Organ Preservation and Survival by Clinical Response Grade in Patients With Rectal Cancer Treated With Total Neoadjuvant Therapy: A Secondary Analysis of the OPRA Randomized Clinical Trial.

Importance: Assessing clinical tumor response following completion of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer is paramount to select patients for watch-and-wait treatment. Objective: To assess organ preservation (OP) and oncologic outcomes according to clinical tumor response grade. Design, Setting, and Participants: This was secondary analysis of the Organ Preservation in Patients with Rectal Adenocarcinoma trial, a phase 2, nonblinded, multicenter, randomized clinical trial. Randomization occurred between April 2014 and March 2020. Eligible participants included patients with stage II or III rectal adenocarcinoma. Data analysis occurred from March 2022 to July 2023. Intervention: Patients were randomized to induction chemotherapy followed by chemoradiation or chemoradiation followed by consolidation chemotherapy. Tumor response was assessed 8 (±4) weeks after TNT by digital rectal examination and endoscopy and categorized by clinical tumor response grade. A 3-tier grading schema that stratifies clinical tumor response into clinical complete response (CCR), near complete response (NCR), and incomplete clinical response (ICR) was devised to maximize patient eligibility for OP. Main Outcomes and Measures: OP and survival rates by clinical tumor response grade were analyzed using the Kaplan-Meier method and log-rank test. Results: There were 304 eligible patients, including 125 patients with a CCR (median [IQR] age, 60.6 [50.4-68.0] years; 76 male [60.8%]), 114 with an NCR (median [IQR] age, 57.6 [49.1-67.9] years; 80 male [70.2%]), and 65 with an ICR (median [IQR] age, 55.5 [47.7-64.2] years; 41 male [63.1%]) based on endoscopic imaging. Age, sex, tumor distance from the anal verge, pathological tumor classification, and clinical nodal classification were similar among the clinical tumor response grades. Median (IQR) follow-up for patients with OP was 4.09 (2.99-4.93) years. The 3-year probability of OP was 77% (95% CI, 70%-85%) for patients with a CCR and 40% (95% CI, 32%-51%) for patients with an NCR (P < .001). Clinical tumor response grade was associated with disease-free survival, local recurrence-free survival, distant metastasis-free survival, and overall survival. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, most patients with a CCR after TNT achieved OP, with few developing tumor regrowth. Although the probability of tumor regrowth was higher for patients with an NCR compared with patients with a CCR, a significant proportion of patients achieved OP. These findings suggest the 3-tier grading schema can be used to estimate recurrence and survival outcomes in patients with locally advanced rectal cancer who receive TNT. Trial Registration: ClinicalTrials.gov Identifier: NCT02008656.

Cost-Effectiveness Analysis: Selective Use of Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer.

