Improving access to cancer clinical research in Brazil: recent advances and new opportunities. Expert opinions from the 4th CURA meeting, São Paulo, 2023.

Clinical research is the cornerstone of improvements in cancer care. However, it has been conducted predominantly in high-income countries with few clinical trials available in Brazil and other low-and-middle-income countries (LMIC). Of note, less than one-third of registered clinical trials addressing some of the most commonly diagnosed cancers (breast, lung and cervical) recruited patients from LMIC in the last years. The Institute Project CURA promoted the fourth CURA meeting, discussing barriers to cancer clinical research and proposing potential solutions. A meeting was held in São Paulo, Brazil, in June 2023 with representatives from different sectors: Brazilian Health Regulatory Agency (Anvisa), National Commission of Ethics in Research (CONEP), non-governmental organisations, such as the Latin American Cooperative Oncology Group, the Brazilian Society of Clinical Oncology (SBOC), Contract Research Organisations, pharmaceutical companies and investigators. A total of 16 experts pointed out achievements as shortening the time of regulatory processes involving Anvisa and CONEP, development of staff training programs, maintenance of the National Program of Oncological Attention (PRONON), and the foundation of qualified centres in North and Northeast Brazilian regions. Participants also highlighted the need to be more competitive in the field, which requires optimising ongoing policies and implementing new strategies as decentralisation of clinical research centres, public awareness campaigns, community-centered approaches, collaborations and partnerships, expansion of physicians-directed policies, exploring the role of the steering committee. Active and consistent reporting of the initiatives might help to propagate ongoing advances, increasing Brazilian participation in clinical cancer research. Engagement of all players is crucial to maintain continuous progress with further improvements in critical points including regulatory timelines and increments in qualified human resources which aligned with new educational initiatives focused on physicians and the general population will expand access to cancer clinical trials in Brazil.

Current scenario and future perspectives of clinical research in Brazil: a national survey.

Background: Epidemiological and clinical cancer research is essential to understanding tumour behaviour and developing new therapies in oncology. However, several countries including Brazil as well as many other regions of the world have limited participation in cancer research. Despite 625,000 new cancer cases recorded in Brazil in 2022, only 2.2% of ongoing cancer clinical trials are available in the country. We conducted an online survey to describe physician engagement with research and to identify the main barriers precluding participation in and conduct of clinical cancer research in the country. Methods: An anonymous online survey of 23 objective questions was sent by e-mail to Brazilian members of the Latin American Cooperative Oncology Group and the Brazilian Society of Clinical Oncology. The first 13 questions addressed demographic information, medical training and previous research participation. In the second part, the main barriers to engagement and participation in clinical trials in Brazil were addressed. Continuous variables were measured by median and range. Analyses were performed using SAS statistical software (version 9.4; SAS Institute, Inc. Cary, NC). Results: 109 physicians answered the survey. Most participants were oncologists (N = 98, 89.9%), living in capital cities (N = 84, 77.1%), were from the Southeast region of Brazil (N = 63, 57.8%) and worked at institutions providing exclusively private healthcare (N = 59, 54.1%). Of the 109 respondents, 83 (76.1%) reported working in research centres (as investigators or sub-investigators). Surprisingly, 31.2% of physicians recognised they invite less than 1% of their patients to participate in clinical trials, even though 98 (89.9%) considered the participation of patients in clinical trials extremely relevant. The main barriers compromising the conduct of research in the country were the low number of available trials (48.2%) and the lack of qualified human resources to staff research sites (22.9%). Other reported barriers were the lengthy regulatory approval process (42.2%), followed by a lack of awareness of clinical research by patients resulting in low recruitment rates (24.1%). Of the 26 (23.8%) respondents not working with research, 25 (96.1%) reported interest in being involved, 31.8% have tried participating in research and 62.4% reported limited knowledge of trial procedures. Conclusion: These results suggest a clear need to further engage physicians in clinical research activities in Brazil. Patient education strategies should improve the low recruitment rates and secondarily increase the number of proposed trials in the country.

Biosimilar Use in Breast Cancer Treatment: A National Survey of Brazilian Oncologists' Opinions, Practices, and Concerns.

