Surgical versus clinical staging prior to primary chemoradiation in patients with cervical cancer FIGO stages IIB-IVA: oncologic results of a prospective randomized international multicenter (Uterus-11) intergroup study.

OBJECTIVE: Revised staging of patients with locally advanced cervical cancer is based on clinical examination, imaging, and potential surgical findings. A known limitation of imaging techniques is an appreciable rate of understaging. In contrast, surgical staging may provide more accurate information on lymph node involvement. The aim of this prospective study was to evaluate the impact of pre-treatment surgical staging, including removal of bulky lymph nodes, on disease-free survival in patients with locally advanced cervical cancer. METHODS: Uterus-11 was a prospective international multicenter study including patients with locally advanced cervical cancer who were randomized 1:1 to surgical staging (experimental arm) or clinical staging (control arm) followed by primary platinum-based chemoradiation. Patients with histologically proven squamous cell carcinoma, adenocarcinoma, or adenosquamous cancer International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IIB-IVA underwent gynecologic examination and pre-treatment imaging including abdominal computed tomography (CT) and/or abdominal magnetic resonance imaging (MRI). Patients had chest imaging (any of the following: X-ray, CT, or PET-CT). The primary endpoint was disease-free survival and the secondary endpoint was overall survival. An ad hoc analysis was performed after trial completion for cancer-specific survival. Randomization was conducted from February 2009 to August 2013. RESULTS: A total of 255 patients (surgical arm, n=130; clinical arm, n=125) with locally advanced cervical cancer were randomized. Of these, 240 patients were eligible for analysis. The two groups were comparable with respect to patient characteristics. The surgical approach was transperitoneal laparoscopy in most patients (96.6%). Laparoscopic staging led to upstaging in 39 of 120 (33%) patients. After a median follow-up of 90 months (range 1-123) in both arms, there was no difference in disease-free survival between the groups (p=0.084). For patients with FIGO stage IIB, surgical staging is superior to clinical staging with respect to disease-free survival (HR 0.51, 95% CI 0.30 to 0.86, p=0.011). In the post-hoc analysis, surgical staging was associated with better cancer-specific survival (HR 0.61, 95% CI 0.40 to 0.93, p=0.020). CONCLUSION: Our study did not show a difference in disease-free survival between surgical and clinical staging in patients with locally advanced cervical cancer. There was a significant benefit in disease-free survival for patients with FIGO stage IIB and, in a post-hoc analysis, a cancer-specific survival benefit in favor of laparoscopic staging. The high risk of distant metastases in both arms emphasizes the need for further evaluation.

Recommendations for hypofractionated whole-breast irradiation

SUMMARY This recommendation consensus for hypofractionated whole-breast radiotherapy (RT) was organized by the Brazilian Society of Radiotherapy (SBRT) considering the optimal scenario for indication and safety in the technology applied. All controversies and contraindication matters (hypofractionated RT in patients who underwent chemotherapy [CT], hypofractionated RT in lymphatic drainage, hypofractionated RT after mastectomy with or without immediate reconstruction, boost during surgery, hypofractionated RT in patients under 50 years old, hypofractionated RT in large breasts, hypofractionated RT in histology of carcinoma in situ [DCIS]) was discussed during a meeting in person, and a consensus was reached when there was an agreement of at least 75% among panel members. The grade for recommendation was also suggested according to the level of scientific evidence available, qualified as weak, medium, or strong. Thus, this consensus will aid Brazilian radiotherapy experts regarding indications and particularities of this technique as a viable and safe alternative for the national reality.

