Oxaliplatin-Based Adjuvant Chemotherapy for Rectal Cancer After Preoperative Chemoradiotherapy (ADORE): Long-Term Results of a Randomized Controlled Trial.

PURPOSE: We evaluated the role of oxaliplatin as adjuvant chemotherapy in patients with rectal cancer who received preoperative chemoradiotherapy (CRT) with fluoropyrimidine monotherapy and total mesorectal excision (TME). METHODS: The ADORE trial (adjuvant oxaliplatin in rectal cancer) is a multicenter, randomized trial in patients with postoperative ypStage II (ypT3-4N0) or III (ypTanyN1-2) rectal cancer after fluoropyrimidine-based preoperative CRT and TME. Patients were randomly assigned (1:1) to receive adjuvant chemotherapy either with FL (fluorouracil 380 mg/m2 and leucovorin 20 mg/m2) or FOLFOX (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and fluorouracil bolus 400 mg/m2 on day 1, fluorouracil infusion 2,400 mg/m2 for 46 hours). Stratification factors included ypStage and participating center. Primary end point was disease-free survival (DFS). RESULTS: A total of 321 patients were enrolled between November 19, 2008, and June 12, 2012. Six-year DFS rates were 68.2% in the FOLFOX arm versus 56.8% in the FL arm, with a stratified hazard ratio of 0.63 (95% CI, 0.43 to 0.93; P = .018) by intention-to-treat analysis. In the subgroup analysis for DFS, FOLFOX was favorable versus FL in patients with ypStage III, ypN1b, ypN2, high-grade histology, minimally regressed tumor, and an absence of lymphovascular or perineural invasion. Six-year overall survival rate was 78.1% in the FOLFOX arm versus76.4% in the FL arm (hazard ratio, 0.73; 95% CI, 0.45 to 1.19; P = .21). In the subgroup analysis for OS, FOLFOX was favorable versus FL in patients with ypN2 and minimally regressed tumor. CONCLUSION: Adjuvant FOLFOX improved DFS in patients with rectal cancer with ypStage II and III disease after preoperative CRT. Adjuvant FOLFOX may be considered on the basis of the postoperative pathologic stage in those who received preoperative CRT and TME.

Microsatellite Instability was not Associated with Survival in Stage III Colon Cancer Treated with Adjuvant Chemotherapy of Oxaliplatin and Infusional 5-Fluorouracil and Leucovorin (FOLFOX).

BACKGROUND: The impact of microsatellite instability (MSI) on survival in stage III colon cancer treated with adjuvant 5-fluorouracil-oxaliplatin combination (FOLFOX) chemotherapy is not clear. We evaluated the association between MSI and survival in this population. METHODS: We analyzed 598 patients with curatively resected stage III colon cancer treated with adjuvant FOLFOX chemotherapy. We determined MSI status using polymerase chain reaction amplification; tumors were classified as high MSI (MSI-H, ≥2 unstable markers), low MSI (MSI-L, 1 unstable marker), or microsatellite stable (MSS, no unstable marker). RESULTS: Of 598 patients, 8.4% showed MSI-H. Tumors classified as MSI-H were more commonly located in the ascending colon (54.0 vs. 27.7%, p < 0.0001) and had poorly differentiated features (32.0 vs. 8.0%, p < 0.0001). After the median follow-up of 52.8 months, 5-year disease-free (DFS) and overall survival (OS) rates were 77.0 and 85.9%, respectively. In univariate analysis, pathologic T4 (pT4) and pathologic N2 (pN2) was associated with reduced DFS (p < 0.0001 and p < 0.0001, respectively) and OS (p = 0.002 and p = 0.001, respectively), whereas MSI status did not affect either DFS (p = 0.114) or OS (p = 0.525). In patients with pN2 tumors; however, MSI-H was associated with better survival compared with MSS/MSI-L; DFS and OS in patients with MSI-H/pN2 were comparable to those in patients with pN1 tumors. CONCLUSIONS: In patients with stage III colon cancer treated with adjuvant FOLFOX, pT4 and pN2 was associated with reduced survival, but MSI status alone did not affect survival.

