The efficacy of chemotherapy re-challenge in third-line setting for metastatic colorectal cancer patients: a real-world study / 中华肿瘤杂志

Objective: To explore the efficacy of chemotherapy re-challenge in the third-line setting for patients with metastatic colorectal cancer (mCRC) in the real world. Methods: The clinicopathological data, treatment information, recent treatment efficacy, adverse events and survival data of mCRC patients who had disease progression after treatment with oxaliplatin-based and/or irinotecan-based chemotherapy and received third-line chemotherapy re-challenge from January 2013 to December 2020 at Tianjin Medical University Cancer Institute and Hospital were retrospectively collected. Survival curves were plotted with the Kaplan-Meier method, and the Cox proportional hazard model was used to analyze the prognostic factors. Results: A total of 95 mCRC patients were included. Among them, 32 patients (33.7%) received chemotherapy alone and 63 patients (66.3%) received chemotherapy combined with targeted drugs. Eighty-three patients were treated with dual-drug chemotherapy (87.4%), including oxaliplatin re-challenge in 35 patients and irinotecan re-challenge in 48 patients. The remaining 12 patients were treated with triplet chemotherapy regimens (12.6%). Among them, as 5 patients had sequential application of oxaliplatin and irinotecan in front-line treatments, their third-line therapy re-challenged both oxaliplatin and irinotecan; 7 patients only had oxaliplatin prescription before, and these patients re-challenged oxaliplatin in the third-line treatment. The overall response rate (ORR) and disease control rate (DCR) reached 8.6% (8/93) and 61.3% (57/93), respectively. The median progression free survival (mPFS) and median overall survival (mOS) were 4.9 months and 13.0 months, respectively. The most common adverse events were leukopenia (34.7%) and neutropenia (34.7%), followed by gastrointestinal adverse reactions such as nausea (32.6%) and vomiting (31.6%). Grade 3-4 adverse events were mostly hematological toxicity. Cox multivariate analysis showed that gender (HR=1.609, 95% CI: 1.016-2.548) and the PFS of front-line treatments (HR=0.598, 95% CI: 0.378-0.947) were independent prognostic factors. Conclusion: The results suggested that it is safe and effective for mCRC patients to choose third-line chemotherapy re-challenge, especially for patients with a PFS of more than one year in front-line treatments.

The efficacy of chemotherapy re-challenge in third-line setting for metastatic colorectal cancer patients: a real-world study / 中华肿瘤杂志

Objective: To explore the efficacy of chemotherapy re-challenge in the third-line setting for patients with metastatic colorectal cancer (mCRC) in the real world. Methods: The clinicopathological data, treatment information, recent treatment efficacy, adverse events and survival data of mCRC patients who had disease progression after treatment with oxaliplatin-based and/or irinotecan-based chemotherapy and received third-line chemotherapy re-challenge from January 2013 to December 2020 at Tianjin Medical University Cancer Institute and Hospital were retrospectively collected. Survival curves were plotted with the Kaplan-Meier method, and the Cox proportional hazard model was used to analyze the prognostic factors. Results: A total of 95 mCRC patients were included. Among them, 32 patients (33.7%) received chemotherapy alone and 63 patients (66.3%) received chemotherapy combined with targeted drugs. Eighty-three patients were treated with dual-drug chemotherapy (87.4%), including oxaliplatin re-challenge in 35 patients and irinotecan re-challenge in 48 patients. The remaining 12 patients were treated with triplet chemotherapy regimens (12.6%). Among them, as 5 patients had sequential application of oxaliplatin and irinotecan in front-line treatments, their third-line therapy re-challenged both oxaliplatin and irinotecan; 7 patients only had oxaliplatin prescription before, and these patients re-challenged oxaliplatin in the third-line treatment. The overall response rate (ORR) and disease control rate (DCR) reached 8.6% (8/93) and 61.3% (57/93), respectively. The median progression free survival (mPFS) and median overall survival (mOS) were 4.9 months and 13.0 months, respectively. The most common adverse events were leukopenia (34.7%) and neutropenia (34.7%), followed by gastrointestinal adverse reactions such as nausea (32.6%) and vomiting (31.6%). Grade 3-4 adverse events were mostly hematological toxicity. Cox multivariate analysis showed that gender (HR=1.609, 95% CI: 1.016-2.548) and the PFS of front-line treatments (HR=0.598, 95% CI: 0.378-0.947) were independent prognostic factors. Conclusion: The results suggested that it is safe and effective for mCRC patients to choose third-line chemotherapy re-challenge, especially for patients with a PFS of more than one year in front-line treatments.

Relationship between Expression of Runt-related Transcription Factor 3 and Enhancer of zeste Homolog 2 Proteins and Sensitivity to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer / 中国医学科学院学报

Objective To investigate the expression and correlation of Runt-related transcription factor 3(RUNX3)and enhancer of zeste homolog 2(EZH2)in rectal cancer,and to reveal the relationship between the expression of RUNX3 and EZH2 and the sensitivity of XELOX regimen to neoadjuvant chemotherapy in locally advanced rectal cancer patients. Methods The carcinoma and paracancerous tissues of 31 patients with rectal adenocarcinoma and no preoperative antitumor therapy were selected as cancer group and paracancer group,respectively.The relative mRNA levels of RUNX3 and EZH2 in the two groups were measured by real-time quantitative reverse transcription-polymerase chain reaction,and the protein levels were determined by immunohistochemical assay.The expression of RUNX3 and EZH2 was compared between cancer tissue and paracancerous tissue.The pre-treatment wax blocks of 26 patients with locally advanced rectal cancer who received 3 cycles of XELOX regimen as neoadjuvant chemotherapy before surgery were selected as the pre-neoadjuvant therapy group,and the postoperative pathological wax blocks were selected as the post-neoadjuvant treatment group.Tumor regression grade(TRG)was determined to evaluate the efficacy of neoadjuvant therapy.Immunohistochemical assay was used to detect the protein levels of RUNX3 and EZH2 in the two groups,and then the relationship between the expression patterns of the two proteins and the efficacy of neoadjuvant chemotherapy was analyzed. Results Compared with paracancerous tissue,the cancer tissue showed down-regulated mRNA level and reduced positive protein expression rate of RUNX3,while up-regulated mRNA level(

Adjuvant chemotherapy in locally advanced rectal cancer: deciding on the optimal strategy