BACKGROUND: Locally advanced rectal cancer has high cure rates with trimodal therapy. Studies sparing neoadjuvant chemoradiation in selected patients show comparable outcomes. OBJECTIVE: This study aimed to determine the cost-effectiveness of selective use of neoadjuvant chemoradiation in this population. DESIGN: A cost-effectiveness analysis model compared selective and blanket use chemoradiation for locally advanced rectal cancer. SETTINGS: Literature review, expert consensus, and a prospective database populated the model. Health care utilization costs were based on information from the Centers for Medicare and Medicaid Services. PATIENTS: Adult patients with stage II and III rectal cancer were selected. MAIN OUTCOMES MEASURES: Primary outcomes were cost, effectiveness in quality-adjusted disease-free life years, net monetary benefit, and incremental cost-effectiveness ratios in dollars per quality-adjusted disease-free life years. Base-case 5-year disease-free survival for both strategies was 65%. One-way sensitivity analysis found the probability of 5-year disease-free survival for selective ranged between 40% and 65%. Probabilistic sensitivity analysis assessed second-order variability. RESULTS: Base-case 5-year disease-free survival demonstrated selective use is dominant with lower cost and higher quality-adjusted disease-free life years. For selective use, cost is $153,176, effectiveness is 2.71 quality-adjusted life years, and net monetary benefit is -$17,564 and for blanket use cost is $176,362, effectiveness is 2.64 quality-adjusted life years, and net monetary benefit is -$44,217. One-way sensitivity analysis shows selective use is dominant for disease-free survival above 61.25% and is preferred for disease-free survival above 53.7%. Probabilistic sensitivity analysis shows selective use is optimal in 88% of the iterations for a population of 10,000 patients. LIMITATIONS: Model was based on data from the literature, prospective database, and expert consensus. CONCLUSION: In a population of patients with locally advanced rectal cancer with base-case disease-free survival of 65%, selective use of neoadjuvant chemoradiation is the superior strategy as long as disease-free survival in this group remains above 53%. See Video Abstract at http://links.lww.com/DCR/C199. ANLISIS DE COSTOEFECTIVIDAD USO SELECTIVO DE QUIMIORRADIACIN NEOADYUVANTE EN CNCER DE RECTO LOCALMENTE AVANZADO: ANTECEDENTES:El cáncer de recto localmente avanzado tiene altas tasas de curación con la terapia trimodal. Los estudios que evitan la quimiorradiación neoadyuvante en pacientes seleccionados muestran resultados comparables.OBJETIVO:Determinar la relación costo-efectividad del uso selectivo de quimiorradiación neoadyuvante en esta población.DISEÑO:Un modelo de análisis de costo-efectividad comparó la quimiorradiación selectiva y de uso general para el cáncer de recto localmente avanzado.AJUSTES:Revisión de literatura, consenso de expertos y una base de datos prospectiva poblaron el modelo. Los costos de utilización de la atención médica se basaron en los Centros de Servicios de Medicare y Medicaid.PACIENTES:Se seleccionaron pacientes adultos con cáncer de recto en estadio II y III.PRINCIPALES MEDIDAS DE RESULTADOS:Los resultados primarios fueron el costo, efectividad en años de vida sin enfermedad ajustados por calidad, el beneficio monetario neto y la relación costo-efectividad incremental en $/años de vida sin enfermedad ajustados por calidad. La supervivencia libre de enfermedad a 5 años del caso base para ambas estrategias fue del 65%. El análisis de sensibilidad unidireccional varió la probabilidad de supervivencia libre de enfermedad a 5 años para uso selectivo entre 40%-65%. El análisis de sensibilidad probabilístico evaluó la variabilidad de segundo orden.RESULTADOS:El caso base de 5 años de supervivencia libre de enfermedad demostró que el uso selectivo es dominante con menor costo y años de vida libre de enfermedad ajustados de mayor calidad. El costo, la efectividad y el beneficio monetario neto para el uso selectivo y general fueron ($153 176; 2,71 QALY; -$17 564) y ($176 362; 2,64 QALY; -$44 217). El análisis de sensibilidad unidireccional demostró que el uso selectivo es dominante para la supervivencia sin enfermedad por encima del 61,25% y se prefiere para la supervivencia sin enfermedad por encima del 53,7%. El análisis de sensibilidad probabilístico demostró que el uso selectivo es óptimo en el 88% de las iteraciones para una población de 10 000 pacientes.LIMITACIONES:Modelo basado en datos de literatura, base de datos prospectiva y consenso de expertos.CONCLUSIÓN:En una población de pacientes con cáncer de recto localmente avanzado con caso base de supervivencia libre de enfermedad del 65%, el uso selectivo de quimiorradiación neoadyuvante para el cáncer de recto localmente avanzado es la estrategia superior, siempre y cuando la supervivencia libre de enfermedad en este grupo se mantenga por encima del 53%. Consulte Video Resumen en http://links.lww.com/DCR/C199. (Traducción-Dr. Fidel Ruiz Healy).

Surveillance Intensity Comparison by Risk for T1NX Locally Excised Rectal Adenocarcinoma: a Cost-Effective Analysis.

