Neoadjuvant chemoradiotherapy for locally advanced rectal cancer: The debate continues

Rectal carcinoma represents the 30% of all colorectal cancers, with about 40000 new cases/years. In the past two decades, the management of rectal cancer has made important progress, highlighting the main role of a multimodality strategy approach, combining surgery, radiation therapy and chemotherapy. Nowadays, surgery remains the primary treatment and neo-adjuvant chemoradiotherapy, based on fluoropyrimidine (5-FU) continuous infusion, is considered the standard in locally advanced rectal carcinoma. The aim is to reduce the incidence of local recurrence and to perform a conservative surgery. To improve these purposes different drugs combination have been tested in the neo-adjuvant setting. At American Society of Clinical Oncology 2014 an important abstract was presented focusing on the role of adding oxaliplatin to concomitant treatment, in patients with locally advanced rectal carcinoma. Rodel et al reported on the CAO/ARO/AIO-04 randomized phase III trial that compared standard treatment with 5-FU and radiation therapy, to oxaliplatin plus 5-FU in association with radiation therapy. The addition of oxaliplatin to the neo-adjuvant treatment has been shown to improve disease-free survival from 71.2% to 75.9% (P = 0.03). This editorial was planned to clarify the optimal treatment in patients with locally advanced rectal cancer, considering the results from CAO/ARO/AIO-04 study.     

Current debate in the oncologic management of rectal cancer

Despite the considerable amount of research in the field, the management of locally advanced rectal cancer remains a subject to debate. To date, effective treatment centers on surgical resection with the standard approach of total mesorectal resection. Radiation therapy and chemotherapy have been incorporated in order to decrease local and systemic recurrence. While it is accepted that a multimodality treatment regimen is indicated, there remains significant debate for how best to accomplish this in regards to order, dosing, and choice of agents. Preoperative radiation is the standard of care, yet remains debated with the option for chemoradiation, short course radiation, and even ongoing studies looking at the possibility of leaving radiation out altogether. Chemotherapy was traditionally incorporated in the adjuvant setting, but recent reports suggest the possibility of improved efficacy and tolerance when given upfront. In this review, the major studies in the management of locally advanced rectal cancer will be discussed. In addition, future directions will be considered such as the role of immunotherapy and ongoing trials looking at timing of chemotherapy, inclusion of radiation, and non-operative management.     

The metastasis of rectal cancer

Eight hundred and eighty-six cases of rectal cancer diagnosed and reported to the National Cancer Registry in 1980 were submitted to obduction. Metastases were identified in 46.8%. Liver, lung and bones were affected in 38.7%, 16.1 and 3.5% of cases, respectively. Pattern of metastatic spread was determined by histology, with adenocarcinoma giving rise to blood-borne metastases, mucinous adenocarcinoma producing mostly lymphogenic metastases and signet-ring cell carcinoma spreading in either way. Isolated liver involvement was established in 9% of patients showing liver metastases at radical surgery. The parameter reached 22% when cases of presacral recurrence were excluded. A histologically oriented scheme is suggested to assure complete diagnostic coverage of metastases and to develop a concept for the treatment of liver secondaries. Targeted intraperitoneal and endolymphatic application of cytotoxic agents for the treatment of liver metastases aimed at reduction of extrahepatic dissemination is discussed.     

The initial forms of rectal cancer

The paper discusses the tumor characteristics and long-term results of treatment of 6875 cases of rectal cancer admitted to oncological institutions of the USSR within 1968-1980. Stage I-IIa ("minimal") tumors were detected in 9.4% of patients. Organ-saving procedures (local excision included) were performed in 57%. Five-year actuarial survival following surgery was 63% according to the All-Union Center for Research on Effectiveness of Cancer Treatment and 74%--according to the N. N. Petrov Research Institute of Oncology data.     

The role of radiotherapy in rectal cancer

In Europe, short-term radiotherapy is increasingly used in the primary management of rectal cancer. In the United States, postoperative chemoradiotherapy is the standard treatment of choice. The rationale and indications for radiotherapy and possible combinations with chemotherapy are discussed and an overview of all of the randomised trials containing radiotherapy as one randomisation arm is given. Three major indications for radiotherapy can be identified: the reduction of local recurrences in mobile rectal cancer, downstaging of the tumour in primary irresectable tumours and downsizing of low-lying tumours in attempts to more frequently perform a sphincter-saving procedure. For reduction of local recurrences, radiotherapy can be given either pre- or postoperatively, although preoperative therapy is more dose-efficient. Short-term preoperative radiotherapy reduces the number of recurrences and improves survival. Improved survival is also reported after postoperative radiotherapy in combination with chemotherapy, however, the relevance of the radiotherapy component is discussed. Although the debate about radiotherapy is still ongoing, we strongly believe that the results demonstrate that short-term preoperative radiotherapy is the treatment of choice for resectable rectal cancer.     

