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.     

Neoadjuvant therapy of rectal cancer new treatment perspectives

During the past two decades, significant advances have been made in the management of patients with rectal cancer. A number of clinical studies have demonstrated the efficacy of preoperative chemoradiation therapy with 5-fluorouracil (5-FU)-based regimens in decreasing local recurrences and improving survival and the likelihood of sphincter preservation. Although 5-FU has been the standard drug used in combination with radiation therapy for many years, new effective drugs including capecitabine, raltitrexed, irinotecan and oxaliplatin have been recently investigated in combination with radiation therapy in the preoperative setting. In addition, novel targeted biological agents including epidermal growth factor receptor inhibitors and vascular endothelial growth factor inhibitors have been shown to enhance the antitumor effect of both radiation and chemotherapy and are currently being explored in initial clinical trials. In the present review we summarize the results of adjuvant therapy. In addition, we will discuss the recently reported phase I-II trials with new drug plus radiation combinations in the preoperative treatment of patients with rectal cancer.     

Preoperative chemoradiation for locally advanced rectal adenocarcinoma-the University of Florida experience

To evaluate the efficacy of preoperative radiotherapy alone or combine with chemotherapy. Between 1975 to 1997, 318 patients with locally advanced rectal adenocarcinomas were treated with preoperative radiation therapy. Between 1991 and 1997, approximately 60% of patients received fluorouracil (5-FU)-based adjuvant chemotherapy. Patients treated since 1991 had improved downstaging compared with those treated prior to 1991. Patients treated between 1991 and 1997 were also more likely to undergo a sphincter preserving surgical procedure. Preoperative chemoradiation probably results in improved downstaging and survival compared with preoperative irradiation alone.     

Adjuvant radiation therapy of patients with rectal cancer

The standard in rectal cancer has been to add adjuvant radiation therapy to surgery in patients with stage II and III disease. Total mesorectal excision has led to lower local recurrence rates, and, if properly performed, may make adjuvant radiation unnecessary for certain stage II and III patients, such as T3 N0 patients with proximal lesions. There is also debate about the best method of delivering adjuvant radiotherapy. Preoperative radiotherapy at low dose per fraction with concurrent chemotherapy offers the advantages of maximizing sphincter preservation and greater tolerability. However, this will occasionally result in treating patients who are overstaged by ultrasound and may lead to greater postoperative morbidity and mortality than postoperative radiation. Preoperative radiotherapy has stronger data to support a survival advantage when added to surgery than postoperative radiation. Two randomized, phase III European studies may answer the question of which radiation technique is best for the near future. Protracted venous infusion of 5-fluorouracil (5-FU) is the standard method of radiosensitization. However, studies are ongoing using concurrent oxaliplatin, irinotecan, and oral 5-FU prodrugs. For now, we recommend that stage II and III rectal cancer patients receive protracted venous infusion 5-FU concurrent with preoperative radiation.     

Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114.

PURPOSE: The gastrointestinal Intergroup studied postoperative adjuvant chemotherapy and radiation therapy in patients with T3/4 and N+ rectal cancer after potentially curative surgery to try to improve chemotherapy and to determine the risk of systemic and local failure. PATIENTS AND METHODS: All patients had a potentially curative surgical resection and were treated with two cycles of chemotherapy followed by chemoradiation therapy and two additional cycles of chemotherapy. Chemotherapy regimens were bolus fluorouracil (5-FU), 5-FU and leucovorin, 5-FU and levamisole, and 5-FU, leucovorin, and levamisole. Pelvic irradiation was given to a dose of 45 Gy to the whole pelvis and a boost to 50.4 to 54 Gy. RESULTS: One thousand six hundred ninety-five patients were entered and fully assessable, with a median follow-up of 7.4 years. There was no difference in overall survival (OS) or disease-free survival (DFS) by drug regimen. DFS and OS decreased between years 5 and 7 (from 54% to 50% and 64% to 56%, respectively), although recurrence-free rates had only a small decrease. The local recurrence rate was 14% (9% in low-risk [T1 to N2+] and 18% in high-risk patients [T3N+, T4N]). Overall, 7-year survival rates were 70% and 45% for the low-risk and high-risk groups, respectively. Males had a poorer overall survival rate than females. CONCLUSION: There is no advantage to leucovorin- or levamisole-containing regimens over bolus 5-FU alone in the adjuvant treatment of rectal cancer when combined with irradiation. Local and distant recurrence rates are still high, especially in T3N+ and T4 patients, even with full adjuvant chemoradiation therapy.     

