Adoption Of Total Mesorectal Excision Research Articles

The Role of Adjuvant Treatment in Resected T3N0 Rectal Cancer

Since the adoption of total meso-rectal excision as the standard surgical approach for management of locally advanced rectal cancer, there has been a significant reduction in local recurrence. Neoadjuvant combined modality treatment with 5-fluorouracil-based chemotherapy and radiation has further improved local disease control and overall survival. Given the excellent survival obtained with this combined approach in T3N0 rectal cancer, there are concerns about the need for further exposure to chemotherapy with unproven benefit. We review the evidence for adjuvant chemotherapy in this setting and set out clinico-pathologic variables that may be useful for making a decision in favor of offering adjuvant therapy or observation.

Promises and pitfalls of total mesorectal excision: getting the best outcomes

The management of patients with rectal cancer has seen a number of important advances over the past 30 years. The most important of these has been the improvement and standardization of surgical technique. Combined with advances in preoperative imaging, neoadjuvant and adjuvant therapies and expert pathological assessment, widespread adoption of total mesorectal excision has led to improved results for this challenging but eminently curable cancer.

Adjuvant Chemotherapy for Locally Advanced Rectal Cancer: Is It a Given?

Adjuvant therapy for solid tumors is designed to cure patients more often than surgery alone, and the first principles of adjuvant therapy include gaining both local and systemic control. Locally advanced rectal cancer isdefinedbyeitherT3ornodepositivity,andhistorically ithashad a high risk for both local recurrence (LR) and distant recurrence. Unlike other solid tumors, local control in rectal cancer is a worthy pursuit, even in the absence of systemic therapy, as a result of the profound morbidity associated with LR and the inability to salvage most LRs with surgery. Consequently, combined-modality therapy with chemotherapy, radiation,andsurgeryemergedinthe1980sand1990sastheoptimumtherapy for reducing the risk of both LR and distant recurrence. Adjuvant (postoperative) chemotherapy has been accepted as a component of multimodality therapy for locally advanced rectal cancer for two primary reasons. First, postoperative fluorouracil was associated with an improvement in overall survival (OS) in patients with Dukes’ B and C rectal cancer from the era preceding total mesorectal excision. Second, the relative 25% to 30% risk reduction in distant metastases and death in these studies is concordant with the benefits of adjuvant chemotherapyseenincoloncancer. Subsequently, randomizedtrials inpatients with locally advanced rectal cancer adopted as standard therapy that all patients receive fluorouracil after completion of surgery and radiation therapy.Accordingly, theNationalComprehensiveCancerNetworkVersion 2.2015 recommends the routine use of infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPEOX) chemotherapy for a total perioperative therapeutic period (includingchemoradiotherapy)of6months.Inthemostcommonlyused treatment paradigm for patients with stage II or III rectal cancer, patients receive preoperative chemoradiotherapy or short-course radiation followed by total mesorectal excision (TME) which is then followed by 4 months of an adjuvant fluoropyrimidine with or without oxaliplatin. Yet the field of rectal cancer has changed substantially in three ways that make applying information from the early trials problematic. First, neoadjuvant chemoradiotherapy is routinely used now. Moreover, the downstaging effect of preoperative therapy leaves many clinicians afraid to omit postoperative chemotherapy “in case the nodes were originally positive.” Second, the adoption of TME has substantially decreased LR from 25% to 50% to less than 10%. Finally, imaging with chest-abdominal-pelvic computed tomography scans, rectal magnetic resonance imaging scans, positron emission tomography scans, and liver magnetic resonance imaging scans has caused stage migration. Many patients in the earlier studies undoubtedly had early stage IV disease and would have been excluded in modern trials. Are there any studies in the modern era that take into account these changes and support the routine use of postoperative chemotherapy in patients who received preoperative radiation therapy? The simple answer is no (Table 1). The study at the heart of this controversy is the European Organisation for Research and Treatment of Cancer (EORTC) 22921 (Radiation Therapy, Surgery, and Chemotherapy in Treating Patients With Rectal Cancer That Can Be Surgically Removed), which randomly assigned 1,011 patients with clinical stage II or III rectal cancer who were receiving preoperative radiation 45 Gy in a 2 2 factorial design to two separate chemotherapy regimens. In the first step, patients were randomly assigned to concurrent fluorouracil with preoperative radiotherapy or radiotherapy alone. In the second step, patients were randomly assigned to four cycles of adjuvant fluorouracil/leucovorin given every 3 weeks. The study was designed and powered to demonstrate an absolute 10% OS benefit. With long-term follow-up (median, 10.4 years), there was no differenceinOSat10years(51.8%[adjuvantchemotherapy]v48.4%[no chemotherapy]), disease-free survival (DFS) at 10 years (47.0% [adjuvant chemotherapy] v 43.7% [no chemotherapy]) or cumulative incidence of distant metastases (P .52). Interestingly, all three arms receiving any chemotherapy had decreased LR at 10 years (21.9% [radiotherapy alone] v11.8%to14.5%[threechemotherapyarms];P .0017),butthisdidnot translate into an OS advantage, perhaps because the trial was underpowered to determine an absolute survival advantage of less than 10%. Interestingly, the benefit of adjuvant chemotherapy in patients with ypT0-2 seen in the first analysis has disappeared. The unexpected outcome of this study led to controversy. First, the chemotherapy delivered was not the standard in the United States. The concurrent fluorouracil was given as a bolus regimen in the Mayo Clinic schedule(albeitatadosereductionof350mg/m asopposedto400to425 mg/m) rather than infusional. Adjuvant chemotherapy was given at the same dose-reduced schedule. Second, this study has been criticized for being underpowered for a four-arm comparison trial, with only 252 to 253patientsperarm.However, thestudywasdesignedasa2 2factorial trial, which allows for an appropriate comparison between the approximately500patientswhoreceivedadjuvantchemotherapycomparedwith the approximately 500 patients who did not. These numbers appropriately drove the power calculation seeking a 10% OS benefit at 5 years. Thus, although the comparison of adjuvant chemotherapy or not was appropriatelystratifiedbypreoperative treatment, thereporteddifference reflects the entire 1,011 patients randomly assigned in the intent-to-treat analysis. JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 33 NUMBER 17 JUNE 1

Locally advanced rectal cancer: time for precision therapeutics.

