Morbidity Associated with Diverting Loop Ileostomies: Weighing Diversion in Rectosigmoid Resection.

Anterior resection with primary anastomosis is the procedure of choice for patients with rectosigmoid cancers with good sphincter function. Surgeons may perform an associated diverting loop ileostomy (DLI) to minimize the likelihood and/or the severity of an anastomotic leak. To examine the morbidity of DLIs, we performed a review of a prospectively maintained database. Participants included all patients at the Massachusetts General Hospital who underwent anterior resection from January 2013 to July 2015 for rectosigmoid cancers and who subsequently underwent adjuvant chemotherapy. The primary outcome was time to start of adjuvant chemotherapy. Secondary outcomes included length of hospitalization, perioperative complications, and 60-day postoperative complications. Inclusion criteria were met in 57 patients and DLI was performed in 21 (37%). The DLI group had higher estimated blood loss (431.7 vs 192.1 mL, P = 0.03) and a longer operation time (3.7 vs 2.3 hours, P = 0.0007). The DLI group took over a week longer to start adjuvant chemotherapy than the non-DLI group (median time to chemo: 43 vs 34 days, P = 0.002). Postoperatively, DLI was associated with a longer hospitalization (6.7 vs 3.1 days, P = 0.0003), more perioperative complications (57.1% vs 13.9%, P = 0.0006), and more 60-day readmissions or emergency department visits (38.1% vs 5.6%, P = 0.002). Ostomies are associated with appreciable morbidity. In turn, they do not eliminate postoperative complications. Surgeons should closely consider ostomy morbidity in rectosigmoid resection and institute a proactive approach toward identification and prevention of complications.

Transanal endoscopic resection with peritoneal entry: a word of caution.

BACKGROUND: Peritoneal entry during transanal endoscopic microsurgery (TEM) can usually be managed transanally with full-thickness suture closure by experienced operators. The preliminary safety of transanal minimally invasive surgery (TAMIS) has been demonstrated, but the reported experience with upper rectal tumors is limited. The incidence and management of peritoneal entry during transanal endoscopic surgery across various platforms have not been previously evaluated. METHODS: Retrospective analysis of a prospectively maintained database of all transanal endoscopic resections performed at a single institution between January 2008 and December 2014 was conducted. Cases with and without peritoneal entry were evaluated with respect to transanal platform used, surgical indication, size, location and distance from the anal verge, and incidence of postoperative complications. RESULTS: A total of 78 transanal endoscopic procedures were performed on 76 patients using the rigid transanal endoscopic operation (TEO, 65.4 %), TEM (26.9 %), and TAMIS platform (7.7 %). The most common surgical indication included endoscopically unresectable adenomas (50 %). The average distance of lesions from the anal verge (AV) was 9.6 cm (range 4-20 cm). Peritoneal entry occurred in 22 cases (28.2 %). Platform used (TAMIS vs. rigid, p < 0.05), mean distance from the AV (p < 0.0001), location along the rectum (p = 0.01), and mean specimen size (p = 0.01) were associated with a higher likelihood of peritoneal entry. All rectal defects associated with peritoneal entry were successfully closed transanally except for two (TEM and TEO) cases that required conversion to laparoscopic low anterior resection and laparoscopic Hartmann's, respectively. There were four TAMIS cases that required conversion to TEO platforms. CONCLUSION: In this high-risk TEM, TEO, and TAMIS series (one-third of rectal lesions located in the upper rectum), 91 % of all peritoneal entries were managed transanally without increased morbidity. TAMIS for upper rectal lesions was associated with a high risk of complicated peritoneal entry requiring conversion to a rigid platform.

Natural history of perianal Crohn's disease after fecal diversion.

BACKGROUND: Temporary fecal diversion has been used to allow severe perianal Crohn's disease (CD) to heal. Most data on intestinal reconnection rates precede the biological era with limited patient follow-up after reconnection. We, therefore, sought to evaluate the natural history of perianal CD after fecal diversion. METHODS: We identified 49 patients with CD and perianal involvement who underwent fecal diversion between 1991 and 2011 at a tertiary referral care center. Demographics, medication use, onset and extent of disease, and surgical interventions were abstracted. We determined the percentage of patients who were able to restore intestinal continuity and assessed the sustainability of this reversal. Time to intestinal reconnection and subsequent procedures were determined. We also examined temporal trends in the proportion of patients with perianal CD undergoing diversion or management with seton/EUA/fistulotomy between 2000 and 2011. RESULTS: Fifteen of 49 patients (31%) reestablished intestinal continuity during the study follow-up period. Ten of 15 patients (67%) who had reestablished intestinal continuity required an additional procedure to divert the fecal stream. Of the 5 patients who remained reconnected, 3 patients required further procedures to control sepsis. The proportion of patients with CD requiring perianal surgical interventions declined between 2000 and 2011. CONCLUSIONS: Severe perianal CD remains a challenging problem. In patients with CD with perianal disease requiring fecal diversion, the likelihood of sustained intestinal continuity remains low, despite greater biological use. However, there has been a temporal decline in the rate of surgical interventions required for perianal CD from 2000 to 2011.

