A Comprehensive Review of Randomized Clinical Trials Shaping the Landscape of Rectal Cancer Therapy

Colorectal carcinoma is the second leading cause of cancer-related deaths in the United States, with rectal cancer accounting for approximately one third of newly diagnosed cases. Surgery remains the cornerstone of curative therapy, with total mesorectal excision being the standard of care. Although minimally invasive procedures might be appropriate for a subset of patients with early-stage, superficial tumors, the standard of care for medically operable patients with nonmetastatic rectal cancer includes a comprehensive multimodality approach of neoadjuvant chemoradiotherapy, surgery with total mesorectal excision, and systemic chemotherapy. However, the morbidity and mortality related to both local and distant organ relapse have remained challenging. In the present review, we have discussed the trial-level evidence that has shaped the current clinical practice patterns in the treatment of curable, nonmetastatic rectal cancer. In addition, we have discussed the anticipated results of ongoing clinical trials and outlined pragmatic opportunities for future investigation to optimize the current status quo and, hopefully, provide prospective validation of novel approaches in the treatment of rectal cancer.     

低位直肠癌保肛手术的质量控制

 随着对盆腔解剖和直肠癌生物学特性认识的加深,越来越多的低位直肠癌患者能够保留肛门,保肛手术已成为目前临床上治疗直肠癌最常用的术式。高质量的手术需要同时在肿瘤学和功能学方面使患者受益,因而低位直肠癌保肛手术需兼顾肿瘤根治和肛门功能。全直肠系膜切除（total mesorectal excision,TME）原则、安全的远切缘和环周切缘是保证肿瘤学效果的关键,能够有效降低直肠癌局部复发率和远处转移率。而保留更多的肛门括约肌以及术中对盆腔植物神经的保护则是改善术后肛门功能,提高患者生活质量的重要因素。       

局部进展期直肠癌新辅助治疗后器官保留策略进展

新辅助放化疗联合全直肠系膜切除术为分期T 3-T 4期或N+的局部进展期直肠癌(LARC)的标准治疗,但往往会带来一系列术后并发症,尤其是接受腹会阴联合直肠癌根治术(Mile′s术)不能保留肛门者,严重影响生活质量。对于新辅助治疗后肿瘤(近)临床完全缓解者,器官保留策略在与根治性手术达到相似治疗疗效...     

Local excision for early rectal cancer: transanal endoscopic microsurgery and beyond

The goal of treatment for early stage rectal cancer is to optimize oncologic control while minimizing the long-term impact of treatment on quality of life. The standard of care treatment for most stage I and II rectal cancers is radical surgery alone, specifically total mesorectal excision (TME). For early rectal cancers, this procedure is usually curative but can have a substantial impact on quality of life, including the possibility of permanent colostomy and the potential for short and long-term bowel, bladder, and sexual dysfunction. Given the morbidity associated with radical surgery, alternative approaches to management of early rectal cancer have been explored, including local excision (LE) via transanal excision (TAE) or transanal endoscopic microsurgery (TEM) and transanal minimally invasive surgery (TAMIS). Compared to the gold standard of radical surgery, local procedures for strictly selected early rectal cancers should lead to identical oncological results and even better outcomes regarding morbidity, mortality, and quality of life.     

Organ Preservation in Rectal Cancer: An Overview of the Dutch Perspective and Recent Developments

Although current guidelines on rectal cancer treatment often recommend rectal resection with or without neoadjuvant (chemo)radiotherapy, there is growing interest in organ-preserving treatment approaches among patients and clinicians in the Netherlands. Currently, multiple ongoing studies are investigating the value of different non-operative treatment modalities to improve tumour response rates and increase the chance of successful organ preservation. Papillon contact X-ray brachytherapy is a promising treatment modality to improve the chance of organ preservation, which seems especially relevant for elderly and frail patients unable or refusing to undergo total mesorectal excision surgery. The elderly and frail patient with rectal cancer poses a significant challenge and warrants a thorough multidisciplinary approach to provide the most optimal organ-preserving treatment. In this overview, an insight into the Dutch perspectives and developments within the field of organ preservation and the set-up of a Papillon facility to complete the spectrum of organ-preserving treatment options in a tertiary referral centre for rectal cancer treatment has been provided.     