BACKGROUND: Controversy exists regarding the optimal surveillance strategy following local excision of T1NX rectal adenocarcinoma. This study aims to determine the cost-effectiveness of surveillance strategies for locally excised T1NX rectal adenocarcinoma based on histopathologic and local staging risk factors. METHODS: A Markov model with 10-year follow-up was developed for cost-effectiveness analysis of high-, medium-, and low-intensity surveillance strategies after local excision of T1NX rectal adenocarcinoma. Literature review and expert consensus were utilized to populate state/transition probabilities and rewards. Based on this data, 87% of T1NX patients undergoing local excision were low risk. Healthcare utilization costs were based on Centers for Medicare and Medicaid Services data. The primary outcomes were costs in 2018 US dollars and effectiveness in life-years presented as net monetary benefit and incremental cost-effectiveness ratios. One-way sensitivity and probabilistic sensitivity analyses were performed. RESULTS: Net monetary benefit for low-, medium-, and high-intensity surveillance strategies ($393,117.00, $397,978.80, and $397,290.00) shows medium-intensity surveillance to be optimal. One-way sensitivity analysis shows medium-intensity surveillance to be optimal when the cohort is 73-94% low risk. High-intensity surveillance is preferred when less than 73% of the cohort is low risk. Low-intensity surveillance is preferred when greater than 94% is low risk. Probabilistic sensitivity analysis of the base-case shows medium-intensity surveillance is the optimal strategy for 51.5% of the iterations performed. CONCLUSIONS: Medium-intensity surveillance is the most cost-effective surveillance strategy for locally excised T1NX rectal adenocarcinoma in a clinically representative population model.

Hemorrhoid Banding: A Cost-Effectiveness Analysis.

BACKGROUND: Hemorrhoid banding is an established treatment for symptomatic internal hemorrhoids with proven efficacy, low cost, and limited discomfort. Although the costs and quality of life following individual banding treatments have been investigated, little is known about cumulative cost and quality of life from sequential banding therapy or how these cumulative costs compare to surgical therapy. OBJECTIVE: This study aimed to determine the cost-effectiveness of sequential hemorrhoid banding therapy. DESIGN: A retrospective review of historic banding treatment patterns was performed. Cost estimates and quality-of-life predictions were applied to observed treatment patterns in a decision-analytic cost-effectiveness model to compare sequential banding therapy with hypothetical surgical intervention. SETTING: A retrospective billing record review for patients treated in a colorectal specialty clinic between 2012 and 2017 was performed. PATIENTS: Patients initially treated with banding therapy for symptomatic internal hemorrhoids were included. MAIN OUTCOME MEASURE: The primary outcomes measured were hemorrhoid banding treatment patterns, cost-effectiveness, and net monetary benefit. RESULTS: Treatment of 2026 patients undergoing hemorrhoid banding identified 94% resolution with sequential banding and 6% requiring delayed surgical intervention. Average cumulative estimated cost for banding therapy was $723 (range, $382-$4430) per patient with an average quality-of-life deficit of -0.00234 (range, -0.00064 to -0.02638) quality-adjusted life-years. Estimates for hypothetical hemorrhoid artery ligation, stapled hemorrhoidopexy, or surgical hemorrhoidectomy found significantly higher cost (3.15×, 4.39×, and 2.75× more expensive) and a significantly worse quality-of-life deficit (1.55×, 5.64×, and 9.45× worse). For patients with persistent disease, continued sequential banding remained the dominant cost-effective therapy. LIMITATIONS: This cost-effectiveness model relies on a retrospective review of billing records with estimated cost and quality of life. CONCLUSIONS: Hemorrhoid banding is a valuable treatment modality with favorable cost-effectiveness. The majority of patients selected for banding find resolution without surgery. For patients with persistent disease, further banding procedures remain cost-effective compared with delayed surgical therapy. See Video Abstract at http://links.lww.com/DCR/A982. BANDA HEMORROIDAL: UN ANÁLISIS DE COSTO-EFECTIVIDAD: La banda para hemorroides es un tratamiento establecido para las hemorroides internas sintomáticas con eficacia comprobada, bajo costo y malestar limitado. Si bien se han investigado los costos y la calidad de vida después de los tratamientos de bandas individuales, se sabe poco sobre el costo acumulativo y la calidad de vida de la terapia de bandas secuencial o cómo estos costos acumulativos se comparan con la terapia quirúrgica. OBJETIVO: Determinar el costo-efectividad de la terapia secuencial de bandas hemorroidales. DISEÑO:: Se realizó una revisión retrospectiva de la historia de los patrones de tratamiento con bandas. Las estimaciones de costos y las predicciones de la calidad de vida se aplicaron a los patrones de tratamiento observados en un modelo analítico de costo-efectividad para comparar la terapia de bandas secuencial con la intervención quirúrgica hipotética. AJUSTE: Revisión retrospectiva de los registros de facturación de los pacientes tratados en una clínica de especialidad colorrectal entre 2012 y 2017. PACIENTES: Pacientes tratados inicialmente con terapia de bandas para hemorroides internas sintomáticas. PRINCIPALES MEDIDAS DE RESULTADO: Patrones de tratamiento con bandas de hemorroides, costo-efectividad y beneficio monetario neto. RESULTADOS: El tratamiento de 2026 pacientes con bandas identificó una resolución del 94% con bandas secuenciales y el 6% requirió una intervención quirúrgica tardía. El costo promedio acumulado estimado para la terapia de banda fue de $ 723 (Rango: $382-$4430) por paciente con un déficit de calidad de vida promedio de -0.00234 (Rango: -0.00064 a -0.02638) años de vida ajustados por calidad. Las estimaciones para la hipotética ligadura de la arteria hemorroidal, la hemorroidopexia con grapas o la hemorroidectomía quirúrgica encontraron un costo significativamente mayor (3.15×, 4.39×, 2.75× más caro) y un déficit de la calidad de vida significativamente peor (1.55×, 5.64×, 9.45× peor). Para los pacientes con enfermedad persistente, la colocación de bandas secuenciales continuas siguió siendo la terapia rentable dominante. LIMITACIONES: Este modelo de costo-efectividad se basa en una revisión retrospectiva de los registros de facturación con el costo y la calidad de vida estimados. CONCLUSIONES: Las bandas de hemorroides son una valiosa modalidad de tratamiento con una favorable relación costo-efectividad. La mayoría de los pacientes seleccionados para terapia con bandas encuentran resolución sin cirugía. Para los pacientes con enfermedad persistente, los procedimientos de colocación de bandas adicionales siguen siendo rentables en comparación con el tratamiento quirúrgico tardío. Vea el Resumen del video en http://links.lww.com/DCR/A982.