PURPOSE: Breast cancer is the most common malignancy in Brazilian women, with 66,280 new cases in 2020 (with 20% overexpressing human epidermal growth factor receptor 2 [HER2]). The trastuzumab biosimilar was the first oncology biosimilar approved in Brazil for HER2-positive breast cancer treatment. This study aimed to assess the current level of knowledge of biosimilars, comfort of use, extrapolation indications, and switching of practices among oncologists in Brazil. METHODS: A 24-question survey was developed using an online platform that sought information regarding responders' characteristics and use of biosimilars. The survey analyzed the basic knowledge of biosimilars, trastuzumab biosimilars, level of comfort with extrapolation, switching treatment regimens, and opinions concerning the cost of HER2-positive breast cancer therapy. Data were collected between July and September 2019 and included 144 oncologists from five Brazilian regions. RESULTS: In total, 95% of respondents could identify the most appropriate definition of biosimilars and 96% felt comfortable prescribing trastuzumab biosimilars. Although 63% of respondents would use the biosimilar in all settings wherein the reference biologic was approved, 35% would use the biosimilar for cases involving metastatic disease. Although 82% of oncologists were in favor of switching from a reference biologic to a biosimilar, 18% would avoid switching regimens. The lack of studies detailing switching to other regimens and the correct timing to switch was the major concern. The cost of HER2 therapy was a significant concern for most oncologists. CONCLUSION: Oncologists demonstrated a high level of knowledge of biosimilars and encouraging levels of prescriber use; however, extrapolation and switching treatment regimens are barriers to the effective use of biosimilars in cancer treatment. Efforts should be concentrated on strategies involving medical education programs on biosimilars.

Sentinel lymph node biopsy using single-agent mapping tracer (blue dye) after neoadjuvant chemotherapy in a Brazilian cohort of breast cancer patients. Real world evidence.

PURPOSE: To reduce false-negative rates (FNR) in sentinel lymph node biopsy (SLNB) of clinically positive (cN+) axilla in patients undergoing neoadjuvant chemotherapy (NAC). The removal of three or more lymph nodes with dual-tracer mapping including a radioisotope was used. However, in the Brazilian Unified Health System, the radioisotope tracer is not feasible in some hospitals. We conducted a cross-sectional study to evaluate the detection rate of sentinel lymph node (SLN) in patients who converted from cN+ to ycN0 after NAC using blue dye as a single-agent mapping tracer. METHODS: During the period of March 2018 to September 2019, 34 patients who underwent NAC with cN+ who converted to ycN0 were enrolled in the study. The SLNB was performed using blue dye as a single-agent mapping followed by axillary lymph node dissection (ALND). RESULTS: The detection rate of sentinel lymph node was of 85.3%, being SLNB not possible for five patients (14.7%), due to fibrosis. The mean number of removed SLN was 2.5. CONCLUSIONS: The use of blue dye as a single-agent mapping tracer demonstrated an acceptable detection rate of 85.3%. Although the FNR was possible to be determined, the small sample size might overestimate this rate. The removal of three or more lymph nodes with single-agent mapping tracer might be indicated for breast cancer patients who converted to ycN0 after NAC in the Brazilian health public services, in which radioisotope tracer is not suitable.

Axillary management for patients with breast cancer after neoadjuvant chemotherapy: Results of a survey among Brazilian breast surgeons.

BACKGROUND: Currently, there are broadly differing patterns in the management of the axilla after neoadjuvant chemotherapy (NAC) and no consensus with clinically strong evidence on the subject. A survey was performed to assess the current axillary management after NAC among Brazilian breast cancer surgeons. METHODS: The Brazilian Society of Mastology members were invited by email to complete an anonymous online survey and a total of 426 responses were collected. RESULTS: The majority of responders (67%) indicated performing routine axillary staging by physical exam, ultrasound, and fine needle biopsy in case of a suspicious node before NAC. Among breast surgeons working in the Brazilian Public Unified Health System, 11.3% answered that sentinel lymph node biopsy (SLNB) is not reasonable after NAC in their services. Seventy-seven responders (18.2%) reported performing SLNB instead of axillary lymph node dissection (ALND) only in patients who are clinically node-negative before NAC. Axillary complete pathologic response is necessary to omit ALND for 42.8% of responders. The molecular profile of a breast tumor is not considered when choosing axillary management after NAC for 73.7% of responders. CONCLUSIONS: Our survey highlighted the trend towards de-escalation of axillary surgery and observed high heterogeneity in axillary management after chemotherapy in a group of brazilian breast surgeons.

