Multimodal Treatment Of Rectal Cancer Research Articles

Expression levels of circulating miRNAs as biomarkers during multimodal treatment of rectal cancer - TiMiSNAR-mirna: a substudy of the TiMiSNAR Trial (NCT03962088)

BackgroundNeoadjuvant chemoradiotherapy followed by surgery is the mainstay treatment for locally advanced rectal cancer, leading to significant decrease in tumor size (downsizing) and a shift towards earlier disease stage (downstaging). Extensive histopathological work-up of the tumor specimen after surgery including tumor regression grading and lymph node status helped to visualize individual tumor sensitivity to chemoradiotherapy, retrospectively. As the response to neoadjuvant chemoradiotherapy is heterogeneous, however, valid biomarkers are needed to monitor tumor response. A relevant number of studies aimed to identify molecular markers retrieved from tumor tissue while the relevance of blood-based biomarkers is less stringent assessed. MicroRNAs are currently under investigation to serve as blood-based biomarkers. To date, no screening approach to identify relevant miRNAs as biomarkers in blood of patients with rectal cancer was undertaken. The aim of the study is to investigate the role of circulating miRNAs as biomarkers in those patients included in the TiMiSNAR Trial (NCT 03465982). This is a biomolecular substudy of TiMiSNAR Trial (NCT03962088).MethodsAll included patients in the TiMiSNAR Trial are supposed to undergo blood collection at the time of diagnosis, after neoadjuvant treatment, after 1 month from surgery, and after adjuvant chemotherapy whenever indicated.DiscussionTiMiSNAR-MIRNA will evaluate the association of variation between preneoadjuvant and postneoadjuvant expression levels of miRNA with pathological complete response. Moreover, the study will evaluate the role of liquid biopsies in the monitoring of treatment, correlate changes in expression levels of miRNA following complete surgical resection with disease-free survival, and evaluate the relation between changes in miRNA during surveillance and tumor relapse.Trial registrationClinicaltrials.gov NCT03962088. Registered on 23 May 2019.

"Watch and Wait" for complete clinical response after neoadjuvant chemoradiotherapy for rectal cancer.

The management of rectal cancer has evolved substantially over recent decades, becoming increasingly complex. This was once a disease associated with high mortality and limited treatment options that typically necessitated a permanent colostomy, has now become a model for multidisciplinary evaluation, treatment and surgical advancement. Despite advances in the rates of total mesorectal excision, decreased local recurrence and increased 5-year survival rates, the multimodal treatment of rectal cancer is associated with a significant impact on long-term functional and quality of life outcomes including risks of bowel, bladder and sexual dysfunction, and potential need for a permanent stoma. There is great interest in strategies to decrease the toxicity of treatment, including selective use of radiation, chemotherapy or even surgery. The modern concept of selective use of surgery for patients with rectal cancer are based on the observed pathological complete response in approximately 10-20% of patients following long-course chemoradiation therapy. While definitive surgical resection remains the standard of care for all patients with non-metastatic rectal cancer, a growing number of studies are providing supportive evidence for a watch-and-wait, organ preserving approach in highly selected patients with rectal cancer. However, questions regarding the heterogeneity of patient selection, optimal method for inducing pathological complete response, methods and intervals for assessing treatment response and adequacy of follow-up remain unanswered. The aim of this review is to provide an up-to-date summary of the current evidence for the watch-and-wait management of rectal cancer following a complete clinical response after neoadjuvant chemoradiation.

OC-0384 QoL after multimodal treatment of rectal cancer with/without oxaliplatin (phase 3, CAO/ARO/AIO-04)

OC-0384 QoL after multimodal treatment of rectal cancer with/without oxaliplatin (phase 3, CAO/ARO/AIO-04)

602TiP - Re-RAD-I external beam radiotherapy for pelvic recurrences in rectal cancer patients previously treated with radiotherapy

