Adjuvant External Beam and Intraoperative Radiation Therapy in Rectal Cancer

The use of radical surgery has maximized local control, sphincter preservation, and overall survival in patients with rectal cancer. Despite the advances in surgical techniques, local recurrence still remains a problem. Following potentially curative surgery, the incidence of local recurrence inpatients with stages B2,C disease varies from 15% to 65%. There are four major approaches in which radiation therapy (RT) has been used in the adjuvant treatment of rectal cancer. These include postoperative RT ± chemotherapy, preoperative RT ± chemotherapy, both pre-and postoperative RT (sandwich technique), and intraoperative RT in conjunction with preoperative external beam RT. In patients with resectable rectal cancer, adjuvant RT has been shown to decrease the incidence of local recurrence and, in some series, may influence survival rates. In patients with locally advanced, unresectable, or recurrent rectal cancer, the use of preoperative radiation therapy, attempted surgical resection, and intraoperative RT further enhances local control.     

Rectal cancer radiotherapy

Adjuvant therapy for rectal cancer has undergone significant modifications over the past 30 years, including the addition of radiation therapy, significant improvements in surgical technique, and the administration of systemic therapy. Historically, curative resection commonly required an abdominoperineal resection and permanent colostomy. Adjuvant radiation therapy not only improved local control and overall survival, but allowed the opportunity for sphincter-preserving resections in patients with adequate sphincter function and tumors located approximately 1-2 cm from the dentate line. Local recurrence, a primary mode of failure in rectal cancer, has been improved by the development of the total mesorectal excision, with en-bloc resection of the rectum and its lymphovascular mesentery, the mesorectum. Removing micrometastatic disease within the mesorectum has also enhanced sphincter preservation without compromising local control or survival. Locoregional recurrence has remained a significant issue for patients with locally advanced disease (node positive or high T stage). Multiple studies have shown that the addition of chemotherapy further improves outcomes versus surgery alone or combined surgery and radiation, due both to the radiosensitizing properties of certain systemic agents as well as to the direct cytotoxic effect of the chemotherapy on micrometastatic disease. Adjuvant concurrent chemoirradiation in locally advanced rectal cancer confers a significant improvement in local control and overall survival compared with either modality alone. The future direction of treatment for rectal cancer will certainly consist of improved imaging and other diagnostic techniques to determine more accurately the need for adjuvant therapy. Multimodality therapy with radiotherapy administered in combination with systemic and biologic agents as radiation sensitizers is currently under investigation and may allow for improved local control and perhaps allow for minimizing the extent of surgery in selected situations.     

Adjuvant and neoadjuvant chemoradiation therapy for primary colorectal cancer

The management of rectal cancer presents substantial challenges. Patients with T3 and/or node-positive rectal cancers are at high risk for local failure and distant metastases (DM). Adjuvant radiation has been shown to decrease local recurrence (LR) rates; however, this local therapy has not been demonstrated to improve survival when compared to surgery alone. In several prospective randomized trials adjuvant chemoradiation with 5-fluorouracil-(5-FU)-based chemotherapy improved LR rates, DM rates, and overall survival (OS). The optimal chemotherapeutic regimen has not been determined; however, studies comparing standard IV bolus 5-FU administration with continuous infusion (CI) 5-FU demonstrated that CI administration was superior. Preoperative therapy has potential advantages over adjuvant therapy such as less acute bowel toxicity and improved sphincter preservation. Preoperative chemoradiation has been shown in several studies to improve LR rates and OS when compared to surgery alone. Our current approach to patients with resectable T3 or N1 cancer in the distal two-thirds of the rectum on preoperative staging is preoperative chemoradiation with planned postoperative chemotherapy. This regimen offers the best chance for local control and disease-free survival while potentially downstaging the tumor and improving sphincter preservation.     

Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer: A systematic review and meta‐analysis

Combining chemotherapy with preoperative radiotherapy (RT) has a sound radiobiological rationale. We performed a systematic review and meta‐analysis of trials comparing preoperative RT with preoperative chemoradiation (CRT) in rectal cancer patients. The Cochrane Central Register of Controlled Trials, Web of Science, Embase and Medline (Pubmed) were searched from 1975 until June 2007. Dichotomous parameters were summarized using the odds ratio while time to event data were analyzed using the pooled hazard ratio for death. From the primary search result of 324 trials, 4 relevant randomized trials were identified. The addition of chemotherapy significantly increased grade III and IV acute toxicity (p = 0.002) while no differences were observed in postoperative morbidity or mortality. Preoperative CRT significantly increased the rate of pathological complete response (p < 0.001) although this did not translate into a higher sphincter preservation rate (p = 0.29). The local recurrence rate was significantly lower in the CRT group (p < 0.001). No statistically significant differences were observed in disease free survival (p = 0.89) or overall survival (p = 0.79). Compared to preoperative RT alone, preoperative CRT improves local control in rectal cancer but is associated with a more pronounced treatment related toxicity. The addition of chemotherapy does not benefit sphincter preservation rate or long‐term survival. Future trials should address improvements in the rate of distant metastasis and overall survival by incorporating more active chemotherapy. © 2008 UICC     

Alternative clinical end points in rectal cancer—are we getting closer?

BACKGROUND: In rectal cancer a high risk of local recurrence has been reported for patients treated by surgery alone. It is also recognised that 20%-40% of rectal cancer patients continue to develop distant metastases and die, even when a very low risk of local recurrence has been achieved with the use of preoperative radiotherapy and total mesorectal excision (TME). Hence, the current design of randomised trials in rectal cancer continues to use the standard end points of local control and survival. This strategy is time-consuming. The recently published EORTC 22921 trial, which compared radiotherapy with chemoradiotherapy and tested the role of postoperative adjuvant chemotherapy, has taken 14 years from planning to results. The aim of this review was to use the evidence from both phase II and phase III trials to provide a comprehensive survey of alternative clinical trial end points in rectal cancer, where preoperative chemoradiation has now become the standard treatment. We describe their strengths and weaknesses. Some are clearly defined, easy to assess and can be obtained early, because surgical resection usually takes place within 6-8 weeks of the completion of treatment. Some pathological response end points reflect biological activity, although their effect on survival has yet to be validated in randomised controlled trials. We will propose measurement and analytical techniques for minimising bias and intra- and inter-observer variability of the non-validated end points in the hope of basing these judgements on as firm a ground as possible. METHODS: A literature search identified both randomised and non-randomised trials of preoperative radiation therapy (RT) and chemoradiation therapy (CRT) in rectal cancer from 1993 to 2005. The aim was to find those studies that documented potential alternative end points. RESULTS: Pathological parameters have been used as early end points to compare studies of preoperative radiotherapy or chemoradiation. In the light of the German CAO/ARO/AIO-94 study, which demonstrated an improved therapeutic ratio for preoperative treatment, enthusiasm for preoperative chemoradiation in the management of rectal cancer is increasing. Current evidence cannot indicate whether the degree of response to chemoradiation (e.g. complete pathological response; downsizing the primary tumour; sterilizing the regional nodes; tumour regression grades or residual cell density) or the achievement of a curative resection (CRM/R0 resection) is the best early clinical end point. Problems with these end points include lack of structured measurement and analysis techniques to control for intra- and inter-observer variation and lack of validation as surrogates for long-term clinical end points such as local control and survival. However, retrospective studies in rectal cancer have confirmed a strong association between the presence of microscopic tumour cells within 1 mm of the CRM and increased risks of both local recurrence and distant metastases. Further end points of current clinical relevance for which adequate methodologies for assessment are lacking include sphincter sparing end points, and assessment of long-term toxicities, ano-rectal function and their specific impact on quality of life. Recommendations are made as to the most appropriate information, which should be documented in future trials. CONCLUSIONS: Pathological complete response following preoperative chemoradiation does not reliably predict late outcome. There are other events not mediated through this end point and there are also unintended effects (often an excess of non-cancer related deaths). Disease-free survival currently remains the best (because it is relatively quick) primary end point in designing randomised phase III studies of preoperative chemoradiation in rectal cancer, although it is necessary to control for postoperative adjuvant chemotherapy. However, the CRM status can substantially account for effects on disease-free and overall survival after chemoradiation, radiation or surgery alone. Hopefully, randomised controlled trials, which utilise these alternative clinical end points, will in future determine the precise percentages of the effect of different chemoradiation schedules on disease-free and overall survival.     