Cost-Effectiveness Analysis of Total Neoadjuvant Therapy Followed by Radical Resection Versus Conventional Therapy for Locally Advanced Rectal Cancer.

BACKGROUND: Definitive surgery with total mesorectal excision is the mainstay of treatment for locally advanced rectal cancer. Multimodality therapy improves long-term survival. Current standards advise neoadjuvant chemoradiation followed by radical surgery and adjuvant chemotherapy. Nationally, compliance with adjuvant chemotherapy is only 32%. New research evaluates the effectiveness of total neoadjuvant therapy: complete chemotherapy and chemoradiation before surgery. OBJECTIVE: The aim of this study is to determine the favored treatment for locally advanced rectal cancer by comparing the cost-effectiveness of total neoadjuvant therapy and the current standard of care. DESIGN: Decision analytical modeling using long-term costs and 5-year disease-free survival was performed to determine the cost-effectiveness after total neoadjuvant therapy and the current standard of care. Sensitivity analysis was used to investigate the effect of uncertainty in model parameters. SETTINGS: Centers for Medicare & Medicaid Services billing data perspective was adopted and outcomes modeled according to local and national databases and literature consensus. PATIENTS: Adult patients with stage II or III rectal cancer were selected. MAIN OUTCOME MEASURES: Cost-effectiveness in disease-free life-years, incremental cost-effectiveness ratio, and net monetary benefit were determined over a 5-year posttreatment period. The favored strategy was determined based on cost-effectiveness and sensitivity analyses. RESULTS: Cost-effectiveness for total neoadjuvant therapy was 40,708 $/life-year, and, for conventional therapy, cost-effectiveness was 44,248 $/life-year. Sensitivity analysis showed that, for an estimated total neoadjuvant therapy completion rate of 90%, total neoadjuvant therapy would remain the dominant strategy for any adjuvant chemotherapy completion rate of less than 93%. LIMITATIONS: The samples used to calculate completion rates are small, and survival probabilities are based on existing literature, local database values, and consensus estimates. The model encompasses a 5-year time period from diagnosis. CONCLUSIONS: Cost-effectiveness analysis shows that a strategy of total neoadjuvant therapy followed by radical surgery is favored over the current standard of care for locally advanced rectal cancer. Sensitivity analysis shows that a low rate of adjuvant chemotherapy administration plays a key role in decreasing the cost-effectiveness of the current standard of care. See Video Abstract at http://links.lww.com/DCR/A942.