The management of rectal cancer in the elderly

INTRODUCTION: The majority of patients with rectal cancer are elderly. Due to the increasingly aging population the number of people with colorectal cancer is increasing. As medical advances in the areas of local therapy, radiation therapy, and surgical technique, such as, laparoscopy are made more elderly patients are offered various types of treatment for rectal cancer. As the number of treatment options increase, the debate on how to treat elderly patients' with rectal cancer intensifies. METHODS: A Medline search using "rectal cancer," "elderly," "local therapy," "radical surgery," and "radiation therapy" as key words was performed for English-language articles. Further references were obtained through cross-referencing the bibliography cited in each work. DISCUSSION: Numerous treatment options exists for elderly patients with rectal cancer. These range from transanal local excision to radical surgery. The best treatment option for a certain elderly patient is multifactorial and includes tumor stage, operative curability, preoperative functioning of the patient, patient comorbidities, quality of life goals, and patient preference. CONCLUSION: Age, taken as an independent variable, is not a contraindication to any specific type of therapy, including radical surgery with primary anastomsis. Patients' who meet the criteria for local resection should undergo this procedure. However, for tumors which are not amenable to local resection, these patients should be considered for radical surgery if this provides the best chance for cure. Elderly patients who can tolerate a major operation, and have good preoperative sphincter function should undergo a resection with primary anastomosis.     

直肠癌术后并发症的防治

目的探讨临床工作中直肠癌术后并发症的防治方法。方法136例手术治疗直肠癌患者,统计其术后并发症的发生情况。结果18例发生并发症。其中15例存活,包括骶前大出血3例,单侧输尿管损伤2例,后尿道损伤1例,早期粘连性肠梗阻2例,结肠旁沟疝1例,切口裂开3例,人工肛门狭窄2例,吻合口瘘1例,上述并发症均经手术或相应处理治愈;3例死亡,包括术后发生多器官功能衰竭抢救无效死亡2例,肺部感染死亡1例。结论直肠癌术后并发症经相应处理,预后良好。     

The importance of MRI for rectal cancer evaluation

Magnetic resonance imaging (MRI) has gained increasing importance in the management of rectal cancer over the last two decades. The role of MRI in patients with rectal cancer has expanded beyond the tumor-node-metastasis (TNM) system in both staging and restaging scenarios and has contributed to identifying “high” and “low” risk features that can be used to tailor and personalize patient treatment; for instance, selecting the patients for neoadjuvant chemoradiation (NCRT) before the total mesorectal excision (TME) surgery based on risk of recurrence. Among those features, the status of the circumferential resection margin (CRM), extramural vascular invasion (EMVI), and tumor deposits (TD) have stood out. Moreover, MRI also has played a role in surgical planning, especially when the tumor is located in the low rectum, when the relationship between tumor and the anal canal is important to choose the best surgical approach, and in cases of locally advanced or recurrent tumors invading adjacent pelvic organs that may require more complex surgeries such as pelvic exenteration. As approaches using organ preservation emerge, including transanal local excision and “watch-and-wait”, MRI may help in the patient selection for those treatments, follow up, and detection of tumor regrowth. Additionally, potential MRI-based prognostic and predictive biomarkers, such as quantitative and semi-quantitative metrics derived from functional sequences like diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE), and radiomics, are under investigation. This review provides an overview of the current role of MRI in rectal cancer in staging and restaging and highlights the main areas under investigation and future perspectives.     

The current landscape of locally advanced rectal cancer

Postoperative adjuvant chemoradiotherapy was recommended as the standard treatment for patients with rectal cancer because it reduces local recurrence. This paradigm shifted with the use of neoadjuvant chemoradiotherapy, which not only reduces local recurrence but also improves sphincter preservation and surgical outcomes. However, the treatment of rectal carcinoma remains complicated. The accuracy of tumor staging can be compromised depending on the imaging modality used. The addition of modern chemotherapeutics and biologics to 5-fluorouracil as radiation sensitizers is questionable. Oxaliplatin as a radiation sensitizer has minimal effects on the pathologic complete response, but improves the radiographical response at the expense of an increased risk of toxicities. The role of biologics in addition to radiation therapy continues to be explored. Attention has focused on improving diagnostic imaging, radiation oncology, and surgical techniques, treatment regimens, and on exploring a role of molecular markers for patients with rectal cancers. We review the pivotal trials that have led to the current treatment paradigm for locally advanced rectal cancer and discuss novel methodologies that are being developed for the treatment of this prevalent malignancy.     

