Hénin-beaumont, France

Longterm Functional Outcomes in Patients Undergoing Organ Preserving Treatment for Rectal Cancer With or Without Local Excision After Chemoradiotherapy

Local Excision for Organ Preservation in Early REctal Cancer With No Adjuvant Treatment

Registry´s main hypothesis: Exclusive LE is insufficient for in situ rectum preservation in cT1N0M0 extraperitoneal rectal adenocarcinoma in ≥20% of the patients treated with this approach in real everyday´s clinical practice. A database will be design recording demographics, tumor details, type of intervention, complications, histological details and further necessity of treatments and rectal preservation along time. It will be hosted online through the REDCap system. Data entry will be done baseline, after surgical procedure, and at different follow-up periods, at 30 postoperative day and at 6, 12, 18, 24 and 36 months after surgical intervention. Sample size calculation: Previous evidence states that most patients would be willing to assume a recurrence risk of 20% (IQR 10-35%) in locally advanced rectal cancer after chemo-radiotherapy in order to join the watch and wait strategy for organ preservation. In the project the investigators propose a salvage TME rate of less than 20% at three years to be acceptable. With this approach, accepting a risk α of 0.05 and a risk β of 0.2, a two-tailed test would require a total of 145 patients to identify a difference of 0.1 units. A proportion in the reference group of 0.2 and a loss rate of 5% has been estimated. Clinical variables Clinical and demographic data will be collected from each patient, using their computerised clinical history, and a data collection notebook will be prepared. - Centre code: Each participating centre will receive a unique code that will be the first variable in the database in order to identify the participation of each centre in the study. - Patient code: Each patient included in each centre will receive a consecutive numerical code to identify the different cases registered in the study. - Demographic variables: Sex, date of birth, weight (kg), height (cm). - Comorbidities and cardiovascular risk factors: ASA classification, diabetes mellitus, hypertension, dyslipidaemia, smoking, heart disease, immunosuppression. - Preoperative laboratory values: haemoglobin (mg/dl), albumin (mg/dl), carcinoembryonic antigen (mg/dl). - Preoperative clinical staging: Tests performed (MRI, endoanal ultrasound, endoscopic techniques), distance of the tumour to the ano-rectal ridge, distance of the tumour to the external anal margin, tumour size (cranial-caudal axis), percentage of rectal circumference occupation (<25%, 25-50%, >50%). - Operative data: Date of resection, resection approach (endoscopic vs. surgical), transanal resection devices (TEM, TEO, TAMIS, Robot-TAMIS), technique used (local full-wall resection vs. submucosal dissection), intraoperative complications (bleeding, vaginal perforation, tumour perforation/rupture), medical complications). - Postoperative complications: Clavien-Dindo classification, wound dehiscence, surgical site infection, bleeding. - Pathological data: pT classification, histological grade, circumferential margins, vascular, lymphatic and perineural infiltration, micron infiltration of submucosa and tumour budding. - Need to complete treatment: Reason (local resection complication, high risk factors, inadequate surgical margins, piecemeal resection, local recurrence, final pathological staging greater than pT1), radical surgery (dichotomous), technique used (total mesorectal excision, abdominoperineal amputation of rectum), time from local excision to radical surgery (date), stoma preparation (dichotomous), type of stoma (ileostomy vs. Colostomy, temporary vs. definitive), transit reconstruction within the study period (in temporary stomas), adjuvant radiotherapy, adjuvant radio-chemotherapy, - Follow-up: complications recorded prospectively at 60 days by means of periodic visits to the coloproctology clinic, with the end of follow-up for the patient within the study being the annual check-up. The number of consultations during the first year, recurrence (indicating date and management) and death will be assessed. Oncological follow-up will be carried out with control of tumour markers (CEA), control imaging tests (CAT scan associated with PET/CT in the case of recurrence), and selected biopsies according to the results. Statistical method: The data obtained from each patient will be entered into a database and the analysis will be performed with a statistical programme Stata 13.1 (StataCorp, Texas, USA). A descriptive analysis of demographic and clinical variables will be performed. Categorical variables will be presented as percentages and frequencies. Qualitative variables will be presented as percentages and frequencies. Quantitative variables will be described as mean and standard deviation (SD) if they follow a normal distribution or as median and interquartile range (IQR), in case of skewness. The association between the variables collected and the target variables of the study will be performed by Pearson's Chi-square test or Fisher's exact test, as appropriate, in the case of categorical variables and, for continuous variables, by Student's t-test for independent samples or Mann-Whitney U-test, respectively, depending on whether or not their distribution conforms to the normal distribution. Overall survival, disease-free survival, local recurrence-free survival and overall mesorectal resection-free survival will be estimated using the Kaplan-Meier method and the Cox proportional hazards model. Patients lost to follow-up will be censored. Chronogram and study´s stages: - March - September, 2023: Study´s protocol design and approval by the promoter center´s local ethics committee. Recruitment period for other participant centers. - October,- December 2023: Unique registry database design in the REDCap platform. - January 2024 - December 2024: Recruitment of the necessary cases according to the sample size calculation. - January - December 2025: 1-year follow-up of patients included in the study. - January - April 2026: Interim analysis after the first year of oncologic follow-up for assessment of the primary endpoint of the study (organ preservation with exclusive local resection) as well as some of the secondary endpoints. - December 2027: Follow-up period to complete the study at 3 years. Ethical and legal aspects: The investigation will be conducted according to the 2013 Fortaleza´s update of the the Helsinki Declaration, and to each participant´s country law.