Oncologic Safety of Local Excision Compared With Total Mesorectal Excision for ypT0-T1 Rectal Cancer: A Propensity Score Analysis.

Good oncologic outcomes, demonstrated by a complete pathologic response after preoperative chemoradiotherapy (PCRT), have led to local excision (LE) in selected patients with rectal cancer. We evaluated the oncologic safety of LE compared with total mesorectal excision (TME) in patients with ypT0-T1 rectal cancer.A retrospective review of 304 patients who underwent PCRT, followed by LE or TME, for ypT0-T1 rectal cancer was performed. Propensity scores were computed and used to match groups (LE:TME = 1:1), and analysis of disease-free survival (DFS) and overall survival (OS) was made by comparing patients who underwent LE or TME. Prognostic factors of relapse were analyzed for all patients.Tumor categories were ypT0 in 25 (61.9%) cases, ypTis in 6 (14.3%) cases, and ypT1 in 11 (26.2%) cases for the LE group, and ypT0 in 28 (66.7%) cases, ypTis in 4 (9.5%) cases, and ypT1 in 10 (23.8%) cases for the matched TME patients. There was no significant difference between the matched LE and TME groups in relapse (4.8% and 7.14%, respectively; P = 0.646), 5-year DFS (95.2% vs 91.6%; P = 0.33) and 5-year OS (96.6% vs 88.0%; P = 0.238). In the multivariate Cox regression analysis, tumor distance from the anal verge (hazard ratio [HR] = 0.78; 95% confidence interval (CI) = 0.616-0.992) and the tumor grade (HR = 4.29; 95% CI = 1.430-12.886) were significantly associated with the recurrence risk.LE results in oncologic outcomes that are comparable to those achieved by TME in selected patients with ypT0-T1 rectal cancer after PCRT.

Role of Adjuvant Chemotherapy in ypT0-2N0 Patients Treated with Preoperative Chemoradiation Therapy and Radical Resection for Rectal Cancer.

OBJECTIVE: To explore the role of adjuvant chemotherapy for patients with ypT0-2N0 rectal cancer treated by preoperative chemoradiation therapy (PCRT) and radical resection. PATIENTS AND METHODS: A national consortium of 10 institutions was formed, and patients with ypT0-2N0 mid- and low-rectal cancer after PCRT and radical resection from 2004 to 2009 were included. Patients were categorized into 2 groups according to receipt of additional adjuvant chemotherapy: Adj CTx (+) versus Adj CTx (-). Propensity scores were calculated and used to perform matched and adjusted analyses comparing relapse-free survival (RFS) between treatment groups while controlling for potential confounding. RESULTS: A total of 1016 patients, who met the selection criteria, were evaluated. Of these, 106 (10.4%) did not receive adjuvant chemotherapy. There was no overall improvement in 5-year RFS as a result of adjuvant chemotherapy [91.6% for Adj CTx (+) vs 87.5% for Adj CTx (-), P=.18]. There were no differences in 5-year local recurrence and distant metastasis rate between the 2 groups. In patients who show moderate, minimal, or no regression in tumor regression grade, however, possible association of adjuvant chemotherapy with RFS would be considered (hazard ratio 0.35; 95% confidence interval 0.14-0.88; P=.03). Cox regression analysis after propensity score matching failed to show that addition of adjuvant chemotherapy was associated with improved RFS (hazard ratio 0.81; 95% confidence interval 0.39-1.70; P=.58). CONCLUSIONS: Adjuvant chemotherapy seemed to not influence the RFS of patients with ypT0-2N0 rectal cancer after PCRT followed by radical resection. Thus, the addition of adjuvant chemotherapy needs to be weighed against its oncologic benefits.

Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial.

