T-level downstaging and complete pathologic response after preoperative chemoradiation for advanced rectal cancer result in decreased recurrence and improved disease-free survival

PURPOSE: Preoperative chemoradiation therapy is used widely in the treatment of rectal cancer. The predictive value of response to neoadjuvant remains uncertain. We retrospectively evaluated the impact of response to preoperative and, specifically, of T-level downstaging, nodal downstaging, and complete pathologic response after chemoradiation therapy on oncologic outcome of patients with locally advanced rectal cancer. METHODS: There were 88 patients with ultrasound Stage T3/T4 midrectal (n = 37) and low rectal (n = 51) cancers (63 males; mean age 62.6 years). All patients were treated by preoperative 5-fluorouracil-based chemotherapy and pelvic radiation followed by surgical resection in six weeks or longer (56 sphincter-preserving resections). RESULTS: T-level downstaging after neoadjuvant treatment was demonstrated in 36 (41 percent) of 88 patients, and complete pathologic response was observed in 16 (18 percent) of the 88. Of the 42 patients with ultrasound-positive nodes, 27 had no evidence of nodal involvement on pathologic evaluation (64 percent). The overall response rate (T-level downstaging or nodal downstaging) was 51 percent. At a median follow-up of 33 months, 86.4 percent of patients were alive. The overall recurrence rate was 10.2 percent (three patients had local and six had metastatic recurrences). Patients with T-level downstaging and complete pathologic response were characterized by significantly better disease-free survival (P = 0.03, P = 0.04) and better overall survival (P = 0.07, P = 0.08), according to Wilcoxons test comparing Kaplan-Meier survival curves. None of the patients with complete pathologic response developed recurrence or died during the follow-up period. CONCLUSION: T-level downstaging and complete pathologic response after preoperative chemoradiation therapy followed by definitive surgical resection for advanced rectal cancer resulted in decreased recurrence and improved disease-free survival. Advanced rectal cancers that undergo T-level downstaging and complete pathologic response after chemoradiation therapy may represent subgroups that are characterized by better biologic behavior.     

Response to Preoperative Chemoradiation in Stage II and III Rectal Cancer

PURPOSE: The purpose of this study was to determine whether a complete pathologic response after neoadjuvant therapy in rectal cancer patients improves disease control and survival. METHODS: The study reviewed Stage II and III rectal cancer patients treated with preoperative chemoradiation and resected for cure. Complete pathologic response was defined as no cancer in the resected specimen. The main outcome measures were cancer-specific and disease-free survival in patients achieving a complete pathologic response and a noncomplete pathologic response. Kaplan-Meier curves were evaluated using log-rank analysis. RESULTS: Eighty-nine rectal cancer patients received neoadjuvant chemoradiation followed by radical resection for cure. Twenty-one patients (24 percent) achieved a complete pathologic response. Median follow-up for the complete pathologic response group was 23.5 months and 31 months for the noncomplete pathologic response group. There were more Stage III patients in the noncomplete pathologic response group than the complete pathologic response group (P = 0.005). Complete pathologic response patients were less likely to receive postoperative adjuvant chemotherapy than noncomplete pathologic response patients (P = 0.004). Cancer-specific and disease-free survival were not statistically different between the two groups. However, a trend was noted toward improved survival and decreased recurrence in association with a complete pathologic response. CONCLUSION: Stage III patients were less likely to be in the complete pathologic response group than Stage II patients. Complete pathologic response patients were less likely to receive postoperative adjuvant chemotherapy than noncomplete pathologic response patients. Complete pathologic response after neoadjuvant chemoradiation for rectal cancer patients demonstrated a trend toward improved survival and decreased recurrence compared with noncomplete pathologic response patients.     

Use of preoperative ultrasound staging for treatment of rectal cancer

INTRODUCTION: Transrectal ultrasound is the standard method for preoperative staging of rectal cancer. This study reviews the accuracy of transrectal ultrasound staging for T3 disease and its use in the selection of patients for neoadjuvant chemoradiation. METHODS: One hundred seventeen patients underwent preoperative transrectal ultrasound evaluation for rectal cancer. Accuracy of transrectal ultrasound was evaluated among 70 patients not receiving preoperative chemoradiation. Forty-seven patients received neoadjuvant chemoradiation based on transrectal ultrasound results. Tumor downstaging and early recurrence were evaluated among 45 of 47 patients receiving neoadjuvant chemoradiation. RESULTS: Among 70 nonirradiated patients, 19 were pathologic Stage pT3. Transrectal ultrasound correctly identified 18 of 19 patients with Stage pT3 (sensitivity, 94.7 percent). Transrectal ultrasound correctly identified 44 of 51 patients with less than pT3 disease (specificity, 86.3 percent). After preoperative chemoradiation in 45 patients with ultrasound Stage uT3 or uT4 tumors, 56 percent of them experienced a reduction in T stage. Residual nodal disease was found in 31 percent of patients. A complete pathologic response with no residual disease at operation was observed in 22 percent of patients. During a median follow-up period of 21 months after diagnosis, seven patients experienced a recurrence of their disease at a median of 12 months after diagnosis. Five of seven patients with recurrence were among a subgroup of ten patients who both failed to downstage T and had residual nodal disease at operation. CONCLUSION: Transrectal ultrasound is an accurate modality for selecting patients for neoadjuvant treatment. Preoperative chemoradiation produced downstaging in 56 percent of patients. Factors related to early recurrence included residual nodal disease and failure to downstage T after neoadjuvant chemoradiation.Presented at the meeting of The American Society of Colon and Rectal Surgeons, San Antonio, Texas, May 4 to 8, 1998.     