ABSTRACT Background: Neoadjuvant therapy, followed by surgery, reduces the risk of local relapse in rectal cancer, but approximately 30% will relapse with distant metastases, highlighting the importance of adjuvant chemotherapy (aCT). Objective: The objective of the study was to study two regimens of adjuvant treatment in patients with locally advanced rectal cancer and analyze their efficacy and toxicity. Methods: Between January 2009 and December 2016, 193 patients with Stage II-III rectal cancer who had received neoadjuvant therapy were included by consecutive non-probability sampling. The decision to administer aCT, as well as the specific regimen, was at the discretion of the medical oncologist. Disease-free survival (DFS) and overall survival (OS) were calculated. Results: The mean DFS was 84.85 (95% confidence interval [CI]: 79-90) months in 164 patients receiving aCT, compared to 57.71 (95% CI: 40-74) months in 29 who did not receive aCT (p < 0.001). Then, mean OS was 92.7 (95% CI: 88-97) months and 66.18 (95% CI 51-81) months, respectively (p < 0.001). DFS was 83.6 (95% CI: 76-91) months in 74 patients receiving adjuvant 5-fluorouracil (5-FU), and 82.9 (95% CI: 75-90) months in 90 receiving 5-FU plus oxaliplatin (p = 0.49). OS was 87 (95% CI: 80-94) versus 93.65 (95% CI: 88-99) months, respectively (p = 0.76). The multivariate analysis identified aCT hazard ratio (HR) 0.30 (95% CI: 0.1-0.46), perineural invasion HR 3.36 (95% CI: 1.7-6.5), and pathological complete response HR 0.10 (95% CI; 0.01-0.75) as independent markers of DFS. Conclusions: In our study, aCT was associated with longer DFS and OS. 5-FU plus oxaliplatin showed greater toxicity with no added benefit in DFS or OS.

Rectal carcinoma with synchronous liver metastases / Carcinoma retal com metástases hepáticas síncronas

Abstract Introduction Colorectal cancer is amongst the most prevailing malignancies in the world and it is associated with a relatively high mortality rate. Rectal cancer occurs in 20-30% of all colorectal cancer cases, and 25% of this present synchronous metastatic disease. This study aims to review the current treatment approaches for rectal cancer patients with synchronous liver metastases, as there are no specific guidelines for the management of this group of patients. Methods A systematic literature search was performed on Pubmed database with a 10 year timeline limitation from 2008 to 2018. Results Currently, the only potentially curative approach remains to be the surgical resection. Conventionally, the classical strategy of these patients involves resection of rectal tumor, followed by liver resection, with chemotherapy sessions between the two procedures. However, recent studies have reported no inferiority, in safety and survival outcomes, when compared with other approaches (liver-first resection or simultaneous resection), except when symptoms of primary tumor are present. Hence, treatment strategy should be individualized based on the assessment of metastatic extent, primary tumor symptoms and the patient's overall clinical status. Chemotherapy and targeted agents have substantially contributed to overall survival improvements, allowing enhanced tumor down staging. Conclusion Complete resection of liver metastases is considered the major condition for a potential survival outcome in these patients. Management of these patients should include a multidisciplinary team with consideration of each individual specificities. Prospective randomized trials are needed to elucidate the optimal treatment strategy.

Introdução: O câncer colorretal está entre as neoplasias mais prevalentes no mundo, apresentando a uma taxa de mortalidade relativamente alta. Ele corresponde a 20% a 30% de todos os casos de câncer colorretal; 25% dos casos apresentam doença metastática síncrona. Este estudo teve como objetivo revisar as abordagens atuais de tratamento para pacientes com câncer retal com metástases hepáticas síncronas, uma vez que não existem diretrizes específicas para o manejo deste grupo de pacientes. Métodos: Uma busca sistemática da literatura foi realizada no banco de dados PubMed com uma limitação temporal de 10 anos (2008 a 2018). Resultados: Atualmente, a ressecção cirúrgica ainda é a única abordagem potencialmente curativa. Tradicionalmente, a estratégia clássica para o tratamento desses pacientes envolve a ressecção do tumor retal, seguida de ressecção hepática, com sessões de quimioterapia entre os dois procedimentos. No entanto, ao comparar a abordagem tradicional com outras técnicas (ressecção em primeiro plano do fígado ou ressecção simultânea), estudos recentes não relataram inferioridade nos desfechos de segurança e sobrevida, exceto quando sintomas de tumor primário estão presentes. Portanto, a estratégia de tratamento deve ser individualizada com base na avaliação da extensão metastática, nos sintomas primários do tumor e no estado clínico geral do paciente. A quimioterapia e os agentes dirigidos contribuíram substancialmente para as melhorias gerais na sobrevida, permitindo uma maior redução do estadiamento tumoral. Conclusão: A ressecção completa de metástases hepáticas é considerado o principal requisito para um possível resultado de sobrevida nesses pacientes. O manejo desses pacientes deve incluir uma equipe multidisciplinar e considerar as características específicas de cada paciente. Estudos prospectivos randomizados são necessários para elucidar a estratégia de tratamento ideal.

Rectal cancer and chemoradiation in Iraq: systematic review and meta-analysis / Câncer retal e quimiorradioterapia no Iraque: revisão sistemática e metanálise

Abstract Background: Rectal cancer is one of the most common malignant tumors of gastrointestinal tract. Combining chemotherapy with radiotherapy has a sound effect on its management. Objectives: Assessment the patterns of characterizations of rectal cancer. Evaluation of the efficacy, and long-term survival of pre-/ postoperative chemoradiation. Collecting all eligible evidence articles and summarize the results. Methods: By this systematic review and meta-analysis study, we include data of chemoradiation of rectal cancer articles from 2015 until 2019. The research was carried out at Baghdad Medical City oncology centers. Accordance with the PRISMA guidelines, and the Newcastle-Ottawa Scale used. Results: Starting with gender distribution as M:F ratio of 0.94:1.06. Regarding the age, recorded mean ± SD of 48.7 ± 14.2 years. Rectosigmoid represented the most common site as 50(49.5%), and adenocarcinoma was common histopathology as 76(75.2%) of patients, with localized stage in 50(49.5%). The moderate differentiation was most grade as 65(64.4%). The distant from anal verge mostly seen was 5-10 cm in 59(58.4%). The pulmonary was commonest site of metastasis in 11(10.9%). Most patients undergo APR operation, which has done in 41(40.6%). Adjuvant chemoradiation received by 40(39.6%) patients, whereas neoadjuvant chemoradiation gave to 25 patients. A total of 2609 articles from 12 databases met our search strategies. The highest Newcastle-Ottawa score (8) demonstrated in three studies, and median score (7) calculated in five studies. Conclusions: The incidence belonged to 5th and 6th decade of life. Rectosigmoid represented the most common site. Mostly, the 5-10 cm distant of tumor from anal verge was common finding. The pulmonary was most site of metastasis. We concluded the formulation of a novel point that survival benefit found in many pre or postoperative chemoradiation trials in rectal cancer.