BACKGROUND: The role of adjuvant chemotherapy for patients with rectal cancer is controversial, especially when used after preoperative chemoradiotherapy. Fluoropyrimidine-based adjuvant chemotherapy, including fluorouracil and leucovorin, has been widely used; however, the addition of oxaliplatin to fluorouracil and leucovorin (FOLFOX), a standard adjuvant regimen for colon cancer, has not been tested in rectal cancer. We aimed to compare the efficacy and safety of adjuvant fluorouracil and leucovorin with that of FOLFOX in patients with locally advanced rectal cancer after preoperative chemoradiotherapy. METHODS: In this open-label, multicentre, phase 2, randomised trial, patients with postoperative pathological stage II (ypT3-4N0) or III (ypTanyN1-2) rectal cancer after preoperative fluoropyrimidine-based chemoradiotherapy and total mesorectal excision were recruited and randomly assigned (1:1) via a web-based software platform to receive adjuvant chemotherapy with either four cycles of fluorouracil and leucovorin (fluorouracil 380 mg/m(2) and leucovorin 20 mg/m(2) on days 1-5, every 4 weeks) or eight cycles of FOLFOX (oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil bolus 400 mg/m(2) on day 1, and fluorouracil infusion 2400 mg/m(2) for 46 h, every 2 weeks). Stratification factors were pathological stage (II vs III) and centre. Neither patients nor investigators were masked to group assignment. The primary endpoint was 3-year disease-free survival, analysed by intention to treat. This study is fully enrolled, is in long-term follow-up, and is registered with ClinicalTrials.gov, number NCT00807911. FINDINGS: Between Nov 19, 2008, and June 12, 2012, 321 patients were randomly assigned to fluorouracil and leucovorin (n=161) and FOLFOX (n=160). 141 (95%) of 149 patients in the fluorouracil plus leucovorin group and 141 (97%) of 146 in the FOLFOX group completed all planned cycles of adjuvant treatment. Median follow-up was 38·2 months (IQR 26·4-50·6). 3-year disease-free survival was 71·6% (95% CI 64·6-78·6) in the FOLFOX group and 62·9% (55·4-70·4) in the fluorouracil plus leucovorin group (hazard ratio 0·657, 95% CI 0·434-0·994; p=0·047). Any grade neutropenia, thrombocytopenia, fatigue, nausea, and sensory neuropathy were significantly more common in the FOLFOX group than in the fluorouracil plus leucovorin group; however, we noted no significant difference in the frequency of these events at grade 3 or 4. The most common grade 3 or worse adverse events were neutropenia (38 [26%] of 149 patients in the fluorouracil plus leucovorin group vs 52 [36%] of 146 patients in the FOLFOX group), leucopenia (eight [5%] vs 12 [8%]), febrile neutropenia (four [3%] vs one [<1%]), diarrhoea (four [3%] vs two [1%]), and nausea (one [<1%] vs two [1%]). INTERPRETATION: Adjuvant FOLFOX improves disease-free survival compared with fluorouracil plus leucovorin in patients with locally advanced rectal cancer after preoperative chemoradiotherapy and total mesorectal excision, and warrants further investigation. FUNDING: Korea Healthcare Technology R&D Project (South Korean Ministry of Health and Welfare).

Oncologically safe distal resection margins in rectal cancer patients treated with chemoradiotherapy.

INTRODUCTION: Although current guidelines recommend distal resection margins (DRM) of 2-5 cm in rectal cancer operation, smaller margins may be safe. We therefore assessed the impact of distal margins on outcomes in patients with rectal cancer treated with neoadjuvant chemoradiotherapy (CRT) followed by radical resection or resection followed by adjuvant CRT. MATERIALS AND METHODS: This study involved 376 patients who underwent sphincter-saving resection for rectal adenocarcinoma and pre- or postoperative CRT between 2000 and 2006. DRMs were measured on pinned fixed specimens. We excluded patients who did not complete planned CRT and those with stage IV disease. A retrospective cross-sectional analysis was performed. RESULTS: No significant differences in local recurrence (9.8 versus 7.3%; P = 0.324) and systemic recurrence (16.4 versus 18.7%; P = 0.731) were observed in patients with DRMs of ≤5 and >5 mm, respectively. Moreover, in each DRM category, there were no differences in local and systemic recurrence rates between patients who received pre- or postoperative CRT. DRM did not affect overall survival (P = 0.880) or 5-year survival rate (80.3 versus76.8%; P = 0.340). CONCLUSION: A distal margin of at least 5 mm with negative resection margin on frozen section does not reduce oncological safety in rectal cancer patients who receive pre- or postoperative CRT.