The Evolving Field of Neoadjuvant Therapy in Locally-advanced Rectal Cancer: Evidence and Prospects

The standard treatment of locally advanced rectal cancer comprises neoadjuvant chemoradiation followed by total mesorectal excision. This strategy provides low local recurrence rate, however distant recurrence is still an issue and may impact on survival rates. Novel approaches in the neoadjuvant setting have been tested to improve early and late outcomes, as well as to reduce treatment-related toxicity and morbidity. In this review, we discuss the current literature of neoadjuvant treatment in locally advanced rectal cancer, including total neoadjuvant methods, protocols for radiation delivery, chemotherapy regimen and efforts to add novel targeted therapies, selective withdrawal of surgery or radiotherapy, and future perspectives. Moreover, we highlight relevant issues that have emerged with these new treatment possibilities.     

Local Excision for Early Rectal Cancer

Local excision is an established treatment for significant benign rectal tumours and early-stage cancers. It provides cure for most patients with pT1 disease, with minimum impact on quality of life. It is particularly suitable for elderly or comorbid patients. Local excision is associated with a risk of local recurrence, and this may vary from 5 to 30%, as determined by pathological risk factors. Recurrent cancer may be challenging to manage, but this may be mitigated by early detection with intensive surveillance and the use of adjuvant radiotherapy. This approach offers a realistic option for organ preservation in carefully selected early-stage disease compared with primary treatment with radiotherapy or total neoadjuvant treatment.     

Significance of surgery in the multimodality treatment of rectal cancer

Since the NIH recommendations in 1990 the majority of patients with rectal cancer are treated by a multimodality approach. The last decade has seen considerable improvements in the overall management of rectal cancer, therefore a certain reorientation seems justified. Although many questions remain to be answered, some general recommendations for the treatment of rectal cancer focussed on the small pelvis can be given. Surgery with total mesorectal excision is the standard therapy for cancers of the middle and low rectum in stages T1/2 N0. Adjuvant radiochemotherapy and shortterm pre-operative radiotherapy are both feasible approaches for the treatment of stage II and stage III rectal carcinomas. The superiority of either concept awaits clarifying randomised trials. Patients with T4 rectal cancers should undergo long-term neoadjuvant radiochemotherapy with consecutive oncological resection. The exact mode of the neoadjuvant regimen combining high remission rates with low treatment-associated morbidity needs further refinements. Local excision should be restricted to patients with well-differentiated, less than semi-circumferential T1 carcinomas. Tumours with less favourable histologies should not be treated locally unless general patient conditions forbid oncological resections. In these instances, additional radiochemotherapy appears able to reduce the risk of local recurrence.     

Role of Combined-Modality Therapy in the Management of Locally Advanced Rectal Cancer

The majority of patients with nonmetastatic rectal cancer are candidates for an aggressive multimodality approach with curative intent. Preoperative staging is critical in determining which patients should be offered neoadjuvant therapy. Available staging tools include digital rectal examination, transrectal ultrasound, computed tomography, positron-emission tomography, and magnetic resonance imaging scans. Magnetic resonance imaging has emerged as the most accurate staging modality in experienced centers. Multidisciplinary preoperative patient evaluation, better staging techniques, neoadjuvant chemoradiation, acceptance of shorter distal rectal margins, and transanal excision of T1 N0 rectal tumors in close proximity to the anal sphincter have resulted in decreased rates of abdominoperineal resections. Total mesorectal excision has been adopted as the standard surgical approach because of a reduction in rates of pelvic relapse. Preoperative and postoperative radiation therapy was shown to decrease the local recurrence rate, but not overall survival, in patients with resectable rectal cancer. The addition of chemotherapy to radiation was consistently shown to improve local control, and in some trials, improved overall survival. Neoadjuvant combined chemotherapy and radiation therapy are superior to adjuvant combined-modality therapy because of higher rates of sphincter preservation, less toxicity, and lower local recurrence rates. For patients with stage II or III disease, neoadjuvant continuous-infusion 5-fluorouracil (5-FU), concurrently with pelvic radiation, followed by postoperative 5-FU–based chemotherapy, remains the standard multimodality approach. Ongoing trials are testing the integration of newer cytotoxic agents such as capecitabine, oxaliplatin, irinotecan, and biologic agents such as cetuximab and bevacizumab to chemoradiation.     