The impact of sociodemographic factors and health insurance coverage in the diagnosis and clinicopathological characteristics of breast cancer in Brazil: AMAZONA III study (GBECAM 0115).

PURPOSE: In Brazil, the available cancer registries are deficient in number and quality and, hence, little information is known regarding sociodemographic, clinicopathological characteristics, treatment patterns, and outcomes of breast cancer (BC) patients. We performed the AMAZONA III/ GBECAM 0115 study and in this analysis, we describe patients' characteristics at diagnosis and their association with health insurance type. METHODS: This is a prospective cohort study developed in 23 sites in Brazil including women with newly diagnosed invasive BC from January 2016 to March 2018. In order to compare healthcare insurance type, we considered patients who were treated under the Brazilian public health system as publicly insured, and women who had private insurance or paid for their treatment as privately insured. RESULTS: A total of 2950 patients were included in the study. Median age at diagnosis was 53.9 years; 63.1% were publicly insured. The majority of patients (68.6%) had stage II-III breast cancer and ductal carcinoma histology (80.9%). The most common breast cancer subtype was luminal A-like (48.0%) followed by luminal B-HER2 positive-like (17.0%) and triple-negative (15.6%). Luminal A was more frequent in private (53.7% vs. 44.2%, p < .0001) than public, whereas Luminal B HER2-positive (19.2% vs. 14.2%, p = 0.0012) and HER2-positive (8.8% vs. 5.1%, p = 0.0009) were more common in patients with public health system coverage. Only 34% of patients were diagnosed by screening exams. Privately insured patients were more frequently diagnosed with stage I disease when compared to publicly insured patients; publicly insured patients had more stage III (33.5% vs. 14.7%; p-value < 0.0001) disease than privately insured ones. Breast cancer was detected by symptoms more frequently in publicly than in privately insured patients (74.2% vs 25.8%, respectively; p-value < 0.0001). CONCLUSIONS: Patients with public health coverage were diagnosed with symptomatic disease, later stages and more aggressive subtypes when compared to privately insured patients.

Advanced Stage at Diagnosis and Worse Clinicopathologic Features in Young Women with Breast Cancer in Brazil: A Subanalysis of the AMAZONA III Study (GBECAM 0115).

PURPOSE: Breast cancer (BC) in young women is uncommon and tends to present with more aggressive characteristics. To better understand and characterize this scenario in Brazil through real-world data, we performed a subanalysis of AMAZONA III study (ClinicalTrials.gov identifier: NCT02663973). METHODS: The AMAZONA III study (GBECAM 0115) is a prospective registry that included 2,950 women newly diagnosed with invasive BC in Brazil from January 2016 until March 2018 at 22 sites. Valid data were obtained from 2,888 patients regarding age at diagnosis and complete baseline information. To compare epidemiologic and clinicopathological features at the time of diagnosis, patients with BC were divided into two groups according to age: ≤ 40 years and > 40 years. Quantitative variables were described as means, and categorical variables were described as frequencies and percentages and compared using the Pearson's χ2 test. RESULTS: Of 2,888 women diagnosed with BC, 486 (17%) were ≤ 40 years old. Young women had higher educational level, most were employed and a significant number were married (P < .001 for all associations). Younger patients were more symptomatic at BC diagnosis (P < .001), and they also presented more frequently with stage III, T3/T4, grade 3 tumors, HER-2-positive, luminal B, and triple-negative subtypes. CONCLUSION: Brazilian women younger than age 40 years have unfavorable clinicopathological features of BC at diagnosis, with more aggressive subtypes and advanced stage when compared with older women. These differences are not explained by socioeconomic or ethnic imbalances. The causes of a higher prevalence of BC among young women in Brazil deserve additional investigation.

Combination chemotherapy versus single-agent chemotherapy during preoperative chemoradiation for resectable rectal cancer.