Background: Multimodal treatment of rectal cancer has improved outcome, but some patients still experience local recurrence, which is a major therapeutic challenge after previous radiotherapy (RT). Re-irradiation may improve the rate of radical surgery (R0), as reported in previous studies, where hyperfractionated chemo-RT resulted in 35% R0 rate. Surgery, RT techniques, and imaging have improved recent years, allowing for increased treatment precision with less morbidity. This study investigates re-irradiation of patients with local recurrence in a phase II clinical, imaging and translational study. Trial design: A prospective multicenter phase II, open label, non-randomised study. Therapy: External beam RT of 40.8 Gy / 1.2 F BID by intensity-modulated RT + CBCT guidance, concomitant capecitabine 825 mg/m2 BID all RT days, and surgery 8 weeks post-RT. The primary endpoint is R0 rate. Secondary objectives: Recurrence-free, disease-free and overall survival, acute and late toxicity, patient reported outcomes, translational research, imaging studies for future adaptive RT, mapping of recurrences according to previous RT, and simulation studies of other RT modalities (proton therapy). Main inclusion criteria: Locally recurrent rectal cancer, previous pelvic RT and surgery, potentially resectable tumor, age ≥18 years, adequate organ function, acceptable bowel and bladder function, acceptance for translational research. Main exclusion criteria; central small recurrences deemed resectable, non-resectable distant metastases, medical comorbidities precluding radical surgery, previous RT <12 months prior to recurrence, unability for MRI or PET-CT. Statistics; Simons two-stage design, with expected R0 of 30% by ITT and expected R0 increase to 45%, σ = 0:05; 1 − β= 0:8. Total sample size is 65 patients. Centers in Denmark and Norway are currently recruiting.

The chemokines CXCL9 and CXCL13 as prognostic markers for metastasis and survival in rectal cancer patients after neoadjuvant chemoradiation.

627 Background: Distant metastasis is a challenging problem in multimodal treatment of rectal cancer. Valid prognostic markers for the occurrence of metachronous metastasis could help to stratify patients who qualify for adjuvant chemotherapy and intensified follow-up procedures after preoperative chemoradiotherapy (CRT). Methods: We analysed 9 different genes known to prominently figure in crucial pathways of the tumor cell metabolism. mRNA was isolated and quantified from surgical specimens of 77 rectal cancer patients undergoing neoadjuvant CRT. The panel contains genes with relevant function in apoptosis (Birc5, XIAP, SMAC) and epithelial-mesenchymal transitions (SNAI2) as well as the cancer stem-cell marker CD133, the transcription factor ESR1 and the lymphocyte-chemokines CXCL9 and 13. The expression levels in post-CRT rectal cancers were correlated with the development of distant metastasis and with disease-free (DFS) and cancer-specific overall survival (CSS). Results: Intratumoral mRNA expression of the T-cell chemokine CXCL9 (p&lt;0.001) and the B-cell chemokine CXCL13 (p&lt;0.01) was inversely correlated with the occurrence of distant metastasis. Patients with isolated high CXCL9 (p&lt;0.0001) and CXCL13 levels (p&lt;0.01) had a significantly prolonged DFS. Patients with simultaneous expression of CXCL9 and 13 had an excellent DFS compared to patients without expression of any of the chemokines (p&lt;0.0001). Additionally, CXCL9 expression was correlated with an improved CSS (p&lt;0.05). There was no significant correlation between expression levels of the other genes tested and metastasis or survival. Conclusions: The post-CRT expression of the lymphocyte-chemokines CXCL9 and 13 is associated with reduced rates of distant metastases and improved survival in rectal cancers after CRT. Further investigations are needed to prospectively validate these results and characterize the underlying cellular and molecular mechanisms.

245. Local excision after complete clinical response or minimal residual tumour following neoadjuvant therapy for rectal cancer

Background: Multimodal treatment of rectal cancer, by combination of radiation therapy, chemotherapy and radical surgery including total mesorectal excision, has become the standard approach in patients with locally advanced rectal cancer. The use of neoadjuvant therapy results in additional benefits such as significant tumor downsizing and downstaging and a better chance of sphincter preservation in selected case. Complete rectal wall tumor regression or minimal residual lesion may be associated with the absence of viable cancer cells in the mesorectum, suggesting the possibility of a less invasive surgical treatment as an alternative to radical surgery.

Rektumkarzinom: Aktueller Stand der multimodalen Therapie – wann und wie?