Adjuvant chemotherapy with or without pelvic radiotherapy after simultaneous surgical resection of rectal cancer with liver metastases: analysis of prognosis and patterns of recurrence.

PURPOSE: To investigate the outcomes of adjuvant chemotherapy (CT) or chemoradiotherapy (CRT) after simultaneous surgical resection in rectal cancer patients with liver metastases (LM). MATERIALS AND METHODS: One hundred and eight patients receiving total mesorectal excision for rectal cancer and surgical resection for LM were reviewed. Forty-eight patients received adjuvant CRT, and 60 were administered CT alone. Recurrence patterns and prognosis were analyzed. Disease-free survival (DFS) and overall survival (OS) rates were compared between the CRT and CT groups. The inverse probability of the treatment-weighted (IPTW) method based on the propensity score was used to adjust for selection bias between the two groups. RESULTS: At a median follow-up period of 47.7 months, 77 (71.3%) patients had developed recurrences. The majority of recurrences (68.8%) occurred in distant organs. By contrast, the local recurrence rate was only 4.7%. Median DFS and OS were not significantly different between the CRT and CT groups. After applying the IPTW method, we observed no significant differences in terms of DFS (hazard ratio [HR], 1.347; 95% confidence interval [CI], 0.759-2.392; p = 0.309) and OS (HR, 1.413; CI, 0.752-2.653; p = 0.282). Multivariate analyses showed that unilobar distribution of LM and normal preoperative carcinoembryonic antigen level (<6 mg/mL) were significantly associated with longer DFS and OS. CONCLUSIONS: The local recurrence rate after simultaneous resection of rectal cancer with LM was relatively low. DFS and OS rates were not different between the adjuvant CRT and CT groups. Adjuvant CRT may have a limited role in this setting. Further prospective randomized studies are required to evaluate optimal adjuvant treatment in these patients.

Effectiveness of biofeedback therapy in the treatment of anterior resection syndrome after rectal cancer surgery.

BACKGROUND: Although anterior resection syndrome commonly occurs after anal sphincter-saving surgery, no standard treatment option is currently available. OBJECTIVE: The aim of the present study was to evaluate the clinical effectiveness of biofeedback in patients with anterior resection syndrome after sphincter-saving surgery for rectal cancer. DESIGN: This study was a retrospective review of data collected during the course of treatment. SETTINGS: Patients were treated at a teaching hospital (Asan Medical Center) in Seoul, Korea, from January 2003 through December 2008. PATIENTS: Patients who received biofeedback therapy for anterior resection syndrome after rectal cancer surgery were included. MAIN OUTCOME MEASURES: The Cleveland Clinic Florida fecal incontinence score, number of bowel movements per day, a visual analog scale for assessing patient satisfaction, and anorectal manometry were used to assess outcome of biofeedback treatment. RESULTS: : After biofeedback therapy, significant improvements were observed in fecal incontinence score (P < .001), number of bowel movements (P < .001), and anorectal manometry data (maximum resting pressure, P = .010; maximum squeeze pressure, P = .006; rectal capacity, P = .003). Compared with patients who started biofeedback treatment less than 18 months after surgery, those who started biofeedback at 18 months or longer after surgery showed greater improvements in fecal incontinence score (P = .032). Only patients with fecal incontinence as the primary symptom showed significant improvements in all variables, including fecal incontinence score, P < .001; defecation frequency, P < .001; and anorectal manometry (maximum resting pressure, P = .027; maximum squeeze pressure, P = .021; rectal capacity, P = .004). Patients who received radiation therapy in addition to surgery reported a significantly higher satisfaction score than those receiving surgery alone (P = .041). LIMITATIONS: This is a nonrandomized retrospective study. Anorectal manometry was not regularly performed in all patients. CONCLUSIONS: Biofeedback therapy produced significant clinical benefits for patients with severe fecal incontinence and may be an effective treatment for patients with anterior resection syndrome after surgery for rectal cancer.