Resumo Introdução: O câncer retal é um dos tumores malignos mais comuns do trato gastrointestinal. A combinação de quimioterapia e radioterapia em seu tratamento é eficaz. Objetivos: Avaliar os padrões de caracterização do câncer retal. Avaliar a eficácia e sobrevida a longo prazo em pacientes submetidos a quimiorradioterapia pré- ou pós-operatória. Coletar todos os artigos de evidências qualificados e resumir os resultados. Métodos: Esta revisão sistemática e metanálise incluiu dados de ensaios clínicos randomizados por cluster de 2015 até 2019. A pesquisa foi realizada nos centros de oncologia do Baghdad Medical City. As diretrizes PRISMA e a escala de Newcastle-Ottawa foram utilizadas para avaliar os estudos. Resultados: Quanto à distribuição por sexo, observou-se uma relação homem:mulher de 0,94:1,06. Em relação à idade, a média ± DP foi de 48,7 ± 14,2 anos. O retossigmoide fpo o local mais comum em 50 pacientes (49,5%); a histopatologia mais comum foi adenocarcinoma, observada em 76 pacientes (75,2%), com estágio localizado em 50 (49,5%). Diferenciação moderada foi observada em 65 pacientes (64,4%). A distância da borda anal variou entre 5 e 10 cm em 59 pacientes (58,4%). O pulmão foi o local mais comum de metástase, sendo observado em 11 pacientes (10,9%). A maioria dos pacientes (41 [40,6%]) foi submetida à ressecção abdominoperineal. Um total de 40 pacientes (39,6%) foram submetidos a quimiorradioterapia adjuvante e 25, a quimiorradioterapia neoadjuvante. Na revisão da literatura, foram encontrados 2.609 artigos que atendiam aos critérios de pesquisa utilizados em 12 bancos de dados. Três estudos atingiram o escore máximo na escala de Newcastle-Ottawa (8); cinco estudos atingiram o escore mediano (7). Conclusões: No presente estudo, a maior incidência de câncer retal foi observada entre a quinta e sexta décadas de vida. O retossigmoide foi o sítio tumoral mais comum. A maioria dos tumores estava localizado entre 5 a 10 cm de distância da margem anal. O pulmão foi o local mais importante de metástase. No presente estudo, quimiorradioterapia pré- ou pós-operatória estava relacionada a uma maior sobrevida em casos de câncer retal.

Integrated care pathway for rectal cancer treatment: cross-sectional post-implementation study using a logic model framework

ABSTRACT BACKGROUND: Management of rectal cancer has become more complex with multimodality therapy (neoadjuvant chemoradiotherapy and surgery) and this has led to the need to organize multidisciplinary teams. The aim of this study was to report on the planning, implementation and evaluation of an integrated care pathway for neoadjuvant treatment of middle and lower rectal cancer. DESIGN AND SETTING: This was a cross-sectional post-implementation study that was carried out at a public university cancer center. METHODS: The Framework for Program Evaluation in Public Health of the Centers for Disease Control and Prevention (CDC) was used to identify resources and activities; link results from activities and outcomes with expected goals; and originate indicators and outcome measurements. RESULTS: The logic model identified four activities: stakeholders' engagement, clinical pathway development, information technology improvements and training programs; and three categories of outcomes: access to care, effectiveness and organizational outcomes. The measurements involved 218 patients, among whom 66.3% had their first consultation within 15 days after admission; 75.2% underwent surgery < 14 weeks after the end of neoadjuvant treatment and 72.7% completed the treatment in < 189 days. There was 100% adherence to the protocol for the regimen of 5-fluorouracil and leucovorin. CONCLUSIONS: The logic model was useful for evaluating the implementation of the integrated care pathways and for identifying measurements to be made in future outcome studies.

Assessment of the non-surgical treatment of patients with rectal cancer who underwent neoadjuvant treatment with chemotherapy and radiotherapy at the oncology department / Avaliação do tratamento não cirúrgico de pacientes com câncer de reto submetido ao tratamento neoadjuvante com quimioterapia e radioterapia no serviço de oncologia

ABSTRACT Objective: To describe the partial results of a study in patients with rectal cancer who underwent neoadjuvant treatment with chemotherapy and radiotherapy regarding the rate of complete clinical response, disease-free survival, anorectal function, and quality of life. Material and methods: This was a prospective study from June 2015 to June 2018, in patients with low- or mid-rectum adenocarcinoma and clinical stage II or III, treated with radiotherapy and chemotherapy (IMRT 54 Gy for six weeks) concomitant with 5-fluorouracil (5-FU) 380 mg/m2 and folinic acid (LV) 20 mg/m2 for five days in the first and fifth weeks and two cycles after radiotherapy (5-FU 400 mg/m2 and LV 20 mg/m2) every 28 days. After the treatment, clinical examination, rectosigmoidoscopy, pelvic magnetic resonance imaging, chest and upper abdomen computed tomography, and CEA testing were performed. Resection surgery was performed in those with incomplete clinical response (iCR). Those with complete clinical response (cCR) are under observation (wait-and-see policy). Manometry and scintigraphic function and quality of life scales were collected before treatment and at 30 and 90 days after the end of treatment. Results: As of June 2018, 11 patients were recruited. One was excluded from the analysis for presenting severe toxicity, suggestive of dihydropyrimidine dehydrogenase (DPD) deficiency, after the first chemotherapy cycle. All others completed the treatment. Two patients presented toxicity grade 3/4 related to chemotherapy and had their doses reduced. Seven patients (70%) presented iRC; three underwent rectosigmoidectomy, and the anatomopathological evaluation indicated complete pathological response in two cases (28.5%). Three (30%) presented cCR and did not present evidence of disease after a mean follow-up of 19 months. Patients presented improvement of anorectal function and quality of life. Conclusions: Advances in the neoadjuvant treatment of rectal tumors contributed to better rates of complete pathological responses. New paradigms promote an increase in the complete clinical response rates, which would allow organ preservation and consequent reduction of surgical morbidity.