Factors predicting reclassification of variants of unknown significance.

Genetic variants of unknown significance (VUS) are an increasingly common result of genetic testing. VUS present dilemmas for treatment and surveillance. Family history may play a role in VUS reclassification over time. METHODS: All genetic tests performed at a tertiary referral center 2006-2015 were evaluated for the presence of VUS. Patients with VUS were evaluated for demographics, clinical characteristics, family history, and gene characteristics. RESULTS: In total, 2291 individuals were tested from 1639 families; 150 VUS were identified. Twenty-eight VUS reclassified, 21 to benign and 7 to pathogenic. Logistic regression demonstrated the number of family members with associated phenotypic disease was a significant predictor of reclassification. CONCLUSION: The likelihood of VUS reclassification can be predicted by increased positive family history of disease. Most VUS reclassify to benign, but one-fourth reclassify to pathogenic. The actual risk of a VUS should be assessed based on family history and routinely checked for reclassification.

Consolidation mFOLFOX6 Chemotherapy After Chemoradiotherapy Improves Survival in Patients With Locally Advanced Rectal Cancer: Final Results of a Multicenter Phase II Trial.

BACKGROUND: Adding modified FOLFOX6 (folinic acid, fluorouracil, and oxaliplatin) after chemoradiotherapy and lengthening the chemoradiotherapy-to-surgery interval is associated with an increase in the proportion of rectal cancer patients with a pathological complete response. OBJECTIVE: The purpose of this study was to analyze disease-free and overall survival. DESIGN: This was a nonrandomized phase II trial. SETTINGS: The study was conducted at multiple institutions. PATIENTS: Four sequential study groups with stage II or III rectal cancer were included. INTERVENTION: All of the patients received 50 Gy of radiation with concurrent continuous infusion of fluorouracil for 5 weeks. Patients in each group received 0, 2, 4, or 6 cycles of modified FOLFOX6 after chemoradiation and before total mesorectal excision. Patients were recommended to receive adjuvant chemotherapy after surgery to complete a total of 8 cycles of modified FOLFOX6. MAIN OUTCOME MEASURES: The trial was powered to detect differences in pathological complete response, which was reported previously. Disease-free and overall survival are the main outcomes for the current study. RESULTS: Of 259 patients, 211 had a complete follow-up. Median follow-up was 59 months (range, 9-125 mo). The mean number of total chemotherapy cycles differed among the 4 groups (p = 0.002), because one third of patients in the group assigned to no preoperative FOLFOX did not receive any adjuvant chemotherapy. Disease-free survival was significantly associated with study group, ypTNM stage, and pathological complete response (p = 0.004, <0.001, and 0.001). A secondary analysis including only patients who received ≥1 cycle of FOLFOX still showed differences in survival between study groups (p = 0.03). LIMITATIONS: The trial was not randomized and was not powered to show differences in survival. Survival data were not available for 19% of the patients. CONCLUSIONS: Adding modified FOLFOX6 after chemoradiotherapy and before total mesorectal excision increases compliance with systemic chemotherapy and disease-free survival in patients with locally advanced rectal cancer. Neoadjuvant consolidation chemotherapy may have benefits beyond increasing pathological complete response rates. See Video Abstract at http://links.lww.com/DCR/A739.

Robotic Colorectal Surgery Learning Curve and Case Complexity.