Adjuvant Chemotherapy for Rectal Cancer After Neoadjuvant Treatment: FOLFOX, 5-FU,or Observation

A multimodality approach incorporating concurrent chemotherapy with radiotherapy prior to surgery has become the standardized approach in the management of localized rectal cancer. However, it is unknown whether any further therapy after surgery may be beneficial in improving patient outcomes. Previous completed randomized clinical trials have not added any clarity in this regard, whether adjuvant chemotherapy or intensified chemotherapy regimens improve patient outcomes in those who have previously received neoadjuvant therapy. Despite the lack of evidence, based off the survival data in stage III colon cancer, adjuvant chemotherapy has become a standardized practice in the management of resected rectal cancer. Furthermore, recommendations include the consideration of added oxaliplatin to adjuvant therapy in this disease. While it is unclear whether all patients should receive adjuvant chemotherapy, a subset of patients, including those who achieve a pathologic response may benefit from further treatment. Ongoing studies utilizing an individualized, stepwise multimodality approach may define the role of adjuvant therapy and the appropriate regimen in patients with resected rectal cancer.     

Complete clinical response after neoadjuvant chemoradiation for distal rectal cancer

Multimodality treatment of rectal cancer, with the combination of radiation therapy, chemotherapy, and surgery has become the preferred approach to locally advanced rectal cancer. The use of neoadjuvant chemoradiation therapy (CRT) has resulted in reduced toxicity rates, significant tumor downsizing and downstaging, better chance of sphincter preservation, and improved functional results. A proportion of patients treated with neoadjuvant CRT may ultimately develop complete clinical response. Management of these patients with complete clinical response remains controversial and approaches including radical resection, transanal local excision, and observation alone without immediate surgery have been proposed. The use of strict selection criteria of patients after neoadjuvant CRT has resulted in excellent long-term results with no oncological compromise after observation alone in patients with complete clinical response. Recurrences are detectable by clinical assessment and frequently amenable to salvage procedures.     

Assessment of Quality of Life in Rectal Cancer with Organ-Preservation Treatment: Are We There yet?

Rectal cancer is a common cancer and shows an increased incidence with older age. Although the gold standard treatment is surgical excision, minimally invasive approaches are increasingly used and organ preservation is becoming a reasonable approach. The conservative treatment approach includes local excision, external beam radiotherapy and brachytherapy. However, these all carry a risk of side-effects. It is crucial to provide patients with information to quantify the improvement or detriment in quality of life with their cancer treatment. This can only be done with patient-reported outcome measures (PROMs) as tools within current and future trials. Colorectal cancer has numerous publications with specific PROMs. However, PROMs reporting in rectal cancer is more sparse; PROMs are generally extrapolated from colorectal cancer. Rectal PROMs trials hold small population samples and PROMs as an end point is scarce. We present a review of recent literature based on the PROMs reporting of quality of life for rectal cancer patients and introduce the CITRuS trial as an innovative feasibility study related to electronic PROMs data collection.     

Total Neoadjuvant Therapy: A Shifting Paradigm in Locally Advanced Rectal Cancer Management

Colorectal carcinoma is the second leading cause of cancer-related deaths in the United States, with rectal cancer accounting for approximately one-third of newly diagnosed cases, thus representing a major socioeconomic health burden. Although minimally invasive procedures (ie, transanal excision) may be appropriate for a subset of patients with small, superficially invasive tumors, a more comprehensive trimodality approach with neoadjuvant chemoradiotherapy, total mesorectal excision, and systemic chemotherapy is recommended for medically operable patients with nonmetastatic, locally advanced rectal cancer (LARC). Although such multimodality therapy has markedly reduced local recurrence rates, there remains an estimated 5-year distant relapse rate of 35%, representing the leading cause of death in this population. This review critically assesses the literature regarding neoadjuvant therapy for LARC, as well as the available evidence to support selective exclusion of individual modalities from the contemporary therapeutic paradigm, including controversies of nonoperative management, selective radiation sparing, and neoadjuvant systemic therapy. Through the review of existing data and the anticipated results of ongoing clinical trials, we outline the pragmatic opportunities for future investigation into questions of efficacy, safety, and ultimate improvements to the current status quo.     

