VITAL phase 2 study: Upfront 5-fluorouracil, mitomycin-C, panitumumab and radiotherapy treatment in nonmetastatic squamous cell carcinomas of the anal canal (GEMCAD 09-02)

Aim: VITAL, a phase II single-arm study, aimed to evaluate efficacy and safety of panitumumab addition to 5-fluorouracil (5-FU), mitomycin-C (MMC) and radiotherapy (RT) in patients with localized squamous cell carcinoma of the anal canal (SCCAC). Methods: Adult, treatment-naïve SCCAC patients (Stage T2-T4, any N, M0) and ECOG-PS ≤2, received panitumumab (6 mg/kg, day 1 and Q2W; 8 weeks), 5-FU (1000 mg/m2/d, days 1-4 and 29-32), MMC (10 mg/m2, days 1 and 29) and RT 45 Gy (1.8 Gy/fraction) to the primary tumor and mesorectal, iliac and inguinal lymph nodes, plus 10-15 Gy boost dose to the primary tumor and affected lymph nodes. The primary objective was disease free survival rate (DFS) at 3-years (expected 3-year DFS rate: 73.7 ± 12%). Results: Fifty-eight patients (31 women; median age: 59 years; ECOG-PS 0-1:98%; TNM II [29%] (T2 or T3/N0/M0)/IIIA (T1-T3/N1/M0 or T4/N0/M0) [21%]/IIIB (T4/N1/M0 or any T/N2 or N3/M0) [47%]/nonevaluable [4%]) were included. The median follow-up was 45 months. The 3-year DFS rate was 61.1% (95% CI: 47.1, 72.4). The 3-year overall survival rate was 78.4% (95% CI: 65.1, 87.1). Eighteen patients (31.0%) required a colostomy within 2 years posttreatment. Grade 3-4 toxicities were experienced by 53 (91%) patients. Most common grade 3-4 treatment-related events were radiation skin injury (40%) and neutropenia (24%). No toxic deaths occurred. Improved efficacy in colostomy-free survival and complete response rate was observed in human papilloma virus positive patients. Conclusions: Panitumumab addition to MMC-5FU regimen in SCCAC patients increases toxicity and does not improve patients’ outcomes. RT plus MMC-5FU remains the standard of care for localized SCCAC patients.This work was supported by Amgen S.A

La endometriosis atípica como lesión precursora del cáncer de ovario asociado a endometriosis un estudio prospectivo