Incidence and Clinical Impact of Sterilized Disease and Minimal Residual Disease After Preoperative Radiochemotherapy for Rectal Cancer

PURPOSE In advanced rectal cancer, chemoradiation can induce downstaging until complete disappearance of the tumor or its persistence in minimal form. The complete sterilized and the minimal residual disease often are considered similar. We evaluated the specific incidence of these two conditions and analyzed their impact in terms of local recurrence, distant metastasis, and survival. METHODS We studied 139 uT3/T4 N0/N+ rectal cancers, treated with preoperative chemoradiation and curative surgery after six to eight weeks. We evaluated ypTNM stage and tumoral regression, according to the five degrees proposed by Dworak, with special attention to 4 and 3 (sterilized and minimal residual disease). RESULTS Tumor downstaging occurred in 65 patients (46.7 percent), including 25 sterilized lesions (17.9 percent) and 24 minimal residual disease (17.2 percent). In median follow-up of 30 months, none of the patients with sterilized disease developed local or distant recurrence. Among patients with minimal residual disease, none developed local recurrence, whereas two (8.3 percent) developed distant metastasis, and one died from disease. In patients with gross residual disease (Grade 2, 1, 0) the percentage of local recurrence was 8.8 percent, distant recurrence 26.6 percent, and 13.3 percent died from disease. The difference between three groups is statisti-cally significant as regards local and distant recurrence. CONCLUSIONS After preoperative therapy, the sterilized disease shows an excellent prognosis. The minimal residual disease has an important numeric incidence. Its outcome is different, with a not-negligible risk of distant recurrence. The minimal residual disease has a much better prognosis in comparison with the gross residual disease.     

Interpretation of Magnetic Resonance Imaging for Locally Advanced Rectal Carcinoma After Preoperative Chemoradiation Therapy

PURPOSE: Neoadjuvant concomitant chemoradiotherapy has been used in cases of locally advanced rectal cancer to preserve sphincter function, decrease local recurrence, and improve survival. Preoperative staging is essential for planning and providing optimal therapy. The purpose of this study is to determine the accuracy of staging with magnetic resonance imaging and to define any factors that interfere in interpretation of images obtained after preoperative chemoradiation therapy.METHODS: Thirty-six patients with biopsy-proven, locally advanced rectal cancer were treated with preoperative concomitant 5-fluorouracil-based chemotherapy and radiation, followed six to eight weeks later by radical surgery. Preoperative magnetic resonance images were reinterpreted by one radiologist and the results compared with histopathologic staging.RESULTS: T-level downstaging occurred in 10 of 36 patients (28 percent), and N-level downstaging occurred in 29 of 36 patients (80 percent) after completion of chemoradiation therapy. Pathologic complete remission after chemoradiotherapy occurred in five patients (12 percent). Of the 36 patients, 17 (47 percent) were overstaged and 2 (6 percent) were understaged in T-level, whereas 10 patients (28 percent) were overstaged and 3 patients (8 percent) were understaged in N-level. The accuracy of magnetic resonance imaging for determining depth of wall invasion was 47 percent, with 64 percent accuracy for nodal staging.CONCLUSIONS: Magnetic resonance imaging is commonly used in staging of pelvic malignancies because of its fine resolution, but chemoradiotherapy may decrease its accuracy. Thickening of the rectal wall after radiation by marked fibrosis, and peritumoral infiltration of inflammatory cells and vascular proliferation may contribute to overestimation of stage. By contrast, pathologic residual cancer beneath normal mural structure after chemoradiation therapy may result in understaging of rectal cancer.Presented at the Scientific Meeting of the Taiwan Surgical Association, Taipei, Taiwan, March 27 to 28, 2004.     