RESUMO Este consenso de recomendações para a radioterapia (RT) hipofracionada de toda a mama foi organizado pela Sociedade Brasileira de Radioterapia (SBRT) considerando o cenário ideal para indicação e segurança na tecnologia aplicada. Questões de controvérsias e contraindicações (RT hipofracionada em pacientes submetidas à quimioterapia [QT], RT hipofracionada nas drenagens linfáticas, RT hipofracionada após mastectomia com ou sem reconstrução imediata, a realização de reforço de dose em leito cirúrgico [ou boost], RT hipofracionada em pacientes com idade menor que 50 anos, RT hipofracionada em mamas volumosas, RT hipofracionada em histologia de carcinoma in situ [CDIS]) foram discutidas em encontro presencial, sendo o consenso atingido quando existisse concordância de pelo menos 75% dos panelistas. O grau de recomendação foi também sugerido de acordo com o nível de evidência científico disponível, qualificado entre fraco, médio ou forte. Assim, este consenso deverá servir para auxiliar os especialistas da radioterapia brasileira em relação às indicações e particularidades dessa técnica, como uma alternativa segura e viável para a realidade nacional.

Recommendations for hypofractionated whole-breast irradiation.

This recommendation consensus for hypofractionated whole-breast radiotherapy (RT) was organized by the Brazilian Society of Radiotherapy (SBRT) considering the optimal scenario for indication and safety in the technology applied. All controversies and contraindication matters (hypofractionated RT in patients who underwent chemotherapy [CT], hypofractionated RT in lymphatic drainage, hypofractionated RT after mastectomy with or without immediate reconstruction, boost during surgery, hypofractionated RT in patients under 50 years old, hypofractionated RT in large breasts, hypofractionated RT in histology of carcinoma in situ [DCIS]) was discussed during a meeting in person, and a consensus was reached when there was an agreement of at least 75% among panel members. The grade for recommendation was also suggested according to the level of scientific evidence available, qualified as weak, medium, or strong. Thus, this consensus will aid Brazilian radiotherapy experts regarding indications and particularities of this technique as a viable and safe alternative for the national reality.

Role of Surgical Versus Clinical Staging in Chemoradiated FIGO Stage IIB-IVA Cervical Cancer Patients-Acute Toxicity and Treatment Quality of the Uterus-11 Multicenter Phase III Intergroup Trial of the German Radiation Oncology Group and the Gynecologic Cancer Group.

PURPOSE: The Uterus-11 trial was designed to evaluate the role of surgical staging in patients with cervical cancer before primary chemoradiation therapy (CRT). The present report provides the toxicity data stratified by the treatment arm and technique. METHODS AND MATERIALS: A total of 255 patients with carcinoma of the uterine cervix (International Federation of Gynecology and Obstetrics stage IIB-IVA) were randomized to either surgical staging followed by CRT (arm A) or clinical staging followed by CRT (arm B). Patients with para-aortic metastases underwent extended field radiation therapy (RT). Brachytherapy was mandatory. The present report presents the acute therapy-related toxicities stratified by treatment arm and radiation technique. RESULTS: A total of 240 patients were eligible (n=121 in arm A; n=119 in arm B). Of the 240 patients, 236 (98.3%) underwent external beam RT with a median total dose of 50.4 Gy. The mean treatment duration was 53 days. Of the patients, 60% underwent intensity modulated RT (IMRT). A total of 234 patients (97.5%) underwent chemotherapy, and 231 (96.3%) underwent brachytherapy, with a median single dose of 6 Gy covering the tumor to a median nominal total dose of 28 Gy. Treatment was well tolerated, with 0% grade ≥3 genitourinary and gastrointestinal toxicity, 6% grade 3 nausea, 3% grade 3 vomiting, and <2% grade 3 diarrhea. More patients after surgical staging experienced grade 2 anemia (54.3% in arm A vs 45.3% in arm B; P=.074) and grade 2 leukocytopenia (41.4% vs 31.6%; P=.56). Of the patients who received IMRT versus a 3-dimensional technique, 65.3% versus 33.7% presented with grade 2 anemia. Grade 3 gastrointestinal and grade 2 bladder toxicity were significantly reduced with the use of IMRT. CONCLUSIONS: The incidence and severity of acute therapy-related toxicity compared favorably with those from other randomized trials. Excellent adherence to treatment and treatment quality was achieved compared with patterns of care analyses. Surgical staging led to a doubled number of patients treated with extended field RT. The question of whether surgical staging is beneficial in the context of primary CRT requires further study.

