Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer.

BACKGROUND: Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy. METHODS: In this prospective-retrospective analysis, we assessed the efficacy and safety of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) as compared with FOLFOX4 alone, according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%. RESULTS: Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval [CI], 0.58 to 0.90; P=0.004). Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P=0.04). A total of 108 patients (17%) with nonmutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor. No new safety signals were identified. CONCLUSIONS: Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab-FOLFOX4 therapy. (Funded by Amgen and others; PRIME ClinicalTrials.gov number, NCT00364013.).

RAS mutation prevalence among patients with metastatic colorectal cancer: a meta-analysis of real-world data.

AIM: A confirmed wild-type RAS tumor status is commonly required for prescribing anti-EGFR treatment for metastatic colorectal cancer. This noninterventional, observational research project estimated RAS mutation prevalence from real-world sources. MATERIALS & METHODS: Aggregate RAS mutation data were collected from 12 sources in three regions. Each source was analyzed separately; pooled prevalence estimates were then derived from meta-analyses. RESULTS: The pooled RAS mutation prevalence from 4431 tumor samples tested for RAS mutation status was estimated to be 43.6% (95% CI: 38.8-48.5%); ranging from 33.7% (95% CI: 28.4-39.3%) to 54.1% (95% CI: 51.7-56.5%) between sources. CONCLUSION: The RAS mutation prevalence estimates varied among sources. The reasons for this are not clear and highlight the need for further research.

[Prevention of colorectal cancer]. / Prevención del cáncer colorrectal (CCR).

Colorectal cancer (CRC) is the second leading cause of cancer death in Argentina. The cumulative lifetime risk of developing CRC for both men and women is 4-6%. Despite advances in the management of this disease, the 5-year survival rate is about 60% because only 35% of patients are diagnosed when the disease is localized. Risk factors for CRC include age, diet and life style factors, personal or family history of adenomas or CRC and personal history of inflammatory bowel disease. Scientific evidence shows that primary and secondary prevention, through screening programs, permit to reduce incidence and mortality significantly. Chemopreventive agents, including nonsteroidal antiinflammatory drugs, folate, and calcium, have been shown to have some preventive effect. Physical inactivity and excess body weight are consistent risk factors for CRC. Tobacco exposure, diet high in red meat and low in vegetables and alcohol consumption, probably in combination with a diet low in folate, appear to increase risk. The dietary fiber and risk of CRC has been studied but the results are still inconclusive. Screening for CRC is cost-effective compared with no screening, but a single optimal strategy cannot be determined from the currently available data. The advantages and disadvantages or limitations of screening modalities for CRC are analyzed. The literature and clinical practice guidelines are reviewed, with an emphasis on advances and evolving screening methods and recommendations for patients with average, moderate and high-risk CRC.

[Treatment of patients with squamous cell carcinoma of the anal canal in the last 20 years in a gastroenterology hospital]. / El tratamiento de los pacientes con carcinoma epidermoide del canal anal en los últimos 20 años en nuestro hospital.

UNLABELLED: Anal cancers compromise only 1.5% of all digestive tumors. At present, concurrent radiochemotherapy (RT-CT) is the treatment of choice for most of these lesions. OBJECTIVE: To collect and analyze clinical data from the medical records of all consecutive patients with squamous cell carcinoma of the anal canal (SCCAC) treated by the Oncology Section in 20 years. PATIENTS AND METHODS: The medical records of 108 patients with SCCAC were reviewed: 64% were women, mean age was 57.6 years (27-85), only 1 patient was HIV(+). RESULTS: Initial treatment: 87 patients were treated with RT-CT (81%), 5 CT only, 2 RT only, 8 local resection and 6 abdominoperineal resection (APR). 1) Patients initially treated with RT-CT: cobalt therapy was given to 76% of pts and linear accelerator was used in 24% of patients. 24% of patients received Mitomycin C based CT (modified Nigro), 66% Cisplatin based CT and 10% 5FU alone; 66% had clinical complete response (CCR) (26% of them relapsed). Median follow up was 2.16 years (1 month-15.5 years), median time to progression was 11.8 months and overall survival was 76.7% at 3 years (CI 95%: 65.2-87.7). 2) Patients initially treated with local resection: 6 patients NED and 2 relapsed (1 had CCR after RT-CT). 3) Patients initially treated with APR: 5 with curative intent (4 had local recurrence), and 1 was palliative. 4) Surgical rescue after RT-CT in 6 patients with curative intent (4 APR and 2 local resections), and in 15 patients was palliative (2 APR and other surgeries in 13). CONCLUSIONS: Our group is pioneer in the use of Cisplatin based RT-CT for the treatment of patients with SCCAC. Complete response rate and overall survival at 3 years, were similar to those reported by international data. As this is probably one of the largest series of SCCAC in Argentina, we hope that this analysis of our data would be a starting point to develop prospective clinical trials.