Melanoma Margins Trial-II: 1cm v 2cm Wide Surgical Excision Margins for AJCC Stage II Primary Cutaneous Melanoma

This study will determine whether there is a difference in disease-free survival rates for patients with primary cutaneous melanoma with Breslow thickness > 2mm or 1-2mm with ulceration (pT2b-pT4b, AJCC 8th edition), treated with either a 1cm excision margin or 2cm margin. The study is designed to be able to prove or disprove that there is no difference in risk of the tumour recurring around the scar or anywhere else in the body between the two groups of patients. If the study shows no risk of tumour recurrence then we will also be able to determine how much of an impact the narrower excision has on patients in terms of improved quality of life and reduced side effects from the surgery and melanoma disease. This trial will also evaluate and determine the economic impact of narrower excision margins on the health services and society in general.

A Study Evaluating the Effect of Frozen-Section Directed Excision Surgery on Vulvar Dysplasia

This is a randomized, single-blinded study. The target population is adults ≥ 18 years of age with histological or cytological confirmation of VIN 2, VIN 3, VIN 2/3 or High-grade Dysplasia NOS with a planned excisional procedure, with high suspicion by the enrolling investigator that gross surgical margins of ≥ 3 mm can be achieved without laser or other destructive procedures. One group of subjects will be assigned to the Frozen-Section Directed Excision surgery arm and will undergo this procedure. The other group of subjects will be assigned to the Wide Local Excision (standard of care) arm and will undergo this procedure. The randomization will be 1:1, meaning for every subject who gets assigned to the Frozen-Section Directed Excision surgery arm, one will also be assigned to the Wide Local Excision arm. There is a 50% chance of getting randomized to either the Frozen-Section Directed Excision procedure or Wide Local Excision. Information regarding the surgery procedure, the amount of time the surgery procedure takes, and total amount of pain medication required during surgery and while in the surgery recovery area will be collected. The study team will also look at recurrence rates (return of the cancer) in six months, if any other therapies are required, and subject satisfaction related to the surgery, recovery, and sexual function by using questionnaires before and after the procedure.

Organ Preservation First Strategy and Intentional Watch and Wait for MRI Defined Low-risk Rectal Cancer