RESUMO Objetivo: Descrever os resultados parciais de estudo em pacientes com câncer de reto submetidos a tratamento neoadjuvante com quimioterapia e radioterapia quanto à taxa resposta clínica completa, sobrevida livre de doença, função anorretal e qualidade de vida. Material e métodos: Estudo prospectivo desde junho 2015 até junho de 2018, em paciente com adenocarcinoma de reto baixo ou médio e estadio clínico II ou III tratados com RT/QT (IMRT 54 Gy em 6 semanas) concomitante a 5-Fuorouracil (5-FU) 380 mg/m2 e ácido folínico (LV) 20 mg/m2 por 5 dias nas primeira e quinta semanas e dois ciclos após RT (5-FU 400 mg/m2 e LV 20 mg/m2) a cada 28 dias. Após o tratamento, realizou-se exame clínico, retossigmoidoscopia, RNM de pelve, TC de tórax e abdômen superior e dosagem de CEA. Naqueles com Resposta Clínica Incompleta (iRC) procedeu-se à cirurgia de ressecção. Aqueles com Resposta Completa (cRC) estão em observação (wait and see policy). Manometria e escalas de função esfincteriana e qualidade de vida foram obtidas antes e após 30 e 90 dias do término do tratamento. Resultados: Até junho de 2018, recrutaram-se 11 pacientes. Um foi excluído da análise, pois apresentou toxicidade severa sugestiva de deficiência de DPD após o primeiro ciclo de QT. Todos os demais concluíram o tratamento. Toxicidades graus 3/4 relacionadas à QT ocorreram dois pacientes, reduzindo-se sua dose. Sete (70%) apresentaram iRC, submetendo três à retossigmoidectomia cuja avaliação anatomopatológica evidenciou Resposta Completa (pRC) em dois casos (28,5%). Três (30%) apresentaram cRC e estão sem evidência de doença com seguimento médio de 19 meses. Houve melhora da função anorretal e da qualidade de vida. Conclusões: Avanços no tratamento neoadjuvante dos tumores de reto contribuíram para melhores taxas de pRC. Novos paradigmas promovem crescentes índices de cRC, o que possibilitaria a preservação do órgão e consequente redução da morbidade cirúrgica.

Manejo no operatorio del cáncer de recto con respuesta clínica completa luego de quimiorradioterapia neoadyuvante: experiencia en 8 casos / Non-operative management of rectal cancer with complete clinical response after neoadjuvant chemoradiotherapy: experience in 8 cases

Introducción: Se diagnostican hasta 13000 nuevos casos de cáncer colorrectal por año, y esto va en aumento. El cáncer de recto debe ser tratado mediante un abordaje multimodal. Luego de la implementación del tratamiento neoadyuvante y de la aparición de la respuesta patológica completa se implementó el manejo no operatorio. Nuestro objetivo es describir nuestra experiencia con el manejo inicial no operatorio de pacientes con cáncer de recto, que recibieron neoadyuvancia y desarrollaron una respuesta clínica completa inicial. Diseño: Estudio observacional, descriptivo, retrospectivo. Pacientes y Métodos: 49 pacientes con diagnóstico de cáncer de recto bajo (< 8 cm), recibieron tratamiento neoadyuvante con radioquimioterapia (RQT). Se realizó radioterapia (RT), a una dosis de 5040 cGy por un total de 5 semanas, y concomitante a esta, quimioterapia (QT) con 5-Fu-leucovorina en las semanas 1 y 5. Aquellos pacientes en los cuales se encontró cCR inicial a la neoadyuvancia, y la cirugía resectiva implicaba alto riesgo quirúrgico debido a sus comorbilidades y/o imposibilidad de la conservación de esfínteres se planteó la posibilidad de tomar una conducta no operatoria. Resultados: Se incluyeron 8 pacientes con cCR. El promedio de edad de los pacientes fue de 70 años (mediana 69,5 años), el promedio de altura del tumor fue de 5,8 cm; todos en estadio IIa. La mediana de seguimiento fue de 72,5 meses. 3 pacientes presentaron recaídas, todas endoluminales, 2 fueron tempranas (9 y 12 meses) y una tardía (18 meses), los cuales fueron operados, 2 de ellos se encuentran actualmente libres de enfermedad y el tercero óbito a los 30 días POP. La sobrevida global de los pacientes fue de un 87,5% y se evitó una cirugía mayor en 5 pacientes (62,5%). Conclusión: La implementación del tratamiento inicial no operatorio del cáncer de recto en aquellos pacientes que desarrollaron cCR luego del tratamiento neoadyuvante puede ser seguro, siempre y cuando estos pacientes estén incluidos en un programa de seguimiento estricto que permita una cirugía de rescate. El tratamiento conservador sin cirugía debe ser reservado para pacientes de alto riesgo quirúrgico o en los que la cirugía implique la necesidad de una cirugía de amputación abdominoperineal. (AU)

Introduction: 13000 new cases of colorectal cases are diagnosed per year. Rectal cancer must be treated with a multimodal approach. After the administration of neoadjuvant treatment and the appearance of a pathologic complete response, nonoperative management was implemented. Our objective is to describe our experience with nonoperative management of patients with rectal cancer that received neoadjuvant therapy and developed an initial complete clinical response. Design: Retrospective descriptive observational study. Patients and Methods: Forty-nine patients with low rectal cancer (< 8 cm) received neoadjuvant radiochemotherapy. Radiotherapy was performed with a total dose of 5040 cGy for 5 weeks, and concomitant 5-FU-leucovorin-based chemotherapy in weeks 1 and 5. Nonoperative management was attempted on patients experiencing initial cCR to neoadjuvant therapy and with a higher surgical risk due to their comorbidity and/or impossibility of conserving the sphincters. Results: Eight patients with cCR were included. The average age of the patients was 70 years; the average height of the tumor was 5.8 cm; all of them at stage IIA. Median follow-up was 72.5 months. Two patients developed an early endoluminal recurrence (after 9 and 12 months) and one had a late recurrence (18 months). All of them had surgery. Two of them are disease-free and one died 30 days after surgery. Conclusion: Implementation of initial nonoperative treatment of rectal cancer in patients that developed cCR after neoadjuvant therapy can be safe, provided that those patients are included in a strict monitoring programme that would allow for a rescue surgery. Conservative treatment without surgery must be reserved for patients with a higher surgical risk or who require an abdominoperineal resection. (AU)