Longer Time Interval Between Completion of Neoadjuvant Chemoradiation and Surgical Resection Does Not Improve Downstaging of Rectal Carcinoma

PURPOSE: An interval of six to eight weeks between completion of preoperative chemoradiation therapy and surgical resection of advanced rectal cancer has been described. Our purpose was to determine whether a longer time interval between completion of therapy and resection increases tumor downstaging and affects perioperative morbidity. METHODS: Forty patients with advanced adenocarcinoma of the rectum underwent preoperative chemoradiation on a prospective trial with irinotecan (50 mg/m2), 5-fluorouracil (225 mg/m2), and concomitant external-beam radiation (45-54 Gy) followed by complete surgical resection of the tumor with total mesorectal excision. The time interval between completion of chemoradiation and surgical resection ranged from 28 to 97 days. The patients were divided into two groups with 33 eligible patients: Group A (4-week to 8-week time interval; 28-56 days) and Group B (10-week to 14-week interval; 67-97 days). Tumor downstaging was compared between these two groups. The number of patients downstaged by at least one T stage, those downstaged by at least one N stage, those with pathologic complete responses, and those with only residual microscopic tumor foci were compared. Postoperative length of stay, estimated blood loss, perioperative morbidity, and sphincter-sparing procedures were also compared. Chi-squared tests and Student's t-test were calculated. RESULTS: Group A had 19 patients, and Group B had 14 patients. Patient demographics were comparable. Mean age was 52 years, and 70 percent of patients were male. There were no deaths. There were no statistical differences in perioperative morbidity, with three anastomotic leaks in Group A. Tumors were downstaged in 58 percent of patients in Group A and 43 percent of those in Group B (P = 0.61). Nodal downstaging occurred in 78 percent of Group A and 67 percent of Group B (P = 0.9). The pathologic complete response rate was 21 percent in Group A and 14 percent in Group B (P = 0.97), and a residual microfocus of tumor was found in 33 percent of patients in Group A and 42 percent of those in Group B (P = 0.90). These differences were not statistically significant. CONCLUSIONS: Perioperative morbidity is not affected by longer intervals. A longer interval between completion of neoadjuvant chemoradiation and surgical resection may not increase the tumor response rate of advanced rectal cancer in this cohort.     

Mucinous Rectal Adenocarcinoma Can Be Associated to Tumor Downstaging after Preoperative Chemoradiotherapy

Purpose The aim of this study was to evaluate downstaging as primary end point, and progression-free survival and overall survival as secondary end points, in rectal adenocarcinoma patients treated with preoperative chemoradiation. Methods One hundred and thirty-six extraperitoneal adenocarcinoma patients (33 low rectum T2, 74 T3, 29 T4 [without sacral invasion], 25 with mucinous subtype) were treated with posterior pelvis preoperative radiotherapy (5040 cGy total dose, 180 cGy/fr, 5 fr/w, 10–15 MV linac X-rays) and concomitant 5-fluorouracil-based chemotherapy. After 6 to 8 weeks patients underwent surgery and prechemoradiation clinical stage was compared with pathologic stage to evaluate downstaging in each patient. Seventy-four patients received adjuvant chemotherapy. Median follow-up was 39 months (4–84). Results Forty-four patients had macroscopic complete response, 52 patients had partial response, 37 patients showed no change and 3 patients had progression. At multivariate analysis only histotype showed correlation with downstaging (hazard ratio = 0.350 and 0.138 – 0.885 95 percent confidence interval) because of the evidence for poor downstaging in mucinous subtype. There were no significant differences in overall survival and progression-free survival between adenocarcinoma and mucinous subtype. Conclusions The main finding is that mucinous histology is associated with poor downstaging after preoperative chemoradiation but this poor response was not associated with worse outcome in this small study. The good outcome for mucinous histology is at odds with other reports in the literature and requires further study.     

Accuracy of endoscopic ultrasound for restaging rectal cancer following neoadjuvant chemoradiation therapy

OBJECTIVES: Endoscopic ultrasound (EUS) provides important information in the initial staging of patients with rectal cancer. Preoperative combined modality chemotherapy and radiation (neoadjuvant therapy) for patients with locally advanced rectal cancer may reduce local recurrence and improve survival. The accuracy of EUS restaging of rectal cancer after chemoradiation has not been extensively studied and its usefulness is unclear. The aim of this study was to verify the accuracy of EUS in staging rectal cancer after neoadjuvant chemoradiation in a large cohort of patients. METHODS: EUS staging was performed before and after concurrent 5-fluorouracil and hyperfractionated radiotherapy in 82 patients with recently diagnosed locally advanced rectal cancer. All patients underwent subsequent surgical resection and complete pathologic staging. RESULTS: After chemoradiation, 16 patients (20%) had no residual disease at pathologic staging. (T0N0). However, EUS correctly predicted complete response to chemoradiation in only 10 of 16 patients (63%). Overall accuracy of EUS post chemoradiation for pathologic T-stage was only 48%. Fourteen percent were understaged and 38% overstaged. EUS accuracy for N-stage was 77%. The T-category was correctly staged before surgery in 23 of the 56 responders (41%) and in 16 of 24 nonresponders (67%). EUS was unable to accurately distinguish postradiation changes from residual tumor. CONCLUSION: EUS staging of rectal cancer after chemoradiation is inaccurate, especially in the group of patients with visual and EUS evidence of response. Its routine use for staging purposes after neoadjuvant chemoradiation for rectal cancer should be discouraged.     