Endoscopic piecemeal resection of large colorectal polyps with long-term followup.

BACKGROUND: Colonoscopic removal of large colorectal polyps is challenging and requires advanced endoscopic technique. Successful endoscopic management not only avoids the morbidity of surgery but also risks perforation, hemorrhage, and recurrence. METHODS: This study is a retrospective review of a prospectively maintained database of all patients undergoing cautery snare piecemeal polypectomy for large colorectal polyps by a single operator over 20 years with long-term followup. RESULTS: 231 patients underwent 269 piecemeal polypectomies over a 20 year period. The complication rate was 4.3 %. Malignancy was identified in 25 (10.8 %) of patients. Local recurrences occurred in 24 % of patients with benign adenomas. The vast majority of these were managed with repeat endoscopy. Overall, benign large polyps were managed successfully endoscopically in 94.4 % of patients. CONCLUSIONS: Piecemeal polypectomy is effective and safe for the management of large colorectal polyps. With long-term followup, the recurrence rate is appreciable, but most recurrences can be successfully managed with further endoscopic intervention. More complex techniques such as endoscopic submucosal dissection are usually unnecessary.

Early-stage rectal cancer: clinical and pathologic prognostic markers of time to local recurrence and overall survival after resection.

BACKGROUND: Resection without adjuvant therapy results in a low recurrence rate for patients with stage I (T1/2 N0) rectal cancer in the range of 4% to 16% at 5 years. There are limited data, however, regarding clinical or pathologic prognostic markers for recurrence in this population. OBJECTIVE: The aim of this study is to assess the clinical and pathologic factors associated with local recurrence and overall survival in patients with early-stage rectal cancer after resection. DESIGN: This is a retrospective study. SETTING: This study was conducted at 2 tertiary care centers in Boston, Massachusetts. PATIENTS: From 2000 to 2008, 175 patients with stage I rectal cancer treated with local or total mesorectal excision without adjuvant therapy were identified. MAIN OUTCOME MEASURES: Time to local recurrence after resection and overall survival were evaluated for all patients with complete follow-up data. Perioperative data were reviewed to identify staging method, preoperative CEA, type of surgery, tumor size, number of lymph nodes resected, histological grade, circumferential resection margin, perineural invasion, lymphovascular invasion, and tumor ulceration. Data were analyzed by using a Cox proportional hazards regression model. RESULTS: Of the eligible cohort, 137 patients had complete follow-up data for analysis of time to local recurrence, and only 23 (16.8%) patients had local recurrence. Among these 23 patients, the median time to recurrence was 1.1 years (0.1-7.8). On multivariate analysis, male sex, current alcohol use, and tumor ulceration were associated with heightened risk of local recurrence. Of the original cohort, 173 patients had complete follow-up for overall survival analysis. Among these patients, the median overall survival was 12 years. On multivariable analysis, age at diagnosis >65 years and T2 pathologic stage were associated with decreased survival. LIMITATIONS: As in any retrospective study, there is a potential for selection bias. Several patients were excluded from the analysis due to inadequate follow-up data. These results from two academic medical centers with specialized colorectal surgeons may not be generally applicable. The relatively small number of events, ie, recurrences, suggest the findings should be validated in a larger study. CONCLUSIONS: For patients with stage I rectal cancer treated with resection alone, these results provide important prognostic information and may help identify those who could benefit from additional therapy.

Wound dehiscence after abdominoperineal resection for low rectal cancer is associated with decreased survival.