Tumores de reto: diagnóstico e tratamento / Rectal tumors: diagnosis and treatment

Introdução: A incidência de câncer retal tem aumentado na última década. O adenocarcinoma de reto, vasta maioria dos cânceres retais, é uma doença com o diagnóstico relativamente simples e de desfecho positivo através de tratamento e diagnóstico precoces. Métodos: Revisamos na literatura o diagnóstico e o tratamento. O estudo foi realizado de forma qualitativa, por meio de revisão de literatura, tendo como fonte principal artigos científicos disponibilizados em diversas bases de dados. Resultados: O diagnóstico é realizado pela anamnese, exame físico e exames de imagem. A base do tratamento de tumores potencialmente ressecáveis é a cirurgia enquanto que a quimiorradioterapia neoadjuvante apresenta papel importante em casos de invasão transmural. Conclusão: O tratamento curativo do câncer retal baseia-se no procedimento cirúrgico. Neste sentido, deve-se conhecer todos os passos de estadiamento e avaliação, a fim de aumentar as chances de ressecção curativa.

Introduction: The incidence of rectal cancer is increasing in the past decade. Rectal adenocarcinoma, the majority of rectal cancers, is a relatively simple disease in terms of diagnosis and with a positive outcome through right treatment and early diagnosis. Methods: We have reviewed the diagnosis and treatment in the academic literature. The study was carried out in a qualitative way, through a literature review, having as main source scientific articles available in several databases. Results: The diagnosis of this pathology must be established associating physical examination, anamnesis and image exams. The baseline of treatment of potentially resectable tumors is surgery while neoadjuvant chemoradiotherapy plays an important role in transmural invasion. Conclusion: The curative treatment of rectal cancer is based on the surgical procedure. In this sense, it is necessary to know all steps of staging and evaluation, in order to increase the chances of curative resection.

Fatores associados a não reconstrução do trânsito intestinal em pacientes com câncer retal submetidos à ressecção anterior do reto e ileostomia de proteção / Factors preventing restoration of bowel continuity in patients with rectal cancer submitted to anterior rectal resection and protective ileostomy

RESUMO Objetivo: avaliar os fatores associados ao não fechamento de ileostomia protetora após ressecção anterior do reto com excisão total do mesorreto por câncer retal, a morbidade associada ao fechamento destas ileostomias e a taxa de estomia permanente em pacientes com adenocarcinoma retal. Métodos: estudo retrospectivo de 174 pacientes consecutivos com diagnóstico de tumores retais, dos quais 92 foram submetidos à ressecção anterior do reto com intenção curativa, anastomose coloanal ou colorretal e ileostomia de proteção. Foi realizada análise multivariada visando a determinar os fatores associados à permanência definitiva da estomia, assim como o estudo da morbidade nos que se submeteram à reconstrução do trânsito. Resultados: no período de seguimento de 84 meses, 54 dos 92 pacientes avaliados (58,7%) tiveram a ileostomia fechada e 38 (41,3%) permaneceram com a estomia. Entre os 62 pacientes que tiveram a ileostomia fechada, 11 (17,7%) apresentaram algum tipo de complicação pós-operatória: três com deiscência de anastomose ileal, cinco com obstrução intestinal, dois com infecção de ferida operatória e um com pneumonia. Oito destes pacientes necessitaram de um novo estoma. Conclusão: de acordo com a análise multivariada, os fatores associados à permanência da estomia foram fístula de anastomose, presença de metástases e fechamento da ileostomia durante quimioterapia.

ABSTRACT Objective: to evaluate the factors associated with non-closure of protective ileostomy after anterior resection of the rectum with total mesorectum excision for rectal cancer, the morbidity associated with the closure of ileostomies and the rate of permanent ileostomy in patients with rectal adenocarcinoma. Methods: we conducted a retrospective study with 174 consecutive patients diagnosed with rectal tumors, of whom 92 underwent anterior resection of the rectum with coloanal or colorectal anastomosis and protective ileostomy, with curative intent. We carried out a multivariate analysis to determine the factors associated with definite permanence of the stoma, as well as studied the morbidity of patients who underwent bowel continuity restoration. Results: In the 84-month follow-up period, 54 of the 92 patients evaluated (58.7%) had the ileostomy closed and 38 (41.3%) remained with the stoma. Among the 62 patients who had the ileostomy closed, 11 (17.7%) presented some type of postoperative complication: three had ileal anastomosis dehiscence, five had intestinal obstruction, two had surgical wound infection, and one, pneumonia. Eight of these patients required a new stoma. Conclusion: according to the multivariate analysis, the factors associated with stoma permanence were anastomotic fistula, presence of metastases and closure of the ileostomy during chemotherapy.

Respuesta al tratamiento neoadyuvante con capecitabine y radioterapia en el cáncer de recto inferior localmente avanzado / Response to neoadjuvant treatment with capecitabine and radiotherapy in locally advanced lower rectal cancer