Radical vs Local Excision for Rectal Cancer With Clinically Complete Remission

In Taiwan, patients with stage Ⅱ or Ⅲ rectal cancer represented around 30% of all cases of colorectal cancer(n=15,000 annually). Standard treatment of locally advanced rectal cancer consists of neoadjuvant chemoradiotherapy (nCRT), total mesorectal excision (TME), and postoperative adjuvant chemotherapy. This intensive treatment leads to good local tumor control and patient survival, but is associated with short- and long-term morbidity that impairs each patient's quality of life permanently. Although nCRT followed by adjuvant chemotherapy are associated with specific toxicity and may compound surgery-related morbidity, most of the side effects of multimodal treatment that impair the patient's quality of life are attributable to TME with sphincter-preservation or abdomino-perineal resection (APR). Even with the technological advances of robotic and transanal TME, some patients with distal rectal cancer will still require a permanent colostomy. In addition, patients who undergo a sphincter-saving procedure develop a combination of defecatory symptoms known as low anterior resection syndrome. These symptoms are associated with significant impairment of patients' quality of life. With the age-adjusted incidence of rectal cancer increasing steadily in young patients, alternatives to TME are needed. Some patients with locally advanced rectal cancer have a pathological complete response (pCR) to nCRT. Because patients with pCR have excellent prognosis,8 surgeons question the added value of TME for patients with a clinical complete response (cCR) to CRT. Several institutional case series have reported that a watch-and-wait strategy can result in sustained organ preservation in patients with a cCR to nCRT. Remarkably, up to 30% of patients entered in watch-and-wait protocols eventually experienced tumor re-growth, but most of the cases were surgically salvageable.9 In some series, the survival rate in patients with clinical complete response (cCR) entered in a watch-and-wait protocol was equivalent to that in patients found to have a pCR after TME. However, most of these series, recently published together as an international multicenter registry study, are heterogeneous in terms of tumor stages, radiation dosage, sensitizing chemotherapy, the criteria and timing for assessment of response, and surveillance follow-up protocols. Because these series included only selected patients entering in the watch-and-wait protocol without reporting the total number of patients with similar-stage rectal tumors treated with neoadjuvant therapy during the study period, the possibility of selection bias cannot be excluded. Without a reference denominator, the number of patients who would have potentially benefited from organ preservation by using a watch-and-wait strategy is unknown. With above-mentioned reasons, most of the patients, including the international case series and our previous case reports, still receive radical surgery for their rectal cancer with cCR to neoadjuvant CRT; some patients with cCR even received a theoretically unnecessary APR procedure and wore a colostoma for life. To enhance the life quality for such patients with cCR to nCRT, the guidelines of the National Comprehensive Cancer Network for treatment of rectal cancer included total neoadjuvant therapy (TNT; systemic chemotherapy before rather than after TME), which was developed in part as a strategy to increase the rate of tumor response. However, to date, the impact of TNT on the potential for organ preservation through avoidance of surgery is unknown. There is no denying that the organ preservation with no immediate surgery, i.e., the watch-and-wait strategy, in selected patients with a cCR after nCRT is currently at the forefront of rectal cancer management. This strategy is considered as an attractive option to avoid major surgery and the associated morbidity and mortality risks, and functional consequences. However, with the watch-and-wait approach, there is a risk for the development of local regrowth, systemic recurrence, or both, despite the initial achievement of a clinical complete response. Overall, the risk of local re-growth within 3 years from attaining a clinical complete response is 25-30%, and even the occurrence of local re-growth at as long as 7 years from the completion of neoadjuvant chemoradiotherapy has been reported. Therefore, long-term and intensive surveillance protocols have been recommended for patients managed by a watch-and-wait strategy. Remarkably, in consideration of the watch-and-wait policy requires intensive medical resources, it has been not adopted in Taiwan and most of the centers of excellence worldwide. On the other hand, the GRECCAR2 multicenter randomized trial showed that no evidence of difference in oncological outcomes between local excision and total mesorectal excision in term of 5-year overall survival. Local excision can be proposed in selected patients having a small T2-T3 low rectal cancer with a good clinical response after chemoradiotherapy. However, their study subjects were not limited to rectal cancer with cCR to preoperative CCRT. The investigators believe that local excision can be applied to the highly selective patients with rectal cancer, especially those with cCR to operative CCRT. However, up to date, there is still no diagnostics to accurately predict the pCR of the rectal cancer to CCRT. And therefore, both the colorectal surgeons and patients has been receiving radical surgery as the major treatment modality. Remarkably, with advent of genetic technology, it become feasible to utilize ctDNA for predicting the response to neoadjuvant chemoradiotherapy and prognosis assessment in locally advanced rectal cancer. The ctDNA (mutant allele) has been known to be with an extremely short plasma half-life (shorter than 2 hours) compared with tumor markers (such as CEA and CA19-9). After curative resection, therefore, ctDNA rapidly disappears from the blood if no residual cancer exists. Utilizing these characteristics of ctDNA, a diagnostic system for detecting minimal residual disease (MRD) using a next generation sequencing technology is being developed. Remarkably, SignateraTM is a novel ctDNA detection system for MRD detection developed by Natera Inc., U.S.A. First, whole exon analysis of tumor tissue samples is performed, followed by extraction of 16 somatic mutations from the detected tumor-specific single nucleotide variants using an original program, and the primer set that detects these variants is established for each patient and tumor. SignateraTM is a test system that extracts ctDNA from the blood obtained postoperatively, using this primer set, and detects the presence or absence of somatic mutations derived from tumors using a next generation sequencer. In SignateraTM, the sensitivity limit for ctDNA allele frequency is 0.005%, the 90% sensitivity limit is 0.010%, and the specificity is at least 99.5%. In a multicenter prospective cohort study in patients with Stage I-III colorectal carcinoma, 130 patients with Stage I-III colorectal carcinoma were enrolled. The ctDNA positive rate at 30 days after the curative resection was 10.6%, and the relapse rate was 7 times or more higher in the ctDNA positive group than in the ctDNA negative group (hazard ratio [HR] = 7.2; 95% CI, 2.7-19.0). In addition, of the 58 patients who were evaluable for ctDNA after completing postoperative adjuvant chemotherapy, 7 patients (12.0%) were positive for ctDNA, and 51 patients (88.0%) were negative for ctDNA, with relapse observed in all ctDNA-positive patients, which was significantly higher than the relapse rate in ctDNA-negative patients (7/51 patients, 13.7%) (HR = 17.5; 95% CI, 5.4-56.5). Moreover, of the 75 patients who were tested for ctDNA chronologically, 14 out of 15 ctDNA-positive patients (93.3%) had a relapse, and of the 60 patients who were negative for ctDNA, only 2 patients had a relapse. With respect to time-to-relapse, the median time to confirmation of a relapse by ordinary CT scan was 14.2 months, while the median time to detection of positive ctDNA was 5.5 months. In the present project, the investigators plan to more accurately select the rectal cancer patients with pCR to preoperative CCRT, taking advantage of quantification of ctDNA in addition to the current available diagnostic modalities, including CT, MRI, PET and colonoscopy. The patients with suspected pCR to CCRT will be randomized to radical surgery and local excision groups, followed by the comparison of the oncologic outcomes between two treatment methods. The investigators hypothesized that if the pCR for patients with rectal cancer after CCRT can be more accurately predicted, such patients can be safely treated with limited surgery to enhance the post-treatment life quality, in comparison with patients undergoing radical surgery.

