1. IntroductionIn 2012, rectal canc

1. Introduction

In 2012, rectal cancer affected 40,290 Americans. Colon and rectal cancer resulted in a mortality of 51,690 individuals during the same year [1]. Patients affected with rectal cancer who have a clinical stage II (T3-T4, NO, MO) or III (Any T, N1-N3, M0) tumor are treated with pre-operative chemoradiation (CRT) followed by surgical intervention 5-10 weeks after the last CRT treatment. An adequate oncologic operation involves removal of the tumor and the entire mesorectum (total mesorectal excision). This has been demonstrated to decrease local recurrence substantially as the lymphatic drainage of the rectum is contained within the investing fascia (mesorectum). Distal rectal tumors involving the anorectal sphincter complex are classically treated with an abdominoperineal resection (APR); whereas, more proximal tumors might be treated with an anterior protosigmoidectomy with a primary colorectal anastomosis (LAR). There has been a substantial shift in the number of APR operations to LAR procedures over the past decade owing to the implementation of new circular stapling devices and the use of neoadjuvant CRT.
2. The rectum

In a Cochrane review of 19 clinical trials assessing preoperative radiotherapy vs. surgery alone, the rectum was alternatively defined as below the sacral promontory in three studies, below the pelvic brim in one study, and by the distance from the anal verge in several studies: 12 cm (one study), 13 cm (one study), 14 cm (one study), 15 cm (five studies), and 16 cm (one study) [2]. The hazard ratio for recurrence in patients receiving radiotherapy was less if tumors were located within five to 10 cm from the anal verge, but there was no difference in local recurrence in patients treated with combination radiotherapy and surgery vs. surgery alone in patients that had tumors 10.1 cm from the anal verge [3]. Thus, the benefit of radiotherapy appears to be for more distal tumors (0-10 cm from the anal verge). For the purpose of selecting patient to receive pre-operative CRT, practice guide lines in the United States by the National Cancer Institute (NCI) [4]and the National Comprehensive Cancer Network (NCCN) [5] have defined the rectum to be 12 cm from the anal verge.
3. Indications for neoadjuvant chemoradiation

The addition of preoperative radiation therapy to TME decreases locoregional recurrence from approximately 8% to 2%. The combination of chemotherapy and radiation (CRT) further decreases local recurrence. Chemotherapy also increases the number of patients which achieve a pathologic complete response (pCR), i.e. no detectable tumor after resection. This modality also reduces tumor burden in some patients and might allow a sphincter preserving operation (i.e. LAR) as opposed to an APR, allowing a patient to avoid a permanent colostomy. The rate of pCR is approximately 25% [6;7]. Patients who achieve pCR have better long-term outcomes compared to patients who only have a partial response or no response at all [8]. Current guide lines in the United States [4;5] dictate that patients with stage II (T3-T4) or stage III (any T with positive regional lymph nodes) should be treated with neoadjuvant CRT. Patients with stage I (T1-T2) disease or those with distant metastases (stage IV) generally do not receive neoadjuvant CRT. However, in instances of synchronous liver metastases for which liver resection is planned, neoadjuvant radiation may be considered. These recommendations emanate from the low rate of recurrence (4%) in patients with stage I tumors treated with surgery alone [9]. Further, there is no difference in the rate of locoregional recurrence in patients with stage IV tumors treated with radiotherapy and surgery compared to palliative surgery alone [3]. Similarly, there is no difference in outcomes in patients with distant metastases treated with neoadjuvant radiotherapy and surgery vs. palliative surgery alone [3]. Thus, the standard care of practice is to provide neoadjuvant CRT in patients with stage II and III rectal tumors.
4. Clinical staging of rectal cancer

Staging of rectal cancer begins with a thorough history and physical examination. The most common symptom of rectal cancer is bright red blood per rectum. Physical examination of the abdomen is important to identify any evidence of liver disease (ascites) or masses. A lymph node examination is important in any patient suspected of having cancer. Rectal examination will reveal distal tumors and is mandatory in the evaluation of patients with colorectal cancers. In such cases information regarding the size, degree of fixation, distance from the anal sphincters is important. In women, a rectovaginal examination may reveal extent of disease. A full colonoscopy is indicated to identify synchronous lesions (present in approximately 5% of cases). Rigid proctoscopy will define the distance of the lesion from the anus and can be critical in cases where the distance from the anus is not clear.