Introducción: La importancia del tratamiento neoadyuvante con quimio y radioterapia en el manejo de los tumores de recto extraperitoneal localmente avanzado ha quedado claramente demostrada. La droga que ha sido históricamente más utilizada para este fin fue el 5-Fluorouracilo (5-FU). Una nueva molécula de administración por vía oral, la prodroga capecitabine, ha reemplazado al 5-FU en el tratamiento neoadyuvante en los últimos tiempos, con mejores resultados y mayor comodidad. Objetivo: Valorar la eficacia, toxicidad y complicaciones del tratamiento neoadyuvante con capecitabine más radioterapia en el tratamiento del cáncer de recto extraperitoneal localmente avanzado. Diseño: Estudio observacional, descriptivo, retrospectivo. Población y Métodos: Se incluyeron 33 pacientes (66% de sexo masculino) con tumores de recto extraperitoneal localmente avanzado (cT3/cT4 o cN+) con indicación de neoadyuvancia. La dosis de radioterapia fue de 45 Gy más un boost de 5,04 Gy administradas en 25 sesiones durante un período de 5 semanas. La dosis de capecitabine fue de 850 mg/m2, dos veces al día durante los días en que se administraba la radioterapia. Se reevaluó a los pacientes entre la 8º y 10º semana. Aquellos pacientes con respuesta clínica completa (RCC) se les ofreció ingresar al protocolo de Watch & Wait, mientras que aquellos pacientes con respuesta clínica incompleta o nula se les indicó la resección quirúrgica entre las 10-12 semanas posttratamiento neoadyuvante. Resultados: 10 pacientes (30,3%) tuvieron respuesta clínica completa (RCC). De estos, 7 entraron a protocolo Watch & Wait. Se operaron 26 pacientes, luego de un promedio de 11,71 semanas posteriores a la neoadyuvancia, siguiendo en todos los casos la técnica de excisión total del mesorrecto. Se observó un 19,3% de RPC y un downstaging del 57,69%. A dieciséis pacientes (61,53%) se les efectuó una resección anterior ultrabaja con ostomía de protección. Nueve pacientes fueron sometidos a una amputación abdominoperineal (34,61%) y una paciente recibió una operación de Hartmann (3,84%). El principal efecto adverso fue la diarrea grado I en el 36% de los casos, seguida por la dermatitis grado I en el 33%. Tuvimos dos dehiscencias anastomóticas que se resolvieron sin reintervención. Conclusiones: El tratamiento neoadyuvante con capecitabine es una opción segura, con alta tasa de respuesta clínica y patológica completa, con escasa toxicidad y complicaciones, y el beneficio de la comodidad de su administración por vía oral. (AU)

Background: The importance of neoadjuvant chemotherapy and radiation therapy in the management of extraperitoneal rectal tumors locally advanced has been clearly demonstrated. The drug has been historically used for this purpose was 5-fluorouracil (5-FU). A new molecule oral administration, the prodrug capecitabine, has replaced the 5-FU in the neoadjuvant treatment in recent times, with better results and greater comfort. Objective: To evaluate the efficacy, toxicity and complications of neoadjuvant capecitabine plus radiation therapy in the treatment of locally advanced rectal cancer extraperitoneal. Design: Observational, descriptive, retrospective study. Population and Methods: 33 patients (66% male) with extraperitoneal rectal tumors locally advanced (cT3 / cT4 or cN +) with indication of neoadjuvant were included. Radiation dose was 45 Gy plus a boost of 5.04 Gy administered in 25 sessions over a period of 5 weeks. Capecitabine dose was 850 mg / m2 twice daily on days that radiotherapy was administered. It was reevaluated patients between the 8th and 10th week. Patients with clinical complete response (CCR) were offered to enter the protocol Watch & Wait, while patients with incomplete or no clinical response were instructed surgical resection neoadjuvant between 10-12 weeks post-treatment. Results: 10 patients (30.3%) had clinical complete response (CCR). Of these, seven entered Watch & Wait protocol. 26 patients were operated after a mean time of 11,71 weeks (range 10-15), in all cases following the total mesorectal excision technique. 19.3% of RPC and downstaging of 57.69% was observed. Sixteen patients (61.53%) were made ultra-low anterior resection with protective stoma. Nine patients underwent an AP amputation (34.61%) and one patient received a Hartmann operation(3.84%). The main side effect was diarrhea grade I in 36% of cases, followed by the degree I dermatitis in 33%. We had two anastomotic dehiscences which resolved without reoperation. Conclusions: Neoadjuvant capecitabine therapy is a safe choice, with high rate of complete clinical and pathological response with low toxicity and complications, and the benefit from the comfort of oral administration. (AU)

Nueva estrategia terapéutica en cáncer de recto localmente avanzado / A new therapeutic approach of locally advanced rectal cancer

El cáncer de recto es una enfermedad frecuente en la población, siendo un problema de salud importante a nivel nacional, con un probable aumento en la incidencia junto con la transición demográfica y epidemiológica de los últimos años. La cirugía ha sido históricamente el pilar fundamental en el tratamiento de esta patología, pero asociándose a una alta tasa de recurrencia, tanto locorregional como a distancia, como único tratamiento. Es por esto que se ha estudiado el agregar terapias adyuvantes a la cirugía, como lo es la radioterapia y quimioterapia. La evidencia ha demostrado que la adyuvancia con radioterapia más quimioterapia se asocia a mayor sobrevida global y menor recurrencia local y a distancia en comparación con la cirugía exclusiva. En el presente artículo se realiza una revisión de los principales estudios que evidencian la ventaja, tanto en sobrevida global como libre de enfermedad, del uso de la adyuvancia con radioterapia más quimioterapia, mencionando la última evidencia disponible sobre el tratamiento del cáncer de recto localmente avanzado y las perspectivas a futuro.

Rectal cancer is a common disease in general population, being a major health problem in our nation, with a likely increase in incidence associated to demographic and epidemiological transition in recent years. Historically, the surgery has been the mainstay in the treatment of this disease, but surgery alone is associated to a high rate of recurrence, both locoregional and distant. This is why it has been studied adding adjuvant therapies to surgery, as is radiotherapy and chemotherapy. The evidence has shown that adjuvant radiotherapy and chemotherapy is associated with increased overall survival and less local and distant recurrence compared to surgery alone. This article is a review of major studies that demonstrate the advantage of using adjuvant radiotherapy and chemotherapy in both overall and disease-free survival, mentioning the last evidence available in treatment of locally advanced rectal cancer.

Functional outcome and quality of life following treatment for rectal cancer / Resultados funcionais e qualidade de vida após tratamento do câncer retal

Introduction: Over the last decades, treatment for rectal cancer has substantially improved with development of new surgical options and treatment modalities. With the improvement of survival, functional outcome and quality of life are getting more attention. Study objective: To provide an overview of current modalities in rectal cancer treatment, with particular emphasis on functional outcomes and quality of life. Results: Functional outcomes after rectal cancer treatment are influenced by patient and tumor characteristics, surgical technique, the use of preoperative radiotherapy and the method and level of anastomosis. Sphincter preserving surgery for low rectal cancer often results in poor functional outcomes that impair quality of life, referred to as low anterior resection syndrome. Abdominoperineal resection imposes the need for a permanent stoma but avoids the risk of this syndrome. Contrary to general belief, long-term quality of life in patients with a permanent stoma is similar to those after sphincter preserving surgery for low rectal cancer. Conclusion: All patients should be informed about the risks of treatment modalities. Decision on rectal cancer treatment should be individualized since not all patients may benefit from a sphincter preserving surgery "at any price". Non-resection treatment should be the future focus to avoid the need of a permanent stoma and bowel dysfunction.