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.     

Neoadjuvant therapy before surgical treatment

Neoadjuvant treatment in terms of preoperative radiotherapy reduces local recurrence in rectal cancer, but this improvement has little if any impact on overall survival. Currently performed optimal quality-controlled total mesorectal excision (TME) surgery for patients in the trial setting can be associated with very low local recurrence rates of less than 10% whether the patients receive radiotherapy or not. Hence metastatic disease is now the predominant issue. The concept of neoadjuvant chemotherapy (NACT) is a potentially attractive additional or alternative strategy to radiotherapy to deal with metastases. However, randomised phase III trials, evaluating the addition of oxaliplatin at low doses plus preoperative fluoropyrimidine-based chemoradiotherapy (CRT), have in the main failed to show a significant improvement on early pathological response, with the exception of the German CAO/ARO/AIO-04 study. The integration of biologically targeted agents into preoperative CRT has also not fulfilled expectations. The addition of cetuximab appears to achieve relatively low rates of pathological complete responses, and the addition of bevacizumab has raised concerns for excess surgical morbidity. As an alternative to concurrent chemoradiation (which delivers only 5–6 weeks of chemotherapy), potential options include an induction component of 6–12 weeks of NACT prior to radiotherapy or chemoradiation, or the addition of chemotherapy after short-course preoperative radiotherapy (SCPRT) or chemoradiation (defined as consolidation chemotherapy) which utilises the “dead space” of the interval between the end of chemoradiation and surgery, or delivering chemotherapy alone without any radiotherapy.     

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.     

Have the changes in treatment of rectal cancer made a significant difference to our patients?

The treatment for patients with locally advanced, resectable rectal cancer has evolved over the years. Various combinations and sequences of chemotherapy, radiation therapy, and total mesorectal excision (TME)-based surgery are the mainstay of current therapy. Preoperative combined chemoradiation, followed by surgery, is now the preferred treatment strategy, with the majority of patients receiving either infusion fluorouracil (5-FU) or capecitabine (Xeloda) with radiation. Clinical trials with oxaliplatin (Eloxatin)-based neoadjuvant chemoradiation have not shown improvement in the pathologic complete response rate (pCR) compared with 5-FU; however, final data addressing local recurrence rates and disease-free survival are pending.The use of adjuvant chemotherapy following preoperative chemoradiation and surgery has not been optimally defined. Some studies have shown that patients who obtained significant pathologic downstaging after chemoradiation and surgery have improved survival with the use of adjuvant chemotherapy. Since FOLFOX (folinic acid, 5-FU, and oxaliplatin) is the preferred adjuvant chemotherapy regimen for stage III colon cancer based on randomized clinical trial results, FOLFOX is also recommended for rectal cancer patients as an adjuvant therapy approach.     

Adjuvant therapy of rectal cancer.

For patients with clinically resectable stage T3 and/or node-positive rectal cancer, adjuvant radiation therapy decreases the rate of local recurrence. The addition of systemic chemotherapy further enhances local control and improves survival. Compared with postoperative therapy, preoperative treatment may have less toxicity and may increase the chance of sphincter preservation. The acute and long-term toxicity of pelvic radiation is related to the technique of delivery. Therefore, appropriate conventional radiation doses and techniques are recommended. Randomized trials comparing preoperative and postoperative combined modality therapy are in progress.     

Treatment of High Rectal Cancers: Do We Need Radiation?

Before total mesorectal excision (TME) and radiation therapy/chemoradiation therapy (RT/CRT) were widely adopted in the treatment of rectal cancer, surgery alone was the standard. Therapies have since evolved to neoadjuvant RT or CRT followed by TME as the established paradigm for locally advanced disease. More recently, issues of toxicity and systemic metastasis have risen to the forefront, prompting the exploration of individualized strategies in an attempt to maximize potential cure and local control yet minimize late toxicities. In this article, we will focus on the treatment of high rectal cancers, exploring the specific role of pelvic radiotherapy in this setting.     

Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with capecitabine for locally advanced rectal cancer

BACKGROUND:

Although many trials have shown the efficacy of preoperative chemoradiotherapy (CRT) or postoperative CRT compared with surgery alone, the optimal sequence of radiotherapy and surgery is unclear. The authors reported the final results of this single institution prospective randomized phase 3 trial comparing preoperative CRT with postoperative CRT using capecitabine in survival, local control, sphincter preservation, and toxicity for the treatment of locally advanced rectal cancer.

METHODS:

Patients with locally advanced rectal cancer (cT3, potentially resectable cT4 or N+) were randomly assigned to receive preoperative or postoperative CRT. CRT consisted of 50 Gy/25 fractions and concurrent capecitabine (1,650 mg/m²/day). Total mesorectal excision was performed.

RESULTS:

From March 2004 to April 2006, 240 patients were enrolled. Clinical characteristics were well balanced between both arms, except for more low‐lying (<5 cm from anal verge) tumors in the preoperative CRT arm (60% vs 46%, P = .041). After a median follow‐up time of 52 months, the 3‐ and 5‐year disease‐free survival, overall survival, and cumulative incidence of local recurrence were similar between both arms. However, for the patients with low‐lying tumors, the preoperative CRT arm had a higher rate of sphincter preservation (68% vs 42%, P = .008). Acute and late complication rates were similar between both arms.

CONCLUSIONS:

Although significant benefit of preoperative CRT in local control and survival was not demonstrated, the data showed that increased rate of sphincter preservation was possible in low‐lying tumors without jeopardizing local control and surgical complication by preoperative CRT. Cancer 2011;. © 2011 American Cancer Society.     

Outcomes of patients receiving radiation for carcinoma of the rectum. Results of the 1988-1989 patterns of care study

BACKGROUND: Clinical trials of surgical adjuvant treatment for patients with rectal carcinoma (RC) indicate that postoperative radiation therapy with concurrent chemotherapy (CRT) is superior to postoperative radiation alone (RT) or surgery alone. Whether preoperative treatment is superior to postoperative treatment is controversial. This Patterns of Care Study (PCS) surveyed patients with RC treated with radiation during the years 1988-1989 to determine the national practice standards and outcomes and to compare these results with those of clinical trials. METHODS: A national survey of 73 institutions was conducted using 2-stage cluster sampling, and specific information on 406 patients with RC who received radiation at 69 facilities was collected. Follow-up information on 215 patients was subsequently collected by mail survey. There were no significant differences between the known prognostic indicators or treatment-related variables for patients for whom follow-up was available compared with the variables for patients for whom follow-up was not available. Follow-up ranged from 0 to 8.44 years with a median of 4 years. One hundred fifty-four patients (71%) received postoperative treatment, either RT (37%) or CRT (34%); and 40 (18%) received preoperative treatment, either RT (15%) or CRT (3%). Ninety-six patients (45%) received chemotherapy, and for 86% of those patients chemotherapy was administered concurrently with radiation. RESULTS: Survival was stage-dependent (85% Stage I, 69% Stage II, and 54% Stage III at 5 years, P = 0.04). Survival was also substage-dependent, and patients with C(1) cancer had significantly higher 5-year survival than those with C(2)/C(3) cancer (89% vs. 48%, P = 0.008). Local failure was similar for Stage II and Stage III patients (10% vs. 11% at 5 years, respectively). In multivariate analyses, only stage and use of chemotherapy were significant to survival (Stage III vs. Stage I and II, relative risk [RR] = 2.52, and chemotherapy vs. no chemotherapy, RR = 0.46). A significantly higher 5-year survival rate was seen with postoperative CRT than with postoperative RT (69% vs. 50%, P = 0. 011). Preoperative radiation resulted in a significantly higher 5-year survival rate than postoperative radiation (85% vs. 50%, P = 0.0006), but not compared with postoperative CRT. Survival and local failure did not differ according to radiation therapy interruption or the interval between surgery and radiation. CONCLUSIONS: Stage is an important prognostic indicator for survival, and among patients with Stage III malignancies survival in the substage C(1) is significantly higher than in the substages C(2) and C(3). As has been demonstrated in randomized trials, adjuvant postoperative CRT is superior to postoperative RT for patients with RC in this national study. These nationwide results of adjuvant treatment are comparable to those reported in randomized trials. The use of CRT was the only treatment-related factor that resulted in a significant reduction in the risk of death.     