PURPOSE: To understand the role of case complexity in the learning curve for robotic colorectal surgery. MATERIALS AND METHODS: Sixty-two patients who underwent robot-assisted colorectal surgery were retrospectively reviewed. Each case was assigned a category of complexity ranging from I to IV. Overall, groups and categories of segmental colectomy, rectopexy, and proctectomy for cancer were analyzed according to case volume. Forty-eight patients who underwent similar laparoscopic cases during the same period were also reviewed for comparison. RESULTS: Level I complexity cases were identified in 30% of the first 15 cases compared to 3% after the first 15 cases (P < .01). Level IV complexity cases were identified in 10% of the first 15 cases and 34% after 15 cases (P = .03). Mean operative time for the overall group was 426 minutes (range 178-766, standard deviation [SD] = 152) in the first 15 cases and 373 minutes (range 190-593, SD = 109) after more than 15 cases (P = NS). Mean operative time for rectal cancer procedures decreased from 518 minutes (range 425-752, SD = 88) to 410 minutes (range 220-593, SD = 98) after 15 cases (P = .02). Mean operative time for rectopexy decreased from 361 minutes (range 276-520, SD = 85) to 258 minutes (range 215-318, SD = 34) after 15 cases (P = .03). Overall complications were reduced after 15 cases (6.3%) compared with the first 15 cases (27%) (P = .04). When comparing laparoscopic and open cases, laparoscopic cases were associated with a significant shorter operative time (P = < .00001) as well as overall cost (P = < .00001). CONCLUSION: Complex robotic colorectal surgery can be performed early in the experience, with reduced operative time. Overall complications are reduced after 15 robotic cases. This study shows that improvement in robotic surgery operating time and surgical outcomes occur along with application of the technology to more difficult cases, not as a function of choosing less complex cases.

What happens after a failed LIFT for anal fistula?

BACKGROUND: Ligation of the intersphincteric fistula tract (LIFT) was developed to treat transsphincteric anal fistulas. The aftermath of a failed LIFT has not been well documented. METHODS: Retrospective chart review of LIFT procedure for transsphincteric anal fistula between March 2012 and September 2016. RESULTS: 53 patients with LIFT procedure were identified, 20 (37.7%) had persistent fistula with median followup of 4 months. Following LIFT, recurrence of fistula was transsphincteric (75%) or intersphincteric (25%) (p = NS). Persistent transsphincteric fistulas after LIFT were treated with seton (71.4%) followed by advancement flap (20%) or fistulotomy (50%). Of the recurrent intersphincteric fistulas, 50% underwent seton placement followed by fistulotomy, or advancement flap. Of the patients who underwent surgery after failed LIFT, 50% have had resolution of the fistula; 31.7% are still undergoing treatment. CONCLUSION: Patients who underwent surgery after failed LIFT had 50% healing with placement of seton followed by fistulotomy or rectal advancement flap.

Molecular Markers for Colorectal Cancer.

Colorectal cancers develop through at least 3 major pathways, including chromosomal instability, mismatch repair, and methylator phenotype. These pathways can coexist in a single individual and occur in both sporadic and inherited colorectal cancers. In spite of the unique molecular and genetic signatures of colorectal cancers, nonspecific chemotherapy based on the antineoplastic effects of 5-fluorouracil is the cornerstone of therapy for stage III and some stage II disease. Techniques to recognize colorectal cancer at the molecular level have facilitated development of new signature drugs designed to inhibit the unique pathways of colorectal cancer growth and immunity.

Perioperative Management of the Ambulatory Anorectal Surgery Patient.

Ambulatory surgery is appropriate for most anorectal pathology. Ambulatory anorectal surgery can be performed at reduced cost compared with inpatient procedures with excellent safety, improved efficiency, and high levels of patient satisfaction. Several perioperative strategies are employed to control pain and avoid urinary retention, including the use of a multimodal pain regimen and restriction of intravenous fluids. Ambulatory anorectal surgery often utilizes standardized order sets and discharge instructions.

Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial.