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

BACKGROUND: Although many trials have shown the efficacy of preoperative chemoradiotherapy (CRT) or postoperative CRT compared with surgery alone, the optimal sequence of radiotherapy and surgery is unclear. The authors reported the final results of this single institution prospective randomized phase 3 trial comparing preoperative CRT with postoperative CRT using capecitabine in survival, local control, sphincter preservation, and toxicity for the treatment of locally advanced rectal cancer. METHODS: Patients with locally advanced rectal cancer (cT3, potentially resectable cT4 or N+) were randomly assigned to receive preoperative or postoperative CRT. CRT consisted of 50 Gy/25 fractions and concurrent capecitabine (1,650 mg/m(2)/day). Total mesorectal excision was performed. RESULTS: From March 2004 to April 2006, 240 patients were enrolled. Clinical characteristics were well balanced between both arms, except for more low-lying (<5 cm from anal verge) tumors in the preoperative CRT arm (60% vs 46%, P = .041). After a median follow-up time of 52 months, the 3- and 5-year disease-free survival, overall survival, and cumulative incidence of local recurrence were similar between both arms. However, for the patients with low-lying tumors, the preoperative CRT arm had a higher rate of sphincter preservation (68% vs 42%, P = .008). Acute and late complication rates were similar between both arms. CONCLUSIONS: Although significant benefit of preoperative CRT in local control and survival was not demonstrated, the data showed that increased rate of sphincter preservation was possible in low-lying tumors without jeopardizing local control and surgical complication by preoperative CRT.

Randomized trial of postoperative adjuvant therapy in Stage II and III rectal cancer to define the optimal sequence of chemotherapy and radiotherapy: 10-year follow-up.

PURPOSE: To determine the optimal sequence of postoperative adjuvant chemotherapy and radiotherapy in patients with Stage II or III rectal cancer. METHODS AND MATERIALS: A total of 308 patients were randomized to early (n = 155) or late (n = 153) radiotherapy (RT). Treatment included eight cycles of chemotherapy, consisting of fluorouracil 375 mg/m(2)/day and leucovorin 20 mg/m(2)/day, at 4-week intervals, and pelvic radiotherapy of 45 Gy in 25 fractions. Radiotherapy started on Day 1 of the first chemotherapy cycle in the early RT arm and on Day 1 of the third chemotherapy cycle in the late RT arm. RESULTS: At a median follow-up of 121 months for surviving patients, disease-free survival (DFS) at 10 years was not statistically significantly different between the early and late RT arms (71% vs. 63%; p = 0.162). A total of 36 patients (26.7%) in the early RT arm and 49 (35.3%) in the late RT arm experienced recurrence (p = 0.151). Overall survival did not differ significantly between the two treatment groups. However, in patients who underwent abdominoperineal resection, the DFS rate at 10 years was significantly greater in the early RT arm than in the late RT arm (63% vs. 40%; p = 0.043). CONCLUSIONS: After the long-term follow-up duration, this study failed to show a statistically significant DFS advantage for early radiotherapy with concurrent chemotherapy after resection of Stage II and III rectal cancer. Our results, however, suggest that if neoadjuvant chemoradiation is not given before surgery, then early postoperative chemoradiation should be considered for patients requiring an abdominoperineal resection.

Hirschsprung disease and hypoganglionosis in adults: radiologic findings and differentiation.