Introdução: Ao longo das últimas décadas, o tratamento do câncer retal melhorou substancialmente com o desenvolvimento de novas opções terapêuticas. Com a melhoria da sobrevida, os resultados funcionais e a qualidade de vida são cada vez mais tidos em consideração. Objetivos do estudo: Rever as modalidades atuais de tratamento do câncer retal, com enfase nos resultados funcionais e qualidade de vida. Resultados: Os resultados funcionais após tratamento para o câncer retal é influenciado pelas características do doente, do tumor, da técnica cirúrgica, do uso de radioterapia pré-cirúrgica e do método e nível da anastomose. A cirurgia poupadora de esfíncter do câncer retal baixo resulta frequentemente em maus resultados funcionais que prejudicam a qualidade de vida, denominados síndrome da ressecção anterior baixa. A amputação abdominoperitoneal impõe a necessidade de uma colostomia definitiva mas evita os riscos de resultados funcionais deficitários. Contrariamente à crença geral, a qualidade de vida a longo-prazo em doentes com colostomia definitiva é semelhante à qualidade de vida após cirurgia poupadora de esfíncter do câncer retal baixo. Conclusão: Todos os doentes devem ser informados sobre o risco das opções terapêuticas. A decisão do tratamento do câncer retal deve ser individualizada uma vez que nem todos os doentes beneficiarão de uma cirurgia poupadora de esfíncter "a qualquer preço". A possibilidade de tratamento sem ressecção devem ser o foco futuro para evitar a necessidade de uma colostomia definitiva e disfunção gastrointestinal.

A double-blind, randomized and placebo-controlled clinical trial with Agaricus sylvaticus fungus in anthropometric profile of women with colon cancer / Ensaio clínico duplo cego, randomizado e placebo controlado com fungos Agaricus sylvaticus no perfil antropométrico de mulheres com câncer colorretal

INTRODUCTION: Colorectal cancer is a disease influenced by genetic and environmental factors. Medicinal fungi and/or its extracts have been used in the adjuvant therapy of cancer because of their pharmacological, nutritional and immunomodulatory properties. OBJECTIVE: To evaluate the anthropometric profile of colorectal cancer women after dietary supplementation with Agaricus sylvaticus fungus. METHODS: Randomized, double-blind, placebo-controlled clinical trial was conducted in a public hospital in the Federal District - Brazil for six months. Sample of 32 patients with colorectal cancer, female, was separated into two groups: supplemented with Agaricus sylvaticus (30 mg/kg/day) and placebo. We conducted anthropometry (weight, height, body mass index, arm circumference, triceps skinfold, arm muscle circumference and fat percentage) during the treatment. The results were analyzed at three different times (before the start of treatment, three months and after six months supplementation) using the Microsoft Excel 2007 and SPSS 19.0, using Student's t-test and F, with significance for p ≤ 0.05. RESULTS: The Agaricus sylvaticus group showed a significant increase in body mass index, arm circumference, percent body fat and triceps skinfold, and non-significant increase in arm muscle circumference after six months of supplementation. These results were not observed in the placebo group. CONCLUSION: The results suggest that dietary supplementation with Agaricus sylvaticus is capable to have benefits in anthropometric parameters of women with colorectal cancer. (AU)

INTRODUÇÃO: O câncer colorretal é uma doença influenciada por fatores genéticos e ambientais. A utilização de fungos medicinais e/ou de seus extratos tem sido utilizada no adjuvante tratamento do câncer devido às suas propriedades farmacológicas, nutricionais e imunomoduladoras. OBJETIVO: Avaliar o perfil antropométrico de mulheres com câncer colorretal após suplementação dietética com fungos Agaricus sylvaticus. MÉTODOS: Ensaio clínico randomizado, duplo-cego, placebo-controlado realizado em um hospital público do Distrito Federal Brasil por seis meses. Amostra constituída por 32 pacientes com câncer colorretal, sexo feminino, separados em dois grupos: suplementado com Agaricus sylvaticus (30 mg/kg/dia) e placebo. Realizou-se a antropometria (peso, estatura, índice de massa corporal, circunferência do braço, dobra cutânea tricipital, circunferência muscular do braço e percentual de gordura) ao longo do tratamento. Os resultados foram analisados em três momentos distintos (antes do início do tratamento, com três meses e após seis meses de suplementação), utilizando os programas Microsoft Excel 2007 e SPSS 19.0, por meio dos testes T-student e F, com significância para p ≤ 0,05. RESULTADOS: O grupo Agaricus sylvaticus apresentou aumento significativo de índice de massa corporal, circunferência do braço, percentual de gordura corporal e dobra cutânea triciptal e, aumento não significativo de circunferência muscular do braço após seis meses de suplementação. Esses resultados não foram observados no grupo placebo. CONCLUSÃO: Os resultados sugerem que a suplementação dietética com Agaricus sylvaticus é capaz de exercer benefícios nos parâmetros antropométricos de mulheres com câncer colorretal. (AU)

New Perspectives on Predictive Biomarkers of Tumor Response and Their Clinical Application in Preoperative Chemoradiation Therapy for Rectal Cancer

Preoperative chemoradiation therapy (CRT) is the standard treatment for patients with locally advanced rectal cancer (LARC) and can improve local control and survival outcomes. However, the responses of individual tumors to CRT are not uniform and vary widely, from complete response to disease progression. Patients with resistant tumors can be exposed to irradiation and chemotherapy that are both expensive and at times toxic without benefit. In contrast, about 60% of tumors show tumor regression and T and N down-staging. Furthermore, a pathologic complete response (pCR), which is characterized by sterilization of all tumor cells, leads to an excellent prognosis and is observed in approximately 10-30% of cases. This variety in tumor response has lead to an increased need to develop a model predictive of responses to CRT in order to identify patients who will benefit from this multimodal treatment. Endoscopy, magnetic resonance imaging, positron emission tomography, serum carcinoembryonic antigen, and molecular biomarkers analyzed using immunohistochemistry and gene expression profiling are the most commonly used predictive models in preoperative CRT. Such modalities guide clinicians in choosing the best possible treatment options and the extent of surgery for each individual patient. However, there are still controversies regarding study outcomes, and a nomogram of combined models of future trends is needed to better predict patient response. The aim of this article was to review currently available tools for predicting tumor response after preoperative CRT in rectal cancer and to explore their applicability in clinical practice for tailored treatment.