Radiochemotherapy with short daily infusion of low-dose oxaliplatin, leucovorin, and 5-FU in T3-T4 unresectable rectal cancer: a phase II IATTGI study.

PURPOSE: Oxaliplatin (OXA)/5-fluorouracil (5-FU) have confirmed their preclinical synergy in advanced colorectal cancer patients. Chemoradiotherapy with 5-FU + leucovorin (LV) is considered the standard treatment in unresectable rectal cancer patients. The objective was to evaluate OXA with 5-FU + LV and concurrent radiotherapy in unresectable rectal cancer patients. TREATMENT: OXA 25 mg/m(2)/day in 30-min infusions, followed by bolus LV 20 mg/m(2)/day and bolus 5-FU 375 mg/m(2)/day. All drugs were given on 4 days during Weeks 1 and 5 of a standard radiotherapy cycle (50.4 Gy). A single OXA dose (50 mg/m(2)) was also given on the third week of radiotherapy. A cycle of OXA with 5-FU + LV was administered 4 weeks after chemoradiotherapy, with surgery planned 4 weeks later. RESULTS: Between March 1998 and April 2000, 22 patients with T3-T4 unresectable rectal cancer were accrued. Patient characteristics included the following: 11 females, 11 males, median age 58 (range: 18-76). Performance status ECOG (PS) 0: 2 patients, PS 1: 7 patients, and PS 2: 13 patients. The following RTOG Grade 3-4 toxicities were reported: diarrhea, 6 patients; cutaneous, 3 patients; neutropenia-leukopenia, 2 patients; and thrombocytopenia, 1 patient; 1 treatment-related death resulted (febrile neutropenia-sepsis after chemoradiotherapy). Only 1 patient had neurosensory Grade 2 (OXA-specific Levi's scale) toxicity. Nine patients had PS worsening during treatment. Five patients had chemoradiotherapy delay (median: 6 days). Of 22 patients, 16 underwent surgery (without serious surgical complications); 12/16 had a complete resection (5/12 had sphincter preservation). Pathologic examination revealed 3/12 complete remissions, 2/12 minimal microscopic residual disease, 2/12 T2N0, 1/12 T3N0, and 4/12 positive nodes; 4/16 had unresectable disease. Median follow-up was 15 months (range: 3.0-43.4 months), median time to progression was 15.7 months (CI 95%, 0, 31.7), and median overall survival was 19.5 months (CI 95%, 18.0, 21). CONCLUSIONS: Outpatient treatment with low-dose, 30-min daily OXA infusion was feasible and very active, with acceptable toxicity.

A high degree of LINE-1 hypomethylation is a unique feature of early-onset colorectal cancer.

OBJECTIVE: Early-onset colorectal cancer (CRC) represents a clinically distinct form of CRC that is often associated with a poor prognosis. Methylation levels of genomic repeats such as LINE-1 elements have been recognized as independent factors for increased cancer-related mortality. The methylation status of LINE-1 elements in early-onset CRC has not been analyzed previously. DESIGN: We analyzed 343 CRC tissues and 32 normal colonic mucosa samples, including 2 independent cohorts of CRC diagnosed ≤ 50 years old (n=188), a group of sporadic CRC >50 years (MSS n=89; MSI n=46), and a group of Lynch syndrome CRCs (n=20). Tumor mismatch repair protein expression, microsatellite instability status, LINE-1 and MLH1 methylation, somatic BRAF V600E mutation, and germline MUTYH mutations were evaluated. RESULTS: Mean LINE-1 methylation levels (± SD) in the five study groups were early-onset CRC, 56.6% (8.6); sporadic MSI, 67.1% (5.5); sporadic MSS, 65.1% (6.3); Lynch syndrome, 66.3% (4.5) and normal mucosa, 76.5% (1.5). Early-onset CRC had significantly lower LINE-1 methylation than any other group (p<0.0001). Compared to patients with <65% LINE-1 methylation in tumors, those with ≥ 65% LINE-1 methylation had significantly better overall survival (p=0.026, log rank test). CONCLUSIONS: LINE-1 hypomethylation constitutes a potentially important feature of early-onset CRC, and suggests a distinct molecular subtype. Further studies are needed to assess the potential of LINE-1 methylation status as a prognostic biomarker for young people with CRC.

Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.

PURPOSE: Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC. PATIENTS AND METHODS: In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. RESULTS: KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. CONCLUSION: This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC.

Metastatic colorectal cancer: recent advances in its clinical management.

Colorectal cancer (CRC) is frequently complicated by metastatic disease, with the liver being the most common site of metastasis. Surgical resection is the only realistic cure for colorectal liver metastases; however only 10-25% of cases are initially resectable. The introduction of combination chemotherapy has improved survival rates by enabling 10-20% cases with previously unresectable hepatic metastases to become amenable to surgery. Recent results with the biologic agent bevacizumab, a chimeric human-mouse monoclonal antibody against VEGF, and cetuximab, a chimeric human-mouse monoclonal antibody against EGF receptor, have shown that they improve clinical surgical outcomes when added to current first-line regimens in patients with metastatic colorectal cancer. Dual biologic therapy in combination with chemotherapy has, however, yielded disappointing results. Identification of biological markers is expected to help determine which patients are most likely to respond to these newer agents and thus improve targeted therapy.