Complete clinical response after preoperative chemoradiation in rectal cancer: is a "wait and see" policy justified?

PURPOSE: A proportion of patients, who receive preoperative chemoradiation for locally advanced (T3, T4, NX) rectal cancer achieve a complete clinical response and a pathologic complete response in the region of 15 to 30 percent. Support is growing in the United Kingdom for the concept of "waiting to see" and not proceeding to radical surgery when a complete clinical response is observed. The purpose of this review was to use a literature search to assess how often complete clinical response is achieved after neoadjuvant chemoradiation, the concordance of this finding with pathologic complete response, and to determine whether it is feasible to observe patients who achieve complete clinical response rather than proceed to surgery. RESULTS: In total, 218 Phase I/II or retrospective studies and 28 Phase III trials of preoperative radiotherapy or chemoradiation were identified: 96 percent of trials documented the pathologic complete response, but only 38 trials presented data on the achievement of a complete clinical response/partial clinical response. Only five studies were found in which patients with clinically staged T2/T3 tumors were treated with radiotherapy/chemoradiation and did not routinely proceed to surgery and also reported on the long-term outcome of a "wait and see" policy. DISCUSSION: It remains uncertain whether the degree of response to chemoradiation in terms of complete clinical response or pathologic complete response is a useful clinical end point. Studies that include T3 rectal cancer are associated with high local recurrence rates after nonsurgical treatment. Few studies report long-term outcome after achievement of a complete clinical response. CONCLUSIONS: The end point of complete clinical response is inconsistently defined and seems insufficiently robust with only partial concordance with pathologic complete response. The rationale of a "wait and see" policy when complete clinical response status is achieved relies on retrospective observations, which are currently insufficient to support this policy except in patients who are recognized to be unfit for or refuse radical surgery.     

Different prognostic effect of postoperative chemoradiation therapy on diploid and nondiploid high-risk rectal cancers

PURPOSE: DNA ploidy has been shown to play a role in the response to cytotoxic therapy in a variety of malignancies, including breast cancer and melanoma. However, the importance of DNA ploidy in rectal cancer is unknown. The aim of the present study was to determine whether ploidy status might be associated with response to postoperative chemoradiation in TNM Stages II to III rectal cancer. METHODS: This retrospective study analyzed data from 229 patients with TNM Stages II to III rectal cancer who underwent resection between 1979 and 1984. The ploidy status and treatment modalities in relation to outcome were assessed. RESULTS: The recurrence-free ten-year survival rate was 52.2 percent for patients with diploidy and 50.5 percent for patients with nondiploidy (P=0.99). The ten-year survival rates for patients with diploidy and patients with nondiploidy were 55 and 19 percent (P=0.016) in the chemoradiation group, and 51 and 60 percent (P=0.15) in the nonchemoradiation group, respectively. In the chemoradiation group, DNA nondiploidy was associated with an increased recurrence rate (83.3vs. 50.0 percent;P=0.001). The interaction between DNA nondiploidy and chemoradiation remained important in predicting outcome in the Cox regression model. Factors independently correlated with a worse outcome included Stage IIIb (relative risk, 2.9; 95 percent confidence interval, 1.7–5;P=0.0001), perineural invasion (relative risk, 2.5; 95 percent confidence interval, 1.6–4,P=0.0001), distal tumor (relative risk, 1.7; 95 percent confidence interval, 1.1–2.7,P=0.014), and nondiploidy with chemoradiation (relative risk, 2.9; 95 percent confidence interval, 1.2–7.2,P=0.0213). CONCLUSIONS: These findings suggest that DNA nondiploidy is inversely correlated with long-term outcome among patients with high-risk rectal cancer receiving chemoradiation.Supported by a grant (CMRP384) from Chang Gung Memorial Hospital.     

The Effect of Circumferential Tumor Location in Clinical Outcomes of Rectal Cancer Patients Treated With Total Mesorectal Excision