Radiation therapy in the management of rectal cancer

For many years, rectal carcinoma has been treated by surgery alone. However, survival rates have not improved historically and local recurrence remains a problem. Adjuvant radiation therapy does have a role in this disease. While the optimal scheduling and dose are not determined yet, it can certainly prevent local recurrence and potentially increase survival. There are advantages to delivering radiation therapy preoperatively and postoperatively and the combination of low-dose preoperative radiation therapy and postoperative radiation therapy in selected patients ("sandwich" therapy) appears promising. The use of chemotherapy in combination with radiation therapy may further improve survival rates. Care must be taken in patients treated with rectal carcinoma to minimize the normal tissue irradiated to decrease complications and deliver tumoricidal doses to the areas at risk. Techniques are available to both the surgeon and the radiation oncologist to minimize the amount of small bowel irradiated. Radiation therapy also has a role in the treatment of very early rectal cancers as part of a sphincter-saving procedure and in the treatment of advanced or recurrent rectal cancers. In the latter, intraoperative radiation therapy plays an important role in controlling recurrent or residual rectal cancer.     

诱导性同步放化疗治疗侵袭性肺上沟瘤

目的分析同步放化疗(CRT)在NSCLC外科治疗的地位.方法回顾性总结1987～1996年外科手术的30例累及胸顶部的NSCLC,单纯手术组10例,手术+放疗组(RT)9例,含铂方案化疗+放疗组(CRT)11例.结果单纯手术组2、4年生存率分别为30%和20%, RT组为22% 和11%,CRT组为73% 和53%.单因素分析根治性(是与否比较,P=0.027)和诱导性治疗(单纯手术和RT与CRT比较,P=0.0173)是有意义的预后因素.多因素分析仅诱导性治疗,P=0.023 8,是有意义的预后因素.结论与诱导性放疗和单纯手术相比,CRT可提高累及胸顶部的NSCLC患者的生存率.     

Combined modality treatment for rectal cancer

Significant gains have been achieved in the integration of radiation therapy (RT) and chemotherapy with surgery in the management of patients with localized rectal cancer. Treatment combinations of RT and chemotherapy with surgery have evolved to neoadjuvant approaches of these modalities to enhance sphincter preservation, tumor control, and reduction of acute and late treatment-related morbidity. Although 5-fluorouracil (5-FU)-based chemotherapy in combination with RT remains the standard adjuvant therapy for rectal cancer, the integration of novel chemotherapeutic agents and biologic modulators is being actively investigated.     

Utilization of preoperative radiation therapy in the management of rectal cancer: A population-based analysis

PurposePreoperative radiation therapy (RT) improves local control in resectable rectal cancer compared with postoperative RT or surgery alone. Although clinical practice guidelines exist, adherence to recommendations for preoperative RT is unclear. This population-based study examines preoperative RT utilization rates for rectal cancer patients in a Canadian province and investigates factors influencing its usage.Methods and MaterialsBetween 2004 and 2009, all stage II and III rectal cancer patients treated with definitive surgery were identified using the Manitoba Cancer Registry. Patients not receiving resection of the primary tumor, as determined by administrative procedure codes, were excluded. Factors potentially influencing preoperative RT utilization, including age, gender, stage, year of diagnosis, and geographic distance from RT facility, were analyzed using logistic regression analyses. Overall survival outcomes were also examined.ResultsThe registry identified 776 patients meeting the study inclusion criteria. Preoperative RT utilization increased from 3% in 2004 to 41% in 2009. Postoperative RT utilization decreased from 48% to 17% during the same period. Rates of surgery alone remained stable at 40%-50%. Factors influencing preoperative RT utilization were younger age (P < .0001), stage III disease (P = .02), and later year of diagnosis (P < .0001). Elderly patients age 70 years and over were predominantly treated with surgery alone. Actuarial 5-year overall survival for patients receiving preoperative RT postoperative RT, and surgery alone were 80%, 73%, and 58%, respectively.ConclusionsSteadily increasing utilization of preoperative compared with postoperative RT is evident; however, rates of surgery alone remained unchanged. Strategies to improve preoperative RT utilization, particularly among elderly patients, are needed.     