Preoperative 5-fluorouracil-based radiochemotherapy (RCT) followed by quality assessed total mesorectal excision (TME surgery) are the two most important elements of multimodal treatment for patients with locally advanced rectal cancer (UICC stages II and III). The optimum sequence of these neoadjuvant modalities complemented by adjuvant (postoperative) chemotherapy, has been addressed in several randomised trials. Especially within the trials of the German Rectal Cancer Study Group (GRCSG), preoperative RCT has been shown to be superior to postoperative treatment for a variety of endpoints (pathologically confirmed complete tumour remission (pCR), RCT-induced tumour regression, R0 resection rates (including circumferential resection margins) and long-term locoregional control). This neoadjuvant multimodal strategy has decreased the 5-year and 10-year local recurrence rates below 10%, and the development of distant metastases (e.g., 35% to 45% liver metastases) remains the predominant reason for failure. Furthermore, approximately 25% of patients do not receive adjuvant chemotherapy, mainly due to surgical complications, patients' refusal or the investigator's discretion. Thus, today, integrating more effective systemic therapy into (preoperative) multimodal regimens is the most accepted challenge! But from the clinical point of view this demand is also a dilemma. The question to be addressed is how and when to apply intensified systemic therapy with adequate dosage and intensity as well as acceptable treatment-associated toxicity. The increase of therapeutic options requires valid predictive biomarkers that may help to stratify patients into regimens associated with low toxicity (5-FU monotherapy alone) or into more intensified treatment for better long-term outcome. In summary, the use of biomarkers for individualised risk-adapted treatment is one of the most promising areas of clinical investigations, not only in rectal cancer. The assessment of individual tumour response, toxicity, and prognosis during multimodal treatment of rectal cancer as a model of a very common solid tumour offers radiooncologists, surgeons, pathologists, gastroenterologists as well as oncologists immense insights into the under-standing of tumour biology.

Why and How Should We Measure the Long-Term Consequences of Rectal Cancer Treatment?

The multimodal treatment of rectal cancer is a major challenge to the clinicians and implies a significant risk of long-term consequences for the patients. The purpose of this short article is to address why and how we should measure late toxicity of rectal cancer treatment. To illustrate some of the key points we review eight key completed randomized phase 3 trials that have contributed to the evidence for use of radiotherapy with or without chemotherapy for rectal tumors. We highlight an urgent need for the validation of a rectal cancer trial specific questionnaire that can be internationally applied.

Multimodal Treatment of Rectal Cancer - Evaluation of Preoperative Radiotherapy

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Extended total mesorectal excision in locally advanced rectal cancer (T4a) and the clinical role of MRI‐evaluated neo‐adjuvant downstaging

To compare the clinical ability of MRl taken before and after neo-adjuvant treatment in locally advanced rectal cancer (LARC) to predict the necessary extension of TME (ETME) and the possibility to achieve a R0 resection. Prospective registration of 92 MRI evaluated T4a cancers undergoing elective surgery between 2002 and 2007 in a tertiary referral centre for multimodal treatment of rectal cancer. MRI identified patients in need of neo-adjuvant treatment and predicted T-downstaging in 10% and N-downstaging in 59%. Seventy-nine percent R0 resections, 18% R1 and 3% R2 were obtained after ETME in 95% of the patients and TME in the rest. Higher tumour regression grade (TRG) was achieved in higher ypT-stage (P < 0.01). Preoperative chemo radiotherapy resulted in that more patients obtained TRG1-3 compared to those receiving radiotherapy (79% vs. 57%, P = 0.02). The pelvic wall was the area of failure in 70% of the R1 resections. Tumour cells outside the mesorectal fascia scattered within fibrosis was found in 18 TRG2-3 among 33 ypT4 tumours (55%). MRl cannot discriminate tumour within fibrosis. Therefore, if a R0 resection is the goal, we advocate optimal surgery in accordance with the pre-treatment MRI. Post treatment MRI is a poor predictor of final histology and should not be relied upon to guide the extent of surgical resection. The study has initiated a new approach to histopathological classification of the removed specimen where we introduce a MRI assisted technique for investigating the areas at risk outside the mesorectal fascia in the specimen.

Molecular detection (k-ras) of exfoliated tumour cells in the pelvis is a prognostic factor after resection of rectal cancer?

BackgroundAfter total mesorectal excision (TME) for rectal cancer around 10% of patients develops local recurrences within the pelvis. One reason for recurrence might be spillage of cancer cells during surgery. This pilot study was conducted to investigate the incidence of remnant cancer cells in pelvic lavage after resection of rectal cancer. DNA from cells obtained by lavage, were analysed by denaturing capillary electrophoresis with respect to mutations in hotspots of the k-ras gene, which are frequently mutated in colorectal cancer.ResultsOf the 237 rectal cancer patients analyzed, 19 had positive lavage fluid. There was a significant survival difference (p = 0.006) between patients with k-ras positive and negative lavage fluid.ConclusionPatients with k-ras mutated cells in the lavage immediately after surgery have a reduced life expectation. Detection of exfoliated cells in the abdominal cavity may be a useful diagnostic tool to improve the staging and eventually characterize patients who may benefit from aggressive multimodal treatment of rectal cancer.