Prediction in rectal cancer

The treatment of rectal cancer largely depends on disease stage at diagnosis, based on which patients can be classified as low, intermediate, or high risk. Prognostic and predictive markers, specific to each risk category, can be applied for optimal risk classification and subsequent treatment allocation. These markers are either histopathological, determined with imaging, or have a biomolecular background. This review provides an overview of the current status of treatment options and the use of prognostic and predictive markers in each risk category. An effort was made to identify those markers that are currently lacking in, but have the potential to improve, the clinical decision process by discussing the data from recent studies aimed at the development of new prognostic and predictive markers. At this moment, none of the markers studied has been proven to be of significant, independent value, justifying implementation in daily clinical practice. However, recent developments in imaging techniques and biomolecular research do show great potential.     

Genetics of rectal cancer

Two operational subdivisions of hereditary colorectal cancer susceptibility are those with and those without premalignant adenomatous colonic polyp expression. In both of these subdivisions, reliable biomarkers of gene carriage would be of value in patient management as we have previously emphasized. Consideration must also be given to the familial (hereditary) occurrence of inflammatory bowel diseases associating with colorectal cancer susceptibility. The occurrence of rectal cancers should therefore alert the physician to investigate the possibility of a significant family medical history in order to fully elucidate the genetic heterogeneity of susceptibility to this disease. Clinicians should also be alert to the possibility of extracolonic malignancies where probable genetic colorectal cancer susceptibility is evident. Whenever possible, all potential biomarkers should be investigated to aid in definition of genetic heterogeneity.     

Laparoscopy for rectal cancer

Several large case series and single-institution trials have shown that laparoscopy is feasible for rectal cancer. Pending the results of the UK CLASICC, COLOR II, Japanese JCOG 0404, and ACOSOG Z6051 trials, the oncologic and long-term safety of laparoscopic rectal cancer surgery is unclear and the technique is best used at centers that can effectively collect and analyze outcomes data. Robotic and endoluminal techniques may change our approach to the treatment of rectal cancer in the future. Training, credentialing, and quality control are important considerations as new and innovative surgical treatments for rectal cancer are developed.     

Imaging of rectal cancer

Radiologic evaluation of rectal cancer is invaluable in aiding the surgeon, gastroenterologist, and oncologist in the initial and follow-up management of patients with this malignancy. This review highlights recent developments in computed tomography; ultrasonographic, metabolic, and magnetic resonance imaging of rectal cancer; its clinical ramifications; and the direction of future efforts.     

Chemotherapy and rectal cancer

Chemotherapy does not increase the survival time of patients treated for rectal cancer. Chemotherapy given concomitantly to radiotherapy and combined before or after radiation significantly reduces the risk of local recurrence. The sterilization of the tumour (complete pathological response) by chemotherapy is a favourable prognostic factor. New trials on optimisation of pathological complete response rates are based on using drugs effective on metastatic colorectal cancer, given prior to chemoradiotherapy and followed by a resection at least 8 weeks after the end of the radiotherapy. The level of evidence for postoperative chemotherapy is low due to lack of specific study. The indication of postoperative chemotherapy depends on the disease extent after preoperative treatment.     

MicroRNA in rectal cancer

In rectal cancer, one of the most common cancers worldwide, the proper staging of the disease determines the subsequent therapy. For those with locally advanced rectal cancer, a neoadjuvant chemoradiotherapy (CRT) is recommended before any surgery. However, response to CRT ranges from complete response (responders) to complete resistance (non-responders). To date we are not able to separate in advance the first group from the second, due to the absence of a valid biomarker. Therefore all patients receive the same therapy regardless of whether they reap benefits. On the other hand almost all patients receive a surgical resection after the CRT, although a watch-and-wait procedure or an endoscopic resection might be sufficient for those who responded well to the CRT. Being highly conserved regulators of gene expression, microRNAs (miRNAs) seem to be promising candidates for biomarkers. Many studies have been analyzing the miRNAs expressed in rectal cancer tissue to determine a specific miRNA profile for the ailment. Unfortunately, there is only a small overlap of identified miRNAs between different studies, posing the question as to whether different methods or differences in tissue storage may contribute to that fact or if the results simply are not reproducible, due to unknown factors with undetected influences on miRNA expression. Other studies sought to find miRNAs which correlate to clinical parameters (tumor grade, nodal stage, metastasis, survival) and therapy response. Although several miRNAs seem to have an impact on the response to CRT or might predict nodal stage, there is still only little overlap between different studies. We here aimed to summarize the current literature on rectal cancer and miRNA expression with respect to the different relevant clinical parameters.