BACKGROUND: Patients with locally advanced rectal cancer who achieve a pathological complete response to neoadjuvant chemoradiation have an improved prognosis. The need for surgery in these patients has been questioned, but the proportion of patients achieving a pathological complete response is small. We aimed to assess whether adding cycles of mFOLFOX6 between chemoradiation and surgery increased the proportion of patients achieving a pathological complete response. METHODS: We did a phase 2, non-randomised trial consisting of four sequential study groups of patients with stage II-III locally advanced rectal cancer at 17 institutions in the USA and Canada. All patients received chemoradiation (fluorouracil 225 mg/m(2) per day by continuous infusion throughout radiotherapy, and 45·0 Gy in 25 fractions, 5 days per week for 5 weeks, followed by a minimum boost of 5·4 Gy). Patients in group 1 had total mesorectal excision 6-8 weeks after chemoradiation. Patients in groups 2-4 received two, four, or six cycles of mFOLFOX6, respectively, between chemoradiation and total mesorectal excision. Each cycle of mFOLFOX6 consisted of racemic leucovorin 200 mg/m(2) or 400 mg/m(2), according to the discretion of the treating investigator, oxaliplatin 85 mg/m(2) in a 2-h infusion, bolus fluorouracil 400 mg/m(2) on day 1, and a 46-h infusion of fluorouracil 2400 mg/m(2). The primary endpoint was the proportion of patients who achieved a pathological complete response, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00335816. FINDINGS: Between March 24, 2004, and Nov 16, 2012, 292 patients were registered, 259 of whom (60 in group 1, 67 in group 2, 67 in group 3, and 65 in group 4) met criteria for analysis. 11 (18%, 95% CI 10-30) of 60 patients in group 1, 17 (25%, 16-37) of 67 in group 2, 20 (30%, 19-42) of 67 in group 3, and 25 (38%, 27-51) of 65 in group 4 achieved a pathological complete response (p=0·0036). Study group was independently associated with pathological complete response (group 4 compared with group 1 odds ratio 3·49, 95% CI 1·39-8·75; p=0·011). In group 2, two (3%) of 67 patients had grade 3 adverse events associated with the neoadjuvant administration of mFOLFOX6 and one (1%) had a grade 4 adverse event; in group 3, 12 (18%) of 67 patients had grade 3 adverse events; in group 4, 18 (28%) of 65 patients had grade 3 adverse events and five (8%) had grade 4 adverse events. The most common grade 3 or higher adverse events associated with the neoadjuvant administration of mFOLFOX6 across groups 2-4 were neutropenia (five in group 3 and six in group 4) and lymphopenia (three in group 3 and four in group 4). Across all study groups, 25 grade 3 or worse surgery-related complications occurred (ten in group 1, five in group 2, three in group 3, and seven in group 4); the most common were pelvic abscesses (seven patients) and anastomotic leaks (seven patients). INTERPRETATION: Delivery of mFOLFOX6 after chemoradiation and before total mesorectal excision has the potential to increase the proportion of patients eligible for less invasive treatment strategies; this strategy is being tested in phase 3 clinical trials. FUNDING: National Institutes of Health National Cancer Institute.

Overexpression of 5-lipoxygenase in colon polyps and cancer and the effect of 5-LOX inhibitors in vitro and in a murine model.

PURPOSE: Arachidonic acid metabolism via the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways modulates cell growth and apoptosis. Many studies have examined the effects of COX inhibitors on human colorectal cancer, but the role of 5-LOX in colonic cancer development has not been well studied. The purpose of this study was to evaluate the expression of 5-LOX in colonic polyps and cancer and the effect of 5-LOX inhibition on colon cancer cell proliferation. EXPERIMENTAL DESIGN: Colonic polyps, cancer, and normal mucosa were evaluated for 5-LOX expression by immunohistochemistry. Reverse transcription-PCR was used to establish 5-LOX expression in colon cancer cells. Thymidine incorporation and cell counts were used to determine the effect of the nonspecific LOX inhibitor Nordihydroguaiaretic Acid and the 5-LOX inhibitor Rev5901 on DNA synthesis. A heterotopic xenograft model in athymic mice using HT29 and LoVo human colon cancer cells was used to evaluate the effect of the 5-LOX inhibitor zileuton on tumor growth. RESULTS: 5-LOX is overexpressed in adenomatous polyps and cancer compared with that of normal colonic mucosa. LOX inhibition and 5-LOX inhibition decreased DNA synthesis in a concentration- and time-dependent manner in the Lovo cell line (P < 0.05). Inhibition of 5-LOX in an in vivo colon cancer xenograft model inhibited tumor growth compared with that of controls (P < 0.05). CONCLUSIONS: This study showed that 5-LOX is up-regulated in adenomatous colon polyps and cancer compared with normal colonic mucosa. The blockade of 5-LOX inhibits colon cancer cell proliferation both in vitro and in vivo and may prove a beneficial chemopreventive therapy in colon cancer.