PURPOSE A positive circumferential resection margin is associated with a high risk of local recurrence and distant metastasis after total mesorectal excision for rectal cancer. The mesorectum is thinner anteriorly than posteriorly, and the risk of a positive resection margin may be higher for anterior than for posterior tumors. We sought to determine the effect of the tumor's position in the circumference of the rectum on the treatment and outcomes of rectal cancer patients treated by total mesorectal excision. METHODS We retrospectively analyzed 401 patients with rectal cancer staged by preoperative endorectal ultrasound and treated by sharp mesorectal excision with or without neoadjuvant therapy. Tumors were classified into four groups (anterior, posterior, lateral, and circumferential) according to the location of deepest point of penetration on endorectal ultrasound. Differences in recurrence and survival rates were analyzed with logistic regression analysis. RESULTS Of the 401 tumors, 27 percent were anterior, 26 percent posterior, 32 percent lateral, and 15 percent circumferential. The groups did not differ in age, gender, tumor distance from the anal verge, or tumor grade. The ultrasound and pathology stages were more advanced in the circumferential group, and the proportion of uT4 tumors was higher in the anterior group. Circumferential and anterior tumors were more likely to receive preoperative adjuvant radiation. After an average follow-up of 44 months, 20 percent of patients had developed recurrence (13 percent distant, 6 percent local, and 1 percent distant and local). Recurrence was associated with advanced tumor stage, tumor proximity to the anal verge, and no preoperative adjuvant therapy. Early tumor stage and preoperative chemoradiation were associated with lower recurrence and improved survival. When tumor stage was controlled for, patients with poor or undifferentiated tumors and male patients with anterior tumors were shown to have a higher risk of recurrence or death. The estimated five-year disease-free survival for the entire group was 73 percent. CONCLUSIONS Tumor stage is the main criterion to estimate prognosis in rectal cancer patients. The position of the tumor within the circumference of the rectum may provide valuable clinical information. Anterior tumors tend to be more advanced and, at least in male patients, has a higher risk of recurrence and death than tumors in other locations. Presented at the meeting of the Minnesota Surgical Society, St. Paul, Minnesota, April 27, 2001.     

Complete Clinical Response After Preoperative Chemoradiation in Rectal Cancer: Is a “Wait and See” Policy Justified?

Purpose A proportion of patients, who receive preoperative chemoradiation for locally advanced (T3, T4, NX) rectal cancer achieve a complete clinical response and a pathologic complete response in the region of 15 to 30 percent. Support is growing in the United Kingdom for the concept of “waiting to see” and not proceeding to radical surgery when a complete clinical response is observed. The purpose of this review was to use a literature search to assess how often complete clinical response is achieved after neoadjuvant chemoradiation, the concordance of this finding with pathologic complete response, and to determine whether it is feasible to observe patients who achieve complete clinical response rather than proceed to surgery. Results In total, 218 Phase I/II or retrospective studies and 28 Phase III trials of preoperative radiotherapy or chemoradiation were identified: 96 percent of trials documented the pathologic complete response, but only 38 trials presented data on the achievement of a complete clinical response/partial clinical response. Only five studies were found in which patients with clinically staged T2/T3 tumors were treated with radiotherapy/chemoradiation and did not routinely proceed to surgery and also reported on the long-term outcome of a “wait and see” policy. Discussion It remains uncertain whether the degree of response to chemoradiation in terms of complete clinical response or pathologic complete response is a useful clinical end point. Studies that include T3 rectal cancer are associated with high local recurrence rates after nonsurgical treatment. Few studies report long-term outcome after achievement of a complete clinical response. Conclusions The end point of complete clinical response is inconsistently defined and seems insufficiently robust with only partial concordance with pathologic complete response. The rationale of a “wait and see” policy when complete clinical response status is achieved relies on retrospective observations, which are currently insufficient to support this policy except in patients who are recognized to be unfit for or refuse radical surgery.     

Preoperative chemoradiation with capecitabine in locally advanced rectal cancer

BACKGROUND: Preoperative radiation therapy in combination with 5-fluoracil (5-FU) improves local tumour control in locally advanced rectal cancer. The aim of our study was to evaluate the toxicity and efficacy of preoperative chemoradiation using the oral 5-FU prodrug capecitabine in locally advanced rectal cancer. METHODS: Sixty patients with locally advanced rectal cancer were treated with preoperative chemoradiation. Radiotherapy consisted of a total dose of 50 Gy delivered in 25 fractions to the pelvis. Chemotherapy was concurrently administered and consisted of oral capecitabine only on radiotherapy days. Surgery was performed six to ten weeks after completion of chemoradiation. RESULTS: The patient population consisted of 19 females and 41 males, with a median age of 61 years. All but two patients received the full dose of chemoradiation. No grade 3 or 4 haematological toxicities developed. Two patients (3%) developed grade 3 radiation dermatitis and one a grade 3 diarrhoea. All patients underwent definitive surgery; 19 patients underwent an abdominal perineal resection (APR), 25 a low anterior resection (LAR) and 16 patients a Hartmann's procedure. One patient with a low anterior resection developed an anastomotic leakage (4%). Final pathology demonstrated eight patients (13%) with a complete pathological response. Primary tumour and nodal downstaging occurred in 67 and 84% of the patients, respectively. Two patients (3%) had an R1 resection, one after an APR and one after an LAR. CONCLUSION: Preoperative chemoradiation with oral capecitabine is safe and well tolerated in locally advanced rectal cancer patients. This preoperative treatment has a considerable downstaging effect on the tumour and lymph nodes.     

p53, Deleted in Colorectal Cancer Gene,and Thymidylate Synthase as Predictors of Histopathologic Response and Survival in Low,Locally Advanced Rectal Cancer Treated With Preoperative Adjuvant Therapy