Because only stage II and III tumors are treated with pre-operative CRT, clinical staging is pivotal in guiding treatment options. There are currently two modalities to assess tumor stage (T stage) in the pre-operative setting: (1) endorectal ultrasound (EUS) and (2) Magnetic Resonance Imaging (MRI). The efficacy of these modalities has been assessed by two meta-analyses [10;11]. One study favors EUS [10] and the other MRI [11]. In the first analysis, 90 studies were included and assessed the accuracy of EUS, MRI, and CT in pre-operatively staging rectal cancer. The results demonstrated that EUS and MRI were similar in terms of sensitivity (Sn) with regards to tumor depth into the muscularis propia (94%). EUS was superior in determining muscularis propia invasion [specificity (Sp) of 86%] compared to MRI (Sp = 69%) and was an overall sensitive strategy (Sn = 90%) for perirectal tumor invasion compared to MRI (Sn = 82%) [10]. A second meta-analysis interrogated 84 studies. This study showed no difference in these modalities in evaluating the nodes (N-staging) [11]. In seven studies, MRI was a superior strategy in evaluating involved circumferential margins [11]. MRI seems to be emerging as a preferred modality for the assessment of rectal cancer staging in the pre-operative setting. However, the use of either of these modalities is largely based on institutional experience. The sensitivity of EUS following CRT is less compared to virgin tissue. Thus, MRI may be a preferred modality to determine response to neoadjuvant CRT.
5. Neoadjuvant chemoradiotherapy

The management of stage II and stage III rectal cancer is a tri-modality approach (Radiotherapy, Chemotherapy and Surgery) and patients are best managed following discussion at a multidisciplinary conference.
5.1. Radiotherapy

Initial studies evaluated the efficacy of radiotherapy without pre-operative chemotherapy. The data has been summarized in two meta-analyses addressing the benefit of preoperative radiation [12;13]. While the data on overall survival was not clear in these analyses, there was a clear decrease in the rate of local recurrence (46% in patients receiving preoperative radiation vs. 53% in the control group). These data established the benefits of preoperative radiotherapy followed by surgery.
5.1.1. Short course vs. long course radiotherapy

In Europe, small fractions of ionizing radiation 5.0 Grey (Gy) X 5.0 (over five days), for a total of 25.0 Gy without chemotherapy, are employed. With this strategy, the Swedish Rectal Cancer Trial found an improved rate of survival at five years with preoperative radiation [14]. In the United States, the typical IR dose is 45.0 to 50.4 Gy given in small doses (1.8 Gy/day) for five to six weeks [5]. In contrast to short course radiotherapy, in the United States, long course radiotherapy is given in combination with neoadjuvant chemotherapy. The interval between completion of radiation and subsequent operation is an area of some debate (see below) but is typically 5-10 weeks.
5.2. Neoadjuvant chemotherapy

Preoperative chemotherapy is generally used as a radiosensitizer. The EORTC group demonstrated that the addition of chemotherapy (5-FU) to the use of preoperative radiation reduced the risk of local recurrence by approximately 50%, from 17.1% to 8.7%. There was not a significant difference in overall survival in this study. Other trials have shown similar improvements in local control. Based on this data, the most established agent used in the pre-operative setting in combination with radiation has been 5-fluorouracil (5-FU). The oral form of 5-FU (Capecitabine) is also being widely used in place of 5-FU with similar results [15]. Several chemotherapeutic agents used for the management of colon cancer in the adjuvant setting and for patients with metastases have been evaluated as possible radiosensitizers. These agents include: irinotecan [16], oxaliplatin [17], bevacizumab [18] and cetuximab [18]. With such strategies, there is still a wide response to ionizing radiation and these agents are not in widespread use at this time.
5.3. Pathologic complete response

A pathologic complete response (pCR) occurs in patients who undergo resection of the rectum and no residual tumor is identified. Patients who have a pCR demonstrate superior survival than those without. The EORTC 22921 showed an increased rate of pCR in patients who underwent chemoradiotherapy (13.7%) compared to patients who received radiation therapy alone (5.3%). A European trial inclusive of 762 patients receiving preoperative chemoradiation compared to radiation alone, the pCR rate was 11.4% vs. 3.6%, respectively [19]. A recent randomized phase II trial assessing combined chemoradiation for rectal cancer showed 28% of patients achieved a pCR. Further, 78% of patients exhibited tumor down staging [20]. Thus, chemotherapy has an additive effect to radiotherapy and has become the standard of care for patient with stage II/III tumors within 12 cm of the

ผลลัพธ์ (อังกฤษ) 2:

1. Introduction In in 2012, rectal Cancer affected 40.29 thousand Americans. Colon and rectal cancer resulted in a mortality of 51,690 individuals during the same year [1]. Patients affected with rectal cancer who have a clinical stage II (T3-T4, NO, MO) or III (Any T, N1-N3, M0) tumor are treated with pre-operative chemoradiation (CRT) followed by surgical intervention 5-10. weeks after the last CRT treatment. An adequate oncologic operation involves removal of the tumor and the entire mesorectum (total mesorectal excision). This has been demonstrated to decrease local recurrence substantially as the lymphatic drainage of the rectum is contained within the investing fascia (mesorectum). Distal rectal tumors involving the anorectal sphincter complex are classically treated with an abdominoperineal resection (APR); whereas, more proximal tumors might be treated with an anterior protosigmoidectomy with a primary colorectal anastomosis (LAR). There has been a substantial Shift in the Number of APR Operations over the Past Decade to LAR procedures owing to the implementation of Circular stapling New Devices and the use of neoadjuvant CRT. 2. The rectum In a Cochrane review of 19 clinical Trials assessing preoperative radiotherapy alone vs. Surgery, the rectum was alternatively defined as Below the sacral Promontory in Three Studies, Below the pelvic brim in Study one, and by the Distance from the verge in several Anal. studies: 12 cm (one study), 13 cm (one study), 14 cm (one study), 15 cm (five studies), and 16 cm (one study) [2]. The hazard ratio for recurrence in patients receiving radiotherapy was less if tumors were located within five to 10 cm from the anal verge, but there was no difference in local recurrence in patients treated with combination radiotherapy and surgery vs. surgery alone in patients that had tumors. 10.1 cm from the anal verge [3]. Thus, the benefit of radiotherapy appears to be for more distal tumors (0-10 cm from the anal verge). For the purpose of selecting patient to receive pre-operative CRT, practice guide lines in the United States by the National Cancer Institute (NCI) [4] and the National Comprehensive Cancer Network (NCCN) [5] have defined the rectum to be 12. Anal cm from the verge. 3. Indications for neoadjuvant chemoradiation The addition of preoperative Radiation Therapy to TME Locoregional recurrence decreases from approximately 8% to 2%. The combination of chemotherapy and radiation (CRT) further decreases local recurrence. Chemotherapy also increases the number of patients which achieve a pathologic complete response (pCR), ie no detectable tumor after resection. This modality also reduces tumor burden in some patients and might allow a sphincter preserving operation (ie LAR) as opposed to an APR, allowing a patient to avoid a permanent colostomy. The rate of pCR is approximately 25% [6; 7]. Patients who achieve pCR have better long-term outcomes compared to patients who only have a partial response or no response at all [8]. Current guide lines in the United States [4; 5] dictate that patients with stage II (T3-T4) or stage III (any T with positive regional lymph nodes) should be treated with neoadjuvant CRT. Patients with stage I (T1-T2) disease or those with distant metastases (stage IV) generally do not receive neoadjuvant CRT. However, in instances of synchronous liver metastases for which liver resection is planned, neoadjuvant radiation may be considered. These recommendations emanate from the low rate of recurrence (4%) in patients with stage I tumors treated with surgery alone [9]. Further, there is no difference in the rate of locoregional recurrence in patients with stage IV tumors treated with radiotherapy and surgery compared to palliative surgery alone [3]. Similarly, there is no difference in outcomes in patients with distant metastases treated with neoadjuvant radiotherapy and surgery vs. palliative surgery alone [3]. Thus, the standard of Practice Care is to provide neoadjuvant CRT in patients with Stage II and III rectal tumors. 4. Clinical staging of rectal Cancer Staging of rectal Cancer Begins with a thorough physical Examination and History. The most common symptom of rectal cancer is bright red blood per rectum. Physical examination of the abdomen is important to identify any evidence of liver disease (ascites) or masses. A lymph node examination is important in any patient suspected of having cancer. Rectal examination will reveal distal tumors and is mandatory in the evaluation of patients with colorectal cancers. In such cases information regarding the size, degree of fixation, distance from the anal sphincters is important. In women, a rectovaginal examination may reveal extent of disease. A full colonoscopy is indicated to identify synchronous lesions (present in approximately 5% of cases). Rigid proctoscopy Will define the Distance of the lesion from the anus and Can be Critical in Cases where the Distance from the anus is not Clear. Because only