BACKGROUND: Colorectal cancer represents 10% of all cancers and is the third most common cause of death in women and men. Almost two-thirds of all bowel cancers are cancers of the colon and over one-third (34%) are cancers of the rectum, including the anus. Surgery is the cornerstone for curative treatment of rectal cancer. Mesorectal excision decreases the rate of local recurrences; however, it does not improve the overall survival of people with locally advanced rectal cancer. There have been significant research efforts since the mid-1990s to optimise the treatment of rectal cancer. Based on the findings of clinical trials, people with T3/T4 or N+ rectal tumours are now being treated preoperatively with radiation and chemotherapy, mainly fluoropyrimidine. However, the incidence of distant metastases remains as high as 30%. Combination chemotherapy regimens, similar to those used in metastatic disease with the addition of oxaliplatin and irinotecan, have been tested to improve the prognosis of people with rectal cancer. OBJECTIVES: To compare outcomes (including overall survival, disease-free survival and toxicity) between two 5-fluorouracil-containing chemotherapy regimens in people with stage II and III rectal cancer who are receiving preoperative chemoradiation. SEARCH METHODS: We searched the Cochrane Colorectal Cancer Group Specialised Register (January 2015), the Cochrane Central Register of Controlled Trials (2015, Issue 1), Ovid MEDLINE (1950 to January 2015), Ovid EMBASE (1974 to January 2015) and LILACS (1982 to January 2015). We reviewed the reference lists of included studies, checked clinical trials registers and handsearched relevant journal proceedings. We applied no language or publication restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing single-agent chemotherapy (fluoropyrimidine) versus combination chemotherapy (fluoropyrimidine plus another agent including, but not limited to, oxaliplatin) during preoperative radiochemotherapy in people with resectable rectal cancer. DATA COLLECTION AND ANALYSIS: Two review authors (HMR, EMKS) independently extracted data and assessed trial quality. When necessary, we requested additional information and clarification of published data from the authors of individual trials. MAIN RESULTS: We included four RCTs involving 3875 people with resectable rectal cancer. In the preoperative period, the participants of these studies were randomised to receive chemoradiation either with a single fluoropyrimidine agent (capecitabine or 5-fluorouracil) or with a combination of drugs (fluoropyrimidine plus oxaliplatin). The only study that reported overall survival and disease-free survival found no significant differences between the intervention and control groups; we considered this evidence very low quality. For pathological complete response after preoperative treatment (ypCR) there was high quality evidence favouring the intervention group (odds ratio (OR) 1.23, 95% confidence interval (CI) 1.04 to 1.46), but there was also moderate quality evidence suggesting a higher risk for early toxicity in the intervention group (OR 2.07, 95% CI 1.31 to 3.27). Moderate to high quality evidence suggested that the control group had better compliance to radiotherapy (OR 0.32, 95% CI 0.14 to 0.75). There were no significant differences between groups in postoperative mortality within 60 days, postoperative morbidity, resection margins, abdominoperineal resection and Hartmann procedures. AUTHORS' CONCLUSIONS: There was very low quality evidence that people with resectable rectal cancer who receive combination preoperative chemotherapy have no improvements in overall survival or disease-free survival. There was high quality evidence that suggested that combination chemotherapy with oxaliplatin may improve local tumour control in people with resectable rectal cancer, but this regimen also caused more toxicity. The review included four RCTs but only one reported survival; therefore, we cannot make robust conclusions or useful clinical recommendations. The publication of more survival data from these studies will contribute to future analyses.

