Summary 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/m2 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/m2 or 400 mg/m2 , according to the discretion of the treating investigator, oxaliplatin 85 mg/m2 in a 2-h infusion, bolus fluorouracil 400 mg/m2 on day 1, and a 46-h infusion of fluorouracil 2400 mg/m2 . 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.
Locally advanced rectal cancer has high cure rates with trimodal therapy. Studies sparing neoadjuvant chemoradiation in selected patients show comparable outcomes.
This study aimed to determine the ...cost-effectiveness of selective use of neoadjuvant chemoradiation in this population.
A cost-effectiveness analysis model compared selective and blanket use chemoradiation for locally advanced rectal cancer.
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.
Adult patients with stage II and III rectal cancer were selected.
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.
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.
Model was based on data from the literature, prospective database, and expert consensus.
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.
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).
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.
The purpose of this study was to analyze disease-free and overall survival.
This was a nonrandomized phase II trial.
The study was conducted at multiple institutions.
Four sequential study groups with stage II or III rectal cancer were included.
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.
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.
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).
The trial was not randomized and was not powered to show differences in survival. Survival data were not available for 19% of the patients.
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.
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.
•Variants of unknown significance are common.•VUS may reclassify to benign or pathogenic.•Extensive family history may predict reclassification.•Large pedigrees are associated with reclassification.•Patients with VUS should be treated based on the medical/family history.
Abstract
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.
Molecular Markers for Colorectal Cancer Wright, Moriah; Beaty, Jenifer S; Ternent, Charles A
The Surgical clinics of North America,
06/2017, Volume:
97, Issue:
3
Journal Article
Peer reviewed
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.
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