直肠癌的辅助放化疗的临床研究

直肠癌是常见的消化道恶性肿瘤，手术是直肠癌的主要治疗手段，放化疗对可手术直肠癌是重要的辅助治疗手段。无论术前或术后放疗均可提高局部控制，术前放疗可增加保肛的机率，放疗的方式以常规分割较佳。术后放疗在中度复发危险的患者中对生存的影响与化疗相似，但需要两者对局控的资料。本文综述的是术前放疗、术后放疔以及术前与术后放疗的比较。     

Adjuvant therapy for colorectal carcinoma

Adjuvant therapy for colorectal carcinoma has been developed over the last two decades. We have reviewed the history of adjuvant chemotherapy for colorectal carcinoma in the United States, Europe and Japan with regard to the rationale of the chemotherapy regimen and the survival benefit for the establishment of a standard regimen. Treatment with 5-fluorouracil (5-FU) and leucovorin (LV) for postoperative adjuvant chemotherapy had an overall survival benefit, compared with surgery alone, in randomized controlled trials in the United States and Europe for Dukes' C colon carcinoma. In contrast, the survival benefit of adjuvant chemotherapy for Dukes' B colon carcinoma and for rectal carcinoma has not yet been established. In Japan, randomized controlled trials have examined combination treatment with mitomycin (MMC) and oral fluoropyrimidines for colorectal carcinoma compared with surgery alone. A meta-analysis indicated that combination treatment with MMC and oral fluoropyrimidines had a survival benefit for colorectal carcinoma. The survival benefit of combination treatment with irinotecan (CPT-11) + 5-FU + LV or uracil + tegaful (UFT) + LV (Orzel) for adjuvant chemotherapy are currently being compared with 5-FU + LV. Meta-analysis revealed a survival benefit at 2-years in the prevention of liver metastasis following intraportal or intraarterial infusion of 5-FU. The survival benefit of preoperative radiotherapy was superior to postoperative radiotherapy for advanced rectal carcinoma in association with the prevention of local recurrence. Clinical trial data suggest that the current standard regimen of adjuvant chemotherapy is a combination of 5-FU and LV for Dukes' C colon carcinoma and that radiotherapy for local control of rectal carcinoma has a survival benefit.     

Preoperative and adjuvant treatment of localized rectal cancer

Although postoperative chemoradiation has a proven role in the treatment of stage II to III localized rectal cancer, recent trials have demonstrated the role of preoperative chemoradiation. A recent randomized trial has shown that preoperative chemoradiation yields higher rates of local control and sphincter preservation and lower rates of toxicity, compared with postoperative chemoradiation. Randomized trials have also shown that preoperative chemoradiation yields higher rates of pathologic complete response and local control, compared with radiotherapy alone. In this article, we review recent trials on preoperative and adjuvant therapy of localized rectal cancer. The roles of newer agents, such as capecitabine, oxaliplatin, and bevacizumab, are also discussed, and other key issues in the treatment of localized rectal cancer are reviewed.     

Phase I study of preoperative radiation therapy with concurrent infusional 5-fluorouracil and oxaliplatin followed by surgery and postoperative 5-fluorouracil plus leucovorin for T3/T4 rectal adenocarcinoma: ECOG E1297

PURPOSE: Oxaliplatin is a platinum analog and radiosensitizer active in colorectal cancer. We performed a Phase I trial to test the safety and preliminary efficacy of adding oxaliplatin to standard preoperative chemoradiation therapy for rectal cancer. METHODS AND MATERIALS: Eligible patients had T3 to T4 rectal adenocarcinoma. Patients received standard-dose radiation (50.4 Gy for 5.5 weeks) with concurrent infused 5-fluorouracil (5-FU) at 200 mg/m2 per day, 7 days per week. Oxaliplatin was given three times at 14-day intervals at 55, 70, or 85 mg/m2 during the 5.5-week radiation period, before resection. Adjuvant therapy consisted of four cycles of 5-FU (500 mg/m2 per week) with leucovorin (500 mg/m2 per week) given every 6 weeks. The main goals were to identify the maximum tolerated dose of oxaliplatin and the dose-limiting toxicities when given with 5-FU and RT. Secondary goals were to determine resectability, pathologic response, sphincter preservation, and overall survival rates. RESULTS: Twenty-one patients were enrolled, 5 at the 55 mg/m2 oxaliplatin dose level, 5 at 70 mg/m2, and 11 at 85 mg/m2. All patients were able to complete the preoperative chemoradiation regimen with no dose adjustments. No dose-limiting toxicities or differences in the type or extent of toxicity were noted among the groups. Nineteen patients underwent surgery (three abdominopelvic resections and 16 low anterior resections), for an 84% sphincter preservation rate. The pathologic complete response rate was 26% (5 patients), and minimal microscopic residual tumor was found in 21% (4 additional patients). CONCLUSIONS: Oxaliplatin was well tolerated at 85 mg/m2 given every 2 weeks in combination with standard preoperative chemoradiation for rectal cancer. The rates of major pathologic response and sphincter preservation are promising.     