BACKGROUND: Abdominoperineal resection for low rectal adenocarcinoma is a common procedure with high morbidity, including perineal wound complications. OBJECTIVE: The purpose of this study was to determine risk factors for perineal wound dehiscence and to investigate the effect of wound dehiscence on survival. DESIGN: This was a retrospective medical chart review. SETTINGS: The study was conducted in a tertiary care university medical center. PATIENTS: Patients included in the study were those with low rectal adenocarcinoma who underwent abdominoperineal resection between January 2001 and June 2012. MAIN OUTCOMES MEASURES: We assessed the incidence of perineal wound dehiscence, as well as survival, after surgery. RESULTS: A total of 249 patients underwent abdominoperineal resection for rectal carcinoma. The mean age was 62.6 years (range, 23.0-98.0 years), 159 (63.8%) were male, and the mean BMI was 27.9 (range, 16.7-58.5). There were 153 patients (61.1%) who survived for 5 years after surgery. Sixty-nine patients (27.7%) developed wound dehiscence. Multivariable analysis revealed the following associations with dehiscence: BMI (OR, 1.09; 95% CI, 1.03-1.15; p = 0.002), IBD (OR, 6.6; 95% CI, 1.4-32.5; p = 0.02), history of other malignant neoplasm (OR, 3.1; 95% CI, 1.5-6.6), and abdominoperineal resection for cancer recurrence (OR, 2.8; 95% CI, 1.2-6.3; p = 0.01). In the survival analysis, wound dehiscence was associated with decreased survival (mean survival time for dehiscence vs no dehiscence, 66.6 months vs 76.6 months; p = 0.01). This relationship persisted in the multivariable analysis (HR, 1.7; 95% CI, 1.1-2.8; p = 0.02). LIMITATIONS: This was a retrospective, observational study from a single center. CONCLUSIONS: The adjusted risk of death was 1.7 times higher in patients who experienced dehiscence than in those who did not. Attention to perineal wound closure with consideration of flap creation should at least be given to patients with a history of malignant neoplasm, those with IBD, those with rectal cancer recurrence, and women undergoing posterior vaginectomy. Preoperative weight loss should also reduce dehiscence risk.

Does preoperative total parenteral nutrition in patients with ulcerative colitis produce better outcomes?

PURPOSE: Malnutrition is a frequent problem in patients with ulcerative colitis (UC) leading to increased postoperative complication rates. Preoperative total parenteral nutrition (TPN) has been shown to reduce complications in some subgroups of patients, but has not been studied in UC. We investigated the impact of preoperative TPN on postoperative complication rates in patients undergoing surgery for UC. METHODS: This paper is a review of 235 patients who underwent surgery for UC; 56 received preoperative TPN and 179 did not. Postoperative complication rates were compared. RESULTS: Both had similar rates of anastomotic leak (5.4 vs. 2.8 %, p = 0.356), infection (12.5 vs. 20.1 %, p = 0.199), ileus/bowel obstruction (21.4 vs. 15.6 %, p = 0.315), cardiac complications (3.6 vs. 0 %, p = 0.056), wound dehiscence (3.6 vs. 1.7 %, p = 0.595), reoperation (10.7 vs. 3.9 %, p = 0.086), and death (1.8 vs. 0 %, p = 0.238). The TPN group was more malnourished (albumin 2.49 vs. 3.45, p < 0.001), more often on steroids (83.9 vs. 57.5 %, p < 0.001), had more emergent surgery (10.7 vs. 3.4 %, p = 0.029), more severe colitis (89.3 vs. 65.9 %, p = 0.001), and lower Surgical Apgar Score (6.15 vs. 6.57, p = 0.033). After controlling for these with logistic regression, the TPN group still had higher complication rates (OR 2.32, p = 0.04). When line infections were excluded, TPN did not significantly affect outcomes (OR 1.5, p = 0.311) CONCLUSION: There were no differences in postoperative complications when line infections were excluded. Our data does not support routine preoperative TPN in patients with UC. However, it may lead to equal surgical outcomes in the sickest and most malnourished patients at the cost of line-related morbidity.

Short-term outcomes in obese patients after colectomy for adenocarcinoma at a bariatric center.

INTRODUCTION: Obesity (body mass index ≥30) is associated with worse outcomes after colon cancer surgery. Most research, however, has been performed outside bariatric centers of excellence. We sought to determine the relationship between obesity and outcomes after colon cancer resection when performed at a center with bariatric expertise. METHODS: We performed a retrospective review of 245 consecutive patients undergoing elective colectomy for adenocarcinoma at a single institution from 2008 to 2009. Body mass index, major and minor postoperative complications, tumor characteristics, lymph node yield, type of resection, and operating times were determined. RESULTS: Complication rates, operative times, and lymph node counts were all similar between the two weight groups. Obese patients had similar tumor characteristics at all stages when compared with nonobese patients. On multivariate analysis, obesity did not correlate with tumor size, tumor differentiation, or presence of lymphovascular or perineural invasion. CONCLUSION: We conclude that obese patients undergoing colon cancer resection at a bariatric center of excellence have similar tumor characteristics and equivalent short-term outcomes as do nonobese patients.