Treatment of Adenocarcinoma of the Rectum With Transanal Local Excision for Complete Responders

The purpose of the study is to determine if neo-adjuvant FOLFOX therapy and lengthening the time interval between neo-adjuvant chemotherapy and transanal local excision will increase the percentage of patients with pathologic complete remission. This is a prospective pilot study to examine the impact of two variables: 1) addition of neo-adjuvant FOLFOX chemotherapy, and 2) increasing the time interval between completion of chemo-radiotherapy and subsequent surgery, on the rate of achieving pathologic complete remission with avoidance of radical resection while maintaining an excellent local control with improvement of quality of life. All procedures in this study are standard of care, the study question relates to the use of neo-adjuvant FOLFOX and the timing between the end of radiation and surgery.

Tumor Local Excision +Postoperative Adjuvant Chemoradiotherapy for T1-2N0M0 Low/Ultra-Low Rectal Cancer

Baseline examnation: All enrolled patients in this study, in addition to routine laboratory and imaging examinations such as blood routine, blood biochemistry, serum tumor markers (Incl. CEA, CA-199, CA-724 β2-microglobulin, Ferroprotein), chest CT, abdominal and pelvic MRI, etc., were required to undergo KRAS, NRAS, BREF, PD-L1, MMR/MSS testings before surgery, and blood lymphocyte subgroups were analyzed before surgery. All enrolled patients will first undergo local tumor resection. Adjuvant therapy will be initiated 4-6 weeks postoperatively based on pathological staging: For pT1N0M0 patients without high-risk features: Active surveillance OR Radiotherapy alone (Prescription: Pelvic field irradiation 45Gy in 25 fractions) For pT2N0M0 or pT1N0M0 patients with adverse prognostic factors (including poorly differentiated histology, lymphovascular invasion, positive margins*, tumor infiltration beyond the outer third of the submucosal muscle layer（SM3 level）, or submucosal invasion >1mm): Adjuvant chemoradiotherapy (Prescription:Pelvic field irradiation 45Gy in 25 fractions PLUS Local tumor bed boost 5.4Gy in 3 fractions；Concurrent chemotherapy: Oral capecitabine 825mg/m² twice daily)；For patients with positive margins after local excision: Re-excision followed by adjuvant chemoradiotherapy OR Dose-escalated chemoradiotherapy (Prescription: Pelvic field irradiation 45Gy in 25 fractions PLUS Local tumor bed boost 14.4Gy in 8 fractions)； For patients with staging > pT2N0M0: Total mesorectal excision (TME) Following treatment completion, patients will enter clinical follow-up surveillance.