PURPOSE: To retrospectively evaluate the imaging features of adult Hirschsprung disease (HD) and adult hypoganglionosis (HG) and to compare these features with histopathologic findings. MATERIALS AND METHODS: This study was institutional review board approved, and the requirement for informed consent was waived. The imaging, medical, and histopathologic data of 10 patients (seven women, three men; mean age, 38 years) with histopathologically proved adult HD and/or adult HG were reviewed. Two radiologists reviewed 10 transverse computed tomographic (CT) scans and five double-contrast barium enema radiographs in consensus for the presence or absence and the location of the transition zone. The transverse diameter ratio of the most dilated colonic segment proximal to the transition zone to the narrowed colonic segment distal to the transition zone (ie, transition zone ratio), and the longitudinal length of the transition zone were also determined. The CT findings of HD and HG were compared by using the Mann-Whitney U test. RESULTS: All patients with lifelong or chronic constipation had a transition zone in the upper part of the rectum or rectosigmoid junction (n = 5) or in the descending colon (n = 5) on the CT scans and the double-contrast barium enema radiographs. The transition zone ratio was significantly different between the patients with HD (median ratio, 4.0) and the patients with HG (median ratio, 2.0) (P = .016). However, there was no significant difference in the longitudinal length of the transition zone between the two patient groups (median ratios, 4.4 cm for HD group and 6.0 cm for HG group; P = .190). CONCLUSION: A markedly dilated proximal colonic segment with a transition zone and a narrowed distal colonic segment on CT and double-contrast barium enema images in conjunction with chronic refractory constipation in an adult should suggest the diagnosis of adult HD or adult HG. The detection of a much higher transition zone ratio may help to establish the diagnosis of HD.

Functional constipation with impaired rectal sensation improved by electrical stimulation therapy: report of a case.

Patients with intractable constipation often complain of social, physical, and psychologic stress. Recently, biofeedback therapy has been widely used for the management of intractable constipation, particularly in cases of constipation associated with pelvic floor dyssynergia. However, some constipated patients often complain of absent or diminished sense of wanting to defecate. It is unclear whether impaired rectal sensation is a cause or outcome of constipation and what specific treatment is available for these patients. We treated a 25-year-old female patient who complained of intractable constipation for ten years. Colon transit time study and defecography showed nonspecific findings. Her anorectal manometric findings were within normal ranges with the exception of impaired rectal sensation. Rectal sensory threshold volumes for desire and urge to defecate and maximal tolerated volume were greatly increased. She was treated by electric stimulation therapy for the purpose of improving impaired rectal sensory function. After 14 sessions of electric stimulation therapy, her constipated symptoms improved dramatically. Furthermore, the desire and urge threshold volumes were remarkably decreased. We report this case of constipation with impaired rectal sensation possibly treated by electric stimulation therapy.

Randomized trial of postoperative adjuvant therapy in stage II and III rectal cancer to define the optimal sequence of chemotherapy and radiotherapy: a preliminary report.

PURPOSE: We conducted a prospective randomized trial to define the optimal sequence of chemotherapy and radiotherapy of postoperative adjuvant treatment in stage II and III rectal cancer. PATIENTS AND METHODS: Three hundred eight patients were enrolled onto the study. We randomly assigned 155 to arm I (early radiotherapy group) and 153 to arm II (late radiotherapy group). Treatment included eight cycles of chemotherapy at 4-week intervals and pelvic radiotherapy of 45 Gy in 25 fractions. Radiotherapy started on day 1 of the first chemotherapy cycle in arm I and on day 1 of the third chemotherapy cycle in arm II. The chemotherapy regimen consisted of fluorouracil 375 mg/m(2)/d and leucovorin 20 mg/m(2)/d. Chemotherapy was administered for 3 days per cycle in two cycles during the period of radiotherapy and for 5 days per cycle in the remaining six cycles. RESULTS: Twenty patients in arm I and 14 in arm II were not eligible. We included 274 patients in the analysis. With a median follow-up of 37 months for surviving patients, disease-free survival was significantly prolonged in arm I compared with arm II (81% v. 70% at 4 years; P =.043). Twenty-three recurrences occurred in arm I and 38 in arm II (P =.047). Overall survival was not significantly different between arms I and II (84% v. 82% at 4 years; P =.387). CONCLUSION: Early radiotherapy with concurrent chemotherapy after resection of stage II and III rectal cancer demonstrated a statistically significant advantage for disease-free survival compared with late radiotherapy with chemotherapy.