En la presente tesis hemos estudiado la probable transformación maligna de la endometriosis en cáncer de ovario asociado a endometriosis (COAE). Nuestra hipótesis de trabajo se basa en el potencial papel que juega la "endometriosis atípica" en la patogénesis del COAE, fundamentalmente en los histotipos, adenocarcinoma de células claras (AcCC) y el adenocarcinoma endometrioide (AcE). Exploramos la posibilidad de que represente una etapa evolutiva entre la endometriosis "típica" y el COAE. Además, nos planteamos si la atipia celular (EAC) y la hiperplasia o atipia arquitectural (EAA), los dos hallazgos histológicos globalmente referidos como endometriosis atípica (EA), tienen un significado diferente en la etiopatogenia del COAE. OBJETIVOS Objetivo Principal: Establecer la Prevalencia de EA y de sus subtipos histológicos: EAC y EAA en las pacientes con Endometriosis y COAE. Objetivos secundarios: Objetivo 1.- Establecer las diferencias en la prevalencia de los subtipos histológicos AcCC y AcE en las pacientes con COAE vs CO. Objetivo 2.- Comparar las características clínico-epidemiológicas y Factores de riesgo y pronósticos de los grupos de estudio: pacientes con diagnóstico postquirúrgico de Endometriosis, COAE y CO. MATERIAL Y MÉTODO: Estudio observacional prospectivo de serie de casos desde Enero 2014 hasta Abril de 2017 en pacientes asistidas en el Servicio de Ginecología y Obstetricia del Hospital Clínico Universitario Virgen de la Arrixaca, con el diagnóstico de endometriosis y/o cáncer de ovario sometidas a cirugía. Se realizó un análisis anatomopatológico e inmunohistoquímico de las piezas quirúrgicas de los diferentes grupos (EN, CO y COAE). RESULTADOS: Se incluyeron 266 pacientes. Se confirmó endometriosis en 185 pacientes, de las cuales, 159 casos tenían endometriosis aislada y 26 presentaban COAE. Del total de los 107 cánceres de ovario registrados (COT), 26 (24,3%) eran COAE y 81 (75,7%) cáncer de ovario sin endometriosis asociada (CO). El 53,1% de los CO el tipo histológico fue el seroso frente al 15,4% observado en los COAE. Así mismo, el 23,1% de los COAE fueron AcCC y el 42,3% eran AcE, versus el 6,2% y 14,8% respectivamente de los encontrados en CO (p<0,001). De las 185 pacientes con endometriosis, había 23 casos (12,43%) con características de EA. Estos 23 casos se distribuyen en 11 con EAC y 12 con EAA. Además 10 de los 11 casos de EAC se observan en endometriosis no asociada a CO mientras, que 8 de los 12 casos de EAA se objetivan en los COAE (p=0,009). De los estudios inmunohistoquímicos encontramos asociación (p=0,004) entre Ki-67 alto con EAA. No hayamos diferencias significativas ni para COX-2 ni BAF250a. En cuanto a la diferencias entre los tipos histológicos, se relacionan los carcinomas serosos con el grupo de CO, y los AcCC y AcE con COAE (p<0,001). En los estadios tumorales vimos asociación del estadio I con COAE (76,9% vs 44,45% en CO) (p<0,001). CONCLUSIONES: 1. Existe una asociación significativa entre Endometriosis Atípica y Cáncer de Ovario Asociado a Endometriosis. 2. Los tipos histológicos de Cáncer de Ovario asociados de forma significativa a Endometriosis fueron el Adenocarcinoma de Células Claras y el Adenocarcinoma Endometrioide, ambos incluidos en el tipo I del modelo de Kurman y Shild. 3. Nuestros datos sugieren que el Cáncer de Ovario Asociado a Endometriosis podría presentar un mejor pronóstico dentro del Cáncer de Ovario. 4. Existe una asociación significativa entre Endometriosis Atípica Arquitectural y Cáncer de Ovario Asociado a Endometriosis. 5. Nuestros datos apoyan la hipótesis de que la Endometriosis Atípica Arquitectural o Hiperplásica podría constituir una lesión precursora en la patogénesis del Cáncer de Ovario Asociado a Endometriosis.In this thesis we have studied the possible malignant transformation of endometriosis in endometriosis-associated ovarian cancer (EAOC). Our hypothesis is based on the potential role played by "atypical endometriosis" in the pathogenesis of EAOC, mainly in histotypes, clear cell adenocarcinoma (CCAc) and endometrioid adenocarcinoma (EAc). We have explored the possibility that it represents an evolutionary stage between "typical" endometriosis and EAOC. In addition, we have considered whether cellular atypia (ECA) and architectural atypia or hyperplasia (EAA), the two histological findings globally referred to as atypical endometriosis (AE), have a different meaning in the etiopathogenesis of EAOC. OBJETIVES Main objetive: To establish the prevalence of AE and its histological subtypes: ECA and EAA in patients with Endometriosis and EAOC. Other objetives: Objetive 1.- To establish differences in prevalence of histological subtypes CCAc and EAc between patients with EAOC and ovarian cáncer (OC). Objetive 2.- To compare the clinical and epidemiological characteristics, risk factors and prognoses of the study groups: patients with postoperative diagnosis of Endometriosis, EAOC and OC. MATERIAL AND METHOD: Prospective observational study of case series from January 2014 to April 2017 in patients assisted in the Gynecology and Obstetrics Service of the Virgen de la Arrixaca Clinical Universitary Hospital, with the diagnosis of endometriosis and / or OC undergoing surgery. An anatomopathological and immunohistochemical analysis of the surgical pieces of the different groups (Endometriosis, OC and EAOC) was performed. RESULTADOS: 266 patients were included. Endometriosis was confirmed in 185 patients, of whom 159 had isolated endometriosis and 26 had EAOC. Of the total of 107 registered ovarian cancers (TOC), 26 (24.3%) were EAOC and 81 (75.7%) ovarian cancer without associated endometriosis (OC). The 53.1% of the OC were serous carcinomas, compared to the 15.4% seen in the EAOC. Likewise, 23.1% of the EAOC were CCAc and 42.3% were EAc, versus 6.2% and 14.8% respectively of those found in OC (p<0.001). There were 23 cases (12.43%) with characteristics of AE in the 185 patients with endometriosis. An analysis of the 23 cases of atypical endometriosis found that 11 (47.8%) patients had ECA and 12 (52.2%) had EAA. In addition, we observed that 10 of 11 patients with ECA had atypical endometriosis without neoplasm, and 8 of 12 patients with EAA had EAOC (p = 0.009) From the immunohistochemical studies, we found association (p= 0.004) between high Ki-67 and EAA. There are no significant differences for COX-2 or BAF250a. Regarding the differences between the histological types of the OC and EAOC, the serous carcinomas were associated with the OC group, and the CCAc and EAc with EAOC (p<0.001). According to EAOC staging, 76.9% patients of EAOC cases and 44.45% of non-EAOC were stage I (p< 0.001). CONCLUSIONS: 1. There is a significant association between Atypical Endometriosis and Endometriosis-associated Ovarian Cancer. 2. The histological types of Ovarian Cancer significantly associated with Endometriosis were Clear Cell Adenocarcinoma and Endometrioid Adenocarcinoma, both included in type I of the Kurman and Shild model. 3. Our data suggest that ovarian cancer associated with endometriosis could present a better prognosis in ovarian cancer. 4. There is a significant association between Atypical Architectural Endometriosis and Endometriosis-associated Ovarian Cancer. 5. Our data support the hypothesis that Hiperplasia or Atypical Architectural Endometriosis could constitute a precursor lesion in the pathogenesis of Endometriosis-Associated Ovarian Cancer