Pure Florid and Pleomorphic Lobular Carcinoma in Situ of the Breast: Towards an Increasingly Uniform Management

Classical lobular carcinoma in situ (CLCIS) of the breast is considered a non-obligate precursor of invasive carcinoma. Histologically, it is categorized as a lesion with uncertain malignancy potential, and clinical management often parallels that of benign neoplastic conditions. In contrast, its two variants, florid LCIS (FLCIS) and pleomorphic LCIS (PLCIS), have distinct morphological and genetic characteristics and a higher probability of being obligatory precursors to invasive carcinoma. PLCIS shows marked cellular-nuclear pleomorphism, resembling high-grade ductal carcinoma in situ (often initially misdiagnosed as such). FLCIS, on the other hand, displays a complete architectural subversion of lobular structure due to the increased rate of cell replication. Both variants may show foci of comedonecrosis, a distinctive but not specific diagnostic feature. A significant difference from CLCIS is their breast distribution; CLCIS tends to be multifocal, while the two variants typically present as unifocal. Genetically, the two variants differ from CLCIS, with higher genetic instability, and increased alterations in genes coding for tumor suppressors and proteins involved in cell growth regulation and replication. Immunohistochemically, both FLCIS and PLCIS regularly express estrogen and progesterone receptors, and they may present higher HER2 (ERBB2 gene) over-expression compared to CLCIS. Many controversies persist in the clinical management of these variants, largely due to their rarity in pure, isolated forms. Often, they are associated with an invasive carcinoma, which becomes the primary therapeutic focus, according to well established treatment protocols. Dedicated studies, both prospective and retrospective, are completely lacking in the literature, especially for pure FLCIS. Consequently, there is no consensus or approved international guidelines for accurate diagnostic-therapeutic strategies. Even the histological categorization of biopsy tests still remains a subject of debate. Presently, there is unanimous consensus on the indication for surgical excision of these lesions to improve histological definition and exclude the presence of an invasive neoplastic focus. However, there is no consensus on the need of surgical margins cavity shaving and the management of resection margins when they are proved to be close or involved at the final specimen pathological report. Furthermore, there is a lack of evidence-based recommendations for adjuvant therapies like radiotherapy or endocrine therapy. Some scientific international associations, such as ESMO (European Society of Medical Oncology), suggest a similar approach to pleomorphic variants as for ductal carcinoma in situ due to their morphological similarity; yet, in the absence of robust evidence, this stance does not definitively support the benefit of adjuvant therapeutic strategies and poses a relative risk of overtreatment. To address these challenges, the investigators propose international multicenter retrospective collection of cases involving the pure forms of FLCIS and PLCIS. Our goal is to comprehensively analyze the diagnostic and therapeutic management of this specific patient group and, notably, to fill the gap in the scientific literature regarding their treatment.

Organ Preservation in Rectal Cancer: Contact X-ray Brachytherapy vs Extending the Waiting Interval and Local Excision