Sigmoidectomy syndrome? Patients' perspectives on the functional outcomes following surgery for diverticulitis.

BACKGROUND: Bowel function following surgery for diverticulitis has not previously been systematically described. OBJECTIVE: This study aimed to document the frequency, severity, and predictors of suboptimal bowel function in patients who have undergone sigmoid colectomy for diverticulitis. DESIGN: This study is a retrospective analysis. SETTING: This study was conducted at a large, academic medical center. PATIENTS: Three hundred twenty-five patients who underwent laparoscopic or open sigmoid colectomy with restoration of intestinal continuity for diverticulitis were included in the study population. Of these, 249 patients (76.6%) returned a 70-question survey incorporating the Fecal Incontinence Severity Index, the Fecal Incontinence Quality of Life Scale, and the Memorial Bowel Function Instrument. MAIN OUTCOME MEASURES: Survey responders and nonresponders were compared with the use of χ and t tests. Responders with suboptimal bowel function (fecal incontinence, urgency and/or incomplete emptying) were then compared with those with good outcomes by the use of logistic regression analysis to determine the predictors of poor function. RESULTS: Of the responders, 24.8% reported clinically relevant fecal incontinence (Fecal Incontinence Severity Index ≥ 24), 19.6% reported fecal urgency (Memorial Bowel Function Instrument Urgency Subscale ≥ 4), and 20.8% reported incomplete emptying (Memorial Bowel Function Instrument Emptying Subscale ≥ 4). On logistic regression analysis, fecal incontinence was predicted by female sex (OR = 2.3, p = 0.008) and the presence of a preoperative abscess (OR = 1.4, p < 0.05). Fecal urgency was associated with female sex (OR = 1.3, p < 0.05) and a diverting ileostomy (OR = 2.1, p < 0.001). Incomplete emptying was associated with female sex (OR = 1.4, p < 0.05) and postoperative sepsis (OR = 1.9, p < 0.05). LIMITATIONS: This study was limited by the fact that we did not use a nondiverticulitis control group and we had limited preoperative data on the history of bowel impairment symptoms. CONCLUSION: One-fifth of patients reported fecal urgency, fecal incontinence, or incomplete emptying after surgery for diverticulitis. Despite the limitations of our study, these results are concerning and should be investigated further prospectively.

Determining the need for radical surgery in patients with T1 rectal cancer.

HYPOTHESIS: In the era of modern preoperative staging of patients with rectal cancer, lymph node metastases can be reliably predicted by the histological features of the tumor and preoperative imaging. Local resection can then be safely offered to the patients who are at low risk of having malignant lymph nodes. DESIGN: We reviewed the records of 109 consecutive patients with preoperative imaging results suggestive of T1N0 or T2N0 disease who underwent total mesorectal excision. All patients underwent preoperative endorectal ultrasonography or magnetic resonance imaging and computed tomography, with or without positron emission tomography. Final pathologic investigation identified T3 disease in 27 patients. History, physical examination results, and radiologic and pathologic data were evaluated for predictors of positive nodes in the remaining 82 patients. SETTING: Tertiary care referral center. PATIENTS: Patients with preoperative imaging suggestive of T1N0 or T2N0 rectal cancer. MAIN OUTCOME MEASURES: To evaluate different clinical and pathologic tumor features as predictors of positive lymph nodes in T1 and T2 rectal cancers with negative radiographic nodes. BACKGROUND: Local resection of T1 and T2 rectal cancer results in lower morbidity compared with radical resection. However, recurrence rates after local resection are higher, likely owing to unresected nodal metastasis. Reports on predictors of lymph node metastasis remain inconsistent in the literature. Although local resection may be appropriate for some rectal cancers, selection criteria remain unclear. RESULTS: Despite indications of negative nodes on radiographic examination, 4 of 35 patients with T1 disease (11%) and 13 of 47 with T2 disease (28%) had positive nodes. On univariate analysis, the only significant predictor was depth of invasion: 24 of 65 patients with negative nodes (37%) vs 13 of 17 patients with positive nodes (76%) had tumors invading the lower third of the submucosa and beyond (P = .02). On logistic regression analysis accounting for depth of invasion (lower third of the submucosa and beyond), size, distance from anal verge, differentiation, and lymphovascular and small-vessel invasion, only depth of invasion remained a significant predictor. CONCLUSIONS: In all, 89% of patients with T1 disease (31 of 35) and 72% of those with T2 disease (34 of 47) underwent unnecessary radical resection. Endorectal ultrasonography or magnetic resonance imaging and computed tomography, with or without positron emission tomography, for preoperative staging could not identify these patients reliably. In addition, histologic markers of aggressive disease were not helpful. Thus, local resection for T2 rectal cancer is not justified. Local resection should be offered only to patients with superficial T1 tumors who will adhere to aggressive postoperative surveillance.