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.     

Chemotherapeutic and biologic agents as radiosensitizers in rectal cancer

Over the past 25 years, important advances have been made in the management of patients with resectable rectal cancer. Clinical studies have shown the efficacy of combined chemoradiation therapy in enhancing resectability and sphincter preservation rates, decreasing local recurrence, and improving survival of patients with rectal cancer. Although 5-fluorouracil (5-FU) remains the standard chemotherapeutic agent used concurrently with radiation therapy, newer chemotherapeutic agents including capecitabine, irinotecan, and oxaliplatin have also been studied as radiosensitizers in this setting. Novel targeted biologic agents including celecoxib and bevacizumab are being explored in combination with standard chemotherapy and radiation therapy. In this review, we will discuss the mechanism of action and the key clinical studies of each agent as a radiosensitizer.     

Cisplatin-based combined modality therapy for anal carcinoma: a wider therapeutic index

BACKGROUND: Definitive chemoradiation therapy is the standard of care for anal carcinoma. The chemotherapy regimen comprising 5-fluorouracil (5-FU) and mitomycin-C is the most commonly used among patients with anal carcinoma but causes well documented toxicities. In the current study, the authors evaluated their experience in treating anal carcinoma with combined modality therapy using cisplatin and 5-FU. METHODS: A retrospective analysis was performed of 92 patients with nonmetastatic squamous cell carcinoma of the anus who were treated between 1989 and 1998. The primary tumor and involved lymph nodes received a total dose of 55 grays (Gy) administered in more than 30 daily fractions. Cisplatin (4 mg/m(2)/day) and 5-FU (250 mg/m(2)/day) were given as a continuous infusion, 5 days each week during the entire radiation course. Kaplan-Meier methodology was used to determine local control (LC), disease-free survival (DFS), and overall survival (OS). RESULTS: Ten patients had T1 or Tx, 43 had T2, 27 had T3, and 12 patients had T4 disease. There were 21 male and 71 female patients. Sixty-five patients (71%) were lymph node negative. With a median follow-up duration of 44 months, the actuarial 5-year OS rate was 85%, the DFS rate was 77%, and the colostomy-free survival rate was 82%. Local recurrences occurred in 16 patients (17%). Distant metastases (DM) occurred in eight patients (9%). Advanced T classification (> T2) predicted lower LC and DFS rates. Advanced N classification (> N1) predicted worse DFS, OS, and DM rates. Greater than 90% of patients completed treatment without significant treatment interruption. Only five patients developed acute toxicities of Radiation Therapy Oncology Group (RTOG) Grade 4 or higher and only three patients developed chronic toxicities of RTOG Grade 4 or higher. CONCLUSIONS: Combined modality therapy with continuous infusion of cisplatin and 5-FU is a well tolerated regimen that results in high rates of LC, OS, and sphincter preservation. These rates are comparable to the best results reported with mitomycin-C and 5-FU. Without the normally severe toxicity, cisplatin-based therapy results in a wider therapeutic index.     

Validation of a rectal cancer outcome prediction model with a cohort of Chinese patients