Imatinib mesylate-induced interstitial lung disease in a patient with prior history of Mycobacterium tuberculosis infection

No abstract available.

Qualidade de vida em mulheres no climatério atendidas na Atenção Primária / Quality of life of postmenopausal women attended at Primary Health Care / Calidad de vida de las mujeres en climaterio tratadas en la Atención Primaria

A vivência do climatério está cada vez mais presente, e demanda estratégias que melhorem a qualidade de vida das mulheres nesse período. A pesquisa objetivou avaliar a qualidade de vida de mulheres na fase do climatério, com ou sem uso da terapia de reposição hormonal (TRH). Estudo epidemiológico longitudinal, com amostra de 99 mulheres para cada grupo. Avaliaram-se as características sociodemográficas, clínicas e comportamentais. Foram aplicados à amostra a Menopause Rating Scale (MRS) e o Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). Utilizaram-se os testes t de student, Qui-quadrado e Tukey. As usuárias de TRH apresentaram média etária de 50,76 ± 3,63 anos, e as não usuárias de 48,95 ± 6,27anos (p=0,01). Relataram maior frequência de sintomas climatéricos de intensidade leve a moderada. Os aspectos sociais apresentaram escore abaixo de 50 para os dois grupos. Houve diferenças entre os grupos em relação aos componentes do SF-36 e MRS para estado geral de saúde, capacidade funcional, menor capacidade, depressão, insônia e fenômenos vasomotores.

The experience of menopause is increasingly present, and demand strategies to improve the quality of life of women during this period. This research aimed to evaluate the quality of life for women in the climacteric phase, with or without the use of hormone replacement therapy (HRT). This is a longitudinal epidemiological study of a sample of 99 women per group. It was evaluated the sociodemographic, clinical and behavioral characteristics. It was used the Menopause Rating Scale (MRS) and the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). For data analysis, it was used the Student t test, chi-square and Tukey. HRT users had an average age of 50.76 ± 3.63 years, and nonusers of 48.95 ± 6,27anos (p = 0.01). It was identified a higher frequency of moderate climacteric symptoms of mild intensity. The social aspects evidenced scores below 50 for the two groups. There were differences between groups with respect to the components of the SF-36 and MRS to general health, functional capacity, lower capacity, depression, insomnia and vasomotor phenomena.

La experiencia de la menopausia es cada vez más presente, demandando estrategias para mejorar la calidad de vida de las mujeres durante este periodo. Esa investigación tuvo como objetivo evaluar la calidad de vida de las mujeres en la fase climatérica, con o sin el uso de la terapia de reemplazo hormonal (TRH). Trata-se dé un estudio epidemiológico longitudinal, con una muestra de 99 mujeres por grupo. Fueran evaluadas las características sociodemográficas, clínicas y de comportamiento. Fueran aplicados a la muestra el Menopause Rating Scale (MRS) e el Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). Utilizaran-se los testes t de Student, Qui-quadrado e Tukey. Las usuarias de TRH tenían una edad media de 50,76 ± 3,63 años, y las no usuarias de 48,95 ± 6,27anos (p = 0,01). Fue reportada una mayor frecuencia de síntomas climatéricos intensidad leve o moderada. Los aspectos sociales tuvieran puntuaciones por debajo de 50 para los dos grupos. Hubo diferencias entre los grupos con respecto a los componentes del SF-36 y el MRS para la salud en general, la capacidad funcional, la capacidad más baja, la depresión, el insomnio y los fenómenos vasomotores.

Study on adherecce to capecitabine among patiens with colorectal cancer and meetastatic breast cancer / Estudo de aderência a capecitabina em pacientes com câncer colorretal e câncer de mama metastático

Context Capecitabine, an oral drug, is as effective as traditional chemotherapy drugs. Objectives To investigate the adhesion to treatment with oral capecitabine in breast and colorectal cancer, and to determine any correlation with changes in patient’s quality of life. Methods Patients with colorectal cancer or breast cancer using capecitabine were included. The patients were asked to bring any medication left at the time of scheduled visits. The QLQ-C30 questionnaire was applied at the first visit and 8-12 weeks after treatment. Results Thirty patients were evaluated. Adherence was 88.3% for metastatic colon cancer, 90.4% for non-metastatic colon cancer, 94.3% for rectal cancer and 96.2% for metastatic breast cancer. No strong correlation between adherence and European Organisation for Research and Treatment of Cancer QLQ-C30 functional or symptom scale rates had been found. There was no statistically significant correlation between compliance and the functional and symptom scales of the questionnaire before and after chemotherapy, with the exception of dyspnea. Conclusions Although no absolute adherence to oral capecitabine treatment had been observed, the level of adherence was good. Health professionals therefore need a greater focus in the monitoring the involvement of patients with oral treatment regimens. Patients with lesser degrees of dyspnea had greater compliance. .

Contexto A capecitabina, uma droga oral, é tão eficaz quanto as drogas quimioterápicas tradicionais. Objetivos Investigar a adesão ao tratamento oral com capecitabina para câncer de mama e colorretal e determinar qualquer correlação com as mudanças na qualidade de vida do paciente. Métodos Pacientes com câncer colorretal ou de mama em uso de capecitabina foram incluídos. A cada consulta os pacientes trouxeram a medicação restante. O questionário de qualidade de vida QLQ- C30 foi aplicado na primeira visita e 8-12 semanas após o tratamento. Resultados Trinta pacientes foram avaliados. A adesão foi de 88,3% para o câncer de cólon metastático, 90,4% para o de cólon não-metastático, 94,3% para o de reto e 96,2% para o de mama metastático. Com exceção da dispnéia, não houve forte correlação entre adesão e as taxas European Organisation for Research and Treatment of Cancer QLQ-C30 em relação a escala funcional ou de sintomas no início ou após quimioterapia. Conclusões O nível de adesão foi bom, embora não houvesse adesão absoluta ao tratamento com capecitabina oral. Os profissionais de saúde, portanto, precisam dar maior atenção a pacientes em regimes de tratamento oral. Os pacientes com menor grau de dispneia tiveram maior adesão. Neoplasias colorretais, terapia .