Stage II and III tumors are treated with pre-Operative CRT, clinical staging is pivotal in guiding Treatment. options. There are currently two modalities to assess tumor stage (T stage) in the pre-operative setting: (1) endorectal ultrasound (EUS) and (2) Magnetic Resonance Imaging (MRI). The efficacy of these modalities has been assessed by two meta-analyses [10; 11]. One study favors EUS [10] and the other MRI [11]. In the first analysis, 90 studies were included and assessed the accuracy of EUS, MRI, and CT in pre-operatively staging rectal cancer. The results demonstrated that EUS and MRI were similar in terms of sensitivity (Sn) with regards to tumor depth into the muscularis propia (94%). EUS was superior in determining muscularis propia invasion [specificity (Sp) of 86%] compared to MRI (Sp = 69%) and was an overall sensitive strategy (Sn = 90%) for perirectal tumor invasion compared to MRI (Sn = 82%. ) [10]. A second meta-analysis interrogated 84 studies. This study showed no difference in these modalities in evaluating the nodes (N-staging) [11]. In seven studies, MRI was a superior strategy in evaluating involved circumferential margins [11]. MRI seems to be emerging as a preferred modality for the assessment of rectal cancer staging in the pre-operative setting. However, the use of either of these modalities is largely based on institutional experience. The sensitivity of EUS following CRT is less compared to virgin tissue. Thus, MRI May be a response to neoadjuvant CRT Preferred modality to Determine. 5. Neoadjuvant chemoradiotherapy Stage II and Stage III The Management of rectal Cancer is a TRI-modality approach (Radiotherapy, Chemotherapy and Surgery) and patients are managed following discussion at a multidisciplinary Best Conference. 5.1. Radiotherapy Initial Studies evaluated the efficacy of radiotherapy Without pre-Operative chemotherapy. The data has been summarized in two meta-analyses addressing the benefit of preoperative radiation [12; 13]. While the data on overall survival was not clear in these analyses, there was a clear decrease in the rate of local recurrence (46% in patients receiving preoperative radiation vs. 53% in the control group). Benefits of preoperative radiotherapy the Data established these followed by Surgery. 5.1.1. Long vs. short course radiotherapy course In Europe, Small fractions of ionizing Radiation 5.0 Grey (Gy) X 5.0 (over Five days), for a total of 25.0 Gy Without chemotherapy, are employed. With this strategy, the Swedish Rectal Cancer Trial found an improved rate of survival at five years with preoperative radiation [14]. In the United States, the typical IR dose is 45.0 to 50.4 Gy given in small doses (1.8 Gy / day) for five to six weeks [5]. In contrast to short course radiotherapy, in the United States, long course radiotherapy is given in combination with neoadjuvant chemotherapy. The interval between completion of Radiation and Subsequent Operation is an Area of Some debate (See Below) but is typically 5-10 weeks. 5.2. Neoadjuvant chemotherapy Preoperative chemotherapy is generally used as a Radiosensitizer. The EORTC group demonstrated that the addition of chemotherapy (5-FU) to the use of preoperative radiation reduced the risk of local recurrence by approximately 50%, from 17.1% to 8.7%. There was not a significant difference in overall survival in this study. Other trials have shown similar improvements in local control. Based on this data, the most established agent used in the pre-operative setting in combination with radiation has been 5-fluorouracil (5-FU). The oral form of 5-FU (Capecitabine) is also being widely used in place of 5-FU with similar results [15]. Several chemotherapeutic agents used for the management of colon cancer in the adjuvant setting and for patients with metastases have been evaluated as possible radiosensitizers. These agents include: irinotecan [16], oxaliplatin [17], bevacizumab [18] and cetuximab [18]. Strategies with such, there is still a Wide response to ionizing Radiation and these agents are not in widespread use at this time. 5.3. Complete pathologic response A Complete pathologic response (Pcr) occurs in patients undergo resection of the rectum Who and no residual tumor is identified. Patients who have a pCR demonstrate superior survival than those without. The EORTC 22921 showed an increased rate of pCR in patients who underwent chemoradiotherapy (13.7%) compared to patients who received radiation therapy alone (5.3%). A European trial inclusive of 762 patients receiving preoperative chemoradiation compared to radiation alone, the pCR rate was 11.4% vs. 3.6%, respectively [19]. A recent randomized phase II trial assessing combined chemoradiation for rectal cancer showed 28% of patients achieved a pCR. Further, 78% of patients exhibited tumor down staging [20]. Thus, chemotherapy has an additive effect to radiotherapy and has become the standard of care for patient with stage II / III tumors within 12 cm of the.