PURPOSE: Adjuvant therapy, either preoperatively or postoperatively, and modifications of surgery have been used to try to improve outcome of surgery for rectal cancer in regard to both local recurrence and survival. Assessment of prognosis in patients after resection is currently primarily based on clinicopathologic factors. These predict the subsequent behavior of the tumor only imperfectly. The aim of this study was to evaluate three potential molecular genetic markers of prognosis (p53, deleted in colorectal cancer gene, and thymidylate synthase) in Dukes Stage B and C low rectal tumors treated with adjuvant therapy and to determine whether they correlate with survival, local recurrence, or the pathologic response to adjuvant therapy (assessed by extent of tumor regression and tumor down-staging). METHODS: Sixty locally advanced low rectal tumors resected after preoperative chemoradiotherapy or radiotherapy alone were studied by immunohistochemical staining for p53, deleted in colorectal cancer gene, and thymidylate synthase. In addition, p53 gene mutations were sought by polymerase chain reaction–single-strand conformation polymorphism analysis. These results were correlated with survival, local recurrence, and pathologic response to adjuvant therapy. RESULTS: Lack of thymidylate synthase staining by immunohistochemistry was associated with tumor down-staging after preoperative chemoradiotherapy but not after radiotherapy or for these two combined groups. There was no correlation between p53, deleted in colorectal cancer gene, or thymidylate synthase immunohistochemical staining or between p53 polymerase chain reaction–single-strand conformation polymorphism and local recurrence or survival in locally advanced low rectal cancers treated with preoperative adjuvant therapies. CONCLUSION: Prediction of prognosis in patients with locally advanced low rectal cancers treated with preoperative adjuvant therapies continues to be problematic. Thymidylate synthase immunohistochemistry appears to be the most promising factor of those assessed in predicting tumor down-staging after preoperative chemoradiotherapy for locally advanced low rectal cancers.     

Preoperative radiotherapy for locally advanced rectal cancer and prognostic factors influencing outcome

The aim of presented study was to evaluate the impact of different factors on survival, local recurrence and development of metastatic disease in patients with rectal cancer treated with preoperative radiotherapy or 5-fluorouracil (5-FU) based concurrent chemoradiation. Retrospective clinical evaluation was performed in 165 patients (33% women and 67% men) with locally advanced rectal adenocarcinoma treated with preoperative radiotherapy or chemoradiotherapy in the period January 1998 - March 2003. Tumor extent was evaluated by CT and/or MRI and/or TRUS examination and tumor biopsy was performed during colonoscopy. The median follow up is 21 month. All patients received preoperative external beam radiation to primary tumor, adjacent lymphnodes and presacral region. Computed tomography localisation of target volume was used for 3D radiotherapy treatment planning. Accelerated short term regimen (25 Gy/5 fraction/1 week) was performed in 14% of patients especially in year 1998-2000 and normofractionated regimen (40-50 Gy/20-25 fractions/4-5 weeks) was performed in 86% of patients. Chemoradiotherapy with 5-FU was carried out in 22% of patients. Radical resection underwent 85% of patients, inoperable tumor persisted in 7% and distant metastases were detected peroperatively in 8%. The 2-year overall survival (OS) was 84% and 5-year OS was 60% following radical resection. The important prognostic factors affecting survival were postradiotherapy determined pathological staging (p=0.005), postradiotherapy tumor grade (p<0.001) and the presence of angioinvasion and/or perineural spread (p=0.023). Prognostic factors for disease-free survival were identical with those for OS. Higher local recurrence rate was associated in preradiotherapy tumor staged T4 (p=0.048) and in presence of angioinvasion and/or perineural spread (0.049). Age, tumor location, histological grade before radiotherapy and tumor downstaging were not statistically significant for survival and/or for local recurrence rate. The best survival rates were obtained in patients with postradiotherapy grade 1 tumors (5-years survival 100%), tumors without angioinvasion and perineural spread (5-years survival 65%) and in patients who obtained complete remission after preoperative radiotherapy (5-years survival 86%).     

Preliminary results of preoperative 5-fluorouracil, low-dose leucovorin, and concurrent radiation therapy for clinically resectable T3 rectal cancer

PURPOSE: We report the downstaging, sphincter preservation, acute toxicity, and preliminary local control and survival results of preoperative 5-fiuorouracil (5-FU), low-dose leucovorin (LV), and concurrent radiation therapy followed by postoperative LV/5-FU for treatment of patients with clinically resectable T3 rectal cancer. MATERIALS AND METHODS: A total of 32 patients received two monthly cycles of preoperative LV/5-FU (bolus daily×5). Radiation therapy (5,040 cGy) began concurrently on day 1. Postoperatively, patients received a median of two monthly cycles of LV/5-FU (range, 0–10). RESULTS: The complete response rate was 9 percent pathologic and 13 percent clinical, for a total of 22 percent. Total Grade 3+ acute toxicity during the preoperative combined modality segment was 25 percent (8/32). Of the 20 patients who were thought to initially require an abdominoperineal resection and for whom the intent of treatment was sphincter preservation, 17 (85 percent) were able to undergo sphincter-preserving surgery. With a median follow-up of 22 (3–59) months, none have developed local failure, and the three-year actuarial diseasefree survival rate was 60 percent. CONCLUSION: Our data reveal encouraging downstaging, sphincter preservation, and acute toxicity with this regimen. Additional follow-up is needed to assess the long-term local control and survival rates.Presented at the meeting of the American Society of Therapeutic Radiology and Oncology, Los Angeles, California, October 25 to 29, 1996.     