Overexpression of the ITGAV gene is associated with progression and spread of colorectal cancer.

BACKGROUND/AIM: The interaction of neoplastic cells with the extracellular matrix is a critical event for the initiation of cancer invasion and metastasis. We evaluated the relationship between the expression of SPARC, ITGAV, THBS1 and VCAM-1 genes of extracellular matrix in the progression and dissemination of colorectal cancer (CRC). PATIENTS AND METHODS: Adult patients (N=114) underwent resection of CRC. Gene expression in CRC was determined by quantitative real-time polymerase chain reaction (PCR). Protein expression was analyzed by immunohistochemistry (IHC). Correlation with pathway-related molecules (p53, Bcl-2, Ki-67, EGFR and VEGF) was assessed. RESULTS: Tumors with perineural invasion showed overexpression (p=0.028) of the ITGAV gene with regard to cancers without perineural invasion and validation of the result through IHC expression of the corresponding proteins, was significant for the expression of ITGAV protein (p=0.001). CONCLUSION: The overexpression of ITGAV gene was associated with higher progression and spread of CRC via perineural invasion.

Expressão da proteína tgfbeta1 em coração irradiado in vivo / In vivo evaluation of expression of TGFbeta1 in the irradiated heart

OBJETIVO: Avaliar, no coração, por imuno-histoquímica, a localização das proteínas TGFbeta1 latente e TGFbeta1 ativa, se ocorre ativação radioinduzida da proteína TGFbeta1 latente, e a distribuição das fibras colágenas em diversos períodos de tempo após irradiação. MATERIAIS E MÉTODOS: Trinta e dois camundongos isogênicos (C57BL) foram divididos em dois grupos: GI (não irradiado), com 12 animais, e GII (irradiado), com 20 animais. Os animais do GII receberam radiação gama (telecobaltoterapia, 60Co, com rendimento de 0,97 Gy/min., dose única de 7 Gy em corpo inteiro). Os camundongos dos grupos I e II foram sacrificados por estiramento cervical nos períodos de 1, 14, 30 e 90 dias após irradiação. RESULTADOS: Os corações irradiados apresentaram: 1) alterações nucleares e diminuição das estriações das células musculares cardíacas; 2) aumento significante da deposição de fibras colágenas aos 90 dias depois da irradiação; 3) ativação da proteína TGFbeta1 latente em cardiomiócitos e células do conjuntivo depois da irradiação. CONCLUSÃO: Nossos resultados mostram a importância da proteína TGFbeta1 no processo de fibrose cardíaca radioinduzida e sugerem que células do parênquima (cardiomiócitos) e do conjuntivo podem participar deste mecanismo atuando como fontes da proteína TGFbeta1 ativa.

OBJECTIVE: To assess the latent and active TGFb1 localization in the heart, to evaluate whether or not radiation induces latent TGFb1 activation, and to study the distribution of collagen fibers in the irradiated heart. MATERIALS AND METHODS: Thirty-two C57BL mice were randomly assigned in two groups: GI (non irradiated animals) and GII (irradiated animals). The mice from GII received a single whole-body radiation dose of 7Gy, using a 60Co source at a dose rate of 0.97 Gy/min. The animals were sacrificed by cervical dislocation at 1, 14, 30 and 90 days after irradiation. RESULTS: The irradiated hearts showed: 1) nuclear changes and muscle cells with decreased striations; 2) significant increase in the collagen deposition 90 days after irradiation; 3) latent TGFb1 activation in the cardiomyocytes and connective tissue cells after irradiation. CONCLUSION: Our results show the importance of TGFbeta1 protein in the process of radiation-induced heart fibrosis and suggest that cardiomyocytes and connective cells may play a role in this mechanism acting as cellular sources of active TGFbeta1