ANTECEDENTES: El cáncer colorrectal representa el 10% de todos los cánceres y es la tercera causa más frecuente de muerte en mujeres y hombres. Casi dos tercios de todos los cánceres intestinales son cánceres de colon y más de un tercio (34%) son cánceres del recto, incluido el ano. La cirugía es la base del tratamiento curativo del cáncer rectal. La escisión mesorrectal disminuye la tasa de recidivas locales; sin embargo, no mejora la supervivencia general de las personas con cáncer de recto localmente avanzado. Desde mediados de los años noventa se han realizado esfuerzos significativos de investigación para optimizar el tratamiento del cáncer rectal. Según los resultados de los ensayos clínicos, actualmente las personas con tumores rectales T3/T4 o N+ se tratan preoperatoriamente con radiación y quimioterapia, principalmente fluoropirimidina. Sin embargo, la incidencia de metástasis distantes todavía es tan alta como del 30%. Para mejorar el pronóstico de las personas con cáncer rectal se han probado regímenes de quimioterapia combinada, similares a los utilizados en la enfermedad metastásica con el agregado de oxaliplatino e irinotecán. OBJETIVOS: Comparar los desenlaces (incluida la supervivencia general, la supervivencia sin enfermedad y la toxicidad) entre dos regímenes de quimioterapia que contienen 5­fluorouracilo en personas con cáncer rectal estadio II y III que reciben quimiorradioterapia preoperatoria. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en el Registro especializado del Grupo Cochrane Colorrectal (Cochrane Colorectal Cancer Group) (enero de 2015), Registro Cochrane central de ensayos controlados (Cochrane Central Register of Controlled Trials) (2015, número 1), Ovid MEDLINE (1950 hasta enero de 2015), Ovid EMBASE (1974 hasta enero de 2015) y en LILACS (1982 hasta enero de 2015). Se revisaron las listas de referencias de los estudios incluidos, se verificaron los registros de ensayos clínicos y se hicieron búsquedas manuales en los resúmenes de revistas relevantes. No se aplicaron restricciones de idioma ni de publicación. CRITERIOS DE SELECCIÓN: Ensayos controlados aleatorizados (ECA) que compararon la quimioterapia de agente único (fluoropirimidina) versus la quimioterapia combinada (fluoropirimidina más otro agente que incluyó, pero no se limitó a oxaliplatino) durante la radioquimioterapia preoperatoria en personas con cáncer rectal resecable. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión (HMR, EMKS) de forma independiente extrajeron los datos y evaluaron la calidad de los ensayos. Cuando fue necesario, se solicitó información adicional y aclaraciones sobre los datos publicados de los autores de los ensayos individuales. RESULTADOS PRINCIPALES: Se incluyeron cuatro ECA con 3875 personas con cáncer rectal resecable. En el período preoperatorio, los participantes de estos estudios se asignaron al azar a recibir quimiorradioterapia con el agente único fluoropirimidina (capecitabina o 5­fluorouracilo) o con una combinación de fármacos (fluoropirimidina más oxaliplatino). El único estudio que informó sobre la supervivencia general y la supervivencia sin enfermedad no encontró diferencias significativas entre los grupos de intervención y control; esta evidencia se consideró de calidad muy baja. Para la respuesta patológica completa después del tratamiento preoperatorio (ypCR) hubo evidencia de calidad alta a favor del grupo de intervención (odds ratio [OR] 1,23; intervalo de confianza [IC] del 95%: 1,04 a 1,46), pero también hubo evidencia de calidad moderada que indicó un mayor riesgo de toxicidad temprana en el grupo de intervención (OR 2,07; IC del 95%: 1,31 a 3,27). Evidencia de calidad moderada a alta indicó que el grupo control tuvo un mejor cumplimiento de la radioterapia (OR 0,32; IC del 95%: 0,14 a 0,75). No hubo diferencias significativas entre los grupos en la mortalidad posoperatoria en el transcurso de 60 días, la morbilidad posoperatoria, los márgenes de resección, la resección abdominoperineal ni los procedimientos de Hartmann. CONCLUSIONES DE LOS AUTORES: Hubo evidencia de calidad muy baja de que las personas con cáncer rectal resecable que reciben quimioterapia combinada preoperatoria no tienen mejorías en la supervivencia general ni la supervivencia sin enfermedad. Hubo evidencia de calidad alta que indicó que la quimioterapia combinada con oxaliplatino podría mejorar el control tumoral local en las personas con cáncer rectal resecable, pero este régimen también provocó más toxicidad. La revisión incluyó cuatro ECA, pero sólo uno informó sobre la supervivencia; por lo tanto, no se pueden establecer conclusiones sólidas ni recomendaciones clínicas útiles. La publicación de más datos de la supervivencia de estos estudios contribuirá a futuros análisis.