直肠癌新辅助放化疗临床效果的评估

直肠癌是常见的恶性肿瘤，直肠癌发病率近年有上升趋势。全直肠系膜切除术（total mesorectal excision ，TME ）是直肠癌的最主要治疗手段，但局部进展期直肠癌患者术后局部复发率高、保肛率低，新辅助放化疗成为局部晚期直肠癌的优选治疗手段。直肠癌新辅助治疗后的临床效果是临床医生关注的焦点。直肠癌新辅助治疗效果的预测及评估关系到后续治疗方案的选择，影响患者的生存期及生活质量。      

Radiation Therapy for Rectal Cancer: Executive Summary of an ASTRO Clinical Practice Guideline

PurposeThis guideline reviews the evidence and provides recommendations for the indications and appropriate technique and dose of neoadjuvant radiation therapy (RT) in the treatment of localized rectal cancer.MethodsThe American Society for Radiation Oncology convened a task force to address 4 key questions focused on the use of RT in preoperative management of operable rectal cancer. These questions included the indications for neoadjuvant RT, identification of appropriate neoadjuvant regimens, indications for consideration of a nonoperative or local excision approach after chemoradiation, and appropriate treatment volumes and techniques. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength.ResultsNeoadjuvant RT is recommended for patients with stage II-III rectal cancer, with either conventional fractionation with concurrent 5-FU or capecitabine or short-course RT. RT should be performed preoperatively rather than postoperatively. Omission of preoperative RT is conditionally recommended in selected patients with lower risk of locoregional recurrence. Addition of chemotherapy before or after chemoradiation or after short-course RT is conditionally recommended. Nonoperative management is conditionally recommended if a clinical complete response is achieved after neoadjuvant treatment in selected patients. Inclusion of the rectum and mesorectal, presacral, internal iliac, and obturator nodes in the clinical treatment volume is recommended. In addition, inclusion of external iliac nodes is conditionally recommended in patients with tumors invading an anterior organ or structure, and inclusion of inguinal and external iliac nodes is conditionally recommended in patients with tumors involving the anal canal.ConclusionsBased on currently published data, the American Society for Radiation Oncology task force has proposed evidence-based recommendations regarding the use of RT for rectal cancer. Future studies will look to further personalize treatment recommendations to optimize treatment outcomes and quality of life.     

Laparoscopic intersphincteric resection for low rectal cancer

The goal of this review is to outline some of the important surgical issues surrounding the management of patients with low rectal cancer submitted to laparoscopic intersphincteric resection (ISR). Surgery for rectal cancer continues to develop towards the ultimate goals of improved local control and overall survival, maintaining quality of life, and preserving sphincter, genitourinary, and sexual function. Nevertheless, all progress in the development of oncologic therapy (i.e., radiation and chemotherapy), radical surgical removal of the tumour is the only chance for permanent cure of rectal cancer. Beside this main objective, the preservation of faecal continence is the second-most important goal to reach an acceptable quality of life with preservation of sphincter function. Information concerning the depth of tumour penetration through the rectal wall, lymph node involvement, and presence of distant metastatic disease is of crucial importance when planning a curative rectal cancer resection. Preoperative staging is used to determine the indication for neoadjuvant therapy as well as the indication for local excision versus radical cancer resection. In appropriate patients, minimally invasive procedures, such as local excision, TEM, and laparoscopic resection with ISR allow for improved patient comfort, shorter hospital stays, and earlier return to preoperative activity level. Data from small, non-randomized studies evaluating laparoscopic ISR suggest that this procedure is feasible by experienced surgeons. A literature search identified five studies [Uchikoshi F, Nishida T, Ueshima S, Nakahara M, Matsuda H. Laparoscope-assisted anal sphincter-preserving operation preceded by transanal procedure. Tech Coloprocto 2006;10:5-9; Bretagnol F, Rullier E, Couderc P, Rullier A, Saric J. Technical and oncological feasibility of laparoscopic total mesorectal excision with pouch coloanal anastomosis for rectal cancer. Colorectal Disease 2003;5:451-3; Rullier E, Sa Cunha A, Couderc P, Rullier A, Gontier R, Saric J. Laparoscopic intersphincteric resection with coloplasty and coloanal anastomosis for mid and low rectal cancer. British Journal of Surgery 2003;90:445-51; Watanabe M, Teramoto T, Hasegawa H, Kitajima M. Laparoscopic ultralow anterior resection combined with per anum intersphincteric rectal dissection for lower rectal cancer. Diseases of the Colon and Rectum 2000;43(Suppl. 10):S94-7; Miyajima N, Yamakawa T. Laparoscopic surgery for early rectal carcinoma. Nippon Geka Gakkai Zasshi 1999;100:801-5]. The aim was to find those studies that documented potential clinical application of laparoscopic ISR. These studies concluded that a laparoscopic approach can be considered in most patients with low rectal cancer in which laparoscopic ISR represents a feasible alternative to conventional open surgery. Hopefully, randomized controlled trials, which utilize these alternative procedures, will in future determine the results of laparoscopic ISR in terms of sphincter function, faecal continence, disease free and overall survival. The reviewed studies concluded that high quality and less invasive surgery could be achieved if ISR and laparoscopic surgery were combined.     