The effect of neoadjuvant chemoradiation therapy on the prognostic value of lymph nodes after rectal cancer surgery.

BACKGROUND: Neoadjuvant therapy may affect the prognostic impact of total lymph node harvests and lymph node positivity after surgery for rectal cancer. METHODS: We performed a retrospective review of 390 consecutive patients with histologically confirmed rectal cancer. Postoperative follow-up evaluation and survival were confirmed via medical record review. The impacts of lymph node positivity and total lymph node harvest on survival and recurrence are reflected as proportional hazard ratios (HRs). RESULTS: A total of 221 patients underwent neoadjuvant therapy, of whom 75 had positive nodes. Node-positive patients showed a significantly shorter survival time (HR, 2.89; P = .002) and time to local recurrence (HR, 6.36; P = .031) compared with patients without positive nodes. Survival and recurrence were not significantly different between patients with a total harvest of fewer than 12 nodes and patients with a higher lymph node harvest. CONCLUSIONS: After neoadjuvant treatment and total mesorectal excision, lymph node positivity is associated with significantly shorter survival and time to local recurrence in rectal cancer patients, whereas absolute total lymph node harvests likely have little impact on prognosis.

A safety and survival analysis of neoadjuvant bevacizumab with standard chemoradiation in a phase I/II study compared with standard chemoradiation in locally advanced rectal cancer.

INTRODUCTION: Bevacizumab is increasingly being tested with neoadjuvant regimens in patients with localized cancer, but its effects on metastasis and survival remain unknown. This study examines the long-term outcome of clinical stage II/III rectal cancer patients treated in a prospective phase II study of bevacizumab with chemoradiation and surgery. As a benchmark, we used data from an analysis of 42 patients with locally advanced rectal cancer treated with a contemporary approach of preoperative fluoropyrimidine-based radiation therapy. MATERIALS AND METHODS: Outcome analyses were performed on 32 patients treated prospectively with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery as well as 42 patients treated with standard fluoropyrimidine-based chemoradiation. RESULTS: Overall survival, disease-free survival, and local control showed favorable trends in patients treated with bevacizumab with chemoradiation followed by surgery. Acute and postoperative toxicity appeared acceptable. CONCLUSIONS: Neoadjuvant bevacizumab with standard chemoradiation and surgery shows promising long-term efficacy and safety profiles in locally advanced rectal cancer patients.

Plasma soluble VEGFR-1 is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced rectal cancer.

We explored plasma and urinary concentrations of two members of the vascular endothelial growth factor (VEGF) family and their receptors as potential response and toxicity biomarkers of bevacizumab with neoadjuvant chemoradiation in patients with localized rectal cancer. The concentrations of VEGF, placental growth factor (PlGF), soluble VEGF receptor 1 (sVEGFR-1), and sVEGFR-2 were measured in plasma and urine at baseline and during treatment. Pretreatment values and changes over time were analyzed as potential biomarkers of pathological response to treatment as well as for acute toxicity in patients with locally advanced rectal cancer treated prospectively in 2002-2008 with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery in a phase I/II trial. Of all biomarkers, pretreatment plasma sVEGFR-1-an endogenous blocker of VEGF and PlGF, and a factor linked with "vascular normalization"-was associated with both primary tumor regression and the development of adverse events after neoadjuvant bevacizumab and chemoradiation. Based on the findings in this exploratory study, we propose that plasma sVEGFR-1 should be further studied as a potential biomarker to stratify patients in future studies of bevacizumab and/or cytotoxics in the neoadjuvant setting.

Preoperative infliximab treatment in patients with ulcerative and indeterminate colitis does not increase rate of conversion to emergent and multistep abdominal surgery.