The risk of local recurrence (LR), distant metastases (DM) and overall survival (OS) of locally advanced rectal cancer after preoperative chemoradiation can be estimated by prediction models and visualized using nomograms, which have been trained and validated in European clinical trial populations. Data of 277 consecutive locally advanced rectal adenocarcinoma patients treated with preoperative chemoradiation and surgery from Shanghai Cancer Center, were retrospectively collected and used for external validation. Concordance index (C-index) and calibration curves were used to assess the performance of the previously developed prediction models in this routine clinical validation population. The C-index for the published prediction models was 0.72 ± 0.079, 0.75 ± 0.043 and 0.72 ± 0.089 in predicting 2-year LR, DM and OS in the Chinese population, respectively. Kaplan-Meier curves indicated good discriminating performance regarding LR, but could not convincingly discriminate a low-risk and medium-risk group for distant control and OS. Calibration curves showed a trend of underestimation of local and distant control, as well as OS in the observed data compared with the estimates predicted by the model.In conclusion, we externally validated three models for predicting 2-year LR, DM and OS of locally advanced rectal cancer patients who underwent preoperative chemoradiation and curative surgery with good discrimination in a single Chinese cohort. However, the model overestimated the local control rate compared to observations in the clinical cohort. Validation in other clinical cohorts and optimization of the prediction model, perhaps by including additional prognostic factors, may enhance model validity and its applicability for personalized treatment of locally advanced rectal cancer.     

Improving chemoradiotherapy in rectal cancer

The optimal management of rectal cancer remains a major challenge for oncologists. The treatment of stage II/III rectal cancer has historically been associated with a high risk of local recurrence and poor survival, which led to the development of adjuvant treatments in the hope of improving outcomes. The approach to adjuvant therapy for rectal cancer currently varies widely between Europe and the U.S. Postoperative adjuvant chemoradiation is the standard of care in the U.S. In contrast, in Europe, because there is a greater emphasis placed on preoperative imaging, meticulous surgical technique, and accurate pathologic reporting of the circumferential or radial margin, preoperative treatment (radiotherapy and chemoradiation) is used widely. The aims of preoperative radiotherapy and chemoradiation are to facilitate a curative resection (R0) and to increase the chance of performing sphincter-sparing procedures, and, therefore, to improve both survival and quality of life. This article reviews the clinical trials that led to these diverging standards of care. An interesting new approach in chemoradiation is the use of the oral fluoropyrimidine capecitabine as a combination partner for radiotherapy. Preclinical studies have demonstrated that the combination of capecitabine and radiotherapy has highly enhanced antitumor activity. This is most likely attributable to the upregulation of thymidine phosphorylase (the rate-limiting enzyme needed to convert capecitabine to 5-fluorouracil [5-FU]) in tumor cells following radiotherapy. A phase I study has consequently been performed to establish a feasible chemoradiotherapy combination. Capecitabine has the potential to replace bolus or continuous infusion 5-FU as the standard treatment for rectal cancer and offers a potentially enhanced therapeutic ratio. Oral chemotherapy has the additional advantage of simplifying chemoradiation and providing a treatment that is more appealing to patients.     

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.     

Preoperative chemotherapy and pelvic radiation for tethered or fixed rectal cancer: a phase II dose escalation study

PURPOSE: To study the impact of preoperative radiation dose escalation and postoperative adjuvant chemotherapy on the outcome of tethered and fixed rectal carcinoma. METHODS AND MATERIALS: We have treated 156 patients with 3 consecutive preoperative chemoradiation protocols with escalating treatment intensity. Schedule 1 consisted of 40 Gy radiation with concurrent 5-fluorouracil (5-FU) infusion and mitomycin C. Schedule 2 used a sandwich design with preoperative (40 Gy) and postoperative (18 Gy) radiation with concomitant 5-FU infusion, leucovorin, and mitomycin C. In schedule 3, the preoperative radiation dose was increased to 50 Gy and adjuvant 5-FU/leucovorin chemotherapy was added following surgery. There were 54, 27, and 75 patients treated in schedules 1, 2, and 3, respectively. RESULTS: The resectability was 91% for schedule 1 and 100% for both schedules 2 and 3. A dose-response relationship was observed between the radiation dose and the tumor downstaging and local control. The pathological complete response (T0N0M0) rates for schedules 1, 2, and 3 were 4%, 15%, and 25%, respectively. The respective rates of tumor downstaging were 41%, 33%, and 68%, respectively. The 5-year local relapse-free rates were 67% for schedule 1 (40 Gy), 96% for schedule 2 (58 Gy), and 92% for schedule 3 (50 Gy) (p = 0.0011). The addition of postoperative chemotherapy appeared to improve both the survival and the relapse-free survival. The 5-year survival was increased from 52% to 84% (p = 0.0004) and the 5-year progression-free survival was improved from 48% to 74% (p = 0.0008). CONCLUSION: Preoperative 5-FU infusion, leucovorin, mitomycin C, and 50-Gy pelvic radiation, followed by postoperative bolus 5-FU/leucovorin chemotherapy, appeared to be an effective treatment for tethered/fixed rectal cancers. However, its therapeutic efficacy could only be validated in randomized studies.     