Linfomas del intestino delgado y cirugía / Primary small bowel lymphomas and surgery

Se presentan 45 casos de linfomas primarios de intestino delgado estudiados entre 1983 y febrero de 1995, de los cuales 2 correspondieron a la variedad Hodgkin (4,4 por ciento) y 43 a linfomas No Hodgkin (95,6 por ciento), incluyendo en éstos tres casos de enfermedad linfoproliferativa de intestino delgado. Se destaca que la localización más frecuente fue el yeyuno (51,2 por ciento), seguida del ileón y el duodeno encontrándose localizaciones múltiples en 23,2 por ciento. Las complicaciones obstructivas, perforativas y hemorrágicas fueron en el 93 por ciento de los pacientes lo que motivó la indicación quirúrgica. Se pone énfasis sobre la necesidad de la laparotomía exploradora con el fin de lograr el estudio histopatológico correcto, estadificar la lesión y evaluar la posibilidad de resección con criterio curativo o paliativo. Se analiza la supervivencia global de los linfomas No Hodgkin, que demuestra una diferencia significativa entre los operadores con criterio paliativo y curativo, 26 por ciento para los primeros y 47 por ciento en los segundos a los 70 meses, marcando también una significativa diferencia cuando existe o no compromiso ganglionar, 27 por ciento contra 52 por ciento a los 5 años

Linfoma gástrico primario y cirugía / Primary gastric lymphoma and surgery

Antecedentes: Los linfomas primarios no Hodgkin gástricos (LPNHG) presentan aspectos clínicos controvertidos en cuanto al diagnóstico, clasificación y tratamiento. Objetivos: Evaluar el rol de la cirugía en los LPNHG en el diagnóstico, estadificación, tratamiento y supervivencia. Diseño: Estudio retrospectivo analizando los hallazgos anatomopatológicos, estadificación y tratamiento en relación con la supervivencia. Pablación: 39 pacientes estudiados entre 1983 y aabril 1999. Métodos: Se estudian los pacientes por imágenes y endoscopía. La estadificación fue efectuadasiguiendo la clasificación de Ann Arbor y TNM. En base a la clasificación de Ann Arbor se siguió un algoritmo diagnóstico-tratamiento. Se consideran linfomas primarios los IE y IIE. La secuencia en el tratamiento es 1ro. Cirugía y después tratamiento quimioterápico. Quirúrgicamente se obtiene material para estudio histopatológico de la lesión, de ambos lóbulos hepáticos y de médula ósea de cresta iliaca. Se efectuaron técnicas habituales y de inmunohistoquímica especiales. Se siguió la clasificación REAL de los linfomas no Hodgkin. Los pacientes con lesiones avanzadas no resecados y en los resecados cuando tenían serosa y/o ganglios positivos fueron sometidos a quimioterapia (CHOP). La supervivencia fue valorada con el método actuarial de Kaplan-Meir y la diferencia de curvas con el test de log-reank. Resultados: De 39 LPNHG pertenecian al sexo masculino el 56.4 por ciento (22/39), el promedio de edad 55.8 años (33-78). El diagnóstico preoperatorio se estableció en el 51.2 por ciento. Fueron operados 35 y en el 46.2 por ciento la resección fue con criterio curativo. Los tipos histológicos fueron: linfoma T2 casos y linfoma B37 casos (94.9 por ciento); siendo éstos malt 36 y 1 del monton...

Tratamiento médico de 44 pacientes con carcinoma del conducto anal / Medical treatment of 44 patients with anal canal carcinoma

Con el objeto de investigar el tratamiento médico del carcinoma del conducto anal (CAA), 27 pacientes fueron tratados con cisplatino, fluorouracilo y radioterapia en un esquema alternante; 11 pacientes recibieron mitomicina C en lugar del platino,m y 6 pacientes ingresaron a un nuevo protocolo ambulatorio con cisplatino, fluorouracilo, leucovorina y mitomicina C asociado a radioterapia concurrente. Con el primer esquema llegaron a respuesta completa 18/25 pacientes evaluables, y todos se mantienen libres de enfermedad hasta la fecha. Con el segundo plan, 7/10 pacientes evaluables lograron respuesta completa y 5 están vivos, libres de enfermedad. Finalmente con el último plan, 6/6 pacientes ingresados obtuvieron respuesta completa. Nuestra experiencia es una de las primeras en estudiar la utildiad del cisplatino como droga de primera línea en el tratamiento no quirúrgico del CCA. Creemos que es factible utilizar cisplatino y que su toxicidad no resulta limitante. La efectividad, comparable a la de otros esquemas, puede ser mejorada con la administración concurrente de radioterapia, tal como se observa en el útimo esquema implementado