Distal cT2N0 rectal cancer: is there an alternative to abdominoperineal resection?

PURPOSE: Patients with cT2N0 distal rectal cancer do not require adjuvant therapy. However, when a patient refuses an abdominoperineal resection (APR), is there an alternative? The purpose of this trial is to determine whether preoperative external-beam radiation therapy can increase the rate of sphincter preservation for patients with distal cT2N0 adenocarcinoma of the rectum. PATIENTS AND METHODS: Between April 1988 and October 2003, 27 patients with distal rectal adenocarcinoma staged T2 by clinical and/or endorectal ultrasound who were judged by the operating surgeon to require an APR were treated with preoperative pelvic radiation alone (50.4 Gy). Surgery was performed 4 to 7 weeks later. If pathologic positive pelvic nodes were identified, postoperative adjuvant chemotherapy was recommended. The median follow-up was 55 months (range, 9 to 140 months). RESULTS: The pathologic complete response rate was 15% and 78% of patients underwent a sphincter-sparing procedure. The crude incidence of local failure for patients undergoing a sphincter sparing procedure was 10% and the 5-year actuarial incidence was 13%. The actuarial 5-year survival for patients undergoing sphincter preservation was as follows: disease-free, 77%; colostomy-free, 100%; and overall, 85%. Using the Memorial Sloan-Kettering Cancer Center sphincter function score, 54% of those undergoing a sphincter-sparing procedure had good/excellent bowel function at 12 to 24 months after surgery, and 77% had good/excellent function at 24 to 36 months after surgery. CONCLUSION: Our data suggest that for patients with cT2N0 distal rectal cancer who require an APR, preoperative pelvic radiation improves sphincter preservation without an apparent compromise in local control or survival.     

Unique considerations in the patient with rectal cancer

In the past two decades, substantial progress has been made in the adjuvant management of colorectal cancer. Chemotherapy has improved overall survival in patients with node-positive (N+) disease. In contrast with colon cancer, which has a low incidence of local recurrence, patients with rectal cancer have a higher incidence requiring the addition of pelvic radiation therapy (chemoradiation). Patients with rectal cancer have a number of unique management considerations: for example, the role of short-course radiation, whether postoperative adjuvant chemotherapy is necessary for all patients, and if the type of surgery following chemoradiation should be based on the response rate. More accurate imaging techniques and/or molecular markers may help identify patients with positive pelvic nodes to reduce the chance of overtreatment with preoperative therapy. Will more effective systemic agents both improve the results of radiation as well as modify the need for pelvic radiation? This review will address these and other controversies specific to patients with rectal cancer.     

Locally advanced rectal cancer: what is the evidence for induction chemoradiation?

The concept of spatial cooperation in neoadjuvant chemoradiation (CRT) for locally advanced rectal cancer is attractive. Chemotherapy may, as a component of CRT, not only act as a radiosensitizing agent but also potentially eradicate distant micrometastases. Recent trials have demonstrated that the addition of concurrent 5-fluorouracil (5-FU)-based chemotherapy to radiation increases the pathological complete response rate, and reduces local recurrence, but as yet, a survival advantage has not been observed. AIMS: This review aims to examine the evidence for induction CRT in locally advanced rectal cancer. The endpoints of pathological complete response, a negative circumferential margin, sphincter-sparing surgery, local control, disease-free survival (DFS), and overall survival (OS) are examined, as are acute and late morbidity, surgical complications, and late functional results. METHODS: The information to produce this review was compiled by searching PubMed and MEDLINE for English language articles published until April 2007. The search term included "induction, neoadjuvant, chemotherapy, radiotherapy, chemoradiation, combined modality" in association with rectal cancer. CONCLUSIONS: CRT in the European randomized trials of rectal cancer improves tumor downstaging, pathological complete response, and local control over radiotherapy alone, but does not translate into a benefit in terms of longer DFS or OS, or a higher chance of sphincter preservation. Metastatic disease remains a significant problem, which provides a strong rationale for the integration of a second cytotoxic drug, or biologically targeted agents.