The year 2015 marks the 30th anniversary of the publication of NSABP-R01, a landmark trial demonstrating the benefit of adding pelvic radiation to the treatment regimen for locally advanced rectal cancer with a resultant decrease in local recurrence from 25% to 16%. These results ushered in the era of multimodal therapy for rectal cancer, heralding modern treatment and changing the standard of care in the United States. We have seen many advances over the past 3 decades, including optimization of the administration and timing of radiation, widespread adoption of total mesorectal excision (TME), and the implementation of more effective systemic chemotherapy. The current standard is neoadjuvant chemoradiation with 5-fluorouracil (5-FU) and a radiosensitizer, TME, and adjuvant chemotherapy including 5-FU and oxaliplatin. The results of this regimen have been impressive, with a reported local recurrence rate of less than 10%. However, the rates of distant relapse remain 30% to 40%, indicating room for improvement. In addition, trimodality therapy is arduous and many patients are unable to complete the full course of treatment. In this article we discuss the current standard of care and alternative strategies that have evolved in an attempt to individualize therapy according to risk of recurrence.

De l’œsophage au rectum : les facteurs pronostiques ganglionnaires et chirurgicaux

Surgery has still a key role in curative treatment of digestive carcinomas, and for almost all localisations, lymph node status is a major prognostic factor. As far as oesophageal and gastric cancer are concerned, there is not yet any internationally standardized approach. Occidental guidelines recommend more limited lymph node dissections than Asiatic ones. Lymph node numbers requested during surgery of such cancers remain high, at least 23 lymph nodes for oesophageal cancer, and 25 for a D2 or D1.5 lymphadenectomy for gastric cancer. Generalisation of neo-adjuvant and adjuvant treatments has not yet modified these standards. On the other hand, rectal cancer surgery is well standardized since the global adoption of Total Mesorectal Excision (TME) for the late eighties. Development of mini-invasive techniques (laparoscopy and robot-assisted surgery) enabled an important decrease of surgery related morbidity as well as an enhanced post-operative recovery. However, rectal cancer surgery still has an important morbidity. Development of neo-adjuvant chemo-radiotherapy as well as in-depth knowledge of risk factor of lymph node invasion opened up the path for transanal full thickness resection without lymphadenectomy. The goal of such an approach is to avoid TME's morbidity without risking local recurrence rate increase. As a consequence, this technique might need to be completed with a TME case histological factors are not favorable.

Preoperative endorectal brachytherapy in the treatment of locally advanced rectal cancer: Rethinking neoadjuvant treatment

Prior to the introduction of preoperative treatment and modern surgical technique, recurrence rates for locally advanced rectal cancer ranged from 30% to 50%. Since the widespread adoption of total mesorectal excision and preoperative chemoradiation therapy (CRT), local recurrence rates have reduced considerably to only 5–10%. However, preoperative treatment comes at a cost with significant acute and late toxicity. Additionally, 2 standards of care have emerged—1 week of radiation alone vs 5 weeks of concurrent chemoradiation. In this review, we evaluate toxicity associated with preoperative treatment as well as the key pathological factors that influence outcome in patients with locally advanced rectal cancer. Additionally, we discuss endorectal brachytherapy, an alternative preoperative treatment that may result in equivalent or improved response rates with less toxicity when compared to conventional CRT.

Pelvic Exenteration: Surgical Approaches

Although the incidence of local recurrence after curative resection of rectal cancer has decreased due to the understanding of the anatomy of pelvic structures and the adoption of total mesorectal excision, local recurrence in the pelvis still remains a significant and troublesome complication. While surgery for recurrent rectal cancer may offer a chance for a cure, conservative management, including radiation and chemotherapy, remain widely accepted courses of treatment. Recent improvement in imaging modalities, perioperative care, and surgical techniques, including bone resection and wound coverage, have allowed for reductions in operative mortality, though postoperative morbidity still remains high. In this review, the techniques, including surgical approaches, employed for management of locally recurrent rectal cancer are highlighted.

Tumor stroma: A determinant role in local recurrence of rectal cancer patients receiving total mesorectal excision?

Local recurrence (LR) dramatically decreases since the adoption of total mesorectal excision (TME) but still could not be avoided. Current mainstream views try to elucidate LR by focusing on tumor cells invasion, such as tumor stage or regional lymph nodes metastasis. But we hypothesize that not tumor cells but the cancer stroma should be responsible for the LR after TME. We believed current resection range of TME may cause remnant cancer stroma, which might act as the determinant role in LR by motivating carcinogenesis of neighboring normal epithelium. A series of supportive evidences are listed and future experiments to test our hypothesis are suggested. Once this hypothesis proved, current standards of TME should be substantially rewritten concerning the resection margins.