Neoadjuvant Therapy for Locally Advanced Rectal Cancer: Recent Advances and Ongoing Challenges

Locally advanced rectal cancer has a rising global incidence. Over the last 4 decades, advances first in surgery and later in radiotherapy and chemoradiotherapy have improved outcomes, particularly with regard to local recurrence. Unfortunately, distant metastases remain a significant problem. In clinical trials of patients with stage II and III disease, distant relapse occurs in 25% to 30% of patients regardless of the treatment approach. Recent phase 3 trials have therefore focused on intensification of systemic therapy for localized disease, with an aim of reducing the distant relapse rate. Early results of trials of total neoadjuvant therapy with combination systemic therapy provided in the neoadjuvant setting are promising; for the first time, a significant improvement in the rate of distant relapse has been noted. Longer-term follow-up is eagerly awaited. On the other hand, trimodal therapy with chemotherapy, radiotherapy, and surgery is toxic. Several trials are currently assessing the feasibility of a watch-and-wait approach, omitting surgery in those with complete response to neoadjuvant treatment, in an attempt to reduce the burden of treatment on patients. The future for rectal cancer patients is likely to be highly personalized, with more intense approaches for high-risk patients and omission of unnecessary therapy for those whose disease responds well to initial treatment. Biomarkers such as circulating tumor DNA will help to more accurately stratify patients into risk groups. Improvements in survival and quality of life are expected as the results of ongoing research become available throughout the next decade.     

Controversies in the multimodality management of locally advanced rectal cancer

Neoadjuvant radiotherapy previous to radical surgery, both as short-course radiotherapy and as long-course radiotherapy combined with 5-FU-based chemotherapy (LCRCT), is routinely used in the management of locally advanced rectal cancer, with consistent benefits in the reduction in the local relapse risk. Unfortunately, survival benefits have been elusive to demonstrate with this approach, especially in the setting of radical surgery in the form of total mesorectal excision (TME). Concerns about over-treating early-stage patients and about the possible long-term side effects have also cast more doubts in a blanket approach of treating all patients with neoadjuvant radiotherapy, especially with LCRCT. In this review of selected controversial topics in locally advanced rectal cancer, we examine the benefits and drawbacks for the use of both neoadjuvant approaches in the TME era, the role of the intensification of the neoadjuvant regimens with new chemotherapy agents and modifications of the radiotherapy regimen, the usefulness of adjuvant chemotherapy, especially after LCRCT and surgery, and the management of elderly and/or frail patients. Finally, we offer some future perspectives in the management of these patients.     

Rectal cancer: Maximizing local control and minimizing toxicity

Adoption of multimodality treatment approach for rectal cancer has resulted in significant improvements in oncologic outcomes. The roles of chemotherapy, radiation, and surgery in rectal cancer treatment are continuously evolving with the goal of achieving the best possible oncologic and functional outcome while minimizing treatment toxicity. The aim of this review is to summarize the most recent trials focusing on organ-sparing treatment strategies and the optimal selection of patients for neoadjuvant radiation therapy.     

Novel Radiation Approaches for the Treatment of Rectal Cancer: Where Are We Now?

Over the past decade, significant strides have been made in improving local control for stage II and III rectal cancer, including the use of neoadjuvant chemoradiation and total mesorectal excision. These advancements have led to a remarkable 10-year local failure rate of just 7.1 %. This has come, however, at the cost of moderate treatment-related morbidity, emphasizing a need for further refinement of management strategies. This article will explore recent innovations and novel approaches involving radiation therapy to address these issues, including the use of intensity-modulated radiation therapy, avoidance of radical resection with the use of chemoradiation alone, total neoadjuvant chemotherapy with the selective use of chemoradiation, and the use of local excision approaches following neoadjuvant treatment. Although many of these novel strategies appear promising, data from prospective randomized trials will be necessary before implementation into standard practice.