Rationale: The organ preservation approach for rectal cancer has been explored increasingly, aiming at improving quality of life by prevention of total mesorectal excision (TME-surgery). In patients with intermediate rectal cancer (IRC) and locally advanced rectal cancer (LARC) who receive neoadjuvant (chemo)radiotherapy (in general a short-course radiotherapy or a long-course chemoradiation, respectively) subsequent TME-surgery is still standard of care. In patients with a good clinical response after neoadjuvant (chemo)radiation, organ preservation may be considered, depending on the extent of the response monitored by radiological and endoscopic assessment. Some patients show a clinical complete response and can be monitored closely in a watch-and-wait approach. In case of a good, but not complete response, it remains unclear which patients may benefit from extension of the observation period after (chemo)radiation in order to achieve a complete clinical response over time, or in whom additional local treatment options (such as contact x-ray brachytherapy or local excision) are beneficial in obtaining organ preservation eventually. Objective: The aim of this study is to investigate which rate of organ preservation can be achieved in patients with rectal cancer treated with neoadjuvant (chemo)radiotherapy with a good clinical response, and to optimize the different treatment strategies. In patients with a near-complete response or a small residual tumour mass, participation is offered in a phase II feasibility trial, in which two potential organ preservation treatment strategies are evaluated: contact x-ray brachytherapy or extension of the waiting interval with or without additional local excision in case of residual disease. Study design: This is a prospective study with a mixed design. It concerns a phase II feasibility study for patients in whom a good, but not complete response has been achieved after (chemo)radiation (OPAXX study): two parallel single study-arms evaluate the efficacy of experimental organ preservation approaches. To allow for a better comparison of secondary parameters (toxicity and morbidity of both additional local treatments) eligible patients will be randomized between two experimental arms. Furthermore, an observational cohort study is established to register rectal cancer patients with a good but not complete clinical response after (chemo)radiation who are not eligible for randomisation in the OPAXX study (OPAXX registration study). Study population: In general, patients with IRC receiving short-course radiotherapy with delayed surgery (patients with initially a cT1-3, cN1-2 lymph nodal status, no involved MRF or cT3c-d, N0-1 lymph nodal status) or patients with LARC receiving neoadjuvant long-course chemoradiation (patients with initially cT4 tumour, cN2 lymph node status, lateral lymph node involvement and/or an involved mesorectal fascia (MRF+)) according to the Dutch national guideline are eligible for this study when at the first response assessment 6-8 weeks after finishing the (chemo)radiation a good clinical response is seen. A good clinical response has been defined as a clinical complete response, a near-complete response or a small residual tumour mass <3 cm on endoscopy, but also no evidence of residual nodal disease on magnetic resonance imaging (MRI) (ycN0). In case of a clinical complete response the current strategy of watchful waiting is offered. Eligible patients in whom a good, but not complete response is detected will be randomized to one of the two experimental OPAXX study arms, provided that both additional local treatment options are technically feasible. Intervention arms OPAXX study: Arm 1: Contact x-ray brachytherapy will be given applied after randomisation with a maximum interval of 14 weeks after finishing the neoadjuvant (chemo)radiation. Contact x-ray brachytherapy consists of three fractions of 30Gy per fraction applied to the tumour, with a 2 week interval between each boost. Response evaluation takes place every 3 months thereafter. Patients in whom a clinical complete response is detected during follow-up are offered a watch-and-wait approach; patients in whom an incomplete response or disease progression is noted, completion or salvage TME-surgery is advised. Arm 2: The waiting interval will be extended with 6-8 more weeks after the first response evaluation, followed by a second (or third in case of ongoing response) re-assessment. Patients with a clinical complete response at the time of the second (or third) response evaluation will be offered a watch-and-wait approach without any surgical treatment. Patients with a remaining small lesion will be offered transanal local excision. Depending on the final pathological staging after local excision, patients are categorized as low-risk or high-risk, and will be offered a watch-and-wait strategy or completion TME-surgery, respectively. Main study parameters/endpoints: The primary endpoint of the OPAXX study reflects the efficacy of both additional treatment options: the rate of successful organ preservation (defined as an in-situ rectum, no defunctioning stoma and absence of active locoregional cancer failure) at one year following randomisation in rectal cancer patients with a good, but not complete clinical response after (chemo)radiation. Secondary endpoints are related to toxicity and morbidity of the two additional treatment options in the randomisation study, as well as to oncological and functional outcomes at one, two and five years of follow-up. For patients with a good but not complete clinical response after (chemo)radiation who are not eligible for randomisation in the OPAXX study an observational cohort study is conducted (OPAXX registration study). Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Standard treatment of IRC and LAR consists of neoadjuvant short-course or long-course (chemo)radiotherapy followed by TME-surgery. If a clinical complete response is seen at response evaluation, a watch-and-wait approach is currently considered a valid strategy in selected patients according to the Dutch national guidelines. In the ongoing Dutch national prospective registry patients with a near-complete response are currently offered an extension of the observation period rather than TME-surgery, and, subsequently, a watch-and-wait policy when a clinical complete response is noted over time. On the other hand, all patients with a persistent residual lesion will proceed to TME-surgery. In the current study, two experimental approaches are introduced that could increase organ preservation rates in patients with a good, but not-complete response at the first response evaluation: additional endoluminal contact x-ray brachytherapy and local excision of the tumour remnant. Prior to randomisation, eligible patients are well informed about the risks of the two experimental treatment strategies (i.e. unclear long-term oncological outcome), and are offered standard-of-care TME-surgery. Moreover, patients will be informed that additional treatment with contact x-ray brachytherapy or local excision might increase the morbidity rates in case completion or salvage TME-surgery is required. Finally, in both arms of this phase II study an intensive surveillance program has been established, in order to detect treatment failure, tumour regrowth or disease recurrence at an early stage, in order to proceed to completion or salvage TME-surgery when needed and when possible.