Multimodal treatment of rectal cancer

Greater understanding of the natural history of rectal cancer, and the knowledge that a histologically involved circumferential margin due to inadequate lateral dissection confers a high risk of local recurrence have driven technical advances in surgical technique with meticulous surgical dissection along embryological planes. Significant improvements in local control and overall survival have been seen for patients with resectable rectal cancer. However, even high-quality surgery cannot always achieve a curative resection for locally advanced cancers that extend below the levators, having transgressed the mesorectal fascia. Magnetic resonance imaging is now accepted as a practical method of clinical staging, and can accurately predict pre-operatively the likelihood of achieving a clear circumferential margin. Technological advances in radiation planning and new effective cytotoxic drugs also give scope for dealing with unresectable rectal cancer, and the potential for controlling distant micrometastases. Hence, modern multimodal treatment of rectal cancer attempts to integrate surgery, radiotherapy and chemotherapy, and address the two distinct problems of local recurrence and metastatic disease. Multidisciplinary teams achieve the best results. This paper discusses the surgical management of rectal cancer, the pathology, the principles of imaging, and the lessons learnt from randomized trials of radiotherapy and chemoradiation.

Surgery, radio- and chemotherapy for multimodal treatment of rectal cancer.

The possibilities and results of multimodal treatment in rectal cancer were reviewed with respect to the results of surgical treatment only. Based on the results of 4 studies, reducing local relapse rates and increasing long term survival rates significantly, postoperative radiochemotherapy (RCT) + chemotherapy (CT) should remain the recommended standard for R0 resected UICC II and III rectal cancers. The addition of RT to adjuvant CT reduces local relapses without significant impact on survival (NSABP R-02). Vice versa, the addition of CT to RT or an improved CT in the RCT-concept prolongs survival. Preoperative neoadjuvant radiotherapy (RT) reduced local relapse rates in 9 studies, and extended survival in one study that evaluated all eligible patients. Preoperative RT reduced local relapse rates in addition to total mesorectal excision (TME) but did not extend survival. The preoperative RCT + CT downstages resectable and nonresectable tumors and induces a higher sphincter preservation rate. Phase III data justifying its routine use in all UICC II + III stages are not yet available. This treatment may be routinely applied in nonresectable primary tumors or local relapses. Preoperative RCT (or RT) may evolve as standard, if the patient selection is improved and postoperative morbidity and long term toxicity reduced. Intraoperative RT could be added to this concept or be used together with preoperative/postoperative RT at the same indications. Postoperative adjuvant RT reduced local relapses significantly in a single trial, and no impact on survival time is reported. Since postoperative RT is inferior to preoperative RT, this treatment cannot be recommended, if RT is chosen as a single treatment modality in adjunction to surgery. The results of local tumor excisions may be improved with pre- or postoperative RCT + CT. In the future, multimodal treatment of rectal cancer might be more effective, if individualized according to prognostic factors.

Role of the surgeon as a variable in the treatment of rectal cancer

Increasingly, data are being accumulated on the influence of intersurgeon variability on outcome after curative surgical treatment of rectal carcinoma. Thus, today the individual surgeon has to be considered as an independent factor influencing locoregional recurrence, as well as survival rates. In general, higher local control and survival can be expected for specialized colorectal surgeons. There are no clear correlations between surgical volume and outcome. Interinstitutional variability in treatment results reflects intersurgeon variability, but analysis is generally more difficult because of a lack of homogeneity with respect to different confounding factors. There are several factors in surgical technique that are important for long-term outcome. Of greatest apparent importance is the adequacy of mesorectal excision (for carcinomas of the middle and lower third, total mesorectal excision; for carcinomas of the upper third, mesorectal excision down to a mesorectal plane 5 cm distal to the gross tumor margin detected by the surgeon in situ). Furthermore, intraoperative local tumor spillage (tumor perforation during mobilization, incision into the tumor), en bloc resection technique, skill, and the extent of regional lymphadenectomy may influence outcome. For quality assurance, detailed operative reports are required, as well as histopathology examinations concerning indicators of surgical oncologic quality discernable from the resection specimens. In future clinical trials of multimodal treatment of rectal cancer, quality assurance of surgery and pathology is necessary for consideration of the surgeon and surgical technique prognostic factors.