Adjuvant therapy for resectable rectal adenocarcinoma

The mainstay of treatment for rectal cancer over the past 100 years has been surgical resection. However, for the majority of rectal cancers treated conventionally by resection alone, locoregional recurrence is the major mode of failure. Over the past several decades, significant progress has been made in developing effective adjuvant regimens. In the United States, postoperative chemoradiation is standard treatment for T3 or node-positive patients. However, preoperative radiation with or without chemotherapy decreases local recurrence, increases sphincter preservation, and may improve survival. The purpose of this article is to review the role of adjuvant therapy in resectable rectal cancers and to update the status of ongoing randomized trials.     

Current status of adjuvant therapy for colorectal cancer

Adjuvant therapy with chemotherapy and/or radiation therapy in addition to surgery improves outcome for patients with high-risk carcinomas of the colon or rectum. For colon cancer, fluorouracil (5-FU) combined with leucovorin is a current standard of care that improves long-term survival. A recent European trial (MOSAIC) has documented significant improvement in 3-year disease-free survival when oxaliplatin (Eloxatin) was added to infusional 5-FU and leucovorin in the FOLFOX regimen. Two US cooperative group trials will evaluate the addition of antiangiogenesis therapy with bevacizumab (Avastin) to chemotherapy. A third trial will evaluate FOLFOX, irinotecan (Camptosar) combined with infusional 5-FU and leucovorin (FOLFIRI), and the sequential use of FOLFOX followed by FOLFIRI. In rectal cancer, postoperative 5-FU-based chemotherapy combined with irradiation can improve both local tumor control and survival. The German Rectal Cancer Group has recently reported that preoperative combined-modality therapy is less toxic and more effective in preventing local tumor relapse compared to similar treatment given postoperatively. A coordinated pair of cooperative group clinical trials will evaluate oral capecitabine (Xeloda) as a radiation enhancer in the preoperative setting, and the FOLFOX and FOLFIRI regimens compared to 5-FU and leucovorin following surgery. Predictive and prognostic molecular markers will be studied in these new adjuvant therapy clinical trials for both colon and rectal cancer with the goal of developing future regimens tailored to individual patients. There has been a recent and dramatic increase in the pace of drug development for colorectal cancer which holds promise to further improve curative therapy as part of a multidisciplinary approach in the surgical adjuvant setting.     

Rectal cancer: Preoperative versus postoperative irradiation as a component of adjuvant treatment

The search for improved disease control and survival for resectable but high-risk rectal cancers has led to studies that combine all 3 modalities. For surgically resected, high-risk rectal cancers, postoperative chemoradiation has been shown to improve both disease control (local and distant) and survival (disease free and overall) and was recommended as standard adjuvant treatment at the 1990 National Institute of Health Colorectal Cancer Consensus Conference. Three randomized studies showed improved overall survival (OS) and local control for patients treated with postoperative irradiation and chemotherapy when compared with surgery alone or surgery plus irradiation control arms. These include 2 US trials, Gastrointestinal Tumor Study Group and Mayo/North Central Cancer Treatment Group (NCCTG) and a Norway trial. Although most preoperative external beam radiation trials show reductions in local relapse with the addition of preoperative EBRT to resection, only the large Swedish trial of 1,100 patients showed a survival improvement when compared with a surgery alone control arm for resectable primary rectal cancers. In a recent pooled analysis of 3 postoperative adjuvant rectal cancer trials (NCCTG 794751, NCCTG 864751, and GI Intergroup 0114) survival and disease relapse were dependent on both TN and NT stage of disease (N substage within T stage and T substage within N stage). Even among N2 patients (4 or more positive nodes), T substage influenced 5-year OS (T1-2, 69%; T3, 48%; and T4, 38%; P < .001). Ongoing randomized trials are being conducted for patients with high-risk, resectable primary rectal cancers. The intent is to help define optimal combinations of postoperative chemoradiation (US GI Intergroup), to test sequencing issues of preoperative versus postoperative chemoradiation (Germany trial), and to determine if concurrent and maintenance 5-FU and leucovorin add to the benefits found with preoperative irradiation (European Organization for Research and Treatment of Cancer). For subsequent trials, it may be preferable to perform separate studies, or a planned statistical analysis, for different risk groups of patients (low, intermediate, moderately high, and high), as defined in the rectal cancer pooled analysis.