Rectal cancer

PURPOSE: This study was designed to assess the local recurrence rate and prognostic factors for local recurrence in patients undergoing curative anterior or abdominoperineal resections without radiotherapy. METHODS: From January 1980 to December 1996, 514 consecutive patients underwent curative resections for rectal cancer. We excluded those with preoperative radiotherapy (n=23), postoperative radiotherapy (n=27), local resection (n=36), and 11 (2.1 percent) patients who died postoperatively. The remaining 417 patients (249 males) with a median age of 64 (range, 21–90) years were analyzed. For upper third lesions, mesorectal tissue was excised down to at least 5 cm below the tumor. Total mesorectal excision was performed for lower and middle tumors. Postoperative chemotherapy was limited to patients with Stage III lesions. Median follow-up (and 95 percent confidence interval) was (5.2 4.3–5.9) years, with 87.7 percent of patients followed up longer than 24 months. Local recurrence was defined as any recurrence within the field of resection, regardless of the presence or absence of distant metastasis. RESULTS: Five-year local recurrence rate(and 95 percent confidence interval) was 9.7 (6.4–13) percent, with a median time to diagnosis of 15 (10–23) months. Local recurrence rates in Stages I, II, and III were: 3.1, 4.1, and 24.1 percent, respectively (P < 0.0001). In relation to node status, local recurrence rates were N0, 4.1 (1.7–6.5) percent; N1, 12.6 (4.6–20.6) percent; N2, 32.1 (12.1–52.1) percent; and N3, 59.3 (22.5–96.1) percent; (P < 0.00001). Lower third tumors had a higher local recurrence rate than middle and upper third tumors: 17.9, 7.1, and 5.1 percent, respectively (P=0.002). Adjusted by stage, this difference was maintained only in Stage III tumors. Among lower tumors, those at 6 and 7 cm from the anal verge had a lower local recurrence rate than those below 6 cm (6.7vs. 26.2 percent, respectively;P=0.02). Accidental rectal perforation at or near the tumor site occurred in 12 cases (2.9 percent), showing a strong correlation with local recurrence (P < 0.0001). Multivariate analysis showed significant higher risk for lower third tumors (hazard ratio, 2.98) and positive nodes (hazard ratio, 4.78). CONCLUSIONS: Appropriate surgery without irradiation achieves excellent local control in N0 rectal cancers. Node metastasis, lower third localization (especially below 6 cm), and accidental rectal perforation at or near the tumor site are significantly associated with a higher local recurrence rate.     

Predictive clinicopathologic factors for limited response of T3 rectal cancer to combined modality therapy

Purpose The response of T3 rectal cancer to combined modality therapy (CMT) is highly predictive of long-term outcome following surgery. The aim of this study was to identify pretreatment factors associated with poor tumor response to neoadjuvant chemoradiation. Methods A prospective institutional database at Memorial Sloan-Kettering Cancer Center was queried for endorectal ultrasound (ERUS) stage T3N0–2 rectal cancer patients, treated with CMT followed by surgical resection, between 1998 and 2003. Preoperative clinicopathologic factors determined by biopsy, ERUS, proctoscopy, and digital rectal examination were correlated with the degree of downstaging of the primary mural lesion (tumor downstaging) in response to neoadjuvant therapy. Associations were analyzed by chi-square, Kaplan–Meier, and logistic regression. Results Of 274 patients, 51% obtained tumor downstaging in response to preoperative treatment, i.e., lower pathologic T-stage compared with pretreatment ERUS. Five-year recurrence-free survival was 89% in the cohort that obtained tumor downstaging compared with only 45% in the cohort that obtained no tumor downstaging. Factors significantly associated with limited or lack of tumor downstaging after CMT included: fixed tumor on digital rectal examination (p < 0.021), near-circumferential tumor (p < 0.011), tumor stenosis (p < 0.025), metastatic disease (p < 0.012), biopsy-proven poorly differentiated pathology (p < 0.002), and radial extension >2.5 mm on ERUS (p < 0.031). On multivariate analysis, deep radial extension on ERUS, metastatic disease, and poorly differentiated pathology were in each, independently associated with limited or lack of tumor downstaging. Conclusions Pretreatment evaluation with biopsy, proctoscopy, and ERUS can identify T3 rectal cancer patients unlikely to respond well to CMT. These patients may be considered for alternative protocols and their tumors studied to ascertain the molecular events responsible for resistance to chemoradiation. Presented at Presented at the 2006 annual meeting of The American Society of Colon and Rectal Surgeons, June 3–7, 2006, Seattle, WA, USA.     

