: Definitive (chemo)radiation as primary treatment modality is offered to esophageal cancer (EC) patients, as an alternative for patients considered medically unfit for surgery or having irresectable tumors. We evaluated the results in our cohort to improve selection of patients for intensified non-surgical strategies and to identify which clinical factors have a prognostic impact on the overall (OS) and disease free survival (DFS). Methods: EC patients treated with definitive radiotherapy (RT) or chemoradiotherapy (CRT) from 4 radiotherapy referral centers between 1996 and 2008 were used. Only patients with squamouscellcarcinoma (SCC) or adenocarcinoma (AC) were included in the analyses. Results: In total 278 patients were identified of whom 106 (38.1%) were treated with CRT (platinum based, median 50.4 (46.8 – 70)Gy) and 172 (61.9%) with RT alone (median 60 (40-70)Gy). T- stage was cT1=5.6%;cT2=15.3%;cT3=60.9% and cT4=18.2%. Nodal stage consisted of cN0=35%;cN1=65%, including cM1a=5.8%. The male/female ratio was 78.3% to 21.7%. AC occurred in 57.6% and 42.4% had a SCC. The median age was 69 years. Median OS time was 11 (1-166) months with an OS of 45%, 22% and 6% and a DFS of 32%, 18% and 6% at 1, 2 and 5 years, respectively. There was no significant difference between the CRT and RT group in OS (p=0.09) and DFS (p=0.17). The DFS after 2 and 5 year was 25% and 12% for SCC patients versus 11% and 0% for AC patients (p=0.007). The OS at 2 and 5 year was 28% and 11% for SCC versus 14% and 0% for AC patients (p=0.020). Initial recurrence was seen locoregionally in 66.7% and distant metastases occurred in 33.3%. Common sites for distant recurrence were the liver with 52.4%, 17.5% bones and 15.5% lungs. Patients with SCC had a better response to (chemo)radiotherapy considering the OS (p=0.02, HR=0.7) and DFS (p=0.01, HR=0.69) in a multivariate analysis. Conclusions: Patients with a SCC esophageal tumor have better long-term results then AC patients after definitive (chemo)radiation. In this patient group SCC seems to be a strong prognostic factor for both OS and DFS. Furthermore the difference between RT and CRT is still small.

Purpose: To determine local control, late toxicity and metastatic free survival (MFS) of patients treated with fractionated stereotactic radiation therapy (fSRT) for uveal melanoma (UM).Methods and materials: Between 1999 and 2007, 102 UM patients were included in a prospective study of a single institution (median follow-up (FU) 32 months; median tumor thickness 6 mm); five fractions of 10 Gy were given. Primary endpoints were local tumor control and late toxicity (including visual outcome and eye preservation). Secondary endpoint was MFS.Results: Local tumor control was achieved in 96% of the patients. Fifteen enucleations were performed, 285 months after radiation. Four eyes were enucleated because of local tumor progression. Nine patients developed grade 3 or 4 neovascular glaucoma (NVG), 19 developed severe retinopathy, 13 developed opticoneuropathy grade 3 or 4, 10 developed cataract grade 3, and 10 patients suffered from keratitis sic-ca. Best corrected visual acuity (BCVA) decreased from a mean of 0.26 at diagnosis to 0.16, 3 months after radiation and it gradually declined to 0.03, 4 years after therapy. The 5-year actuarial MFS was 75% (95% CIs: 62-84%).Conclusions: fSRT is an effective treatment modality for uveal melanoma with a good local control. With that, fSRT is a serious eye sparing treatment modality. However, our FU is relatively short. Also, the number of secondary enucleations is substantial, mainly caused by NVG. (C) 2011 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 102 (2012) 219-224

Multimodality treatment is increasingly used in the treatment for esophageal cancer. We determined the tumor regression grade after preoperative chemoradiation and correlated the effect of specific pathologic and clinical findings to overall survival. For this purpose esophageal biopsies and surgical specimens of 67 patients treated with neoadjuvant paclitaxel and carboplatin concurrent with radiotherapy were reviewed. Neoadjuvant chemoradiotherapy led to a significant downstaging. Complete tumor regression was found in 24% of the patients resulting in a trend towards better survival. It was found more frequently in poorly differentiated tumors. Patients with pre-treatment nodal involvement, assessed by endoscopic ultrasound, had a significantly worse survival compared to patients without. Contrastingly, this was not found for post-treatment nodal involvement, as determined by pathological examination, speculating that survival is more determined by (submicroscopic) distant disease, than by locoregional tumor cells.

BACKGROUND:A surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial.METHODS/DESIGN:The CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm.The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up.DISCUSSION:This study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen.TRIAL REGISTRATION:ISRCTN80832026.