INTRODUCTION: A recent study has raised concerns that infliximab treatment, by postpoing surgery for ulcerative and indeterminate colitis patients, may result in a greater need for high-risk emergent or multistep surgical procedures (subtotal colectomies). Our aim was to assess whether infliximab exposure affects rates of subotal colectomy in a large cohort of patients. METHODS: We evaluated 171 consecutive patients with ulcerative or indeterminate colitis who had a total proctocolectomy or a subtotal colectomy between 1993 and 2006 for symptoms of unremitting disease. Forty-four patients (25.7%) received infliximab prior to surgery. We compared the surgical procedures employed on these 44 patients to the surgical procedures employed on the 127 non-infliximab patients, using Fisher's exact or Student's t test. RESULTS: Infliximab exposure did not appear to affect the rate of emergent surgery (4.5% vs 4.4%, p = 0.98), rate of subtotal colectomy (19.2% vs. 18.0%, p = 0.99), or rate of ileoanal J pouch reconstruction (53.8% vs. 62%, p = 0.98). Nor did it affect intraoperative findings of perforation, toxic megacolon, and active disease. The infliximab and non-infliximab cohorts were similar in age, Charlson Comorbidity Index, concomitant steroid use, and albumin levels, although infliximab patients had higher rates of concomitant exposure to 6-mercaptopurine (34.1% vs 16.6%, p = 0.02) and azathioprine (40.9% vs 22.6%, p = 0.02). CONCLUSION: Infliximab does not appear to increase rates of emergent surgery or multistep procedures in patients undergoing treatment for ulcerative or indeterminative colitis at our institution.

Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer.

Clinical studies converge on the observation that circulating cytokines are elevated in most cancer patients by anti-vascular endothelial growth factor (VEGF) therapy. However, the source of these molecules and their relevance in tumor escape remain unknown. We examined the gene expression profiles of cancer cells and tumor-associated macrophages in tumor biopsies before and 12 days after monotherapy with the anti-VEGF antibody bevacizumab in patients with rectal carcinoma. Bevacizumab up-regulated stromal cell-derived factor 1alpha (SDF1alpha), its receptor CXCR4, and CXCL6, and down-regulated PlGF, Ang1, and Ang2 in cancer cells. In addition, bevacizumab decreased Ang1 and induced neuropilin 1 (NRP1) expression in tumor-associated macrophages. Higher SDF1alpha plasma levels during bevacizumab treatment significantly associated with distant metastasis at three years. These data show that VEGF blockade up-regulates inflammatory pathways and NRP1, which should be evaluated as potential targets for improving anti-VEGF therapy.

Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study.

PURPOSE: To assess the safety and efficacy of neoadjuvant bevacizumab with standard chemoradiotherapy in locally advanced rectal cancer and explore biomarkers for response. PATIENTS AND METHODS: In a phase I/II study, 32 patients received four cycles of therapy consisting of: bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; fluorouracil infusion (225 mg/m(2)/24 hours) during cycles 2 to 4; external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks); and surgery 7 to 10 weeks after completion of all therapies. We measured molecular, cellular, and physiologic biomarkers before treatment, during bevacizumab monotherapy, and during and after combination therapy. RESULTS: Tumors regressed from a mass with mean size of 5 cm (range, 3 to 12 cm) to an ulcer/scar with mean size of 2.4 cm (range, 0.7 to 6.0 cm) in all 32 patients. Histologic examination revealed either no cancer or varying numbers of scattered cancer cells in a bed of fibrosis at the primary site. This treatment resulted in an actuarial 5-year local control and overall survival of 100%. Actuarial 5-year disease-free survival was 75% and five patients developed metastases postsurgery. Bevacizumab with chemoradiotherapy showed acceptable toxicity. Bevacizumab decreased tumor interstitial fluid pressure and blood flow. Baseline plasma soluble vascular endothelial growth factor receptor 1 (sVEGFR1), plasma vascular endothelial growth factor (VEGF), placental-derived growth factor (PlGF), and interleukin 6 (IL-6) during treatment, and circulating endothelial cells (CECs) after treatment showed significant correlations with outcome. CONCLUSION: Bevacizumab with chemoradiotherapy appears safe and active and yields promising survival results in locally advanced rectal cancer. Plasma VEGF, PlGF, sVEGFR1, and IL-6 and CECs should be further evaluated as candidate biomarkers of response for this regimen.