Preoperative Chemoradiotherapy and Total Mesorectal Excision Surgery for Locally Advanced Rectal Cancer: Correlation With Rectal Cancer Regression Grade

PURPOSE Preoperative long-course chemoradiotherapy is recommended for rectal carcinoma when there is concern that surgery alone may not be curative. Downstaging of the tumor can be measured as rectal cancer regression grade (1-3) and may be of importance when estimating the prognosis. The aim of this study was to look at the long-term results of tumor regression in patients receiving long-course chemotherapy before surgical resection of rectal cancer.METHODS We reviewed those patients who received preoperative chemoradiotherapy followed by surgical resection for carcinoma of the mid rectum or distal rectum found to be stage T3/4 between January 1995 and November 1999. Patients received 45 to 50 Gy irradiation in 2-Gy fractions and an infusion of 5-fluorouracil. Surgical specimens were assessed for rectal cancer regression grade. Patients were followed up routinely with clinical examination, computed tomography, and colonoscopy.RESULTS Sixty-five patients with a mean age 65 (range, 32–83) years underwent chemoradiotherapy before surgical resection. Thirty patients (46 percent) were classified as rectal cancer regression Grade 1, with 9 patients (14 percent) having complete sterilization of the tumor. Fifty-three patients (82 percent) underwent a curative resection. Overall survival, with a median follow-up of 39 (range, 24–83) months, was 67 percent and was associated with tumor downstaging. The local recurrence rate was 5.8 percent in those patients who underwent a curative resection and was significantly lower with rectal cancer regression Grade 1 tumors (P = 0.03). Eight of nine patients (89 percent) whose tumor had been sterilized were alive and well with no recurrence of tumor at a median follow-up of 41 (range, 24–70) months.CONCLUSIONS Preoperative chemoradiotherapy resulted in significant regression of tumor. Overall survival was high and was associated with downstaging of tumor. The local recurrence rate was significantly lower with rectal cancer regression Grade 1 tumors and was not seen in patients with sterilized tumors.Presented at the Association of Coloproctology of Great Britain and Ireland, Manchester, United Kingdom, July 2002.Reprints are not available.     

Abdominoperineal resection for rectal cancer at a specialty center

PURPOSE: Although sphincter-preservation procedures have replaced abdominoperineal resection as the treatment of choice for rectal cancer, a subset of patients with rectal cancer will still require abdominoperineal resection. The use of adjuvant radiotherapy has been shown to reduce local recurrence, and combined modality therapy (chemoradiation) improves survival. Sharp mesorectal excision compared with the classic teaching of blunt retrorectal dissection is also an important component of local control. The primary aim of the present study was to evaluate the postoperative complications associated with neoadjuvant therapy in patients requiring complete rectal excision. Oncologic outcomes for all patients with abdominoperineal resection are also provided. METHODS: A prospective database of 5,634 patients who underwent surgery for colorectal cancer at Memorial Sloan-Kettering Cancer Center between the years 1987 and 1997 was reviewed. Patients with primary adenocarcinoma of the rectum who underwent abdominoperineal resection were identified. In 1,622 patients who were operated on for primary rectal cancer, 292 patients (18 percent) underwent abdominoperineal resection and the rest had a sphincter-preserving procedure. Ten patients were excluded from the study because of prior pelvic irradiation for other cancer (8 patients) and insufficient radiation dose (<4,000 cGy; 2 patients). Neoadjuvant radiotherapy was given to 123 patients and postoperative adjuvant radiotherapy to 65 patients, whereas 94 did not receive radiotherapy. Intraoperative radiotherapy combined with preoperative radiotherapy was administered to 23 of the 123 patients given neoadjuvant radiotherapy. RESULTS: The duration of the operation was significantly longer in both neoadjuvant radiotherapy and intraoperative radiotherapy groups compared with the nonradiotherapy group (P = 0.01 and P < 0.0001, respectively). Estimated blood loss, mean number of blood units transfused per patient, and the percentage of patients being transfused were similar among the groups. Early postoperative complications were significantly higher in the neoadjuvant radiotherapy groups compared with the nonradiotherapy group. Late complications, overall survival, disease-free survival, and local recurrence were not significantly different among the groups. CONCLUSIONS: In patients with cancer of the lower one-third of the rectum, sharp pelvic dissection can result in a low rate of local recurrence even without radiotherapy. The role of preoperative radiotherapy, although associated with higher perineal wound complications, is important in increasing resectability and sphincter-preservation rate. Randomized, prospective trials will be needed to establish the role of adjuvant radiotherapy in patients undergoing sharp mesorectal excision for rectal cancer.